NSW Therapeutic Advisory Group Level 5, 376 Victoria Street PO Box 766 Darlinghurst NSW 2010 Phone: 61 2 8382 2852 Fax: 61 2 8382 3529 Email: [email protected] www.nswtag.org.au

Infliximab in ulcerative colitis

Targeted Literature Review

August 2007

Reviews of safety – general and in other Contents therapeutic areas...... 17

Efficacy studies ...... 18 RCTs...... 18

Synopsis...... 3 Safety studies...... 22 IBD...... 22 Background ...... 3 Rheumatoid conditions ...... 27 Current indications and dosage ...... 3 Use in Children...... 38 Current subsidy status ...... 3 Repatriation Pharmaceutical Benefits ..3 Reviews in IBD ...... 38 Efficacy and safety reviews ...... 38 Section 100 items...... 3 Public summary documents ...... 3 Safety reviews ...... 38 Reviews of safety – general and in other Treatment recommendations ...... 4 Disease resistant to conventional therapeutic areas...... 38 Efficacy studies ...... 38 therapy...... 4 Disease that is not steroid refactory.....4 RCTs...... 38 Non-randomised studies...... 38 Preventing colectomy...... 4 Safety ...... 4 Safety studies...... 40 IBD...... 40 General...... 4 Malignancy ...... 5 Predictors of response...... 42 Infection ...... 5 Health economics, resources, risk/benefit Use in children ...... 6 Efficacy...... 6 ...... 42 Safety ...... 6 Acknowledgments ...... 43 Use in the elderly ...... 6 Efficacy...... 6 Safety ...... 6 Cost...... 7 Introduction...... 8 Systematic Reviews, Meta-analyses and Guidelines ...... 9 Cochrane...... 9 Summary: ...... 9 Alimentary Pharmacology & Therapeutics ...... 10 Summary: ...... 10 ACP Journal Club...... 11 Summary: ...... 11 American Gastroenterological Association Institute...... 11 Summary: ...... 11 JAMA...... 12 Summary: ...... 12 National Horizon Scanning Centre...... 12 Summary: ...... 12 Scottish Medicines Consortium...... 13 Summary: ...... 13 NICE Health Technology Appraisal ...... 13 Summary: ...... 13 Use in Adults...... 14 Reviews in IBD...... 14 Efficacy and safety reviews ...... 14 Safety reviews ...... 16

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infusion dose at 2 and 6 weeks after the first Synopsis infusion, then every 8 weeks thereafter. If This Targeted Literature Review is not a patients have not responded to the initial 3 Position Statement and does not represent treatment infusion regimen at weeks 0, 2 recommendations from the NSW and 6 weeks, then careful consideration Therapeutic Advisory Group. The Synopsis should be given before persisting with has been derived from the main points from further treatment. Data supporting the reviews, guidelines and articles identified readministration, other than every 8 weeks, in a search of the published literature. are not available at this time. Summaries or abstracts of these reviews, guidelines and articles have been presented A Cochrane review (2006) recommends a in the main text of this document, either dose of 5 mg/kg but it does not recommend verbatim or edited for conciseness or clarity. an ideal dosing schedule. The American Gastroenterological Association also recommends this dosage (Lichtenstein et al Background 2006) infused over 2 hours in an induction Infliximab is a chimeric humanised murine regimen of 3 doses at weeks 0, 2, and 6 - monoclonal antibody that binds to human followed by maintenance therapy every 8 tumour necrosis factor alpha (TNF α), a weeks in patients who respond. They add proinflammatory and immunoregulatory that for patients with CD who respond and cytokine that, when overexpressed, then lose their response, consideration may mediates chronic inflammation in diseases be given to treatment with 10 mg/kg. In the such as Crohn's disease (CD) and case of nonresponse to 3 infusions, further rheumatoid arthritis (RA). Biological treatment with infliximab is not activities attributed to TNF α include: recommended. An attempt to withdraw or induction of proinflammatory cytokines such taper any concomitant corticosteroid therapy as IL-1 and IL-6; enhancement of leucocyte is sensible in patients who achieve migration by increasing endothelial layer remission with infliximab. permeability and expression of adhesion molecules by endothelial cells and leucocytes; activation of neutrophil and Current subsidy status eosinophil functional activity; and induction The Schedule of Pharmaceutical Benefits of acute phase and other liver proteins (www.pbs.gov.au) lists the following for (summarised from MIMS product infliximab. information.) Repatriation Pharmaceutical Benefits Current indications and Initial treatment, in combination with dosage methotrexate, of specific accepted war- The MIMS lisiting for Infliximab caused or service-related disability of (Remicade™) has indications for RA, refractory RA. Continuing treatment, in ankylosing spondylitis, CD, refactory combination with methotrexate, of specific fistulising CD, psoriatic arthritis, psoriasis accepted war-caused or service-related and ulcerative colitis (UC) (Date of TGA disability of refractory RA. Approval or Manufacturer's Last Amendment 11/01/2007). For UC, the treatment is for moderately severe to severe Section 100 items active UC in patients who have had an Treatment of adult patients with active inadequate response to conventional ankylosing spondylitis, severe active therapy. psoriatic arthritis or severe active RA.

The dosage of infliximab for UC is 5 mg/kg given as an intravenous infusion over a 2 Public summary documents hour period followed by additional 5 mg/kg Date of PBAC Consideration: July 2006

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This submission sought to extend the In the systematic review by Gisbert et al Section 100 (Highly Specialised Drug) listing (2007), they agreed that infliximab is more for infliximab to include the treatment of effective than placebo in treating moderate- severe plaque psoriasis.The PBAC to-severe UC, with a number needed to treat recommended this listing in patients who from 3 to 5 and 40% of patients achieving meet certain criteria on a cost-minimisation clinical remission after 9 months. Cottone et basis with efalizumab. al (2006) comment that the long-term effectiveness of infliximab, in comparison to Date of PBAC Consideration: March 2007 placebo, is not clinically impressive even if it This re-submission requested an extension is statistically significant. to the Section 100 Authority Required listing to include the treatment of severe refractory The Cochrane review states the evidence is Crohn’s disease. The PBAC recommended unclear on whether both corticosteroids and this listing of infliximab for the treatment of immunosuppressive agents should be used patients with severe Crohn’s disease prior to infliximab therapy. (Crohn’s Disease Activity Index ≥ 300) or patients with an ileostomy or colectomy due Thukral et al (2006) state there is insufficient to Crohn’s disease on the basis of high and evidence to recommend the use of infliximab acceptable cost-effectiveness compared to as a first-line agent for UC patients with mild placebo. or moderate-to-severe disease.

Treatment recommendations Disease that is not steroid refactory Disease resistant to conventional Cochrane states there is no evidence to therapy show infliximab is more effective than high- dose corticosteroids in patients who are not A Cochrane review concluded that infliximab steroid-refractory. is effective in patients with moderate-to- severe UC where the disease is resistant to conventional therapy using corticosteroids and/or immunosuppressive agents. The Preventing colectomy primary outcome measure was the number The Cochrane review concluded that of patients achieving remission as defined infliximab helps to avoid colectomy in the by the primary studies. Infliximab was shown short term but that long-term studies are to induce clinical remission and response, required to determine whether infliximab can promote mucosal healing and reduce the prevent colectomy. A recent retrospective need for colectomy in the short term. cohort study of 30 UC patients treated with Thukral et al (2006) commented that a infliximab showed that 16 required significant number of patients who were colectomy after a median of 140 days after receiving oral corticosteroids at the start of first infusion (Jakobovits et al 2007) the 2 main randomized controlled trials (RCTs) (ACT1 and ACT2) remained on corticosteroids despite infliximab therapy. Safety However, the proportions of patients who were in clinical remission and had discontinued corticosteroids at week 30 in General both studies (and at week 54 in ACT1) were ADRAC has received 319 reports involving higher in the infliximab groups than in the TNF α inhibitors since 2000. The more placebo groups. Also, the decreases in the serious of these are: malignant melanoma (3 median daily corticosteroid doses (20mg at reports), lymphoma (5), tuberculosis (4, TB), baseline) were greater among patients in the pneumonia/lower respiratory tract infections infliximab groups than in the placebo (23), sepsis (10), lupus or lupus-like groups. syndrome (22) and anaphylaxis (9).

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The Cochrane review stated that serious 1.1 (95% CI 0.6 - 2.1) - solid cancers adverse events with infliximab in UC occurred at rates little greater than in the patients are not common but uncommon general population. adverse events such as anaphylactic reactions and infections may occur. In the In the Bongartz et al (2006) meta-analysis of systematic review by Gisbert et al (2007), infliximab or adalimumab in RA, it was found they stated that adverse effects were that malignancies developed in 29 of 3192 reported in 83% and 75% of infliximab and (0.9%) patients treated with infliximab or placebo-treated patients in UC studies, adalimumab, compared with 3 of 1428 respectively (odds ratio [OR] = 1.52; 95% (0.2%) patients given placebo. The risk of confidence interval [CI] 1.03-2.24; number- malignancies was not different from placebo needed-to-harm was 14). with low dose TNF α inhibitors but was 4-fold greater with high doses of infliximab or A review of adverse events in 500 adalimumab. The Bongartz study calculated consecutive CD patients treated with a pooled OR for malignancy following anti- infliximab at the Mayo Clinic for a median TNF therapy of 3.3 (95% CI, 1 2 - 9.1). The follow-up of 17 months showed that 43 number needed to harm was 154 (95% CI, patients (8.6%) experienced a serious 91 - 500) for 1 additional malignancy within adverse event, of which 30 (6%) were a treatment period of 6 to 12 months. They related to infliximab (Colombel et al 2004). concluded there is evidence of a dose- Acute infusion reactions occurred in 19 dependent increased risk of malignancies in (3.8%), serum sickness-like disease in 19 patients with RA treated with TNF α (attributed to infliximab in 14, 2.8%), drug- inhibitors. Similar results were reported in a induced lupus in 3. Forty-eight patients had recent ACP Journal Club analysis (2006). an infectious event, of which 41 (8.2%) were They found that the malignancy risk was attributed to infliximab. Twenty patients had greater in RA patients receiving a high dose a serious infection. Nine patients had a of TNF α inhibitors compared with placebo malignant disorder, 3 of which were possibly (OR 4.3, 95% CI 1.6 - 12) than in those related to infliximab. A total of 10 deaths receiving a low dose (OR 1.4, CI 0.3 to 5.7). were observed - 5 were possibly related to Direct comparison of high and low dose also infliximab. showed increased risk for malignancy with high-dose treatment (OR 3.4, CI 1.4 - 8.2).

Malignancy TNF α inhibitors may predispose patients to Infection an increased risk of malignancies or ADRAC advises that patients receiving accelerate their development. Australian TNF α inhibitors should not receive product information advises caution when concurrent vaccination with live vaccines, prescribing TNF α inhibitors in patients with a and that consideration should be given to history of malignancy or when considering screening patients for preexisting infections, continuing treatment in patients who develop particularly hepatitis B and TB, prior to use a malignancy. of TNF α inhibitors.

Early evidence of a potential cancer risk Early evidence of a potential infection risk came from a case series in 2002 where a came from a case series in 2001 where a post market surveillance system run by the post-market surveillance system run by the US Food and Drug Administration found 26 US Food and Drug Administration found 70 cases of lymphoproliferative disorders cases of TB after treatment with infliximab following treatment with etanercept (18 (Keane et al 2001). The estimated incidence cases) or infliximab (8 cases) (Brown et al of TB associated with infliximab in RA 2002). Bandolier (2006) summarised the patients was 1,893 per 100,000 in the year results from a series of observational studies 2000 and 1,113 per 100,000 in the year in RA patients (ie, Askling et al papers in this 2001 in a multicentre active-surveillance document) using etanercept and infliximab report in Spain (Gomez-Reino et al 2003). A mainly. The relative risk of malignancy was prospective cohort study in 83 rheumatoid

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patients suggested that older age and high- than 4 months and prior infusion reactions dose corticosteroid therapy were associated were thought to be risk factors for with an increased risk of severe pyogenic subsequent infusion reactions in children. infection during infliximab therapy (Maillard Jacobstein et al (2005) reported 60 infusion et al 2005). reactions from a total of 1652 infusions given to 243 paediatric inflammatory bowel A recent ACP Journal Club meta-analysis disease (IBD) patients. Kohlo et al (2007) (2006) found that that serious infection risk found that adverse reactions to infliximab with TNF α inhibitors was increased in infusions were common in children with IBD patients with RA. A dose effect was not and that young children seemed to be prone observed for serious infection (high dose vs to severe allergic reactions despite low dose, OR 1.4, CI 1.0 - 2.0). The azathioprine and conventional glucocorticoid Bongartz et al (2006) meta-analysis showed therapy. Candon et al (2006) reported that a 2-fold increased risk of serious infections infliximab therapy induced the appearance with TNF α inhibitors, regardless of dose. of neutralising anti-infliximab antibodies in The number needed to harm was 59 (95% 10 of 28 paediatric CD patients, which CI, 39 - 125) for 1 serious infection within a resulted in a loss of response to treatment period of 3 to 12 months. They maintenance infusions. concluded there is evidence of an increased risk of serious infections in patients with RA treated with TNF α inhibitor therapy. Use in the elderly

MIMS states that no major differences were observed in the pharmacokinetics of Use in children Remicade in elderly (65 to 80 years) RA MIMS states that the efficacy and safety of patients. infliximab in paediatric patients have not been established. No notable differences in single dose pharmacokinetics were Efficacy observed between paediatric and adult CD Clinical studies of Remicade did not include patients. sufficient numbers of CD patients aged 65

and over to determine whether they respond differently from patients aged 18 to 65. Efficacy The Cochrane review states there is an absence of proper RCTs on the Safety effectiveness of infliximab in the paediatric Studies have not been performed in patients population. Several non-randomised trials with liver or renal disease. Since elderly are presented in the Use in Children section patients have a greater frequency of of this document. Positive efficacy results decreased hepatic, renal and/or cardiac were reported, but the trials involved small function and a greater frequency of numbers of patients. Infliximab was more concomitant disease and/or other drug effective in acutely ill UC patients than in therapy, caution in the treatment of elderly patients with chronic steroid-dependent patients is recommended. While changes in disease (Fanjiang et al, 2007). Eight of 12 the ageing immune system may affect the paediatric UC patients were classified as risk of infection, in a cohort study of 15,597 long-term responders in another study US Medicare beneficiaries (>65 years), (Eidelwein et al 2005) Schneeweiss et al (Arthritis and

Rheumatism, 2007 – see Safety section) found no increase in the rate of bacterial Safety infections among TNF α inhibitors compared Crandall et al (2003) reported that the rate of methotrexate. infusion reactions in children receiving infliximab is similar to that in adults. Female gender, immunosuppressive use for less

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Cost The UK National Horizon Scanning Centre (2005) say it is difficult to estimate the cost impact of infliximab use in UC but it may lead to a net saving due to possible reduction in hospitalisation and surgical procedures. They state that minimal additional training of healthcare professionals will be required because infliximab is already used in CD treatment. A UK study states that only a minority of CD and UC sufferers are hospital inpatients but they account for approximately half the direct medical costs of IBD treatment. Drug costs contribute less than a quarter of the total healthcare costs (Luces & Bodger 2006). Lifetime costs for IBD are comparable to a number of major diseases, including heart disease and cancer. They state that in the next 5 to10 years, the contribution of drug costs will increase as biological therapies become used more widely. The key economic question is whether the health gains from these drugs will lead to reduced expenditures on hospitalisation and surgery.

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l. exp Case Control Study or exp Cohort Analysis Introduction m. b and j combined. This document contains summary data from n. limit c to (infant or child published reviews, guidelines and articles to or preschool child <1 to 6 help drug and therapeutic committees make years> or school child <7 to 12 years> or decisions about use of infliximab in adolescent <13 to 17 years>). ulcerative colitis (UC). It is not a Position Statement and does not represent All of the results were assessed, and recommendations from the NSW abstracts of the selected papers are Therapeutic Advisory Group. presented in this document.

The data was collated after searching Summaries of systematic reviews and websites of organisations/publications guidelines are reproduced verbatim where including: ACP Journal Club, ADRAC, possible, but may have been edited for Australian Clinical Trials Registry, Bandolier, conciseness. The abstracts of review Canadian Agency for Drugs and articles and clinical studies are taken Technologies in Health (CADTH), Clinical verbatim from Embase (background Evidence, Cochrane, European Medicines information may have been deleted) and are Agency, Medical Journal of Australia (MJA), presented chronologically (latest studies Medscape, National electronic Library for first). Full citations are given so that readers Medicines, National Guideline Clearing may consult the full papers if required. House (NGC), National Health and Medical research Council (NHMRC), National Heath Service Health Technology Assessment Programme (NHS HTA Programme), National Institute for Health and Clinical Excellence (NICE), National Library for Health (NLH), National Prescribing Centre (NPC, MeReC), Pharmaceutical Benefits Advisory Committee (PBAC), Scottish Intercollegiate Guidelines Network (SIGN), Scottish Medicines Consortium (SMC), Therapeutic Goods Administration, US Food and Drug Administration.

An Embase search (1996 to 2007 week 24) was also performed using the following MESH terms: a. exp Ulcerative Colitis b. exp INFLIXIMAB c. a and b combined. d. “Randomised Controlled Trial” e. a and d combined. f. exp evidence based practice or exp evidence based medicine g. c and f combined. h. economic evaluation or “cost benefit analysis” or “cost control” or “cost effectiveness analysis” or “cost minimization analysis” or “cost of illness” or “cost utilitiy analysis” i. c and h combined. j. exp Adverse Drug Reaction/dt [Drug Therapy] k. b and j combined.

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difference between infliximab and corticosteroids but both had small numbers Systematic Reviews, of patients. Meta-analyses and Safety Four studies (Jarnerot 2005; Ochsenkuhn Guidelines 2004; Probert 2003; Sands 2001) reported no serious adverse events or infusion Cochrane reactions with infliximab, although a few patients receiving infliximab developed Lawson MM, Thomas AG, Akobeng pruritis, headache, upper respiratory or AK. Tumour necrosis factor alpha urinary tract infection and there was 1 case blocking agents for induction of each of renal calculus, cellulitis, central remission in ulcerative colitis. venous catheter septicaemia and Cochrane Database of Systematic pneumothorax following catheter insertion. Reviews 2006, Issue 3. Art. No.: One patient treated with placebo (Probert CD005112. Available at: 2003) developed life-threatening sepsis. www.thecochranelibrary.com Five of 7 patients receiving oral prednisolone (Ochsenkuhn 2004) developed Summary: Cushing-like symptoms, 2 developed facial Efficacy acne and 1 developed dysphoria. In 2 Seven randomised controlled trials (RCTs) studies, Rutgeerts 2005 ACT1 (follow up 54 were identified that satisfied the inclusion weeks) and Rutgeerts 2005 ACT2 (follow up criteria. Five studies (Rutgeerts 2005 ACT1; 30 weeks), the proportion of patients with Rutgeerts 2005 ACT2; Jarnerot 2005; adverse events was generally similar in the Probert 2003; Sands 2001) compared placebo and 2 infliximab groups. In infliximab with placebo for the induction of Rutgeerts 2005 ACT1, one patient treated remission of acute UC in patients who had with infliximab developed tuberculosis (TB) failed to respond to conventional treatment and in Rutgeerts 2005 ACT2, one patient using corticosteroids and receiving infliximab developed immunosuppressants. Two studies (Probert histoplasmosis and died from acute 2003; Sands 2001) failed to show any respiratory distress syndrome. The benefit of infliximab but both had relatively incidence of infusion reactions in the 2 small numbers of patients (n = 43 and 13 studies ranged from 8% to 12% and was respectively). In patients with moderate-to- similar in the placebo and infliximab groups. severe UC whose disease was refractory to In both studies the occurrence of newly conventional treatment using corticosteroids positive results for antinuclear antibodies and/or immunosuppressive agents, and double-stranded anti-DNA antibodies infliximab (3 intravenous infusions at 0, 2, occurred more frequently in the infliximab and 6 weeks) was more effective than groups than the placebo groups. In placebo in inducing clinical remission Rutgeerts 2005 ACT1, 2 patients developed (relative risk [RR] 3.22, 95% confidence possible delayed hypersensitivity reactions interval [CI] 2.18 to 4.76); inducing (1 in placebo & 1 in infliximab group). In endoscopic remission (RR 1.88, 95% CI Rutgeerts 2005 ACT2, a possible delayed 1.54 to 2.28); and in inducing clinical hypersensitivity reaction occurred in 1 response (RR 1.99, 95% CI 1.65 to 2.41) at patient treated with infliximab. 8 weeks. The Jarnerot study showed that a Implications for practice single infusion of infliximab was also more Infliximab is effective in patients with effective than placebo in reducing the need moderate-to-severe UC whose disease is for colectomy within 90 days after infusion resistant to conventional therapy using (RR 0.44, 95% CI 0.22 to 0.87). However, corticosteroids and/or immunosuppressive this was a small study (n = 45) and it agents. In such patients, infliximab was remains unclear whether colectomy can be more effective than placebo for inducing prevented in the long term by infliximab. The clinical and endoscopic remission, clinical studies by Armuzzi and Ochsenkuhn response and helping to avoid colectomy in compared infliximab with corticosteroids. the short term. In the 2 largest studies there They both failed to show any significant was no statistically significant difference

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between a dose of 5 mg/kg and 10 mg/kg. As in CD, there is an absence of proper The authors recommend an intravenous RCTs on the effectiveness of infliximab in dose of 5 mg/kg. The schedule of therapy the paediatric population. Well designed was not consistent between studies. In the 2 clinical trials investigating the use of largest studies which demonstrated the infliximab in childhood inflammatory bowel largest effect, infliximab was given at 0, 2 disease (IBD) are needed. and 6 weeks to induce remission, but in one study (Jarnerot 2005) a single infusion of Alimentary Pharmacology & infliximab was used as a 'rescue therapy' in patients with acute disease judged to have Therapeutics failed to respond to high dose Gisbert JP, Gonzalez-Lama Y, Mate J. corticosteroids. There is, therefore, Systematic review: Infliximab insufficient evidence to provide therapy in ulcerative colitis. recommendations on the ideal dosing Alimentary Pharmacology & schedule. The authors did not find any Therapeutics. Vol. 25(1)(pp 19-37), evidence to suggest that infliximab is more 2007. effective than high-dose corticosteroids in patients who are not steroid-refractory. Summary: Serious adverse events attributable to This was a systematic review and meta- infliximab were not common in the included analysis on the efficacy and tolerance of studies but physicians should be aware of infliximab in UC. Methods: Selection of and be prepared to deal with some of the studies: evaluating efficacy of infliximab in uncommon adverse events such as UC. For the meta-analysis, randomised anaphylactic reactions and infections. The clinical trials comparing infliximab vs. authors found no evidence to support the placebo/steroids. Search strategy: electronic use of other tumour necrosis factor alpha and manual. Study quality: independently α (TNF ) inhibitors in acute UC. assessed by 2 reviewers. Data synthesis: Implications for research meta-analysis combining the odds ratios It is important for researchers to ensure (OR). Results: Thirty-four studies (896 adequate sample size by performing a priori patients) evaluated infliximab therapy in UC, power and sample size calculations. The with heterogeneous results. Mean short- more recent larger studies clearly term (2.3 weeks) response and remission demonstrated a benefit for infliximab in with infliximab was 68% (95% CI 65% - patients who had previously received 71%) and 40% (36% - 44%). Mean long- corticosteroids and/or immunosuppressive term (8.9 months) response and remission agents. It is unclear from the results of was 53% (49% - 56%) and 39% (35% - included studies whether both 42%). Five RCTs compared infliximab with corticosteroids and immunosuppressive placebo, the meta-analysis showing an agents should be used prior to infliximab advantage (P < 0.001) of infliximab in all therapy. The question of when it is endpoints (short/long-term appropriate to use infliximab in clinical response/remission): ORs from 2.7 to 4.6, practice should be addressed in future and number-needed-to-treat (NNT) from 3 to studies. The fact that infliximab is effective in 5. Similar infliximab response was UC does not necessarily mean that other calculated independently of the indication α TNF inhibitors will also be effective, and (steroid refractory/non-steroid refractory) or these agents should be tested in the dose (5/10 mg/kg). Adverse effects were randomised trials. Further long term studies reported in 83% and 75% of the infliximab are required to determine whether infliximab and placebo-treated patients (OR = 1.52; can prevent colectomy in the long term, and 95% CI 1.03-2.24; number-needed-to-harm also to evaluate potential long term adverse (NNH) was 14). Conclusion: Infliximab is events. Future studies should also include more effective than placebo, with an NNT assessment of quality of life as an important from 3 to 5, for the treatment of moderate-to- outcome and such studies should be severe UC, achieving clinical remission in designed to ensure that there is adequate 40% of the patients at approximately 9 statistical power to detect any differences months of follow-up. Further studies are between groups with regard to this outcome.

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necessary to confirm the long-term efficacy American of infliximab in UC. Gastroenterological Association Institute ACP Journal Club Lichtenstein GR, Abreu MT, Cohen R, et al. Anti-tumor necrosis factor antibody American Gastroenterological therapy for rheumatoid arthritis Association Institute Medical increases risk for serious infection Position Statement on and malignancy. ACP Journal Club, Corticosteroids, Immunomodulators, v145(3):65, November/December, and Infliximab in Inflammatory 2006. Bowel Disease. Gastroenterology 2006;130:935–939. Summary: Summary: Question: In patients with RA, does treatment with TNF α inhibitors increase the Recommendations in UC risk for serious infection and malignancy? Current indications for infliximab include the Methods: Search of MEDLINE, treatment of moderately to severely active EMBASE/Excerpta Medica, Cochrane UC in patients who have not responded Library (2005), abstracts from scientific despite complete and adequate therapy with meetings of the European League against a corticosteroid or an immunosuppressive Rheumatism and the American College of agent (azathioprine [AZA], 6-mercaptopurine Rheumatology (1996 to 2005), and drug [6-MP], or methotrexate [MTX]). These manufacturers. Study selection and patients are individuals who are resistant to assessment: RCTs that compared infliximab medical therapy (complete and adequate or adalimumab with placebo (with or without therapy with a corticosteroid or an a traditional disease-modifying antirheumatic immunosuppressive agent) or who cannot drug in each group) in patients with RA, with receive such therapies due to intolerance to duration of treatment ≥ 12 weeks (range 12 medications (corticosteroids or medical to 54 wk). 9 RCTs (n = 5014) met the contraindications [therapy intolerant]). selection criteria. 2 reviewers independently The recommended initial dose of infliximab assessed the RCTs for methodological for all IBD indications is 5 mg/kg body wt, quality, including randomisation, allocation administered by intravenous infusion over 2 concealment, blinding, intention-to-treat hours in an induction regimen of 3 doses at analysis, follow-up, outcome assessment, weeks 0, 2, and 6. This should be followed and attrition. All RCTs were double-blinded. by maintenance therapy every 8 weeks in Outcomes: Serious infection (requiring patients who respond. For patients with CD antimicrobial therapy or hospitalisation) and who respond and then lose their response, malignancy. Main results: TNF α inhibitor consideration may be given to treatment therapy increased risk for both serious with 10 mg/kg. In the case of nonresponse infection and malignancy more than to 3 infusions, further treatment with placebo. For malignancy, risk was greater in infliximab is not recommended. The patients receiving a high dose of TNF α treatment should be administered under the inhibitor compared with placebo (OR 4.3, supervision and control of a specialised 95% CI 1.6 to 12) than in those receiving a health care deliverer, with emergency low dose (OR 1.4, CI 0.3 to 5.7). Direct equipment for severe infusion reactions comparison of high and low dose also available. A follow-up observation period of showed increased risk for malignancy with approximately 1 hour is advocated. If a high-dose treatment (OR 3.4, CI 1.4 to 8.2). patient is on infliximab and achieves A dose effect was not observed for serious remission, an attempt to withdraw or taper infection (high dose vs low dose, OR 1.4, CI any concomitant corticosteroid therapy is 1.0 to 2.0). Conclusion: In patients with RA, sensible. treatment with TNF α inhibitor increases risk Although there is evidence-based data to for serious infection and malignancy. support the use of corticosteroids, immunomodulators, and infliximab in the treatment of patients with IBD, there are

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many aspects of therapy with these agents designed for sparse data) for malignancies for which the data are lacking or inadequate. and serious infections (infection that Additional prospective data are needed to requires antimicrobial therapy and/or resolve the areas of controversy. The hospitalisation) in TNF α inhibitor-treated gastroenterologist who uses these agents patients vs placebo patients. The authors must have a clear understanding of the estimated effects for high and low doses proven benefits and risks of these therapies separately. The pooled OR for malignancy to provide optimal care to the patient with was 3.3 (95% confidence interval [CI], 1.2- IBD. 9.1) and for serious infection was 2.0 (95% CI, 1.3-3.1). Malignancies were significantly more common in patients treated with higher JAMA doses compared with patients who received lower doses of TNF α inhibitors. For patients Bongartz T, Sutton AJ, Sweeting MJ et al. treated with TNF α inhibitors in the included Anti-TNF antibody therapy in trials, the number needed to harm was 154 rheumatoid arthritis and the risk of (95% CI, 91-500) for 1 additional malignancy serious infections and malignancies: within a treatment period of 6 to 12 months. systematic review and meta- For serious infections, the number needed analysis of rare harmful effects in to harm was 59 (95% CI, 39-125) within a randomized controlled trials. JAMA treatment period of 3 to 12 months. 2006; 295:2275-85 CONCLUSIONS: There is evidence of an increased risk of serious infections and a Summary: dose-dependent increased risk of This paper assesses the extent to which malignancies in patients with RA treated TNF α inhibitors may increase the risk of with TNF α inhibitors. The formal meta- serious infections and malignancies in analysis with pooled sparse adverse events patients with RA by performing a meta- data from RCTs serves as a tool to assess analysis to derive estimates of sparse harmful drug effects. harmful events occurring in RCTs of TNF α inhibitors. DATA SOURCES: A systematic literature search of EMBASE, MEDLINE, National Horizon Scanning Cochrane Library, and electronic abstract databases of the annual scientific meetings Centre of both the European League Against Infliximab (Remicade) for ulcerative Rheumatism and the American College of colitis July 2005. Available at: Rheumatology was conducted through www.pcpoh.bham.ac.uk/publichealt December 2005. This search was h/horizon complemented with interviews of the manufacturers of the 2 licensed TNF α Summary: inhibitors. STUDY SELECTION: The authors α Infliximab may be welcomed by patients with included RCTs of the 2 licensed TNF UC who have had an inadequate response inhibitors (infliximab and adalimumab) used to conventional treatment due to the clinical for 12 weeks or more in patients with RA. response, and the induction and Nine trials met the inclusion criteria, α maintenance of clinical remission including 3493 patients who received TNF demonstrated in recently reported phase III inhibitors and 1512 patients who received trials. There are, however, significant side placebo. DATA EXTRACTION: Data on effects associated with therapy with TNF α study characteristics to assess study quality inhibitors. and intention-to-treat data for serious The number of infusions required for infections and malignancies were maximum benefit and long-term response is abstracted. Published information from the uncertain at present. It is also unclear at trials was supplemented by direct contact present the number of patients that will between principal investigators and industry receive infliximab initially if successfully sponsors. DATA SYNTHESIS: The authors licensed for UC. It is therefore difficult to calculated a pooled OR (Mantel-Haenszel estimate the overall cost impact of infliximab methods with a continuity correction

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for the treatment of UC at this time. Treatment with infliximab may lead to a net saving due to a possible reduction in hospitalisation and surgical procedures. Infliximab is already used in the gastrointestinal setting in the treatment of CD and thus minimal additional training of healthcare professionals will be required.

Scottish Medicines Consortium Infliximab 100 mg powder for intravenous infusion. March 2007. Available at: www.scottishmedicines.org.uk

Summary: In the absence of a submission from the holder of the marketing authorisation. Infliximab (Remicade) is not recommended for use within NHSScotland for the treatment of moderately to severely active UC in patients who have had an inadequate response to conventional therapy including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies. The holder of the marketing authorisation has not made a submission to SMC regarding this product in this indication. As a result the authors cannot recommend its use within NHSScotland.

NICE Health Technology Appraisal Infliximab for ulcerative colitis - final scope. March 2007. Available at: www.nice.org.uk

Summary: This is the final scope of an appraisal of the clinical and cost effectiveness of infliximab for moderately to severely active UC. A first review is scheduled for August 2007 and the date of the second review has not been set.

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from these 2 studies showed that in patients with moderate-to-severe UC, treatment with Use in Adults infliximab (5 and 10 mg/kg), compared with placebo, led to significantly higher rates of Reviews in IBD clinical response, clinical remission and mucosal healing. However, a significant Efficacy and safety reviews proportion of patients who were receiving oral corticosteroids at the start of the trials, Baumgart DC, Sandborn WJ. remained on corticosteroids despite Inflammatory bowel disease: clinical infliximab therapy. Additionally, the safety aspects and established and profile of the drug was found to be similar to evolving therapies. Lancet. Vol. what has been reported in clinical studies of 369(9573)(pp 1641-1657), 2007. infliximab in patients with CD. On the basis of currently available data, the authors use Abstract: infliximab as a remission-inducing agent in This paper critically reviews the evidence for patients who have moderate-to-severe UC established (5-aminosalicylic acid [5-ASA] and are either refractory to or intolerant of compounds, corticosteroids, mesalazine products and immunomodulators, calcineurin inhibitors) immunomodulators. Moreover, infliximab and emerging novel therapies-including seems to be a reasonable therapeutic biological therapies-directed at cytokines modality for remission maintenance in those (eg, infliximab, adalimumab, certolizumab patients with UC in whom mesalazine pegol) and receptors (eg, visilizumab, products and immunomodulators have abatacept) involved in T-cell activation, failed. Although data are limited, infliximab selective adhesion molecule blockers (eg, may be considered as a remission-inducing natalizumab, MLN-02, alicaforsen), anti- agent in patients with moderate-to-severe inflammatory cytokines (eg, interleukin 10), UC which is refractory to oral modulation of the intestinal flora (eg, corticosteroids. However, the role of antibiotics, prebiotics, probiotics), leucocyte infliximab in the treatment of UC patients apheresis and many more monoclonal who are dependent on oral corticosteroids is antibodies, small molecules, recombinant still unclear and, therefore, should be growth factors, and MAP kinase inhibitors considered only in patients who cannot be targeting various inflammatory cells and successfully transitioned to or are intolerant pathways. of oral immunomodulators. Furthermore, infliximab may be an alternative to D'Haens G. ciclosporin (cyclosporin) in hospitalised Risk and benefits of biologic therapy patients with severe to moderately severe for inflammatory bowel diseases. but not fulminant UC who do not respond to Gut. Vol. 56(5)(pp 725-732), 2007. intravenous corticosteroids. At present, there is insufficient evidence to advocate No abstract available. using infliximab as a first-line agent for UC patients with mild or moderate-to-severe Thukral C, Cheifetz A, Peppercorn MA. disease. Future randomised, controlled trials Anti-tumour necrosis factor therapy with clearly defined patient populations for ulcerative colitis: Evidence to should further help to clarify the definitive date. Drugs. Vol. 66(16)(pp 2059- role of infliximab in the therapeutic scheme 2065), 2006. for UC.

Abstract: Scholmerich J. Treatment of inflammatory bowel ACT1 and ACT2 trials were large, disease. Schweizerische randomised and placebo-controlled, and Rundschau fur Medizin Praxis. Vol. have shown that infliximab is significantly 96(9)(pp 337-343), 2007. more efficacious than placebo in treating both corticosteroid-responsive and - refractory moderate-to-severe UC. Data

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Abstract: De La Rue SA, Bickston SJ. Standard treatment for IBD with 5-ASA, Evidence-based medications for the steroids and immunosuppressants is rather treatment of the inflammatory bowel effective and currently optimised using diseases. Current Opinion in combinations of drugs or application routes. Gastroenterology. Vol. 22(4)(pp Among the biologics only infliximab has 365-369), 2006. reached the therapeutic arsenal for CD - it is also effective in some patients with UC. Abstract: Early aggressive treatment thus far is not This review is an update on several established. Hormones and growth factors significant analyses that have been may play a role. Probiotics have a place in published recently. It is intended to raise the treatment in particular for UC. awareness of the data, helping clinicians to evaluate new treatments and to revisit older Collins P, Rhodes J. treatments with a critical eye. Ulcerative colitis: Diagnosis and management. British Medical Cottone M, Mocciaro F, Modesto I. Journal. Vol. 333(7563)(pp 340- Infliximab and ulcerative colitis. 343), 2006. Expert Opinion on Biological Therapy. Vol. 6(4)(pp 401-408), No abstract available. 2006.

Nakamura K, Honda K, Mizutani T, et al. Abstract: Novel strategies for the treatment of Despite the fact that the cytokine profiles inflammatory bowel disease: associated with UC and CD are classically Selective inhibition of cytokines and considered different (a Th2 pattern in UC adhesion molecules. World Journal and a Th1 pattern in CD), there are several of Gastroenterology. Vol. 12(29)(pp evidences in vitro and in vivo that TNF α has 4628-4635), 2006. an important role in UC. Infliximab has been evaluated in different clinical settings both in Abstract: adults and in children: in moderate-severe Infliximab has become a standard therapy steroid-dependent UC, in severe refractory for CD and it is also likely to be beneficial for UC as rescue therapy, in active non-steroid- UC. Several TNF α inhibitors have been refractory UC, in resistant pouchitis and in developed but most of them seem to not be maintenance of moderate-severe UC as efficacious as infliximab. Adalimumab responsive to infliximab. On the basis of the may be useful for the treatment of patients RCTs, it is possible to draw the following who lost responsiveness or developed conclusions for adults: infliximab seems intolerance to infliximab. Antibodies against active in severe steroid-refractory UC, IL-12 p40 and IL-6 receptor could be allowing colectomy to be spared even if alternative new anti-cytokine therapies for further controlled trials are needed with a IBD. Anti-interferon-gamma and anti-CD25 larger sample of patients adopting strict and therapies were developed, but the benefit of well-defined inclusion criteria. The drug these agents has not yet been established. seems active in inducing remission after 8 The selective blocking of migration of weeks in steroid-refractory patients, in leukocytes into intestine seems to be a nice patients taking steroids (even if it is not clear approach. Antibodies against a4 integrin and at which dosage of steroid dependence the a4beta7 integrin showed benefit for IBD. drug is more active) and also in patients Antisense oligonucleotide of intercellular failing aminosalicylates therapy. The long- adhesion molecule 1 may be efficacious for term response of infliximab in comparison to IBD. Clinical trials of such compounds have placebo in these subgroups of patients is not been either recently reported or are currently clinically impressive even if it is statistically underway. In this article, the authors review significant. Further trials are warranted in the efficacy and safety of such novel order to establish the role of infliximab in biological therapies for IBD. steroid-dependent UC (defined with clear criteria), in maintaining remission after

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severe UC, in non-steroid-dependent Current Opinion in moderate-severe UC and in refractory Gastroenterology. Vol. 22(1)(pp 30- pouchitis. For children it is not possible to 43), 2006. draw the same conclusions, due to a lack of RCTs, despite the encouraging data coming Abstract: from open studies, mainly in steroid- This review analyses the complications refractory UC. associated with treatment of IBD with biologic agents. The data concerning Travassos WJ, Cheifetz AS. biologics' associated toxicity in patients with Infliximab: Use in inflammatory inflammatory bowel disease are the most bowel disease. Current Treatment robust in the case of infliximab. These data Options in Gastroenterology. Vol. are derived from both prospective, RCTs 8(3)(pp 187-196), 2005. and from post-marketing experience. In the case of the remaining agents the data Abstract: concerning safety in inflammatory bowel Infliximab initially was developed to be used disease are limited, as these agents were in patients with moderate-to-severe luminal not evaluated in as many trials as infliximab; or fistulising CD who are refractory to indeed, some of them included only several standard medical therapy. More and more patients. practitioners now are using infliximab as first-line therapy because of its superior Kamm MA. efficacy. Infliximab rapidly induces remission Safety issues relating to biological in CD, but when given chronically, it can therapies, with special reference to provide long-term maintenance of remission. infliximab therapy. Research & In addition, there are some data to support Clinical Forums. Vol. 24(1)(pp 79- its use as a steroid-sparing agent and 86), 2002. treatment for various extraintestinal manifestations of IBD and, although used Abstract: predominantly to treat CD, recent data The only licensed biological therapy for IBD suggest that infliximab also may have a role is infliximab. Acute infusions can be in the management of UC. Overall, associated with an allergic reaction. infliximab represents a clinically useful, cost- Development of human anti-chimeric effective therapy that works well, even antibodies is associated with acute infusion though careful patient monitoring is required reactions, delayed type hypersensitivity to avoid rare but significant toxicities. The reactions, and altered drug hope is that infliximab, together with other pharmacokinetics with a consequent biologic agents that currently are in diminuation in clinical efficacy. Ultrasound development, will allow us to modify the and MRI studies suggest that the course of IBD, avoid complications such as subcutaneous track of subcutaneous fistulae strictures and abscesses, and reduce the often persist. Mucosal healing can lead to need for surgery. stricture formation. Infliximab increases the risk of infection. The risk of TB has been Knigge K. estimated as approximately 3 per 10,000, Severe, steroid-refractory ulcerative and has led to some deaths. CD is colitis: Infliximab to the rescue? associated with an increased cancer risk. Evidence-Based Gastroenterology. Any increased risk from treatment is Vol. 6(4)(pp 110-111), 2005. controversial; long term, large, cohort studies are required. Teratogenicity is not No abstract available. apparent either experimentally or in early clinical data. TNF α inhibitors are dramatically effective in CD, often when Safety reviews other treatments have failed. As with every new treatment, however, its use should be Blonski W, Lichtenstein GR. judicious and tempered by data on the long- Complications of biological therapy term benefit, side effects and safety issues. for inflammatory bowel diseases.

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receiving TNF α inhibitors should not receive concurrent vaccination with live vaccines Reviews of safety – general and consideration should be given to screening patients for preexisting infections, and in other therapeutic particularly hepatitis B and TB, prior to their areas use.

Anonymous. Anonymous. Tumour necrosis factor alpha Adverse events with TNF inhibitors. Aust Adv Drug Reactions antagonists. Bandolier 2006; 249. Bull Volume 25 (Number 6), 23-24, Available at: December 2006 http://www.jr2.ox.ac.uk/bandolier/ Abstract: Abstract: Currently, 3 TNF α inhibitors are registered in Fiddling with the immune system brings Australia: infliximab (Remicade) - for the dangers, including cancer and serious treatment of CD, RA and ankylosing infections. Trying to measure the rate at spondylitis (AS); etanercept (Enbrel) - for which these rare events occur, and whether RA, polyarticular juvenile chronic arthritis, the rates are different with TNF α inhibitors is psoriatic arthritis and AS; and adalimumab hard because of limited numbers. New (Humira) - for RA. ADRAC has received 319 studies provide at least some insight, and reports involving TNF α inhibitors since 2000. highlight the problems. It is probably best to The more serious of these are: malignant look at the evidence from randomised trials melanoma (3 reports), lymphoma (5), TB first, then compare it with evidence from (4), pneumonia/lower respiratory tract observational studies. infections (23), sepsis (10), lupus or lupus- RCTs like syndrome (22) and anaphylaxis (9). A systematic review and meta-analysis According to Medicare Australia statistics, (Bongartz et al – included in this document) 57,846 prescriptions for the 3 TNF α used trials of infliximab and adalimumab in inhibitors combined have been issued for RA (etanercept was excluded because of a the treatment of RA since 2000. Given their somewhat different mechanism of action). It mechanisms of action, it is possible that the examined published material for serious use of TNF α inhibitors may predispose adverse events, used FDA information, and patients to an increased risk of malignancies discussed serious adverse events with or accelerate their development. A recent trialists and manufacturers for clarification. metaanalysis of randomised trials of The denominator was the number of infliximab or adalimumab in RA found that patients with at least one dose of drug, and malignancies developed in 29/3192 (0.9%) the numerator patients with at least one patients treated with infliximab or serious malignancy or infection. Nine trials adalimumab, compared with 3/1428 (0.2%) lasting at least 12 weeks (8 were 6 months patients given placebo. The risk of to1 year) randomised 5,014 patients. malignancies was not different from placebo Malignancy: There were 29 malignancies in with low dose TNF α inhibitors but was 4-fold 3,192 patients (0.9%) on infliximab or greater with high doses of infliximab or adalimumab, and 3 in 1,428 (0.2%) on adalimumab. An increased risk of placebo; 6 other lymphomas were detected malignancies has also been reported for during follow up, but not included in the etanercept. The Australian Product analysis. The OR was 3.3 (1.2 to 9.1), and Information for these medicines advises the number of patients who needed to be prescribers that caution should be exercised treated for 6 to 12 months with infliximab or when considering TNF α inhibitor therapy for adalimumab for one to be harmed was 154 patients with a history of malignancy or (91 to 500). when considering continuing treatment in Serious infections: There were 126 serious patients who develop a malignancy. The infections in 3,493 patients (3.6%) on recent meta-analysis also showed a 2-fold infliximab or adalimumab, and 26 in 1,512 increased risk of serious infections with (1.7%) on placebo. The OR was 2.0 (1.3 to TNF α inhibitors, regardless of dose. Patients 3.1), and the number of patients who

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needed to be treated for 6 to 12 months with on a handful of events, potential interference infliximab or adalimumab for one to be from the random play of chance is possible. harmed was 59 (39 to 125). One meta-analysis, for instance, had 3 Observational studies malignancies with placebo, and one A series of observational studies come from observational study used 4 and 2 cases of Sweden (see Askling et al papers in this TB to calculate statistics. While on size, document), where the mix of TNF α inhibitors observational studies can involve a lot of was predominantly etanercept and patients, and here observational studies had infliximab. These used several sources of up to 4 times as many patient years of information, a prevalent cohort of 53,000 RA observation than did a meta-analysis of patients, an incidence cohort of 3,700 RA randomised trials. Which brings us to time, patients, and one RA cohort of 4,160 especially important for adverse events. patients treated with TNF α inhibitors. These Some may occur early with treatment, had approximately 300,000, 13,000, and others late, or they can be constant over 10,000 person years of follow up time. Comparing short with long duration respectively, with average follow ups of 6, studies can be problematical. 3.5 and 2.5 years per patient. Linkage between different registries and cancer and And finally, what treatments are being used? other registries meant that outcomes could None of the observational studies seemed to be collected. The entire Swedish population include adalimumab, or any other newer served as a control group for calculation of agents. So while meta-analyses standardised rates. concentrated on some agents but not Malignancies: Haematopoietic others, observational studies reported on a malignancies occurred in 507 patients, at different mix of agents being used in clinical rates higher than the general population. practice. The question, then, is whether like When compared with the prevalent and is being compared with like. If there is a incident RA cohorts not receiving TNF α lesson here, it is that for serious but rare inhibitors, patients receiving TNF α inhibitors adverse events, rushing to judgement may had a RR of 1.1 (95% CI 0.6 to 2.1). Solid not be prudent. If there is an answer, it is cancers occurred in 3,584 patients, at rates that tinkering with the immune system can little greater than in the general population. produce great benefit, but with a risk of When compared with the prevalent and something bad happening. Until it can be incident RA cohorts not receiving TNF α said for certain who will benefit and who will inhibitors, patients receiving TNF α inhibitors be at risk, we have to live with that were little different overall, or when analysed uncertainty. by duration of observation. Serious infections: This is limited by the small number of TB cases in patients treated Efficacy studies with infliximab or etanercept (15, 10 of them pulmonary). Only 4 of these were included in a statistical analysis. The best guess is that RCTs TB rates are increased in RA patients Rutgeerts P, Sandborn WJ, Feagan BG, et treated with TNF α inhibitors. al. Comment Infliximab for induction and It is always tempting to dismiss maintenance therapy for ulcerative observational studies when they disagree colitis. New England Journal of with randomised trials (or meta-analyses of Medicine. Vol. 353(23)(pp 2462- them). This may be hasty, especially when 2476), 2005. both types of study are well done. It is always worth asking a few questions, Abstract: especially when dealing with serious, but Two randomised, double-blind, placebo- rare, adverse events. The first question is controlled studies - the Active Ulcerative about size, about the number of events. Colitis Trials 1 and 2 (ACT1 and ACT2, Because they are rare events, malignancies respectively) - evaluated the efficacy of and serious infections are unlikely to be infliximab for induction and maintenance numerous. If a statistical analysis is based therapy in adults with UC. In each study,

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364 patients with moderate-to-severe active day 3 or on day 6-8 if they fulfilled index UC despite treatment with concurrent criteria on day 5-7 for a severe or medications received placebo or infliximab moderately severe acute attack of UC. (5 mg or 10 mg per kilogram of body weight) Results were analysed according to the intravenously at weeks 0, 2, and 6 and then intention-to-treat principle. The primary end every 8 weeks through week 46 (in ACT1) or point was colectomy or death 3 months after week 22 (in ACT2). Patients were followed randomisation. Secondary end points were for 54 weeks in ACT1 and 30 weeks in clinical and endoscopic remission at that ACT2. In ACT1, 69% of patients who time in patients who did not undergo received 5 mg of infliximab and 61% of operation. Results: Forty-five patients were those who received 10 mg had a clinical included (24 infliximab and 21 placebo). No response at week 8, as compared with 37% patient died. Seven patients in the infliximab of those who received placebo (P<0.001 for group and 14 in the placebo group had a both comparisons with placebo). A response colectomy (P =. 017; OR, 4.9; 95% was defined as a decrease in the Mayo confidence interval, 1.4-17) within 3 months score of at least 3 points and at least 30%, after randomisation. No serious side effects with an accompanying decrease in the occurred. Three patients in the placebo subscore for rectal bleeding of at least 1 group required operation for septic point or an absolute rectal bleeding complications. Conclusions: Infliximab 4-5 subscore of 0 or 1. In ACT2, 64% of patients mg/kg is an effective and safe rescue who received 5 mg of infliximab and 69% of therapy in patients experiencing an acute those who received 10 mg had a clinical severe or moderately severe attack of UC response at week 8, as compared with 29% not responding to conventional treatment. of those who received placebo (P<0.001 for both comparisons with placebo). In both Armuzzi A, De Pascalis B, Lupascu A, et al. studies, patients who received infliximab Infliximab in the treatment of steroid- were more likely to have a clinical response dependent ulcerative colitis. at week 30 (P ≤0.002 for all comparisons). In European Review for Medical & ACT1, more patients who received 5 mg or Pharmacological Sciences. Vol. 10 mg of infliximab had a clinical response 8(5)(pp 231-233), 2004. at week 54 (45% and 44%, respectively) than did those who received placebo (20%, Abstract: P<0.001 for both comparisons). The The authors evaluated the efficacy of authoprs concluded that patients with infliximab in the management of steroid- moderate-to-severe active UC treated with dependent UC. They report preliminary data infliximab at weeks 0, 2, and 6 and every 8 from a randomised, open-label, weeks thereafter were more likely to have a methylprednisolone-controlled trial of clinical response at weeks 8, 30, and 54 infliximab in the induction and maintenance than were those receiving placebo. of remission of patients with moderate-to- severe steroid-dependent UC. Twenty Jarnerot G, Hertervig E, Friis-Liby I, et al. patients received either 3 infusion of Infliximab as rescue therapy in infliximab (5 mg/kg) at 0, 2 and 6 weeks and severe to moderately severe thereafter every 8 weeks (group A) or ulcerative colitis: A randomized, methylprednisolone (0,7-1 mg/kg) daily for 1 placebo-controlled study. week followed by a tapering regimen up to Gastroenterology. Vol. 128(7)(pp the minimal dose to maintain a symptom- 1805-1811), 2005. free condition (group B). Clinical remission was defined as a DAI score less than 3. Abstract: Results: Ten patients in group A (DAI: 8.9 This was a randomised double-blind trial of +/- 1.4) achieved remission after the first infliximab or placebo in severe to moderately infusion (DAI: 1.6 +/- 0,7; p = 0.005) and severe UC not responding to conventional steroids were progressively discontinued. At treatment. Patients were randomised to present (mean follow-up: 9.8 +/- 1.1 infliximab/placebo either on day 4 after the months), 9 out of 10 patients maintain initiation of corticosteroid treatment if they clinical remission, while one patient relapsed fulfilled the index criteria for fulminant UC on at 3 months. Ten patients in group B (DAI:

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8.7 +/- 1.4) reached clinical remission at 1 UC. The obtained data call for larger week (DAI: 1.9 +/- 0.3; p = 0.005). Eight out controlled trials. of 10 patients were maintained at a minimal steroid dosage without any relapse at 9.7 +/- Probert CSJ, Hearing SD, Schreiber S, et al. 1.0 months follow-up. Two patients relapsed Infliximab in moderately severe at 6 and 8 months, respectively. glucocorticoid resistant ulcerative Conclusions: Infliximab seems to be as colitis: A randomised controlled trial. effective as steroids in the management of Gut. Vol. 52(7)(pp 998-1002), 2003. moderate-to-severe steroid-dependent UC. These preliminary data suggest the potential Abstract: efficacy of repeated treatment with infliximab The authors conducted a randomised for short-term maintenance of remission and placebo controlled trial of infliximab (5 steroid withdrawal in glucocorticoid- mg/kg) in the treatment of glucocorticoid dependent UC. resistant UC. Infusions were given at weeks 0 and 2. Disease activity and quality of life Ochsenkuhn T, Sackmann M, Goke B. were recorded over 8 weeks of follow up. Infliximab for acute, not steroid- Remission was defined as an UC symptom refractory ulcerative colitis: A score (UCSS) of ≤2 and/or Baron score of 0 randomized pilot study. European at week 6. Patients not in remission were Journal of Gastroenterology & offered open label infliximab 10 mg/kg and Hepatology. Vol. 16(11)(pp 1167- reviewed 2 weeks later. Results: After 2 1171), 2004. weeks, there was no statistically significant difference between the infliximab and Abstract: placebo groups in the proportion of patients Infliximab, has shown to be effective in the with a Baron score of 0 (13% (3/23) v 5% treatment of steroid-refractory UC in pilot (1/19) (95% confidence interval (CI) -9% to studies. The authors therefore evaluated 24%); p=0.74). After 6 weeks, remission whether infliximab can achieve remission in (UCSS ≤2) rates were 39% (9/23) versus patients with acute ulcerative pancolitis who 30% (6/20) (95% CI -19 to 34%; p=0.76). were not steroid-refractory. Methods and The median improvement in UCSS was 3 for design: Patients were eligible if they had the infliximab group and 2.5 for the placebo acute disease with a modified Truelove and group (p=0.82, Mann-Whitney U test). A Witts activity score of more than 10 for at Baron score of 0 was likely in either group least 2 weeks and if they were currently not (26% (6/23) v 30% (6/20) (95% CI -30% to receiving immunomodulators or more than 23%); p=0.96). Improvement in the IBDQ 10 mg/day prednisolone. Patients were and EuroQol was not significantly different randomly assigned to receive either 3 between the groups (p=0.22 and 0.3, intravenous infusions of infliximab at 5 respectively, Mann-Whitney U test). Twenty mg/kg (group A) or high-dose prednisolone eligible patients were given open labelled (1.5 mg/ kg body weight) daily for 2 weeks, infusions. Remission was achieved in 3/11 followed by 1 mg/kg for 1 week, followed by (27%) patients initially treated with infliximab a weekly reduction of 5 mg (group B). and in 1/9 (11%) patients treated with Therapy success was defined as clinical placebo. Conclusion: These data do not response in terms of a decrease of more support the use of infliximab in the than 5 points from the baseline score and to management of moderately active less than 10 points total after 3 weeks as glucocorticoid resistant UC. well as after 13 weeks. Results: Thirteen patients (7 women, 6 men) were randomised Sands BE, Tremaine WJ, Sandborn WJ, et (6 for group A and 7 for group B). The al. median baseline activity scores were 13.5 Infliximab in the treatment of severe, (12-18) in group A and 14.0 (11-18) in group steroid-refractory ulcerative colitis: A B. Five of 6 patients in group A and 6 of 7 pilot study. Inflammatory Bowel patients in group B showed therapy success Diseases. Vol. 7(2)(pp 83-88), 2001. after 3 weeks as well as after 13 weeks. Conclusions Infliximab could be effective in the treatment of acute moderate or severe

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Abstract: colectomy-free survival. Disease and The authors report the experience of 11 treatment characteristics and complications patients (of 60 planned patients) enrolled in were documented. Results: Thirty patients a double-blind, placebo-controlled clinical were treated with infliximab for refractory trial of infliximab in patients with severe, UC. Sixteen (53%) came to colectomy a active steroid-refractory UC. The study was median of 140 days after their first infusion terminated prematurely because of slow (range 4-607). There was no difference in enrollment. Patients having active disease colectomy between those receiving for at least 2 weeks and receiving at least 5 infliximab for acute severe UC failing days of intravenous corticosteroids were intravenous steroids (8/14) and out-patients eligible to receive a single intravenous with steroid-refractory UC (8/16). Only 17% infusion of infliximab at 5, 10, or 20 mg/kg (5/30) achieved a steroid-free remission body weight. The primary endpoint used in after a median follow-up of 13 months this study was treatment failure at 2 weeks (range 2-72). Univariate analysis showed after infusion. Treatment failure was defined that a younger age at diagnosis of colitis as 1) unachieved clinical response as was significantly associated with an defined by a modified Truelove and Witts increased rate of colectomy (27.5 years vs. severity score, 2) increase in corticosteroid 38.7 years, P = 0.016). Conclusion: Over dosage, 3) addition of immunosuppressants, half the patients studied came to colectomy. 4) colectomy, or 5) death. Safety evaluations Of those avoiding colectomy, only 5 (17%) included physical examination, clinical sustained a steroid-free remission. chemistry and hematology laboratory tests, and occurrence of adverse experiences. Rossetti S, Actis GC, Fadda M, et al. Four of 8 patients (50%) who received The use of the anti-tumour necrosis infliximab were considered treatment factor monoclonal antibody- successes at 2 weeks, compared with none infliximab-to treat ulcerative colitis: of 3 patients who received placebo. Implications and trends beyond the Improvement in erythrocyte sedimentation available data. Digestive & Liver rates and serum concentrations of C- Disease. Vol. 36(6)(pp 426-431), reactive protein and interleukin-6 correlated 2004. with the clinical response observed in patients receiving infliximab. Infusion with Abstract: infliximab produced no significant adverse Infliximab has recently been added to the list events. Infliximab was well tolerated and of off-label therapeutic means for UC. The may provide clinical benefit for some authors conducted a descriptive analysis of patients with steroid-refractory UC. the results from studies on the use of the drug published so far. A total of 187 patients qualified for analysis. They were divided into Non-randomised studies 4 main categories, including steroid- refractory and responsive adults and Jakobovits SL, Jewell DP, Travis SPL. children. The median frequencies of an early Infliximab for the treatment of and a sustained response were 77 and ulcerative colitis: Outcomes in 44.5%. These data suggest that adult non- Oxford from 2000 to 2006. steroid-refractory, and paediatric patients Alimentary Pharmacology & may respond with the highest frequency. Therapeutics. Vol. 25(9)(pp 1055- While it is obligatory to wait for the yield of 1060), 2007. the ongoing controlled trials before any conclusion on these indications is drawn, the Abstract: data provide seminal ideas to further Aims: To review the rate of colectomy after investigations, including the hypothesis to infliximab for UC and to identify factors that inaugurate with infliximab a top-down might predict the need for colectomy. strategy for the treatment of IBD. Methods: The authors conducted a retrospective cohort study of patients with Kohn A, Prantera C, Pera A, et al. active UC treated with infliximab between Infliximab in the treatment of severe 2000 and 2006. The primary outcome was ulcerative colitis: A follow-up study.

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European Review for Medical & 50% at day 7 and 30% at month 1. Pharmacological Sciences. Vol. Concomitant use of antimetabolite agents 8(5)(pp 235-237), 2004. was associated with better results. Conclusions: Infliximab was able to induce a Abstract: rapid response in some patients with UC or Thirteen patients with severe UC, refractory indeterminate colitis refractory to to therapy with methyl-prednisolone, 60 mg conventional treatment. Long-term results IV daily were treated with a single were less favourable, with frequent relapses, intravenous infusion of Infliximab 5 mg/kg. and about one-third of the patients required Ten out of 13 patients (77%) had a clinical a colectomy. response to therapy defined by a CAI ≤ 10 on 2 consecutive days. Two patients (15%) Kohn A, Prantera C, Pera A, et al. underwent total colectomy because of Anti-tumour necrosis factor alpha clinical worsening; one patient refused (Infliximab) in the treatment of surgery and was lost to follow-up. Infusion severe ulcerative colitis: Result of with Infliximab produced no significant an open study on 13 patients. adverse events. The mean time of follow-up Digestive & Liver Disease. Vol. was 25.6 months (range 17-24); in this 34(9)(pp 626-630), 2002. period of time 8 out of 10 patients (80%) maintained clinical remission and were able Abstract: to discontinue corticosteroids therapy. A series of 13 patients with severe UC, Infliximab appears to be an effective agent refractory to therapy with methyl- for inducing long standing remission in prednisolone, 60 mg daily for 7 or more refractory patients with severe UC. days, were treated with a single intravenous infusion of Infliximab 5 mg/kg. There were Gornet J-M, Couve S, Hassani Z, et al. 10 patients (77%) who had a clinical Infliximab for refractory ulcerative response to therapy defined by a clinical colitis or indeterminate colitis: An activity index ≤ 10 on 2 consecutive days. In open-label multicentre study. 2 patients (15%) total colectomy was Alimentary Pharmacology & necessary on account of clinical worsening Therapeutics. Vol. 18(2)(pp 175- whilst one patient refused surgery and was 181), 2003. lost to follow-up. All patients who responded showed very rapid clinical improvement, Abstract: within 2 to 3 days of infusion. Infusion with The records of 30 patients treated with Infliximab produced no significant adverse infliximab for UC (n = 19) or indeterminate events. The mean time of follow-up was colitis (n = 11) were reviewed. Infliximab 10.1 months (range 5-12); during this time, 9 was given because of steroid resistance (n = out of 10 patients (90%) maintained clinical 18), dependence (n = 5) or intolerance (n = remission and were able to discontinue 7); 5 patients had failed on cyclosporin; 19 corticosteroid therapy. Infliximab appears to patients had a severe flare-up. Results: be an effective agent for inducing long- Median duration of follow-up was 10 standing remission in refractory patients with months. In 28 patients with active disease, severe UC. the response rate was 75% at day 7, with 43% having a complete remission, and 50% at month 1, with 32% having a complete Safety studies remission. Among the 22 responders, the probability of relapse was 73% at month 6. IBD The probability of complete remission without steroids, taking into account the re- Atzeni F, Ardizzone S, Sarzi-Puttini P, et al treatment for relapse (n = 11), was 57% Autoantibody profile during short- (95% confidence interval (CI): 45% to 69%) term infliximab treatment for Crohn's at month 6. The probability of colectomy was disease: A prospective cohort study. 33% (95% CI: 23% to 43%) at month 12. In Alimentary Pharmacology & indeterminate colitis, response rate was only Therapeutics. Vol. 22(5)(pp 453- 461), 2005.

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Abstract: agents used in the treatment of IBD. This Aim: To determine the frequency and review discusses the relationship between correlation of autoantibody formation in IBD, treatment of IBD (with AZA/6-MP and patients with CD treated with infliximab in a infliximab) and the risk of lymphoma. routine clinical setting. Methods: Sixty-three patients with refractory/inflammatory (31) Favalli EG, Varenna M, Sinigaglia L. and/or fistulising CD (32), received an Drug-induced agranulocytosis infliximab infusion at a dose 5 mg/kg in during treatment with infliximab in weeks O, 2 and 6, and were evaluated for enteropathic spondyloarthropathy. the development of antinuclear, anti-double- Clinical & Experimental stranded DNA, anti-Sm, anti-RNP, anti-SSA, Rheumatology. Vol. 23(2)(pp 247- anti-SSB and antihistone antibodies. The 250), 2005. correlates with pharmacological treatments, the response to infliximab and adverse Abstract: events were evaluated. Results: Antinuclear The authors describe the case of a 20-year- antibodies were found in 5 of the 63 patients old Caucasian male affected by enteropathic (8%) at baseline and in 26 (42%) after 10 CD spondyloarthropathy HLA B27 negative, weeks (P < 0.001). Of the 26 antinuclear successfully treated with infliximab. After the antibody-positive patients who were further second infliximab infusion, he was found to subtyped, 9 of 63 (17%) had anti-double- have a severe transient neutropenia (0.5 x stranded DNA (P = 0.003), and 1.5% were 10 9/L). Routine serum chemistry and full extractable nuclear antigen (ENA) and blood cell count (apart from neutrophil antihistone-positive. Five patients were count) were normal. Serology excluded an initially positive for anticardiolipin antibodies active infection. Bone marrow needle and 2 more patients became positive during aspirate showed a normal trilineage infliximab treatment. New autoantibody differentiation. Autoantibody assessment formation was more frequent in the patients showed negative ANA, anti-dsDNA, anti- with inflammatory/refractory disease than in ENA, and ANCA, but positive granulocyte- those with fistulising disease (17 vs. 7; P = bound antibodies (GBA) and neutrophil- 0.02). One patient developed drug-induced specific (CD 16+)-bound antibodies (anti- lupus without major organ damage. NA). Ten weeks after infliximab infusion, Conclusions: Autoantibody formation occurs neutrophil count and GBA and anti-NA in 42% of patients (8% of these patients assay returned spontaneously within normal were positive before infliximab treatment) range and the authors observed the same with CD receiving induction treatment with progress after every successive infliximab infliximab, but the clinical significance of this infusion they performed. These data remains to be determined. indicated that infliximab possibly triggered production of granulocyte and neutrophil Blonski W, Kundu R, Lichtenstein GR. autoantibodies with resultant autoimmune Lymphoma risk in inflammatory agranulocytosis. bowel disease: Role of azathioprine/6- mercaptopurine and Seiderer J, Goke B, Ochsenkuhn T. infliximab. Practical Safety aspects of infliximab in Gastroenterology. Vol. 29(2)(pp 17- inflammatory bowel disease 32), 2005. patients: A retrospective cohort study in 100 patients of a German Abstract: University Hospital. Digestion. Vol. There has been controversy regarding the 70(1)(pp 3-9), 2004. prevalence of lymphoma in patients with IBD. Tertiary center studies have reported Abstract: the increased risk of lymphoma in patients The authors reviewed their clinical with IBD whereas the majority of population experience in a retrospective safety study based- studies did not find such a risk when looking upon a single cohort of 100 IBD compared to the general population. AZA/6- patients from a large German University MP and infliximab are immunomodulatory Hospital. Methods: 100 patients with severe

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CD (n = 92), UC (n = 7) or indeterminate cohort comprising 217 patients was colitis (n = 1) treated with infliximab (5 assembled: 191 patients had CD, and mg/kg) from January 2000 to December infliximab was used off label for UC in 22 2003 were retrospectively analysed for patients. Four patients were treated for acute and subacute adverse events by chart indeterminate colitis (IC). Mean age was review. Results: Overall, infliximab therapy 37.6 (0.9) years (range 8-79). The mean was generally well tolerated. No fatal number of infliximab infusions was 2.6 (0.1) complications, malignancies, autoimmune (range 1-11). Forty 2 severe adverse events diseases, neurologic or cardiovascular were registered in 41 patients (CD, n = 35). complications were observed in the cohort Eleven of the severe adverse events during the study period. Overall, adverse occurred postoperatively (CD, n = 6). Three events were observed in 10 patients: 2 patients with CD developed lymphoma (of patients showed an acute infusion reaction, which 2 were fatal), opportunistic infections 1 patient a serum sickness-like reaction, in 4 occurred in 2 patients (one with UC, fatal), patients a bacterial or viral infection and 2 patients with severe attacks of IBD occurred, in 1 patient pancytopenia and 2 died due to sepsis (one with CD, one patients developed surgical complications. postoperatively with UC). One additional Only 6 patients with adverse events required patient with UC died from pulmonary admission to hospital. A case of TB after embolism after colectomy. Mean age in the infliximab was not found. The lack of group with fatal outcome was 62.7 years adverse side-effects was associated with (range 25-79). The overall response rate young median age and infrequent was 75% and did not differ between the comorbidities of the cohort. Conclusion: patient groups. Conclusions: Infliximab was Regarding its strong immunomodulating efficacious as an anti-inflammatory capacity, infliximab appears to be an treatment when assessed in a population efficient and relatively safe therapeutic based cohort of patients with IBD. However, option for patients with severe IBD. there appear to be a significant risk of However, the use of infliximab requires deleterious and fatal adverse events, careful screening and close patient particularly in elderly patients with severe monitoring to identify patients at risk and the attacks of IBD. Off label use of infliximab in infrequent, but sometimes serious UC and IC should be avoided until efficacy complications of infliximab. is proven in randomised controlled trials. The underlying risk of developing Ljung T, Karlen P, Schmidt D, et al. malignancies among patients with severe or Infliximab in inflammatory bowel chronically active CD in need of infliximab disease: Clinical outcome in a treatment is not known but the finding of a population based cohort from 1.5% annual incidence of lymphoma Stockholm County. Gut. Vol. emphasises the need for vigilant 53(6)(pp 849-853), 2004. surveillance with respect to this malignant complication. Abstract: Aim: To assess the use of infliximab in IBD Marchal L, D'Haens G, Van Assche G, et al. in a population based cohort, with special The risk of post-operative emphasis on the occurrence of severe complications associated with adverse events and mortality. Patients: All infliximab therapy for Crohn's patients with IBD treated with infliximab disease: A controlled cohort study. between 1999 and 2001 in Stockholm Alimentary Pharmacology & County were evaluated. Methods: Therapeutics. Vol. 19(7)(pp 749- Prospective registration of clinical data was 754), 2004. carried out. Retrospective analyses were made of possible adverse events occurring Abstract: in relation to infliximab treatment. Adverse Background: By temporarily suppressing the events requiring pharmacological treatment immune response, infliximab may increase or hospitalisation were defined as severe. the risk of peri-operative complications. Aim: Clinical response was assessed as To test this hypothesis for intestinal remission, response, or failure. Results: A resection in a cohort of 313 CD patients

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treated with infliximab. Forty received one or were attributed to infliximab. Twenty patients more infusions prior to intestinal resection had a serious infection: 2 had fatal sepsis, 8 (31/40 within 12 weeks). Methods: The post- had pneumonia (of which 2 cases were operative events of these patients were fatal), 6 had viral infections, 2 had compared with those of a control group abdominal abscesses requiring surgery, one (infliximab naive) of 39 patients adjusted for had arm cellulitis, and one had age, gender and surgical procedure. Early histoplasmosis. Nine patients had a (10 days) and late (3 months) major or minor malignant disorder, 3 of which were possibly complications were identified. Results: The related to infliximab. A total of 10 deaths incidence of early minor (15.0% vs. 12.8%) were observed. For 5 of these patients (1%), and major (12.5% vs. 7.7%) and late minor the events leading to death were possibly (2.5% vs. 5.1%) and major (17.5% vs. related to infliximab. Conclusions: Short- 12.8%) complications and the mean hospital and long-term infliximab therapy is generally stay after surgery (10.3 +/- 4.0 days vs. 9.9 well tolerated. However, clinicians must be +/- 5.5 days) were similar in both groups. A vigilant for the occurrence of infrequent but trend towards an increased early infection serious events, including serum sickness- rate was found in infliximab pre-treated like reaction, opportunistic infection and patients (6 vs. 1: P = 0.10), but more sepsis, and autoimmune disorders. patients in this group received corticosteroids and/ or immunosuppressives Stallmach A, Giese T, Schmidt C, et al. (29 vs. 16 patients; P < 0.05). Conclusion: Severe anaphylactic reaction to The use of infliximab before intestinal infliximab: Successful treatment with resection does not prolong the hospital stay adalimumab - Report of a case. and does not increase the rate of post- European Journal of operative complications. Gastroenterology & Hepatology. Vol. 16(6)(pp 627-630), 2004. Colombel J-F, Loftus Jr EV, Tremaine WJ, et al. Abstract: The Safety Profile of Infliximab in Treatment with infliximab is highly effective Patients with Crohn's Disease: The in the treatment of refractory and fistulising Mayo Clinic Experience in 500 CD. Infliximab has been tolerated well, with Patients. Gastroenterology. Vol. minimal and short-lived adverse effects. The 126(1 SUPPL. 1)(pp 19-31), 2004. likelihood of severe reactions to infliximab, such as acute and delayed hypersensitivity Abstract: infusion reactions, is small; nevertheless, if The medical records of 500 consecutive they do occur, they are life-threatening. The patients treated with infliximab at the Mayo authors report a case of an anaphylaxis-like Clinic were reviewed and abstracted for reaction in a 22-year-old female with long- demographic features and adverse events. standing CD. The patient was treated The likelihood of a causal relationship to successfully with adalimumab. Follow-up infliximab for each adverse event was demonstrated mucosal healing and determined by calculating an intrinsic normalisation of elevated pro-inflammatory likelihood (imputability) score. Results: The cytokine transcripts. 500 patients received a median of 3 infusions and had a median follow-up of 17 Cheifetz A, Smedley M, Martin S, et al. months. Forty-three patients (8.6%) The incidence and management of experienced a serious adverse event, of infusion reactions to infliximab: A which 30 (6%) were related to infliximab. large center experience. American Acute infusion reactions occurred in 19 of Journal of Gastroenterology. Vol. 500 patients (3.8%). Serum sickness-like 98(6)(pp 1315-1324), 2003. disease occurred in 19 of 500 patients and was attributed to infliximab in 14 (2.8%). Abstract: Three patients developed drug-induced A total of 165 consecutive patients who lupus. One patient developed a new received 479 infliximab infusions in the demyelination disorder. Forty-eight patients Division of Clinical Immunology Infusion had an infectious event, of which 41 (8.2%)

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Center at Mount Sinai Medical Center from infusion. RESULTS A mean of 3.9 infusions July, 1998 to January, 2001 were evaluated. (range, 1 to 17) per patient were Specific treatment protocols for initial and administered over a mean period of 10 subsequent acute infusion reactions were months. Antibodies against infliximab were followed and the outcomes documented. detected in 61% of patients. The presence RESULTS: The overall incidence of infusion of concentrations of 8.0 mug per milliliter or reactions to infliximab was 6.1% (29 of 479) greater before an infusion predicted a of infusions, affecting 9.7% (16 of 165) of shorter duration of response (35 days, as patients. Mild, moderate, or severe acute compared with 71 days among patients with reactions occurred in 3.1% (15 of 479), 1.2% concentrations of less than 8.0 mug per (6 of 479), and 1.0% (5 of 479) of infliximab milliliter; P<0.001) and a higher risk of infusions, respectively. Use of treatment infusion reactions (relative-risk, 2.40; 95% protocols resulted in rapid resolution of all confidence interval, 1.65 to 3.66; P<0.001). acute reactions to infliximab. With the Infliximab concentrations were significantly prophylaxis protocol, all patients who lower at 4 weeks among patients who had experienced an initial mild or moderate had an infusion reaction than among acute reaction were able to receive patients who had never had an infusion additional infusions. Four patients reaction (median, 1.2 vs. 14.1 mug per experienced a total of 5 severe acute milliliter; P<0.001). Patients who had reactions. Three patients were retreated: 2 infusion reactions had a median duration of patients had no further problems, whereas clinical response of 38.5 days, as compared one patient had a second severe acute with 65 days among patients who did not reaction that rapidly resolved with treatment. have an infusion reaction (P<0.001). Suggesting that acute infusion reactions are Concomitant immunosuppressive therapy not type I hypersensitivity reactions, in 11 was predictive of low titers of antibodies patients who experienced 14 acute infusion against infliximab (P<0.001) and high reactions, serum tryptase levels were concentrations of infliximab four weeks after normal. Delayed infusion reactions occurred an infusion (P<0.001). CONCLUSIONS The in 0.6% (3 of 479) of infusions. development of antibodies against infliximab CONCLUSIONS: Infliximab infusions were is associated with an increased risk of accompanied by acute reactions in infusion reactions and a reduced duration of approximately 5% of infusions. These response to treatment. Concomitant reactions did not seem to be true IgE- immunosuppressive therapy reduces the mediated type I hypersensitivity events. magnitude of the immunogenic response. Using appropriate treatment protocols, these reactions were effectively treated and Lobel EZ, Korelitz BI, Warman JI. prevented upon retreatment in nearly all Red man syndrome and infliximab patients. Delayed reactions were rare, [5]. Journal of Clinical occurring in <1% of infusions. Gastroenterology. Vol. 36(2)(pp 186), 2003. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the No abstract available. long-term efficacy of infliximab in Crohn's disease. New England Hommes DW, Parlevliet W, Sterringa GJ, et Journal of Medicine. Vol. 348(7)(pp al. 601-608), 2003. Infliximab therapy in patients with Crohn's disease; experience with Abstract: 132 patients. Nederlands Tijdschrift In a cohort of 125 consecutive patients with voor Geneeskunde. Vol. 146(25)(pp CD who were treated with infliximab 1187-1191), 2002. infusions, The authors evaluated the concentrations of infliximab and of Abstract: antibodies against infliximab, clinical data, The aim of this study was to report the side effects (including infusion reactions), experience with infliximab treatment for a and the use of concomitant medications large cohort of CD patients in the before and 4, 8, and 12 weeks after each

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Netherlands. Design. Descriptive. Method. initiated between January 1, 1995 and All I34 CD patients receiving infliximab December 31, 2003 were identified using infusions in the Amsterdam Medical Centre, linked data on all prescription drug the Netherlands, after the drug's registration dispensings, physician services, and in the Netherlands in I999 were followed hospitalizations. Initiation of TNF α inhibitor prospectively (study period: I November therapy, cytotoxic agents other than MTX, I999-3I January 2002). Reliable follow-up noncytotoxic agents, and glucocorticoids data were absent in 2 patients. Clinical was compared with initiation of MTX. The response, adverse effects, laboratory main outcome measure was serious findings, the number of infusions and the bacterial infections that required interval between infusions were assessed hospitalization. The incidence of serious for both active luminal disease and fistulous bacterial infections was, on average, 2.2 per disease. The costs associated with the 100 patient-years in this population (95% CI infliximab therapy were also calculated. 2.0-2.4). Glucocorticoid use doubled the rate Results. A total of 592 infusions were of serious bacterial infections as compared administered to I34 patients. The mean with MTX use, independent of previous number of infusions was 4.4 per patient and DMARD use (rate ratio [RR] 2.1 [95% CI the mean interval between infusions was 45 1.5-3.1]), with a clear dose-response days. The response rate was 78% in active relationship for dosages >5 mg/day (for ≤5 luminal CD and 89% in fistulous disease. mg/day, RR 1.34; for 6-9 mg/day, RR 1.53; Adverse effects were recorded in I7% (n = for 10-19 mg/day, RR 2.97; and for ≥20 22) of the patients, including 3 with serious mg/day, RR 5.48 [P for trend < 0.0001]). allergic reactions. No TB or malignancies Adjusted models showed no increase in the were observed during the study period. The rate of serious infections among initiators of cost per treatment per patient was between TNF α inhibitor therapy (RR 1.0 [95% CI 0.6- 2000 and 2800 euro. Conclusion. Infliximab 1.7]) or other DMARDs as compared with was safe and effective for both the induction initiators of MTX. Thus, in a large cohort of of remission and the maintenance therapy of patients with RA, no increase in serious active luminal and fistulous CD. bacterial infections among users of TNF α inhibitor therapy compared with users of MTX was found. Glucocorticoid use was Rheumatoid conditions associated with a dose-dependent increase in such infections. Schneeweiss S, Setoguchi S, Weinblatt ME, et al Baraliakos X, Listing J, Rudwaleit M, et al Anti-tumor necrosis factor alpha Safety and efficacy of therapy and the risk of serious readministration of infliximab after bacterial infections in elderly longterm continuous therapy and patients with rheumatoid arthritis. withdrawal in patients with Arthritis & Rheumatism. Vol. 56 ankylosing spondylitis. Journal of (pp1754-64), 2007. Rheumatology. Vol. 34(3)(pp 510- 515), 2007. Abstract: The objective was to assess the association Abstract: between the initiation of TNF α inhibitor Objective. To analyse the safety and therapy and the risk of serious bacterial efficacy of infliximab in patients with AS after infections in routine care. This was a cohort discontinuation of long-term therapy over 1 study of patients with RA in whom specific year and readministration, using clinical and disease-modifying antirheumatic drugs laboratory assessments including serum (DMARDs) were initiated. Patients were levels of antibodies to infliximab (ATI). Medicare beneficiaries ages 65 years and Methods. Altogether 42/43 patients with AS older (mean age 76.5 years) who were in a 3-year multicenter trial discontinued concurrently enrolled in the Pharmaceutical therapy after continuous treatment with Assistance Contract for the Elderly provided infliximab (5 mg/kg/6 wks). Infliximab was by the state of Pennsylvania. A total of only readministered in case of a clinical 15,597 RA patients in whom a DMARD was relapse [judged by Bath AS Disease Activity

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Index (BASDAI) and physician global continued TNF α inhibitors preoperatively assessment > 4]. ATIwere measured at (2B), the cutoff point being set at 4 times the different timepoints. The primary outcome half-life time of the drug. Infection rates were was safety, and efficacy outcomes were compared between cohorts, and logistic secondary. Results. One patient dropped regression analysis was performed to out after the eighth infusion after retreatment examine risk factors. Results. In total, 1219 due to repeated local infections. ATI were (768 patients) procedures were included, detected in this patient only. No other and crude infection risks were 4.0% relevant adverse events were observed. (41/1023), 5.8% (6/104), and 8.7% (8/92) in One patient remained in clinical remission cohorts 1, 2A, and 2B, respectively. Elbow without therapy for more than 1 year. The surgery (OR 4.1,95% CI 1.6-10.1), other 40 patients (97.6%) were reinfused foot/ankle surgery (OR 3.2,95% CI 1.6-6.5), because of clinical relapse. There was no and prior skin or wound infection (OR 13.8, correlation between ATI and clinical 95% CI 5.2-36.7) were associated with measures. BASDAI 50% responses were increased risk of SSI, whereas duration of seen in 25 (63%) and partial remission in 12 surgery (OR 0.42,95% CI 0.23-0.78) and (30%) patients. The mean (+/- SD) BASDAI sulfasalazine use (OR 0.21,95% CI 0.05- score dropped from 6.0 +/- 1.4 at the time of 0.89) were associated with decreased risk. relapse to 2.6 +/- 2.0, and the median C- Perioperative use of TNF α inhibitors was not reactive protein from 11.2 to 1.8 mg/1 after 1 significantly associated with an increase in year (all p < 0.05). Conclusion. SSI rates (OR 1.5,95% CI 0.43-5.2). Readministration of infliximab after Conclusion. The most important risk factor discontinuation of longterm treatment was for SSI is history of SSI or skin infection. generally safe and efficacious. Ongoing Although the study was not powered to remission after discontinuation was rare. detect small differences in infection rates, There was only one patient with relevant perioperative continuation of TNF α inhibitors adverse events. ATI were detected only in does not seem to be an important risk factor this patient, but there was no correlation to for SSI. clinical data. Formation of ATI seems to be rare after long-term infliximab therapy in AS. Spanakis E, Sidiropoulos P, Papadakis J, et al. Den Broeder AA, Creemers MCW, Fransen Modest but sustained increase of J, et al. serum high density lipoprotein Risk factors for surgical site cholesterol levels in patients with infections and other complications in inflammatory arthritides treated with elective surgery in patients with infliximab. Journal of Rheumatology. rheumatoid arthritis with special Vol. 33(12)(pp 2440-2446), 2006. attention for anti-tumor necrosis factor: A large retrospective study. Abstract: Journal of Rheumatology. Vol. The authors assessed whether TNF α 34(4)(pp 689-695), 2007. inhibitors modify the unfavorable lipid profile induced by chronic inflammatory arthritides. Abstract: Methods. Sixty patients (24 with RA, 26 AS, Objective. To identify risk factors for surgical and 10 psoriatic arthritis) receiving infliximab site infection (SSI) in patients with RA with because of ongoing disease activity despite special attention for TNF α inhibitors. disease modifying drugs (DMARD) were Methods. All patients with RA who had prospectively studied for 6 months. Lipid undergone elective orthopedic surgery since profile, total cholesterol/high density introduction of TNF α inhibitors were lipoprotein cholesterol (TC/HDL-C), and low included in a retrospective parallel-cohort density lipoprotein cholesterol (LDL-C)/HDL- study with a1-year followup. Primary C ratios, as well as disease activity indices endpoint was a SSI according to the 1992 (DAS28 and BASDAI), were assessed. Centers for Disease Control and Prevention Results. A sustained increase of serum criteria and/or antibiotic use. Cohort 1 did HDL-C was observed [mean increase (95% not use TNF α inhibitors, cohort 2 used TNF α CI)] 5 (3-7) mg/dl, 3.5 (1-6) mg/dl, and 3 (1- inhibitors but had either stopped (2A) or 5) mg/dl at 1, 3, and 6 months, respectively

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(p < 0.01). Compared to nonresponders, treated patients, with an adjusted IRR of HDL-C increased significantly more in 4.28 (95% confidence interval 1.06-17.17). EULAR or BASDAI responders (0.8 vs 5.8 There was no difference in infection risk mg/dl; p = 0.05). Serum TC was significantly between the 3 main TNF α inhibitors. increased [11 (4-8) mg/dl; p = 0.001] only Nineteen serious bacterial intracellular after the first month of treatment. TC/HDL-C infections occurred, exclusively in patients in and LDL-C/HDL-C decreased only after the the TNF α inhibitor-treated cohort. first month [0.3 (0.1-0.4), p < 0.01, and 0.2 Conclusion. In patients with active RA, (0.1-0.4), p < 0.01, respectively]. For TNF α inhibitor therapy was not associated patients with baseline LDL-C > 130 mg/dl, with increased risk of overall serious LDL-C/HDL-C decreased (p < 0.05) during infection compared with DMARD treatment, the whole study period and TC/HDL-C after adjustment for baseline risk. In decreased (p < 0.05) at 1 and 3 months. contrast, the rate of serious skin and soft Conclusion. TNF α inhibitors in patients with tissue infections was increased, suggesting chronic inflammatory arthritides induces a an important physiologic role of TNF in host modest, but sustained, increase in serum defense in the skin and soft tissues beyond HDL-C levels, which may have a favorable that in other tissues. effect in reducing the cardiovascular risk in these patients. Konttinen L, Honkanen V, Uotila T, et al. Biological treatment in rheumatic Dixon WG, Watson K, Lunt M, et al. diseases: Results from a Rates of serious infection, including longitudinal surveillance: Adverse site-specific and bacterial events. Rheumatology International. intracellular infection, in rheumatoid Vol. 26(10)(pp 916-922), 2006. arthritis patients receiving anti-tumor necrosis factor therapy: Results Abstract: from the British Society for The objective of this study was to assess the Rheumatology Biologics Register. long-term safety and tolerability of Arthritis & Rheumatism. Vol. biologicals in a clinical setting. Data on 54(8)(pp 2368-2376), 2006. adverse events (AEs) have been collected over a 5-year period by means of detailed Abstract: reports sent in to the National Register of Objective. To determine whether the rate of Biological Treatment in Finland (ROB-FIN) serious infection is higher in TNF α inhibitor- and validated by information collected by the treated RA patients compared with RA National Agency for Medicines. Three patients treated with traditional disease- hundred and 8 reports on AEs were filed, modifying antirheumatic drugs (DMARDs). concerning a total of 248 patients; this Methods. This was a national prospective corresponds to 17% of all patients in the observational study of 7,664 TNF α inhibitor- ROB-FIN register who started biological treated and 1,354 DMARD-treated patients treatments. Skin reactions and infections with severe RA from the British Society for comprised 35 and 28% of the AEs, Rheumatology Biologics Register. All respectively. Some cases of TB and other serious infections, stratified by site and infections, heart failure and demyelinating organism, were included in the analysis. conditions were seen. This work Results. Between December 2001 and demonstrates no unexpected AEs in a September 2005, there were 525 serious Finnish patient cohort consisting of RA and infections in the TNF α inhibitor-treated spondylarthropathy patients, although many cohort and 56 in the comparison cohort of them were treated with combination (9,868 and 1,352 person-years of followup, treatments in common use in Finland. respectively). The incidence rate ratio (IRR), Biological treatment appears safe in the adjusted for baseline risk, for the TNF α hands of the Finnish rheumatologists. inhibitor-treated cohort compared with the comparison cohort was 1.03 (95% Uthman I, Touma Z, El-Sayyad J, Zaitoun F. confidence interval 0.68-1.57). However, the Successful retreatment with frequency of serious skin and soft tissue infliximab in patients with prior infections was increased in TNF α inhibitor- severe infusion reactions. Clinical

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Rheumatology. Vol. 25(4)(pp 540- Abstract: 541), 2006. The RATIO observatory collects nationwide data on opportunistic infections, severe Abstract: bacterial infections, and lymphomas in Infusion of infliximab can be associated with patients with a past or present history of the development of severe infusion TNF α inhibitor treatment in France. The reactions (IR) during retreatment. The cases are validated by a committee of authors present the case of 2 RA patients experts, and the capture-recapture method with a history of severe acute IR to infliximab is used to check and to improve case who subsequently underwent successful ascertainment. A nested case-control infusion using a prophylactic treatment with comparison is carried out to identify risk a combination of H1 and H2 receptor factors for the events of interest. The blockers, hydrocortisone, and registry differs from other biological diphenhydramine. registries in that the inclusion criterion is occurrence of the event (infection or Mori S, Imamura F, Kiyofuji C, et al. lymphoma) instead of administration of the Development of interstitial treatment. This method ensures collection of pneumonia in a rheumatoid arthritis a far larger number of cases. The RATIO patient treated with infliximab, an observatory is a remarkable example of a 3- anti-tumor necrosis factor a- way partnership of learned societies, neutralizing antibody. Modern pharmaceutical companies, and institutions Rheumatology. Vol. 16(4)(pp 251- (the French research institute INSERM and 255), 2006. the French drug safety agency AFSSAPS). Over 100 events were reported in the first 16 Abstract: months, a large increase compared to Infliximab was introduced to a 66-year-old European registries of fixed patient cohorts woman with MTX-resistant RA. Although the monitored for 4 to 5 years. This result TNF α inhibitor therapy was successful, she validates this original approach, which will developed noninfectious interstitial probably need to be extended to other pneumonia (IP) after a second infusion of biotherapies for inflammatory joint disease infliximab. In most cases reported and to other potential adverse events. The previously, infliximab-associated strong commitment of rheumatologists in noninfectious IP occurred after a second or France, who are the main prescribers of α third infusion of infliximab, and this type of IP TNF inhibitors, and of the French Society was more fatal in comparison with cases for Rheumatology explain the high case- associated with MTX treatment alone. ascertainment and must continue to ensure Keeping a sharp lookout on IP development that answers are rapidly provided to the drug during this period is crucial to the success of safety questions that are vital to patients. infliximab treatment. After MTX discontinuation and steroid pulse therapy, Listing J, Strangfeld A, Kary S, et al. this patient made a dramatic recovery from Infections in patients with IP. rheumatoid arthritis treated with biologic agents. Arthritis & Tubach F, Salmon-Ceron D, Ravaud P, et Rheumatism. Vol. 52(11)(pp 3403- al. 3412), 2005. The RATIO observatory: French registry of opportunistic infections, Abstract: severe bacterial infections, and Objective. To estimate the incidence rates of lymphomas complicating anti-TnFa serious and nonserious infections in patients therapy. Joint, Bone, Spine: Revue with RA who start treatment with a biologic du Rhumatisme. Vol. 72(6)(pp 456- agent, and to compare these rates with 460), 2005. those in patients with RA who receive conventional treatment. Methods. Patients enrolled in the German biologics register between May 2001 and September 2003

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were included. Treating rheumatologists risk of solid cancer after TNF α inhibitor assessed adverse events and serious treatment by obtaining cancer data from adverse events. All adverse events and cohorts treated in routine care rather than serious adverse events experienced within trials. Methods: A population based study of 12 months after study entry were analysed. 3 RA cohorts (one prevalent, admitted to Propensity score methods were applied to hospital 1990-2003 (n = 53 067), one estimate which part of a rate increase was incident, diagnosed 1995-2003 (n = 3703), likely to be attributable to differences in and one treated with TNF α inhibitors 1999- patient characteristics. Results. Data were 2003 (n = 4160)), which were linked with available for 512 patients receiving Swedish nationwide cancer and census etanercept, 346 patients receiving infliximab, registers and followed up for cancer 70 patients receiving anakinra, and 601 occurrence through 2003. Results: With control patients treated with disease- 3379 observed cancers, the prevalent RA modifying antirheumatic drugs. The total cohort was at marginally increased overall number of adverse events per 100 patient- risk of solid cancer, with 20-50% increased years was 22.6 (95% CI 18.7-27.2) among risks for smoke related cancers and +70% patients receiving etanercept, 28.3 (95% CI increased risk for non-melanoma skin 23.1-34.7) among patients receiving cancer, but decreased risk for breast (-20%) infliximab, and 6.8 (95% CI 5.0-9.4) among and colorectal cancer (-25%). With 138 controls (P < 0.0001). Significant differences cancers, the incident RA cohort displayed a in the rate of serious adverse events were similar cancer pattern apart from non- also observed. For patients receiving decreased risks for colorectal cancer. TNF α etanercept, those receiving infliximab, and inhibitor-treated patients displayed solid controls, the total numbers of serious cancer (n = 67) risks largely similar to those adverse events per 100 patient-years were of other patients with RA. Conclusion: The 6.4 (95% CI 4.5-9.1), 6.2 (95% CI 4.0-9.5), cancer pattern in patients treated with TNF α and 2.3 (95% CI 1.3-3.9), respectively (P = inhibitors mirrors those of other 0.0016). After adjusting for differences in the contemporary as well as historic RA cohorts. case patient mix, the RRs of serious The consistent increase in smoking adverse events were 2.2 (95% CI 0.9-5.4) associated cancers in patients with RA for patients receiving etanercept and 2.1 emphasises the potential for smoking (95% CI 0.8-5.5) for patients receiving cessation as a cancer preventive measure in infliximab, compared with controls. RA. Conclusion. Patients treated with biologic agents have a higher a priori risk of Askling J, Fored CM, Baecklund E, et al. infection. However, the data suggest that Haematopoietic malignancies in this risk is increased by treatment with TNF α rheumatoid arthritis: Lymphoma risk inhibitor. and characteristics after exposure to tumour necrosis factor antagonists. Askling J, Fored CM, Brandt L, et al. Annals of the Rheumatic Diseases. Risks of solid cancers in patients Vol. 64(10)(pp 1414-1420), 2005. with rheumatoid arthritis and after treatment with tumour necrosis Abstract: factor antagonists. Annals of the Background: Patients with RA are at Rheumatic Diseases. Vol. 64(10)(pp increased risk of malignant lymphomas, and 1421-1426), 2005. maybe also of leukaemia and multiple myeloma. The effect of TNF α inhibitors on Abstract: lymphoma risk and characteristics is Background: Existing studies of solid unclear. Objective: To assess expected cancers in RA reflect cancer morbidity up rates and RRs of haematopoietic until the early 1990s in prevalent cohorts malignancies, especially those associated admitted to hospital during the 1980s. with TNF α inhibitors, in large population Objective: To depict the cancer pattern of based cohorts of patients with RA. Methods: contemporary patients with RA, from A population based cohort study was updated risk data from prevalent and performed of patients with RA (one incident RA populations. To understand the prevalent cohort (n = 53 067), one incident

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cohort (n = 3703), and one TNF α inhibitor- registers for inpatient care and cause of treated cohort 1999 through 2003 (n = death through December 31, 2001. CVD 4160)), who were linked with the Swedish was defined as the first inpatient care or Cancer Register. Additionally, the lymphoma death from CVD without inpatient care for specimens for the 12 lymphomas occurring CVD prior to study entry. First CVD events in patients with RA exposed to TNF α in those treated versus not treated with inhibitors in Sweden 1999 through 2004 TNF α inhibitors were estimated, using age were reviewed. Results: Study of almost 500 and sex adjusted incidence density observed haematopoietic malignancies computations with treatment and disease showed that prevalent and incident patients severity markers as time-dependent with RA were at increased risk of lymphoma covariates. Results. In the TNF α inhibitor- (SIR =1.9 and 2.0, respectively) and treated patients, the age-sex adjusted leukaemia (SIR = 2.1 and 2.2, respectively) incidence rate of first CVD event was but not of myeloma. Patients with RA treated 14.0/1000 person-years at risk (95% CI 5.7- with TNF α inhibitors had a tripled lymphoma 22.4), compared with 35.4/1000 person- risk (SIR = 2.9) compared with the general years (95% CI 16.5-54.4) in those not population. After adjustment for sex, age, treated. Controlling for disability, the age-sex and disease duration, the lymphoma risk adjusted rate ratio was 0.46 (95% CI 0.25- after exposure to TNF α inhibitors was no 0.85, p = 0.013) in TNF α inhibitor-treated higher than in the other RA cohorts. versus not treated. Conclusion. These Lymphomas associated with TNF α inhibitors findings suggest that the risk of developing had characteristics similar to those of other CVD is lower in patients with RA treated with RA lymphomas. Conclusion: Overall, TNF α inhibitors. This is compatible with the patients with RA are at equally increased hypothesis that inflammation contributes to risks for lymphomas and leukaemias. the development of cardiovascular events. Patients with RA treated with TNF α inhibitors did not have higher lymphoma Maillard H, Ornetti P, Grimault L, et al. risks than other patients with RA. Prolonged Severe pyogenic infections in observation is needed to determine the long patients taking infliximab: A regional term effects of TNF α inhibitors on lymphoma cohort study. Joint, Bone, Spine: risk. Revue du Rhumatisme. Vol. 72(4)(pp 330-334), 2005. Jacobsson LTH, Turesson C, Gulfe A, et al. Treatment with tumor necrosis Abstract: factor blockers is associated with a Objective. - To evaluate the prevalence and lower incidence of first risk factors of severe pyogenic infections in cardiovascular events in patients rheumatology patients taking infliximab in with rheumatoid arthritis. Journal of everyday practice. Methods. - Regional Rheumatology. Vol. 32(7)(pp 1213- prospective cohort study of patients taking 1218), 2005. infliximab for RA or AS with data collection on standardised forms. The medical records Abstract: of patients with severe pyogenic infections Objective. To investigate the risk of were subjected to a detailed retrospective cardiovascular disease (CVD) in patients review. Patients with and without severe with RA treated with TNF α inhibitors, pyogenic infections were compared. compared to a standard RA population. Results. - The cohort included 83 patients Methods. Patients were recruited from a (55 women and 28 men). Severe pyogenic regional register, which includes over 90% infections occurred in 5 (6%) patients (3 of patients with RA started on TNF α women and 2 men), all of whom had acute inhibitors in 1999 or later, and a local or underlying risk factors. Higher values community based cohort of RA patients, were found in these 5 patients for mean age established in 1997. Of a total of 983 (65.8 +/- 12 vs. 53.9 +/- 13 years, P = 0.04) patients in the combined cohort, 531 and mean daily glucocorticoid dosage (15.5 received treatment with etanercept or +/- 9 vs. 6.9 +/- 7 mg/day prednisone- infliximab during the study period. The total equivalent, P = 0.036), as compared to the cohort (n = 983) was linked with national other patients. Conclusion. - Older age and

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high-dose glucocorticoid therapy are may persist over time during treatment and associated with an increased risk of severe is related to both infliximab and etanercept. pyogenic infection during infliximab therapy. Caution is in order when starting and Elkayam O, Burke M, Vardinon N, et al. monitoring infliximab therapy in patients with Autoantibodies profile of rheumatoid risk factors. The data also emphasise the arthritis patients during treatment need for a careful search for risk factors with infliximab. Autoimmunity. Vol. before each infliximab infusion. 38(2)(pp 155-160), 2005.

Askling J, Fored CM, Brandt L,et al. Abstract: Risk and case characteristics of The authors aim was to prospectively tuberculosis in rheumatoid arthritis analyse a wide array of autoantibodies in RA associated with tumor necrosis patients before and 14 weeks after starting factor antagonists in Sweden. infliximab. Material and methods: In this Arthritis & Rheumatism. Vol. study, 26 consecutive active RA patients 52(7)(pp 1986-1992), 2005. participated. All treated with infliximab at a dosage of 3 mg/kg on week 0, 2, 6 and Abstract: every 8 weeks, along with weekly low dose This study sought to determine the risk of MTX. Patients were evaluated at week 0 TB among Swedish patients with RA. and 14. Clinical assessment included the Methods. Using data from Swedish number of tender and swollen joints, nationwide and population-based registers duration of morning stiffness, adverse and data from an ongoing monitoring events (AE) (including SLE-like) and ESR. program of TNF α inhibitors, the RRs of TB Sera were collected before the 1st infusion in patients with RA (versus the general of infliximab at week 0 and 14. The population) and of TB associated with TNF α autoantibodies studied were: fluorescent inhibitors (versus RA patients not treated ANA, anti-double-stranded-DNA (anti-ds- with biologics) were determined by DNA), IgG and IgM anti-cardiolipin (ACA), comparing the incidence of hospitalisation anti-histone-H1 and C (H1, H2A, H2B, H3, for TB in 3 RA cohorts and 2 general H4), anti-SSA, -SSB, -ENA, -scleroderma population cohorts from 1999 to 2001. The 70, -thyroid peroxidase (TPO) and - authors also reviewed the characteristics of neutrophilic cytoplasmatic (ANCA) all reported cases of TB in RA patients antibodies. Results: Of 26 patients, 17 were treated with TNF α inhibitors in Sweden and women. A significant decrease in duration of calculated the incidence of TB per type of morning stiffness, number of tender and TNF α inhibitor between 1999 and 2004. swollen joints and ESR were observed Results. During 1999-2001, RA patients who between week 0 and 14. During follow up were not treated with TNF α inhibitors were (mean of 20.5 +/- 7.3 months), 9 patients at increased risk of TB versus the general stopped infliximab due to inefficacy or AE population (RR 2.0, 95% confidence interval (most of them after the 4th infusion). Two [95% CI] 1.2-3.4). RA patients treated with patients developed lupus-like phenomena. TNF α inhibitors had a 4-fold increased risk ANA was found positive at baseline in 7 out of TB (RR 4.0, 95% CI 1.3-12) versus RA of 26 patients. In 5 of them, an increase in patients not treated with TNF α inhibitors. the titer of ANA was observed at week 14. The reported TB cases during 1999-2004 in ANA negative turned positive for 8 patients. RA patients exposed to TNF α inhibitors (9 A significant increase of anti-cardiolipin infliximab, 4 etanercept, 2 both) were (ACA)-IgM levels was observed in 8 patients predominantly pulmonary. TB occurred up to and of ACA-IgG in 6, in parallel with ANA 3 years following the start of treatment. seroconversion. The mean level of anti- Conclusion. Irrespective of whether TNF α double-stranded-DNA (anti-ds-DNA) -IgG inhibitors are administered, Swedish significantly increased from 66 +/- 33 to 93 patients with RA are at increased risk of TB. +/- 68 IU/ml, in 4 patients to pathological During 1999-2001, TNF α inhibitors were levels. Four patients demonstrated an associated with an increased risk of TB, up increase in anti-histone H1. Levels of ANCA, to 4-fold in magnitude. This increased risk anti-ENA, -SSA, -SSB, -RNP, - scleroderma70 and -thyroid peroxidase

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(TPO) were negative in all patients and administration of I.V. hydrocortisone, remained unchanged during the study. chloropyramine, adrenaline and oxigene. Cessation of treatment with infliximab was Several reports of infliximab-induced found to be associated with the appearance anaphylactic reactions have been published, of ANA. Conclusion: An increased titer or a especially in patients with CD, that have new appearance of ANA was observed in 12 been attributed to a type I (acute or delayed) out of 26 patients. The main autoantibodies hypersensitivity reaction mechanism. found were anti-ds-DNA, ACA-IgM and -IgG and anti-histone. In this cohort, the Sugiura F, Kojima T, Oba M, et al. appearance of some autoantibodies seemed Anaphylactic reaction to infliximab in to predict late cessation of treatment. two rheumatoid arthritis patients who had previously received Vissers WHPM, De Jong EMGJ, Flendrie M, infliximab and resumed. Modern et al. Rheumatology. Vol. 15(3)(pp 201- Infliximab (Remicade) induced skin 203), 2005. reaction in a patient with rheumatoid arthritis. Nederlands Tijdschrift voor Abstract: Dermatologie & Venereologie. Vol. The authors report on 2 cases of 15(5)(pp 213-214), 2005. anaphylactic reaction following infliximab infusion in patients with active RA. Both Abstract: individuals had received infliximab treatment An 87-year-old patient with RA was admitted during a clinical trial approximately 2 years to the inpatient department because of a prior to further therapy; subsequent infusion severely itching skin rash after starting of this agent led to anaphylactic reactions in treatment with the TNF α inhibitor infliximab. both cases. In light of these findings, the Skin rashes on TNF α inhibitors occur authors recommend that future treatments frequently and are described in case- with infliximab in RA patients who have reports. Recently, a cohort study was previously received this agent should be performed at the department of carefully monitored. rheumatology and dermatology comparing the RA patients on TNF α inhibitors with RA Grange L, Nissen MJ, Garambois K, et al. patients in a control group. The frequency Infliximab-induced cerebral and nature of the skin disorders was thrombophlebitis [5]. Rheumatology. recorded. Vol. 44(2)(pp 260-261), 2005.

Chavez-Lopez MA, Delgado-Villafan~a J, No abstract available. Gallaga A, et al. Severe anaphylactic reaction during Wolfe F, Michaud K. the second infusion of infliximab in a Lymphoma in rheumatoid arthritis: patient with psoriatic arthritis. The effect of methotrexate and anti- Allergologia et Immunopathologia. tumor necrosis factor therapy in Vol. 33(5)(pp 291-292), 2005. 18,572 patients. Arthritis & Rheumatism. Vol. 50(6)(pp 1740- Abstract: 1751), 2004. A 33-year-old woman with no history of atopy, diagnosed of psoriatic arthritis, Abstract: received 200 mg I.V. infliximab, with Objective. The risk of lymphoma is previous oral administration of loratadine increased in patients with RA, and and betamethasone, that was well tolerated. spontaneous reporting suggests that MTX Two minutes after a second infusion 2 and TNF α inhibitor therapy might be weeks later, with the same pretreatment, the associated independently with an increased patients suffer dyspnea, laryngeal spasm, risk of lymphoma. However, data from generalised tremor, vomiting, hypotension, clinical trials and clinical practice do not sinusal tachycardia, anxiety and hyposemia. provide sufficient evidence concerning these She recovered in 45 minutes, after the issues because of small sample sizes and

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selected study populations. The objective of combination of leflunomide plus infliximab this study was to determine the rate of and after failure of treatment with other standardised incidence ratio (SIR) for DMARDs. 13 patients were treated for a lymphoma in patients with RA and in RA minimum of 3 months with leflunomide patient subsets by treatment group. without toxicity before beginning infliximab. Additionally, the authors sought to determine Treatment was begun simultaneously with predictors of lymphoma in RA. Methods. The both drugs in 4 patients. Side effects (clinical authors prospectively studied 18,572 and biological) and efficacy (DAS 28) were patients with RA who were enrolled in the evaluated at each infliximab infusion (3 National Data Bank for Rheumatic Diseases mg/kg at week 0, 2, 6 and then every 8 (NDB). Patients were surveyed biannually, weeks). Results. Thirteen patients and potential lymphoma eases received experienced 20 types of side effects and 8 detailed followup. The SEER (Survey, of them stopped the combination therapy. Epidemiology, and End Results) cancer data The causes of discontinuation were resource was used to derive the expected congestive heart failure (1 case), number of cases of lymphoma in a cohort hypertension with thoracic pain (2 cases), that was comparable in age and sex with the eczematous skin patches (2 cases) and RA cohort. Results. The overall SIR for neutropenia (3 cases). No death was lymphoma was 1.9 (95% confidence interval registered. Nine RA patients continuted the [95% CI] 1.3-2.7). The SIR for biologic use therapy with a median follow-up of 22 was 2.9 (95% CI 1.7-4.9) and for the use of weeks. Only 4 of them experienced no side infliximab (with or without etanercept) was effects. Eight patients were positive for 2.6 (95% CI 1.4-4.5). For etanercept, with or antinuclear antibodies (ANA) and 1 for without infliximab, the SIR was 3.8 (95% CI double-stranded DNA (dsDNA) antibodies at L9-7.5). The SIR for MTX was 1.7 (95% CI study entry. After treatment, 13 and 5 0.9-3.2), and was 1.0 (95% CI 0.4-2.5) for patients tested positive respectively for those not receiving MTX or biologics. ANAs and dsDNA antibodies. There was no Lymphoma was associated with increasing relationship between discontinuation and age, male sex, and education. Conclusion. ANA/dsDNA positivity. Conclusion. In this Lymphomas are increased in RA. Although cohort, adverse events were not very the SIR is greatest for TNF α inhibitors, different from those seen in patients on differences between therapies are slight, either treatment alone and the combination and confidence intervals for treatment of leflunomide plus infliximab did not appear groups overlap. The increased lymphoma to be as badly tolerated as described in a rates observed with TNF α inhibitors may previous study. reflect channeling bias, whereby patients with the highest risk of lymphoma Gomez-Reino JJ, Carmona L, Rodriguez preferentially receive TNF α inhibitors. Valverde V, et al. Current data are insufficient to establish a Treatment of rheumatoid arthritis causal relationship between RA treatments with tumor necrosis factor inhibitors and the development of lymphoma. may predispose to significant increase in TB risk: A multicenter Godinho F, Godfrin B, El Mahou S, et al. active-surveillance report. Arthritis & Safety of leflunomide plus infliximab Rheumatism. Vol. 48(8)(pp 2122- combination therapy in rheumatoid 2127), 2003. arthritis. Clinical & Experimental Rheumatology. Vol. 22(3)(pp 328- Abstract: 330), 2004. Objective. The long-term safety of therapeutic agents that neutralise TNF is Abstract: uncertain. Recent evidence based on Objective. To analyse the safety of spontaneous reporting shows an association leflunomide plus infliximab combination with active TB. The authors undertook this therapy, in adult RA patients. Patients. A study to determine and describe the long- retrospective study of 17 adult patients with term safety of 2 of these agents, infliximab active RA (DAS 28 = 5.94 +/- 0.88 at and etanercept, in rheumatic diseases baseline) who were treated with a based on a national active-surveillance

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system following the commercialisation of patients receiving infliximab, mandating the drugs. Methods. The authors analysed appropriate TB screening prior to drug the safety data actively collected in the initiation. Although the frequency of serious BIOBADASER (Base de Datos de drug-related toxicity (requiring Productos Biologicos de la Sociedad discontinuation of the agent) appears to be Espan~ola de Reumatologia) database, quite low, these reports underscore the need which was launched in February 2000 by the for caution and close surveillance with the Spanish Society of Rheumatology. For the administration of TNF α inhibitors, estimation of TB risk, the annual incidence particularly given that strategies aimed at rate in patients treated with these agents preventing toxicity remain unproven. Despite was compared with the background rate and its potential for toxicity, infliximab remains a with the rate in a cohort of patients with RA valuable alternative for patients with RA. assembled before the era of TNF α inhibitor treatment. Results. Seventy-one Favalli EG, Sinigaglia L, Varenna M, et al. participating centers sent data on 1,578 Drug-induced lupus following treatments with infliximab (86%) or treatment with infliximab in etanercept (14%) in 1,540 patients. Drug rheumatoid arthritis. Lupus. Vol. survival rates (reported as the cumulative 11(11)(pp 753-755), 2002. percentage of patients still receiving medication) for infliximab and etanercept Abstract: pooled together were 85% and 81% at 1 The authors report a case of a 69-year-old year and 2 years, respectively. Instances of female with a 5 year history of RA, who was discontinuation were essentially due to successfully treated with low-dose MTX and adverse events. Seventeen cases of TB infliximab (initially 3 mg/kg and from the were found in patients treated with fourth infusion 5 mg/kg) for 23 weeks. infliximab. The estimated incidence of TB Before the sixth infusion, she was diagnosed associated with infliximab in RA patients with DIL by both clinical features (fever > 38 was 1,893 per 100,000 in the year 2000 and degrees C, recurrence of active synovitis, 1,113 per 100,000 in the year 2001. These myalgia, erythematous rash and general findings represent a significant increased malaise) and laboratory findings (antinuclear risk compared with background rates. In the antibodies 1:160, anti-double-stranded DNA first 5 months of 2002, after official positive by ELISA assay, decreased serum guidelines were established for TB complement C3 and C4, prevention in patients treated with biologies, hypergammaglobulinaemia, increased only 1 new TB case was registered (in erythrocyte sedimentation rate). After January). Conclusion. Therapy with discontinuation of treatment and therapy infliximab is associated with an increased with oral prednisone, lupus resolved within 8 risk of active TB. Proper measures are weeks. needed to prevent and manage this adverse event. Brown SL, Greene MH, Gershon SK, et al. Tumor necrosis factor antagonist Mikuls TR, Moreland LW. therapy and lymphoma Benefit-risk assessment of infliximab development: twenty-six cases in the treatment of rheumatoid reported to the Food and Drug arthritis. Drug Safety. Vol. 26(1)(pp Administration. Arthritis Rheum 23-32), 2003. 2002; 46:3151-8.

Abstract: Abstract: Recent reports have highlighted several Relevant data in the MedWatch postmarket potential serious adverse effects associated adverse event surveillance system run by α with infliximab (and other TNF inhibitors), the US Food and Drug Administration were including infusion reactions, congestive reviewed. RESULTS: The authors identified heart failure, drug-induced lupus, and CNS 26 cases of lymphoproliferative disorders demyelination. In addition, recent reports following treatment with etanercept (18 have cited the potential for reactivation of cases) or infliximab (8 cases). The majority mycobacterial and fungal infection in

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of cases (81%) were non-Hodgkin's background rates. CONCLUSIONS: Active lymphomas. The interval between initiation TB may develop soon after the initiation of of therapy with etanercept or infliximab and treatment with infliximab. Before prescribing the development of lymphoma was very the drug, physicians should screen patients short (median 8 weeks). In 2 instances (1 for latent TB infection or disease. infliximab, 1 etanercept), lymphoma regression was observed following discontinuation of TNF α inhibitors, in the absence of specific cytotoxic therapy directed toward the lymphoma. CONCLUSION: Although data from a case series such as this cannot establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease, the known predisposition of patients with RA and CD to lymphoma, the known excess of lymphoma in other immunosuppressed populations, and the known immunosuppressive effects of the TNF α inhibitors provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association.

Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098-104.

Abstract: The authors analysed all reports of TB after infliximab therapy that had been received as of May 29, 2001, through the MedWatch spontaneous reporting system of the Food and Drug Administration. RESULTS: There were 70 reported cases of TB after treatment with infliximab, for a median of 12 weeks. In 48 patients, TB developed after 3 or fewer infusions. Forty of the patients had extrapulmonary disease (17 had disseminated disease, 11 lymph node disease, 4 peritoneal disease, 2 pleural disease, and 1 each meningeal, enteric, paravertebral, bone, genital, and bladder disease). The diagnosis was confirmed by a biopsy in 33 patients. Of the 70 reports, 64 were from countries with a low incidence of TB. The reported frequency of TB in association with infliximab therapy was much higher than the reported frequency of other opportunistic infections associated with this drug. In addition, the rate of reported cases of TB among patients treated with infliximab was higher than the available

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Abstract: Use in Children The authors reviewed the charts of 27 paediatric patients with UC who were treated with infliximab instead of undergoing Reviews in IBD a colectomy. Patients with new-onset UC refractory to intravenous steroids for 5 to 10 Efficacy and safety reviews days and patients with non-steroid- Greifer MK, Markowitz JF. dependent UC with an acute exacerbation Update in the treatment of paediatric were classified as acutely ill (n = 16); ulcerative colitis. Expert Opinion on patients with chronic steroid-dependent UC Pharmacotherapy. Vol. 7(14)(pp were classified as chronically ill (n = 11). 1907-1918), 2006. The Lichtiger Colitis Activity Index (LCAI) was measured for all patients at baseline Abstract: and at 1 and 2 months after treatment with infliximab was initiated. Patients were UC is an important disease in the paediatric regarded as successfully treated if they population. UC is one of the chronic IBDs, remained off steroids and avoided and is medically incurable. However, the colectomy. RESULTS: The acutely ill group arsenal of medications has grown as had a mean LCAI score of 11.4 at induction knowledge of the pathogenesis of this and 0.3 after 2 months. The chronically ill disease advances. This review looks at the group had a mean LCAI score of 11.2 at classical treatments for children with UC, induction and 5.5 after 2 months. Treatment including the 5-ASAs, corticosteroids and with infliximab was successful in 75% of imunomodulators, as well as biological acutely ill patients and in 27% of chronically therapy and other, newer modalities. ill patients. Infliximab was discontinued in 80% of successfully treated patients (83% of acutely ill, 67% of chronically ill). These Safety reviews patients had an average of 10 infusions and No reviews found. a mean follow-up time of 10 months from their last infliximab infusion. CONCLUSIONS: These results suggest that infliximab is more effective in acutely ill UC Reviews of safety – general patients than in patients with chronic steroid- and in other therapeutic dependent UC. In addition, some patients areas treated with infliximab can be weaned from infliximab and maintain remission. No reviews found. Cucchiara S, Latiano A, Palmieri O, et al. Polymorphisms of tumor necrosis Efficacy studies factor-a but not MDR1 influence response to medical therapy in RCTs pediatric-onset inflammatory bowel disease. Journal of Pediatric No studies found. Gastroenterology & Nutrition. Vol. 44(2)(pp 171-179), 2007.

Non-randomised studies Abstract: Fanjiang G, Russell GH, Katz AJ. The authors investigated the contribution of Short- and long-term response to variants of TNF α and MDR1 genes in the and weaning from infliximab therapy predisposition and response to medical in pediatric ulcerative colitis. Journal therapy in a large paediatric cohort of of Pediatric Gastroenterology & patients with Crohn disease and UC. Nutrition. Vol. 44(3)(pp 312-317), PATIENTS AND METHODS: In this study, 2007. 200 patients with CD, 186 patients with UC, 434 parents (217 trios), and 347 healthy

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unrelated controls were investigated. Single- IBD with clinical features suggestive of nucleotide polymorphisms -G308A and - idiopathic UC and pathologic features C857T of the TNF α gene and C3435T of the suggestive of CD. The authors report a MDR1 gene were investigated and patient with HPS which was complicated by correlated with clinical subphenotypes and granulomatous colitis with perineal and efficacy of medical therapy. RESULTS: The rectovaginal fistulas refractory to antibiotics frequency of the -308A allele of the TNF α and AZA but dramatically responded to gene was significantly increased in both repeated infusions of infliximab. patients with CD (15%; OR = 2.79; P < 0.01) and patients with UC (11%; OR = 1.96; P < Eidelwein AP, Cuffari C, Abadom V, et al. 0.003) compared with controls (6%). Infliximab efficacy in pediatric Carriers of this allele were 27% in CD (OR = ulcerative colitis. Inflammatory 2.94; P < 0.01) and 19% in UC (OR = 1.86; Bowel Diseases. Vol. 11(3)(pp 213- P = 0.015) compared with 11% in healthy 218), 2005. controls. No significant difference was found for both the -C857T and C3435T single- Abstract: nucleotide polymorphisms. With the All paediatric patients with UC who received genotype/phenotype analysis, no correlation infliximab between July 2001 and November in patients with UC with the MDR1 gene was 2003 at the Johns Hopkins Children's found. CD carriers of the -308A allele had a Center were identified. Short- and long-term higher frequency of surgical resection (35% outcomes and adverse reactions were vs 20%; OR = 2.1; P = 0.035) and more evaluated. Results: Twelve paediatric frequent resistance to steroids (22% vs 8%; patients with UC received infliximab for OR = 0.29; P = 0.032) compared with treatment of fulminant colitis (3 patients), noncarriers. These findings were confirmed acute exacerbation of colitis (3), steroid- by stepwise logistic regression. dependent colitis (5), and steroidrefractory CONCLUSIONS: In this paediatric cohort, colitis (1). Nine patients had a complete α the promoter -308A polymorphism of TNF short-term response, and 3 had partial but not the MDR1 gene is significantly improvement. The mean per patient dose of involved in the predisposition to both CD corticosteroid after the first infliximab and UC. This polymorphism carries a infusion decreased from 45 mg/day at the significant reduction in response to steroid first infusion to 22.2 mg/day at 4 weeks (P = therapy, probably leading to a more frequent 0.02) and 7.8 mg/day at 8 weeks (P = need for surgical resection. 0.008). Eight patients were classified as long-term responders with a median follow- Akobeng AK. up time of 10.4 months. Of the 4 long-term Infliximab for induction and nonresponders, 3 underwent colectomy, and maintenance therapy for ulcerative the fourth has ongoing chronic symptoms. colitis. Journal of Pediatric Three of 4 long-term nonresponders were Gastroenterology & Nutrition. Vol. steroid-refractory compared with 1 of 8 42(5)(pp 589-590), 2006. longterm responders. Patients receiving 6- MP had a better response to infliximab. No abstract available. Conclusion: Infliximab should be considered in the treatment of children with symptoms Erzin Y, Cosgun S, Dobrucali A, et al. of acute moderate-to-severe UC. Complicated granulomatous colitis in a patient with Hermansky-Pudlak Mamula P, Markowitz JE, Brown KA, et al. syndrome, successfully treated with Infliximab as a novel therapy for infliximab. Acta Gastroenterologica pediatric ulcerative colitis. Journal of Belgica. Vol. 69(2)(pp 213-216), Pediatric Gastroenterology & 2006. Nutrition. Vol. 34(3)(pp 307-311), 2002. Abstract: The bowel disease of the Hermansky- Pudlak syndrome (HPS) is a unique type of

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Abstract: tapered in all but 2 patients, and The authors collected data on all discontinued in 7 patients. Intravenous consecutive paediatric patients with UC who infusion of infliximab was well tolerated. One received infliximab at The Children's patient developed a rash several days after Hospital of Philadelphia until July 2001. The the infusion. A patient who received 6 primary measured outcome was clinical infliximab infusions developed recurrent response at 2 days and 2 weeks after Staphylococcus aureus infections, as well as infliximab infusion, as measured by the septic arthritis and chronic osteomyelitis Lichtiger colitis activity index (LCAI) score during the follow-up period, raising the issue and the Physician Global Assessment of the long-term safety of infliximab. (PGA). Tolerance of the infusions and CONCLUSIONS: Treatment of patients with adverse events were recorded. Results: refractory CD and UC with infliximab was Nine patients qualified for clinical response associated with remarkable clinical analysis. The median Lichtiger colitis activity improvement. Although the drug may have index score decreased from 11 before the an important role in their management, infusion to 1 at 2 days and 2 weeks after the further assessment of long-term safety and infusion, respectively (P = 0.01 for 2 days efficacy is needed. and 2 weeks). Seven of 9 (77%) patients had decreased activity of their disease measured by the Physician Global Safety studies Assessment. Corticosteroid therapy was discontinued in 6 (66%) patients. An infusion IBD reaction developed (generalised pruritus and facial flushing) in 2 patients and an elevated Kolho K-L, Ruuska T, Savilahti E. anti-nuclear antibody (ANA) titer of 1:1280 Severe adverse reactions to developed in one patient. Conclusion: infliximab therapy are common in Infliximab is associated with short-term young children with inflammatory clinical improvement in children and bowel disease. Acta Paediatrica. adolescents with moderate-to-severe UC. Vol. 96(1)(pp 128-130), 2007.

Serrano M-S, Schmidt-Sommerfeld E, Abstract: Kilbaugh TJ, et al. Since 2000 the authors have introduced 141 Use of infliximab in pediatric infliximab infusions to 23 children with patients with inflammatory bowel severe IBD. A total of 7 severe adverse disease. Annals of reactions occurred in 26% (6 of 23) of the Pharmacotherapy. Vol. 35(7-8)(pp children. Four reactions were acute 823-828), 2001. (anaphylaxis n = 2; allergic reaction n = 2) and 3/4 of these children were younger than Abstract: 10 years of age. Two children developed an This was a retrospective review of data abscess and one child had septicaemia and regarding 18 paediatric and adolescent brain lesions related to progressive patients with active CD (n = 15) and UC (n = multifocal leucoencephalopathy. Conclusion: 3) poorly controlled with conventional adverse reactions to infliximab infusions are therapy. All patients received1 to 6 common. Young children seem to be prone intravenous infusions of infliximab 5 mg/kg, to severe allergic reactions although they while receiving their usual medications. are on AZA and conventional glucocorticoid RESULTS: All patients experienced clinical therapy. improvement, including decrease in the frequency of stooling and resolution of Candon S, Mosca A, Ruemmele F, et al. extraintestinal symptoms such as Clinical and biological arthropathy, malaise, and skin consequences of immunization to manifestations after treatment with infliximab in pediatric Crohn's infliximab. All but one patient had a disease. Clinical Immunology. Vol. documented decrease in the erythrocyte 118(1)(pp 11-19), 2006. sedimentation rate. Prednisone dosage was Infliximab therapy induces the appearance of neutralising anti-infliximab antibodies. In

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the paediatric cohort the authors analysed (n among paediatric patients receiving = 28) sensitisation occurred in 35.7% infliximab for IBD. Premedication does not patients and was associated with a loss of seem to prevent the development of IRs; response to maintenance infusions. In 2 however, once an IR has occurred, patients presenting high titers of anti- premedication may be indicated to prevent infliximab antibodies, severe infusion subsequent IRs. reactions were observed, possibly IgE- mediated, precluding further use of the Crandall WV, Mackner LM. medication. Serum concentrations of TNF α Infusion reactions to infliximab in and infliximab were influenced by the children and adolescents: presence of anti-infliximab antibodies. The Frequency, outcome and a authors propose that surveillance of predictive model. Alimentary circulating infliximab and/or TNF α Pharmacology & Therapeutics. Vol. concentration during maintenance therapy 17(1)(pp 75-84), 2003. represents an indirect but reliable method to monitor anti-infliximab immunisation. Abstract: This was a retrospective review of all Jacobstein DA, Markowitz JE, Kirschner BS, infliximab infusions performed at Columbus et al. Children's Hospital from December 1998 Premedication and infusion through September 2001. Results: Fifty-7 reactions with infliximab: Results children received 361 infusions. Three from a paediatric inflammatory hundred and fifty-five of the 361 infusions bowel disease consortium. (98.3%) were completed. Fifty children had Inflammatory Bowel Diseases. Vol. 304 repeat infusions. There were a total of 11(5)(pp 442-446), 2005. 35 infusion related reactions. Female gender and the use of immunosuppressive Abstract: medications for less than 4 months were risk The authors studied the proportion of factors for a reaction to infusion number 2. A paediatric patients receiving infliximab for reaction to infusion 2 and IBD that developed infusion reactions (IRs) immunosuppressive use for less than 4 and the potential effects of premedication on months were risk factors for infusion number IR. Methods: Uniformly collected data from a 3. Conclusions: The rate of infusion cohort of paediatric patients with IBD reactions in children receiving infliximab is enrolled between January 2000 and May similar to that in adults. Female gender, 2003 at 6 paediatric centers were analysed. immunosuppressive use for less than 4 Data were retrospectively reviewed and months and prior infusion reactions may be analysed. Results: A total of 1652 infusions risk factors for subsequent infusion reactions given to 243 patients in 6 centers was in children. analysed. Overall, 60 IRs were recorded in 40 patients (3.6% of infusions, 16.5% of patients). Thirty-three of 243 patients received premedication before the first IR (group 1). Two hundred ten patients did not receive premedication until the development of IRs, if at all (group 2). IRs were more common among patients in group 1 than in group 2 (12/33 versus 28/210, P < 0.01). Of the 28 patients in group 2 with IRs, 10 began receiving premedication with each subsequent infusion, 12 continued without premedications, and 6 had no further infusions recorded. Two of 10 who began receiving premedication had a subsequent IR versus 6 of 12 who did not receive premedication (P = 0.15). Conclusions: IRs occur in a small proportion of infusions

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Health economics, Predictors of response resources, risk/benefit

Ferrante M, Vermeire S, Katsanos KH, et al. Luces C, Bodger K. Predictors of early response to Economic burden of inflammatory infliximab in patients with ulcerative bowel disease: A UK perspective. colitis. Inflamm Bowel Dis. Vol Expert Review of 13(2)(pp 123-8), 2007. Pharmacoeconomics & Outcomes Research. Vol. 6(4)(pp 471-482), Abstract: 2006. The objective was to report the outcome of infliximab in UC patients from a single center Abstract: and to identify predictors of early clinical IBDs are chronic, relapsing conditions that response. METHODS: The first 100 UC have no permanent drug cure, may occur for patients (45 female; median age, 37.9 the first time in early life and have the years) who received infliximab at a single potential to produce long-term morbidity. In center were included. Eighty-four patients the era of emerging biological drug received 5 mg/kg infliximab, and 37 patients therapies, the costs associated with IBD received a 3-dose infliximab induction at have attracted increased attention. This weeks 0, 2, and 6. The Mayo endoscopic review considers the available information subscore, assessed by sigmoidoscopy on the macroeconomics of UC and CD. In before inclusion, was 1, 2, and 3 in 5%, relation to direct medical costs, the 52%, and 43% of patients, respectively. consistent findings are: hospital (in-patient) Sixty percent had pancolitis, 63% were on costs are incurred by a minority of sufferers concomitant immunosuppressive therapy, but account for approximately half the total 9% were active smokers, 64% had C- cost; and drug costs contribute less than a reactive protein ≥5 mg/dL, and 44% were quarter of the total healthcare costs. Data for pANCA+/ASCA-. Five patients received levels of costs associated with lost infliximab because of severe acute colitis productivity are more variable, but some refractory to intravenous corticosteroids. studies have estimated that 'indirect' costs RESULTS: Early complete and partial falling on society exceed medical clinical responses were observed in 41% expenditures. Lifetime costs for IBD are and 24% of patients. Patients with early comparable to a number of major diseases, clinical response were significantly younger including heart disease and cancer. Over than nonresponders (median age, 35.7 the next 5-10 years, the contribution of drug versus 41.6 years, P = 0.041). Patients who costs to the overall profile of cost-of-illness were pANCA+/ASCA- had a significantly will change significantly as biological lower early clinical response (55% versus therapies play an increasing role. A key 76%; odds ratio [OR] = 0.40 (0.16-0.99), P = economic question is whether the health 0.049). Concomitant immunosuppressive gains realised from exciting new drugs will therapy and the use of an infliximab also lead to reduced expenditures on induction scheme did not influence early hospitalisation and surgery. clinical response. Only 1 of 5 patients who received infliximab for acute steroid- refractory colitis required colectomy within 2 months. CONCLUSIONS: infliximab is an efficient therapy in UC, as shown by 65% early clinical response. A pANCA+/ASCA- serotype and an older age at first infliximab infusion are associated with a suboptimal early clinical response.

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Acknowledgments Synopsis author, data search and collation, abstract/summary editing: Dr Gordon Mallarkey, Project Officer, NSW Therapeutic Advisory Group Inc Reviewed by: Editorial Committee members, NSW Therapeutic Advisory Group Inc.

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