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Safety studies

IBD


Atzeni F, Ardizzone S, Sarzi-Puttini P, et al

Autoantibody profile during short-term infliximab treatment for Crohn's disease: A prospective cohort study. Alimentary Pharmacology & Therapeutics. Vol. 22(5)(pp 453-461), 2005.


Abstract:


Aim: To determine the frequency and correlation of autoantibody formation in patients with CD treated with infliximab in a routine clinical setting. Methods: Sixty-three patients with refractory/inflammatory (31) and/or fistulising CD (32), received an infliximab infusion at a dose 5 mg/kg in weeks O, 2 and 6, and were evaluated for the development of antinuclear, anti-double-stranded DNA, anti-Sm, anti-RNP, anti-SSA, anti-SSB and antihistone antibodies. The correlates with pharmacological treatments, the response to infliximab and adverse events were evaluated. Results: Antinuclear antibodies were found in 5 of the 63 patients (8%) at baseline and in 26 (42%) after 10 weeks (P < 0.001). Of the 26 antinuclear antibody-positive patients who were further subtyped, 9 of 63 (17%) had anti-double-stranded DNA (P = 0.003), and 1.5% were extractable nuclear antigen (ENA) and antihistone-positive. Five patients were initially positive for anticardiolipin antibodies and 2 more patients became positive during infliximab treatment. New autoantibody formation was more frequent in the patients with inflammatory/refractory disease than in those with fistulising disease (17 vs. 7; P = 0.02). One patient developed drug-induced lupus without major organ damage. Conclusions: Autoantibody formation occurs in 42% of patients (8% of these patients were positive before infliximab treatment) with CD receiving induction treatment with infliximab, but the clinical significance of this remains to be determined.
Blonski W, Kundu R, Lichtenstein GR.

Lymphoma risk in inflammatory bowel disease: Role of azathioprine/6- mercaptopurine and infliximab. Practical Gastroenterology. Vol. 29(2)(pp 17-32), 2005.


Abstract:


There has been controversy regarding the prevalence of lymphoma in patients with IBD. Tertiary center studies have reported the increased risk of lymphoma in patients with IBD whereas the majority of population based- studies did not find such a risk when compared to the general population. AZA/6-MP and infliximab are immunomodulatory agents used in the treatment of IBD. This review discusses the relationship between IBD, treatment of IBD (with AZA/6-MP and infliximab) and the risk of lymphoma.
Favalli EG, Varenna M, Sinigaglia L.

Drug-induced agranulocytosis during treatment with infliximab in enteropathic spondyloarthropathy. Clinical & Experimental Rheumatology. Vol. 23(2)(pp 247-250), 2005.


Abstract:


The authors describe the case of a 20-year-old Caucasian male affected by enteropathic CD spondyloarthropathy HLA B27 negative, successfully treated with infliximab. After the second infliximab infusion, he was found to have a severe transient neutropenia (0.5 x 109/L). Routine serum chemistry and full blood cell count (apart from neutrophil count) were normal. Serology excluded an active infection. Bone marrow needle aspirate showed a normal trilineage differentiation. Autoantibody assessment showed negative ANA, anti-dsDNA, anti-ENA, and ANCA, but positive granulocyte-bound antibodies (GBA) and neutrophil-specific (CD 16+)-bound antibodies (anti-NA). Ten weeks after infliximab infusion, neutrophil count and GBA and anti-NA assay returned spontaneously within normal range and the authors observed the same progress after every successive infliximab infusion they performed. These data indicated that infliximab possibly triggered production of granulocyte and neutrophil autoantibodies with resultant autoimmune agranulocytosis.
Seiderer J, Goke B, Ochsenkuhn T.

Safety aspects of infliximab in inflammatory bowel disease patients: A retrospective cohort study in 100 patients of a German University Hospital. Digestion. Vol. 70(1)(pp 3-9), 2004.


Abstract:


The authors reviewed their clinical experience in a retrospective safety study looking upon a single cohort of 100 IBD patients from a large German University Hospital. Methods: 100 patients with severe CD (n = 92), UC (n = 7) or indeterminate colitis (n = 1) treated with infliximab (5 mg/kg) from January 2000 to December 2003 were retrospectively analysed for acute and subacute adverse events by chart review. Results: Overall, infliximab therapy was generally well tolerated. No fatal complications, malignancies, autoimmune diseases, neurologic or cardiovascular complications were observed in the cohort during the study period. Overall, adverse events were observed in 10 patients: 2 patients showed an acute infusion reaction, 1 patient a serum sickness-like reaction, in 4 patients a bacterial or viral infection occurred, in 1 patient pancytopenia and 2 patients developed surgical complications. Only 6 patients with adverse events required admission to hospital. A case of TB after infliximab was not found. The lack of adverse side-effects was associated with young median age and infrequent comorbidities of the cohort. Conclusion: Regarding its strong immunomodulating capacity, infliximab appears to be an efficient and relatively safe therapeutic option for patients with severe IBD. However, the use of infliximab requires careful screening and close patient monitoring to identify patients at risk and the infrequent, but sometimes serious complications of infliximab.
Ljung T, Karlen P, Schmidt D, et al.

Infliximab in inflammatory bowel disease: Clinical outcome in a population based cohort from Stockholm County. Gut. Vol. 53(6)(pp 849-853), 2004.


Abstract:


Aim: To assess the use of infliximab in IBD in a population based cohort, with special emphasis on the occurrence of severe adverse events and mortality. Patients: All patients with IBD treated with infliximab between 1999 and 2001 in Stockholm County were evaluated. Methods: Prospective registration of clinical data was carried out. Retrospective analyses were made of possible adverse events occurring in relation to infliximab treatment. Adverse events requiring pharmacological treatment or hospitalisation were defined as severe. Clinical response was assessed as remission, response, or failure. Results: A cohort comprising 217 patients was assembled: 191 patients had CD, and infliximab was used off label for UC in 22 patients. Four patients were treated for indeterminate colitis (IC). Mean age was 37.6 (0.9) years (range 8-79). The mean number of infliximab infusions was 2.6 (0.1) (range 1-11). Forty 2 severe adverse events were registered in 41 patients (CD, n = 35). Eleven of the severe adverse events occurred postoperatively (CD, n = 6). Three patients with CD developed lymphoma (of which 2 were fatal), opportunistic infections occurred in 2 patients (one with UC, fatal), and 2 patients with severe attacks of IBD died due to sepsis (one with CD, one postoperatively with UC). One additional patient with UC died from pulmonary embolism after colectomy. Mean age in the group with fatal outcome was 62.7 years (range 25-79). The overall response rate was 75% and did not differ between the patient groups. Conclusions: Infliximab was efficacious as an anti-inflammatory treatment when assessed in a population based cohort of patients with IBD. However, there appear to be a significant risk of deleterious and fatal adverse events, particularly in elderly patients with severe attacks of IBD. Off label use of infliximab in UC and IC should be avoided until efficacy is proven in randomised controlled trials. The underlying risk of developing malignancies among patients with severe or chronically active CD in need of infliximab treatment is not known but the finding of a 1.5% annual incidence of lymphoma emphasises the need for vigilant surveillance with respect to this malignant complication.
Marchal L, D'Haens G, Van Assche G, et al.

The risk of post-operative complications associated with infliximab therapy for Crohn's disease: A controlled cohort study. Alimentary Pharmacology & Therapeutics. Vol. 19(7)(pp 749-754), 2004.


Abstract:


Background: By temporarily suppressing the immune response, infliximab may increase the risk of peri-operative complications. Aim: To test this hypothesis for intestinal resection in a cohort of 313 CD patients treated with infliximab. Forty received one or more infusions prior to intestinal resection (31/40 within 12 weeks). Methods: The post-operative events of these patients were compared with those of a control group (infliximab naive) of 39 patients adjusted for age, gender and surgical procedure. Early (10 days) and late (3 months) major or minor complications were identified. Results: The incidence of early minor (15.0% vs. 12.8%) and major (12.5% vs. 7.7%) and late minor (2.5% vs. 5.1%) and major (17.5% vs. 12.8%) complications and the mean hospital stay after surgery (10.3 +/- 4.0 days vs. 9.9 +/- 5.5 days) were similar in both groups. A trend towards an increased early infection rate was found in infliximab pre-treated patients (6 vs. 1: P = 0.10), but more patients in this group received corticosteroids and/ or immunosuppressives (29 vs. 16 patients; P < 0.05). Conclusion: The use of infliximab before intestinal resection does not prolong the hospital stay and does not increase the rate of post-operative complications.
Colombel J-F, Loftus Jr EV, Tremaine WJ, et al.

The Safety Profile of Infliximab in Patients with Crohn's Disease: The Mayo Clinic Experience in 500 Patients. Gastroenterology. Vol. 126(1 SUPPL. 1)(pp 19-31), 2004.


Abstract:


The medical records of 500 consecutive patients treated with infliximab at the Mayo Clinic were reviewed and abstracted for demographic features and adverse events. The likelihood of a causal relationship to infliximab for each adverse event was determined by calculating an intrinsic likelihood (imputability) score. Results: The 500 patients received a median of 3 infusions and had a median follow-up of 17 months. Forty-three patients (8.6%) experienced a serious adverse event, of which 30 (6%) were related to infliximab. Acute infusion reactions occurred in 19 of 500 patients (3.8%). Serum sickness-like disease occurred in 19 of 500 patients and was attributed to infliximab in 14 (2.8%). Three patients developed drug-induced lupus. One patient developed a new demyelination disorder. Forty-eight patients had an infectious event, of which 41 (8.2%) were attributed to infliximab. Twenty patients had a serious infection: 2 had fatal sepsis, 8 had pneumonia (of which 2 cases were fatal), 6 had viral infections, 2 had abdominal abscesses requiring surgery, one had arm cellulitis, and one had histoplasmosis. Nine patients had a malignant disorder, 3 of which were possibly related to infliximab. A total of 10 deaths were observed. For 5 of these patients (1%), the events leading to death were possibly related to infliximab. Conclusions: Short- and long-term infliximab therapy is generally well tolerated. However, clinicians must be vigilant for the occurrence of infrequent but serious events, including serum sickness-like reaction, opportunistic infection and sepsis, and autoimmune disorders.
Stallmach A, Giese T, Schmidt C, et al.

Severe anaphylactic reaction to infliximab: Successful treatment with adalimumab - Report of a case. European Journal of Gastroenterology & Hepatology. Vol. 16(6)(pp 627-630), 2004.


Abstract:


Treatment with infliximab is highly effective in the treatment of refractory and fistulising CD. Infliximab has been tolerated well, with minimal and short-lived adverse effects. The likelihood of severe reactions to infliximab, such as acute and delayed hypersensitivity infusion reactions, is small; nevertheless, if they do occur, they are life-threatening. The authors report a case of an anaphylaxis-like reaction in a 22-year-old female with long-standing CD. The patient was treated successfully with adalimumab. Follow-up demonstrated mucosal healing and normalisation of elevated pro-inflammatory cytokine transcripts.
Cheifetz A, Smedley M, Martin S, et al.

The incidence and management of infusion reactions to infliximab: A large center experience. American Journal of Gastroenterology. Vol. 98(6)(pp 1315-1324), 2003.


Abstract:


A total of 165 consecutive patients who received 479 infliximab infusions in the Division of Clinical Immunology Infusion Center at Mount Sinai Medical Center from July, 1998 to January, 2001 were evaluated. Specific treatment protocols for initial and subsequent acute infusion reactions were followed and the outcomes documented. RESULTS: The overall incidence of infusion reactions to infliximab was 6.1% (29 of 479) of infusions, affecting 9.7% (16 of 165) of patients. Mild, moderate, or severe acute reactions occurred in 3.1% (15 of 479), 1.2% (6 of 479), and 1.0% (5 of 479) of infliximab infusions, respectively. Use of treatment protocols resulted in rapid resolution of all acute reactions to infliximab. With the prophylaxis protocol, all patients who experienced an initial mild or moderate acute reaction were able to receive additional infusions. Four patients experienced a total of 5 severe acute reactions. Three patients were retreated: 2 patients had no further problems, whereas one patient had a second severe acute reaction that rapidly resolved with treatment. Suggesting that acute infusion reactions are not type I hypersensitivity reactions, in 11 patients who experienced 14 acute infusion reactions, serum tryptase levels were normal. Delayed infusion reactions occurred in 0.6% (3 of 479) of infusions. CONCLUSIONS: Infliximab infusions were accompanied by acute reactions in approximately 5% of infusions. These reactions did not seem to be true IgE-mediated type I hypersensitivity events. Using appropriate treatment protocols, these reactions were effectively treated and prevented upon retreatment in nearly all patients. Delayed reactions were rare, occurring in <1% of infusions.
Baert F, Noman M, Vermeire S, et al.

Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. New England Journal of Medicine. Vol. 348(7)(pp 601-608), 2003.


Abstract:


In a cohort of 125 consecutive patients with CD who were treated with infliximab infusions, The authors evaluated the concentrations of infliximab and of antibodies against infliximab, clinical data, side effects (including infusion reactions), and the use of concomitant medications before and 4, 8, and 12 weeks after each infusion. RESULTS A mean of 3.9 infusions (range, 1 to 17) per patient were administered over a mean period of 10 months. Antibodies against infliximab were detected in 61% of patients. The presence of concentrations of 8.0 mug per milliliter or greater before an infusion predicted a shorter duration of response (35 days, as compared with 71 days among patients with concentrations of less than 8.0 mug per milliliter; P<0.001) and a higher risk of infusion reactions (relative-risk, 2.40; 95% confidence interval, 1.65 to 3.66; P<0.001). Infliximab concentrations were significantly lower at 4 weeks among patients who had had an infusion reaction than among patients who had never had an infusion reaction (median, 1.2 vs. 14.1 mug per milliliter; P<0.001). Patients who had infusion reactions had a median duration of clinical response of 38.5 days, as compared with 65 days among patients who did not have an infusion reaction (P<0.001). Concomitant immunosuppressive therapy was predictive of low titers of antibodies against infliximab (P<0.001) and high concentrations of infliximab four weeks after an infusion (P<0.001). CONCLUSIONS The development of antibodies against infliximab is associated with an increased risk of infusion reactions and a reduced duration of response to treatment. Concomitant immunosuppressive therapy reduces the magnitude of the immunogenic response.
Lobel EZ, Korelitz BI, Warman JI.

Red man syndrome and infliximab [5]. Journal of Clinical Gastroenterology. Vol. 36(2)(pp 186), 2003.


No abstract available.

Hommes DW, Parlevliet W, Sterringa GJ, et al.

Infliximab therapy in patients with Crohn's disease; experience with 132 patients. Nederlands Tijdschrift voor Geneeskunde. Vol. 146(25)(pp 1187-1191), 2002.

Abstract:


The aim of this study was to report the experience with infliximab treatment for a large cohort of CD patients in the Netherlands. Design. Descriptive. Method. All I34 CD patients receiving infliximab infusions in the Amsterdam Medical Centre, the Netherlands, after the drug's registration in the Netherlands in I999 were followed prospectively (study period: I November I999-3I January 2002). Reliable follow-up data were absent in 2 patients. Clinical response, adverse effects, laboratory findings, the number of infusions and the interval between infusions were assessed for both active luminal disease and fistulous disease. The costs associated with the infliximab therapy were also calculated. Results. A total of 592 infusions were administered to I34 patients. The mean number of infusions was 4.4 per patient and the mean interval between infusions was 45 days. The response rate was 78% in active luminal CD and 89% in fistulous disease. Adverse effects were recorded in I7% (n = 22) of the patients, including 3 with serious allergic reactions. No TB or malignancies were observed during the study period. The cost per treatment per patient was between 2000 and 2800 euro. Conclusion. Infliximab was safe and effective for both the induction of remission and the maintenance therapy of active luminal and fistulous CD.

Rheumatoid conditions


Schneeweiss S, Setoguchi S, Weinblatt ME, et al

Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis & Rheumatism. Vol. 56 (pp1754-64), 2007.


Abstract:


The objective was to assess the association between the initiation of TNFα inhibitor therapy and the risk of serious bacterial infections in routine care. This was a cohort study of patients with RA in whom specific disease-modifying antirheumatic drugs (DMARDs) were initiated. Patients were Medicare beneficiaries ages 65 years and older (mean age 76.5 years) who were concurrently enrolled in the Pharmaceutical Assistance Contract for the Elderly provided by the state of Pennsylvania. A total of 15,597 RA patients in whom a DMARD was initiated between January 1, 1995 and December 31, 2003 were identified using linked data on all prescription drug dispensings, physician services, and hospitalizations. Initiation of TNFα inhibitor therapy, cytotoxic agents other than MTX, noncytotoxic agents, and glucocorticoids was compared with initiation of MTX. The main outcome measure was serious bacterial infections that required hospitalization. The incidence of serious bacterial infections was, on average, 2.2 per 100 patient-years in this population (95% CI 2.0-2.4). Glucocorticoid use doubled the rate of serious bacterial infections as compared with MTX use, independent of previous DMARD use (rate ratio [RR] 2.1 [95% CI 1.5-3.1]), with a clear dose-response relationship for dosages >5 mg/day (for ≤5 mg/day, RR 1.34; for 6-9 mg/day, RR 1.53; for 10-19 mg/day, RR 2.97; and for ≥20 mg/day, RR 5.48 [P for trend < 0.0001]). Adjusted models showed no increase in the rate of serious infections among initiators of TNFα inhibitor therapy (RR 1.0 [95% CI 0.6-1.7]) or other DMARDs as compared with initiators of MTX. Thus, in a large cohort of patients with RA, no increase in serious bacterial infections among users of TNFα inhibitor therapy compared with users of MTX was found. Glucocorticoid use was associated with a dose-dependent increase in such infections.
Baraliakos X, Listing J, Rudwaleit M, et al

Safety and efficacy of readministration of infliximab after longterm continuous therapy and withdrawal in patients with ankylosing spondylitis. Journal of Rheumatology. Vol. 34(3)(pp 510-515), 2007.


Abstract:


Objective. To analyse the safety and efficacy of infliximab in patients with AS after discontinuation of long-term therapy over 1 year and readministration, using clinical and laboratory assessments including serum levels of antibodies to infliximab (ATI). Methods. Altogether 42/43 patients with AS in a 3-year multicenter trial discontinued therapy after continuous treatment with infliximab (5 mg/kg/6 wks). Infliximab was only readministered in case of a clinical relapse [judged by Bath AS Disease Activity Index (BASDAI) and physician global assessment > 4]. ATIwere measured at different timepoints. The primary outcome was safety, and efficacy outcomes were secondary. Results. One patient dropped out after the eighth infusion after retreatment due to repeated local infections. ATI were detected in this patient only. No other relevant adverse events were observed. One patient remained in clinical remission without therapy for more than 1 year. The other 40 patients (97.6%) were reinfused because of clinical relapse. There was no correlation between ATI and clinical measures. BASDAI 50% responses were seen in 25 (63%) and partial remission in 12 (30%) patients. The mean (+/- SD) BASDAI score dropped from 6.0 +/- 1.4 at the time of relapse to 2.6 +/- 2.0, and the median C-reactive protein from 11.2 to 1.8 mg/1 after 1 year (all p < 0.05). Conclusion. Readministration of infliximab after discontinuation of longterm treatment was generally safe and efficacious. Ongoing remission after discontinuation was rare. There was only one patient with relevant adverse events. ATI were detected only in this patient, but there was no correlation to clinical data. Formation of ATI seems to be rare after long-term infliximab therapy in AS.
Den Broeder AA, Creemers MCW, Fransen J, et al.

Risk factors for surgical site infections and other complications in elective surgery in patients with rheumatoid arthritis with special attention for anti-tumor necrosis factor: A large retrospective study. Journal of Rheumatology. Vol. 34(4)(pp 689-695), 2007.


Abstract:


Objective. To identify risk factors for surgical site infection (SSI) in patients with RA with special attention for TNFα inhibitors. Methods. All patients with RA who had undergone elective orthopedic surgery since introduction of TNFα inhibitors were included in a retrospective parallel-cohort study with a1-year followup. Primary endpoint was a SSI according to the 1992 Centers for Disease Control and Prevention criteria and/or antibiotic use. Cohort 1 did not use TNFα inhibitors, cohort 2 used TNFα inhibitors but had either stopped (2A) or continued TNFα inhibitors preoperatively (2B), the cutoff point being set at 4 times the half-life time of the drug. Infection rates were compared between cohorts, and logistic regression analysis was performed to examine risk factors. Results. In total, 1219 (768 patients) procedures were included, and crude infection risks were 4.0% (41/1023), 5.8% (6/104), and 8.7% (8/92) in cohorts 1, 2A, and 2B, respectively. Elbow surgery (OR 4.1,95% CI 1.6-10.1), foot/ankle surgery (OR 3.2,95% CI 1.6-6.5), and prior skin or wound infection (OR 13.8, 95% CI 5.2-36.7) were associated with increased risk of SSI, whereas duration of surgery (OR 0.42,95% CI 0.23-0.78) and sulfasalazine use (OR 0.21,95% CI 0.05-0.89) were associated with decreased risk. Perioperative use of TNFα inhibitors was not significantly associated with an increase in SSI rates (OR 1.5,95% CI 0.43-5.2). Conclusion. The most important risk factor for SSI is history of SSI or skin infection. Although the study was not powered to detect small differences in infection rates, perioperative continuation of TNFα inhibitors does not seem to be an important risk factor for SSI.
Spanakis E, Sidiropoulos P, Papadakis J, et al.

Modest but sustained increase of serum high density lipoprotein cholesterol levels in patients with inflammatory arthritides treated with infliximab. Journal of Rheumatology. Vol. 33(12)(pp 2440-2446), 2006.


Abstract:


The authors assessed whether TNFα inhibitors modify the unfavorable lipid profile induced by chronic inflammatory arthritides. Methods. Sixty patients (24 with RA, 26 AS, and 10 psoriatic arthritis) receiving infliximab because of ongoing disease activity despite disease modifying drugs (DMARD) were prospectively studied for 6 months. Lipid profile, total cholesterol/high density lipoprotein cholesterol (TC/HDL-C), and low density lipoprotein cholesterol (LDL-C)/HDL-C ratios, as well as disease activity indices (DAS28 and BASDAI), were assessed. Results. A sustained increase of serum HDL-C was observed [mean increase (95% CI)] 5 (3-7) mg/dl, 3.5 (1-6) mg/dl, and 3 (1-5) mg/dl at 1, 3, and 6 months, respectively (p < 0.01). Compared to nonresponders, HDL-C increased significantly more in EULAR or BASDAI responders (0.8 vs 5.8 mg/dl; p = 0.05). Serum TC was significantly increased [11 (4-8) mg/dl; p = 0.001] only after the first month of treatment. TC/HDL-C and LDL-C/HDL-C decreased only after the first month [0.3 (0.1-0.4), p < 0.01, and 0.2 (0.1-0.4), p < 0.01, respectively]. For patients with baseline LDL-C > 130 mg/dl, LDL-C/HDL-C decreased (p < 0.05) during the whole study period and TC/HDL-C decreased (p < 0.05) at 1 and 3 months. Conclusion. TNFα inhibitors in patients with chronic inflammatory arthritides induces a modest, but sustained, increase in serum HDL-C levels, which may have a favorable effect in reducing the cardiovascular risk in these patients.
Dixon WG, Watson K, Lunt M, et al.

Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: Results from the British Society for Rheumatology Biologics Register. Arthritis & Rheumatism. Vol. 54(8)(pp 2368-2376), 2006.


Abstract:


Objective. To determine whether the rate of serious infection is higher in TNFα inhibitor-treated RA patients compared with RA patients treated with traditional disease-modifying antirheumatic drugs (DMARDs). Methods. This was a national prospective observational study of 7,664 TNFα inhibitor-treated and 1,354 DMARD-treated patients with severe RA from the British Society for Rheumatology Biologics Register. All serious infections, stratified by site and organism, were included in the analysis. Results. Between December 2001 and September 2005, there were 525 serious infections in the TNFα inhibitor-treated cohort and 56 in the comparison cohort (9,868 and 1,352 person-years of followup, respectively). The incidence rate ratio (IRR), adjusted for baseline risk, for the TNFα inhibitor-treated cohort compared with the comparison cohort was 1.03 (95% confidence interval 0.68-1.57). However, the frequency of serious skin and soft tissue infections was increased in TNFα inhibitor-treated patients, with an adjusted IRR of 4.28 (95% confidence interval 1.06-17.17). There was no difference in infection risk between the 3 main TNFα inhibitors. Nineteen serious bacterial intracellular infections occurred, exclusively in patients in the TNFα inhibitor-treated cohort. Conclusion. In patients with active RA, TNFα inhibitor therapy was not associated with increased risk of overall serious infection compared with DMARD treatment, after adjustment for baseline risk. In contrast, the rate of serious skin and soft tissue infections was increased, suggesting an important physiologic role of TNF in host defense in the skin and soft tissues beyond that in other tissues.
Konttinen L, Honkanen V, Uotila T, et al.

Biological treatment in rheumatic diseases: Results from a longitudinal surveillance: Adverse events. Rheumatology International. Vol. 26(10)(pp 916-922), 2006.


Abstract:


The objective of this study was to assess the long-term safety and tolerability of biologicals in a clinical setting. Data on adverse events (AEs) have been collected over a 5-year period by means of detailed reports sent in to the National Register of Biological Treatment in Finland (ROB-FIN) and validated by information collected by the National Agency for Medicines. Three hundred and 8 reports on AEs were filed, concerning a total of 248 patients; this corresponds to 17% of all patients in the ROB-FIN register who started biological treatments. Skin reactions and infections comprised 35 and 28% of the AEs, respectively. Some cases of TB and other infections, heart failure and demyelinating conditions were seen. This work demonstrates no unexpected AEs in a Finnish patient cohort consisting of RA and spondylarthropathy patients, although many of them were treated with combination treatments in common use in Finland. Biological treatment appears safe in the hands of the Finnish rheumatologists.
Uthman I, Touma Z, El-Sayyad J, Zaitoun F.

Successful retreatment with infliximab in patients with prior severe infusion reactions. Clinical Rheumatology. Vol. 25(4)(pp 540-541), 2006.


Abstract:


Infusion of infliximab can be associated with the development of severe infusion reactions (IR) during retreatment. The authors present the case of 2 RA patients with a history of severe acute IR to infliximab who subsequently underwent successful infusion using a prophylactic treatment with a combination of H1 and H2 receptor blockers, hydrocortisone, and diphenhydramine.
Mori S, Imamura F, Kiyofuji C, et al.

Development of interstitial pneumonia in a rheumatoid arthritis patient treated with infliximab, an anti-tumor necrosis factor a-neutralizing antibody. Modern Rheumatology. Vol. 16(4)(pp 251-255), 2006.


Abstract:


Infliximab was introduced to a 66-year-old woman with MTX-resistant RA. Although the TNFα inhibitor therapy was successful, she developed noninfectious interstitial pneumonia (IP) after a second infusion of infliximab. In most cases reported previously, infliximab-associated noninfectious IP occurred after a second or third infusion of infliximab, and this type of IP was more fatal in comparison with cases associated with MTX treatment alone. Keeping a sharp lookout on IP development during this period is crucial to the success of infliximab treatment. After MTX discontinuation and steroid pulse therapy, this patient made a dramatic recovery from IP.
Tubach F, Salmon-Ceron D, Ravaud P, et al.

The RATIO observatory: French registry of opportunistic infections, severe bacterial infections, and lymphomas complicating anti-TnFa therapy. Joint, Bone, Spine: Revue du Rhumatisme. Vol. 72(6)(pp 456-460), 2005.


Abstract:


The RATIO observatory collects nationwide data on opportunistic infections, severe bacterial infections, and lymphomas in patients with a past or present history of TNFα inhibitor treatment in France. The cases are validated by a committee of experts, and the capture-recapture method is used to check and to improve case ascertainment. A nested case-control comparison is carried out to identify risk factors for the events of interest. The registry differs from other biological registries in that the inclusion criterion is occurrence of the event (infection or lymphoma) instead of administration of the treatment. This method ensures collection of a far larger number of cases. The RATIO observatory is a remarkable example of a 3-way partnership of learned societies, pharmaceutical companies, and institutions (the French research institute INSERM and the French drug safety agency AFSSAPS). Over 100 events were reported in the first 16 months, a large increase compared to European registries of fixed patient cohorts monitored for 4 to 5 years. This result validates this original approach, which will probably need to be extended to other biotherapies for inflammatory joint disease and to other potential adverse events. The strong commitment of rheumatologists in France, who are the main prescribers of TNFα inhibitors, and of the French Society for Rheumatology explain the high case-ascertainment and must continue to ensure that answers are rapidly provided to the drug safety questions that are vital to patients.
Listing J, Strangfeld A, Kary S, et al.

Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis & Rheumatism. Vol. 52(11)(pp 3403-3412), 2005.


Abstract:


Objective. To estimate the incidence rates of serious and nonserious infections in patients with RA who start treatment with a biologic agent, and to compare these rates with those in patients with RA who receive conventional treatment. Methods. Patients enrolled in the German biologics register between May 2001 and September 2003 were included. Treating rheumatologists assessed adverse events and serious adverse events. All adverse events and serious adverse events experienced within 12 months after study entry were analysed. Propensity score methods were applied to estimate which part of a rate increase was likely to be attributable to differences in patient characteristics. Results. Data were available for 512 patients receiving etanercept, 346 patients receiving infliximab, 70 patients receiving anakinra, and 601 control patients treated with disease-modifying antirheumatic drugs. The total number of adverse events per 100 patient-years was 22.6 (95% CI 18.7-27.2) among patients receiving etanercept, 28.3 (95% CI 23.1-34.7) among patients receiving infliximab, and 6.8 (95% CI 5.0-9.4) among controls (P < 0.0001). Significant differences in the rate of serious adverse events were also observed. For patients receiving etanercept, those receiving infliximab, and controls, the total numbers of serious adverse events per 100 patient-years were 6.4 (95% CI 4.5-9.1), 6.2 (95% CI 4.0-9.5), and 2.3 (95% CI 1.3-3.9), respectively (P = 0.0016). After adjusting for differences in the case patient mix, the RRs of serious adverse events were 2.2 (95% CI 0.9-5.4) for patients receiving etanercept and 2.1 (95% CI 0.8-5.5) for patients receiving infliximab, compared with controls. Conclusion. Patients treated with biologic agents have a higher a priori risk of infection. However, the data suggest that this risk is increased by treatment with TNFα inhibitor.
Askling J, Fored CM, Brandt L, et al.

Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Annals of the Rheumatic Diseases. Vol. 64(10)(pp 1421-1426), 2005.


Abstract:


Background: Existing studies of solid cancers in RA reflect cancer morbidity up until the early 1990s in prevalent cohorts admitted to hospital during the 1980s. Objective: To depict the cancer pattern of contemporary patients with RA, from updated risk data from prevalent and incident RA populations. To understand the risk of solid cancer after TNFα inhibitor treatment by obtaining cancer data from cohorts treated in routine care rather than trials. Methods: A population based study of 3 RA cohorts (one prevalent, admitted to hospital 1990-2003 (n = 53 067), one incident, diagnosed 1995-2003 (n = 3703), and one treated with TNFα inhibitors 1999-2003 (n = 4160)), which were linked with Swedish nationwide cancer and census registers and followed up for cancer occurrence through 2003. Results: With 3379 observed cancers, the prevalent RA cohort was at marginally increased overall risk of solid cancer, with 20-50% increased risks for smoke related cancers and +70% increased risk for non-melanoma skin cancer, but decreased risk for breast (-20%) and colorectal cancer (-25%). With 138 cancers, the incident RA cohort displayed a similar cancer pattern apart from non-decreased risks for colorectal cancer. TNFα inhibitor-treated patients displayed solid cancer (n = 67) risks largely similar to those of other patients with RA. Conclusion: The cancer pattern in patients treated with TNFα inhibitors mirrors those of other contemporary as well as historic RA cohorts. The consistent increase in smoking associated cancers in patients with RA emphasises the potential for smoking cessation as a cancer preventive measure in RA.
Askling J, Fored CM, Baecklund E, et al.

Haematopoietic malignancies in rheumatoid arthritis: Lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Annals of the Rheumatic Diseases. Vol. 64(10)(pp 1414-1420), 2005.


Abstract:


Background: Patients with RA are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of TNFα inhibitors on lymphoma risk and characteristics is unclear. Objective: To assess expected rates and RRs of haematopoietic malignancies, especially those associated with TNFα inhibitors, in large population based cohorts of patients with RA. Methods: A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53 067), one incident cohort (n = 3703), and one TNFα inhibitor-treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNFα inhibitors in Sweden 1999 through 2004 were reviewed. Results: Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR =1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNFα inhibitors had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNFα inhibitors was no higher than in the other RA cohorts. Lymphomas associated with TNFα inhibitors had characteristics similar to those of other RA lymphomas. Conclusion: Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNFα inhibitors did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNFα inhibitors on lymphoma risk.
Jacobsson LTH, Turesson C, Gulfe A, et al.

Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. Journal of Rheumatology. Vol. 32(7)(pp 1213-1218), 2005.


Abstract:


Objective. To investigate the risk of cardiovascular disease (CVD) in patients with RA treated with TNFα inhibitors, compared to a standard RA population. Methods. Patients were recruited from a regional register, which includes over 90% of patients with RA started on TNFα inhibitors in 1999 or later, and a local community based cohort of RA patients, established in 1997. Of a total of 983 patients in the combined cohort, 531 received treatment with etanercept or infliximab during the study period. The total cohort (n = 983) was linked with national registers for inpatient care and cause of death through December 31, 2001. CVD was defined as the first inpatient care or death from CVD without inpatient care for CVD prior to study entry. First CVD events in those treated versus not treated with TNFα inhibitors were estimated, using age and sex adjusted incidence density computations with treatment and disease severity markers as time-dependent covariates. Results. In the TNFα inhibitor-treated patients, the age-sex adjusted incidence rate of first CVD event was 14.0/1000 person-years at risk (95% CI 5.7-22.4), compared with 35.4/1000 person-years (95% CI 16.5-54.4) in those not treated. Controlling for disability, the age-sex adjusted rate ratio was 0.46 (95% CI 0.25-0.85, p = 0.013) in TNFα inhibitor-treated versus not treated. Conclusion. These findings suggest that the risk of developing CVD is lower in patients with RA treated with TNFα inhibitors. This is compatible with the hypothesis that inflammation contributes to the development of cardiovascular events.
Maillard H, Ornetti P, Grimault L, et al.

Severe pyogenic infections in patients taking infliximab: A regional cohort study. Joint, Bone, Spine: Revue du Rhumatisme. Vol. 72(4)(pp 330-334), 2005.


Abstract:


Objective. - To evaluate the prevalence and risk factors of severe pyogenic infections in rheumatology patients taking infliximab in everyday practice. Methods. - Regional prospective cohort study of patients taking infliximab for RA or AS with data collection on standardised forms. The medical records of patients with severe pyogenic infections were subjected to a detailed retrospective review. Patients with and without severe pyogenic infections were compared. Results. - The cohort included 83 patients (55 women and 28 men). Severe pyogenic infections occurred in 5 (6%) patients (3 women and 2 men), all of whom had acute or underlying risk factors. Higher values were found in these 5 patients for mean age (65.8 +/- 12 vs. 53.9 +/- 13 years, P = 0.04) and mean daily glucocorticoid dosage (15.5 +/- 9 vs. 6.9 +/- 7 mg/day prednisone-equivalent, P = 0.036), as compared to the other patients. Conclusion. - Older age and high-dose glucocorticoid therapy are associated with an increased risk of severe pyogenic infection during infliximab therapy. Caution is in order when starting and monitoring infliximab therapy in patients with risk factors. The data also emphasise the need for a careful search for risk factors before each infliximab infusion.
Askling J, Fored CM, Brandt L,et al.

Risk and case characteristics of tuberculosis in rheumatoid arthritis associated with tumor necrosis factor antagonists in Sweden. Arthritis & Rheumatism. Vol. 52(7)(pp 1986-1992), 2005.


Abstract:


This study sought to determine the risk of TB among Swedish patients with RA. Methods. Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNFα inhibitors, the RRs of TB in patients with RA (versus the general population) and of TB associated with TNFα inhibitors (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalisation for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. The authors also reviewed the characteristics of all reported cases of TB in RA patients treated with TNFα inhibitors in Sweden and calculated the incidence of TB per type of TNFα inhibitor between 1999 and 2004. Results. During 1999-2001, RA patients who were not treated with TNFα inhibitors were at increased risk of TB versus the general population (RR 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNFα inhibitors had a 4-fold increased risk of TB (RR 4.0, 95% CI 1.3-12) versus RA patients not treated with TNFα inhibitors. The reported TB cases during 1999-2004 in RA patients exposed to TNFα inhibitors (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment. Conclusion. Irrespective of whether TNFα inhibitors are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNFα inhibitors were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.
Elkayam O, Burke M, Vardinon N, et al.

Autoantibodies profile of rheumatoid arthritis patients during treatment with infliximab. Autoimmunity. Vol. 38(2)(pp 155-160), 2005.


Abstract:


The authors aim was to prospectively analyse a wide array of autoantibodies in RA patients before and 14 weeks after starting infliximab. Material and methods: In this study, 26 consecutive active RA patients participated. All treated with infliximab at a dosage of 3 mg/kg on week 0, 2, 6 and every 8 weeks, along with weekly low dose MTX. Patients were evaluated at week 0 and 14. Clinical assessment included the number of tender and swollen joints, duration of morning stiffness, adverse events (AE) (including SLE-like) and ESR. Sera were collected before the 1st infusion of infliximab at week 0 and 14. The autoantibodies studied were: fluorescent ANA, anti-double-stranded-DNA (anti-ds-DNA), IgG and IgM anti-cardiolipin (ACA), anti-histone-H1 and C (H1, H2A, H2B, H3, H4), anti-SSA, -SSB, -ENA, -scleroderma 70, -thyroid peroxidase (TPO) and -neutrophilic cytoplasmatic (ANCA) antibodies. Results: Of 26 patients, 17 were women. A significant decrease in duration of morning stiffness, number of tender and swollen joints and ESR were observed between week 0 and 14. During follow up (mean of 20.5 +/- 7.3 months), 9 patients stopped infliximab due to inefficacy or AE (most of them after the 4th infusion). Two patients developed lupus-like phenomena. ANA was found positive at baseline in 7 out of 26 patients. In 5 of them, an increase in the titer of ANA was observed at week 14. ANA negative turned positive for 8 patients. A significant increase of anti-cardiolipin (ACA)-IgM levels was observed in 8 patients and of ACA-IgG in 6, in parallel with ANA seroconversion. The mean level of anti-double-stranded-DNA (anti-ds-DNA) -IgG significantly increased from 66 +/- 33 to 93 +/- 68 IU/ml, in 4 patients to pathological levels. Four patients demonstrated an increase in anti-histone H1. Levels of ANCA, anti-ENA, -SSA, -SSB, -RNP, -scleroderma70 and -thyroid peroxidase (TPO) were negative in all patients and remained unchanged during the study. Cessation of treatment with infliximab was found to be associated with the appearance of ANA. Conclusion: An increased titer or a new appearance of ANA was observed in 12 out of 26 patients. The main autoantibodies found were anti-ds-DNA, ACA-IgM and -IgG and anti-histone. In this cohort, the appearance of some autoantibodies seemed to predict late cessation of treatment.
Vissers WHPM, De Jong EMGJ, Flendrie M, et al.

Infliximab (Remicade) induced skin reaction in a patient with rheumatoid arthritis. Nederlands Tijdschrift voor Dermatologie & Venereologie. Vol. 15(5)(pp 213-214), 2005.


Abstract:


An 87-year-old patient with RA was admitted to the inpatient department because of a severely itching skin rash after starting treatment with the TNFα inhibitor infliximab. Skin rashes on TNFα inhibitors occur frequently and are described in case-reports. Recently, a cohort study was performed at the department of rheumatology and dermatology comparing the RA patients on TNFα inhibitors with RA patients in a control group. The frequency and nature of the skin disorders was recorded.
Chavez-Lopez MA, Delgado-Villafan~a J, Gallaga A, et al.

Severe anaphylactic reaction during the second infusion of infliximab in a patient with psoriatic arthritis. Allergologia et Immunopathologia. Vol. 33(5)(pp 291-292), 2005.


Abstract:


A 33-year-old woman with no history of atopy, diagnosed of psoriatic arthritis, received 200 mg I.V. infliximab, with previous oral administration of loratadine and betamethasone, that was well tolerated. Two minutes after a second infusion 2 weeks later, with the same pretreatment, the patients suffer dyspnea, laryngeal spasm, generalised tremor, vomiting, hypotension, sinusal tachycardia, anxiety and hyposemia. She recovered in 45 minutes, after the administration of I.V. hydrocortisone, chloropyramine, adrenaline and oxigene. Several reports of infliximab-induced anaphylactic reactions have been published, especially in patients with CD, that have been attributed to a type I (acute or delayed) hypersensitivity reaction mechanism.
Sugiura F, Kojima T, Oba M, et al.

Anaphylactic reaction to infliximab in two rheumatoid arthritis patients who had previously received infliximab and resumed. Modern Rheumatology. Vol. 15(3)(pp 201-203), 2005.


Abstract:


The authors report on 2 cases of anaphylactic reaction following infliximab infusion in patients with active RA. Both individuals had received infliximab treatment during a clinical trial approximately 2 years prior to further therapy; subsequent infusion of this agent led to anaphylactic reactions in both cases. In light of these findings, the authors recommend that future treatments with infliximab in RA patients who have previously received this agent should be carefully monitored.
Grange L, Nissen MJ, Garambois K, et al.

Infliximab-induced cerebral thrombophlebitis [5]. Rheumatology. Vol. 44(2)(pp 260-261), 2005.


No abstract available.

Wolfe F, Michaud K.

Lymphoma in rheumatoid arthritis: The effect of methotrexate and anti-tumor necrosis factor therapy in 18,572 patients. Arthritis & Rheumatism. Vol. 50(6)(pp 1740-1751), 2004.

Abstract:


Objective. The risk of lymphoma is increased in patients with RA, and spontaneous reporting suggests that MTX and TNFα inhibitor therapy might be associated independently with an increased risk of lymphoma. However, data from clinical trials and clinical practice do not provide sufficient evidence concerning these issues because of small sample sizes and selected study populations. The objective of this study was to determine the rate of and standardised incidence ratio (SIR) for lymphoma in patients with RA and in RA patient subsets by treatment group. Additionally, the authors sought to determine predictors of lymphoma in RA. Methods. The authors prospectively studied 18,572 patients with RA who were enrolled in the National Data Bank for Rheumatic Diseases (NDB). Patients were surveyed biannually, and potential lymphoma eases received detailed followup. The SEER (Survey, Epidemiology, and End Results) cancer data resource was used to derive the expected number of cases of lymphoma in a cohort that was comparable in age and sex with the RA cohort. Results. The overall SIR for lymphoma was 1.9 (95% confidence interval [95% CI] 1.3-2.7). The SIR for biologic use was 2.9 (95% CI 1.7-4.9) and for the use of infliximab (with or without etanercept) was 2.6 (95% CI 1.4-4.5). For etanercept, with or without infliximab, the SIR was 3.8 (95% CI L9-7.5). The SIR for MTX was 1.7 (95% CI 0.9-3.2), and was 1.0 (95% CI 0.4-2.5) for those not receiving MTX or biologics. Lymphoma was associated with increasing age, male sex, and education. Conclusion. Lymphomas are increased in RA. Although the SIR is greatest for TNFα inhibitors, differences between therapies are slight, and confidence intervals for treatment groups overlap. The increased lymphoma rates observed with TNFα inhibitors may reflect channeling bias, whereby patients with the highest risk of lymphoma preferentially receive TNFα inhibitors. Current data are insufficient to establish a causal relationship between RA treatments and the development of lymphoma.
Godinho F, Godfrin B, El Mahou S, et al.

Safety of leflunomide plus infliximab combination therapy in rheumatoid arthritis. Clinical & Experimental Rheumatology. Vol. 22(3)(pp 328-330), 2004.


Abstract:


Objective. To analyse the safety of leflunomide plus infliximab combination therapy, in adult RA patients. Patients. A retrospective study of 17 adult patients with active RA (DAS 28 = 5.94 +/- 0.88 at baseline) who were treated with a combination of leflunomide plus infliximab after failure of treatment with other DMARDs. 13 patients were treated for a minimum of 3 months with leflunomide without toxicity before beginning infliximab. Treatment was begun simultaneously with both drugs in 4 patients. Side effects (clinical and biological) and efficacy (DAS 28) were evaluated at each infliximab infusion (3 mg/kg at week 0, 2, 6 and then every 8 weeks). Results. Thirteen patients experienced 20 types of side effects and 8 of them stopped the combination therapy. The causes of discontinuation were congestive heart failure (1 case), hypertension with thoracic pain (2 cases), eczematous skin patches (2 cases) and neutropenia (3 cases). No death was registered. Nine RA patients continuted the therapy with a median follow-up of 22 weeks. Only 4 of them experienced no side effects. Eight patients were positive for antinuclear antibodies (ANA) and 1 for double-stranded DNA (dsDNA) antibodies at study entry. After treatment, 13 and 5 patients tested positive respectively for ANAs and dsDNA antibodies. There was no relationship between discontinuation and ANA/dsDNA positivity. Conclusion. In this cohort, adverse events were not very different from those seen in patients on either treatment alone and the combination of leflunomide plus infliximab did not appear to be as badly tolerated as described in a previous study.
Gomez-Reino JJ, Carmona L, Rodriguez Valverde V, et al.

Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in TB risk: A multicenter active-surveillance report. Arthritis & Rheumatism. Vol. 48(8)(pp 2122-2127), 2003.


Abstract:


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

Benefit-risk assessment of infliximab in the treatment of rheumatoid arthritis. Drug Safety. Vol. 26(1)(pp 23-32), 2003.


Abstract:


Recent reports have highlighted several potential serious adverse effects associated with infliximab (and other TNFα inhibitors), including infusion reactions, congestive heart failure, drug-induced lupus, and CNS demyelination. In addition, recent reports have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate TB screening prior to drug initiation. Although the frequency of serious drug-related toxicity (requiring discontinuation of the agent) appears to be quite low, these reports underscore the need for caution and close surveillance with the administration of TNFα inhibitors, particularly given that strategies aimed at preventing toxicity remain unproven. Despite its potential for toxicity, infliximab remains a valuable alternative for patients with RA.
Favalli EG, Sinigaglia L, Varenna M, et al.

Drug-induced lupus following treatment with infliximab in rheumatoid arthritis. Lupus. Vol. 11(11)(pp 753-755), 2002.


Abstract:


The authors report a case of a 69-year-old female with a 5 year history of RA, who was successfully treated with low-dose MTX and infliximab (initially 3 mg/kg and from the fourth infusion 5 mg/kg) for 23 weeks. Before the sixth infusion, she was diagnosed with DIL by both clinical features (fever > 38 degrees C, recurrence of active synovitis, myalgia, erythematous rash and general malaise) and laboratory findings (antinuclear antibodies 1:160, anti-double-stranded DNA positive by ELISA assay, decreased serum complement C3 and C4, hypergammaglobulinaemia, increased erythrocyte sedimentation rate). After discontinuation of treatment and therapy with oral prednisone, lupus resolved within 8 weeks.
Brown SL, Greene MH, Gershon SK, et al.

Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46:3151-8.


Abstract:


Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed. RESULTS: The authors identified 26 cases of lymphoproliferative disorders following treatment with etanercept (18 cases) or infliximab (8 cases). The majority of cases (81%) were non-Hodgkin's lymphomas. The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short (median 8 weeks). In 2 instances (1 infliximab, 1 etanercept), lymphoma regression was observed following discontinuation of TNFα 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 TNFα 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 background rates. CONCLUSIONS: Active TB may develop soon after the initiation of treatment with infliximab. Before prescribing the drug, physicians should screen patients for latent TB infection or disease.

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