Rates Of Serious Infections Research Articles

CC5-05: Comparative Safety of Infliximab and Etanercept on the Risk of Serious Infections - Does the Association Vary By Patient Characteristics?

Background/AimsInfliximab, a chimeric monoclonal anti-TNF? antibody, has been found to increase the risk of serious infections compared with the TNF receptor fusion protein etanercept in some studies. It is unclear whether the risk varies by patient characteristics. We conducted a study to address this question.MethodsWe identified members of Kaiser Permanente Northern California who initiated infliximab (n=793) or etanercept (n=2,692) in 1997–2007. Using a Cox model, we estimated the propensity score-adjusted hazard ratio (HR) and 95% confidence interval (CI) of serious infections requiring hospitalization or opportunistic infections comparing infliximab with etanercept following treatment initiation. We estimated the stratum-specific HRs by age ( =65 years), sex, race/ethnicity (Non- Hispanic White, African-American, Hispanic, Asian American, Native American, and other/unknown), body mass index ( =25 kg/m2), and smoking status (non, past, and current smokers); and performed likelihood ratio tests to examine whether the HR differed by these patient characteristics.ResultsThe crude incidence rate of serious infections per 100 person-years was 5.4 (95% CI: 3.8, 7.5) in patients =65 years during the first three months following treatment initiation. Compared with etanercept, the adjusted HR during this period was elevated for infliximab in patients =65 years (HR 0.94; 0.41, 2.13). The test for homogeneity was marginally statistically significant (p-value=0.06). Findings did not suggest that the HR varied by other patient characteristics examined.DiscussionAn increased risk of serious infections associated with infliximab relative to etanercept did not appear to be modified by patients’ sex, race/ethnicity, body mass index, or smoking status. There was an indication that the increased risk might vary by age. Additional studies are warranted to verify or refute this finding.

Sustained efficacy of certolizumab pegol added to methotrexate in the treatment of rheumatoid arthritis: 2-year results from the RAPID 1 trial

To evaluate the safety and efficacy of 2-year administration of certolizumab pegol (CZP) + MTX in patients with active RA. Patients completing 52 weeks in the Rheumatoid Arthritis Prevention of Structural Damage (RAPID) 1 trial (52-week completers), or withdrawing at week 16 due to lack of ACR20 response were eligible for open-label treatment (CZP 400 mg every other week + MTX). After 2 years' treatment, HAQ-Disability Index response, ACR20/50/70 responses, DAS-28 and radiographic progression were assessed in 52-week completers. ACR20/50/70 and DAS-28 were also calculated for the intent-to-treat (ITT) population. Adverse events were assessed in patients who received one or more CZP doses during the study. At week 100, 88.9% (n = 216) of 52-week completers who originally received CZP 200 mg + MTX and open-label treatment remained in the study. In this group, ACR20/50/70 at week 100 were 68.2, 55.2 and 35.6%, respectively. HAQ-DI and DAS-28 improvements were sustained throughout the open-label extension (mean change -0.79 and -3.5 at week 100, respectively). A total of 46.7% (n = 113) of CZP 200 mg + MTX 52-week completers achieved low disease activity by week 100. Inhibition of radiographic progression was maintained. Similar findings were observed in 52-week completers who originally received CZP 400 mg + MTX and in the ITT population. Rates of serious infection or malignancies did not increase over time and no new safety signals were observed. CZP + MTX provided sustained, 2-year inhibition of radiographic progression and sustained improvements in RA clinical signs and symptoms, with no new safety signals observed in patients who completed 2 years of treatment. clinicaltrials.gov, http://www.clinicaltrials.gov, NCT00175877.

Systematic Review of Tocilizumab for Rheumatoid Arthritis: A New Biologic Agent Targeting the Interleukin-6 Receptor

BackgroundTocilizumab (TCZ), a humanized anti–interleukin-6 receptor monoclonal antibody, represents a new treatment strategy for patients with rheumatoid arthritis (RA) and is currently approved in the United States for RA patients who have failed to improve with at least one anti–tumor necrosis factor therapy. ObjectiveThe goal of this study was to summarize the efficacy and safety profile of TCZ. MethodsA systematic literature review was conducted to identify English-language articles within PubMed and the Cochrane Library from January 1989 to August 2011 reporting results from Phase III TCZ double-blind, randomized controlled trials (RCTs), noncontrolled clinical trials, and open-label extensions with a duration ≥6 months. Study outcomes had to include at least one of the following: American College of Rheumatology (ACR) 20, 50, or 70 response rates; tender/swollen joint count; Health Assessment Questionnaire–Disability Index; radiographic outcomes and drug persistence. Phase II RCTs were included only if they contained relevant information not available in Phase III RCTs. Relevant studies were selected to evaluate TCZ's pharmacokinetics and pharmacodynamics. ResultsTen published clinical trials (7 Phase III, 3 Phase II) for TCZ were retrieved (7833 articles initially identified) from PubMed and 31 from the Cochrane library. Compared with methotrexate (MTX) monotherapy, TCZ 8 mg/kg IV monotherapy had higher rates of ACR20 (P < 0.001), ACR50 (P = 0.002), and ACR70 (P < 0.001) scores at week 24. TCZ 8 mg/kg IV plus oral MTX had a higher ACR20 response rate than oral MTX plus placebo in patients with RA who failed to respond to MTX or anti–tumor necrosis factor therapy (P < 0.001). Patients receiving TCZ 8 mg/kg had less radiographic progression on the Genant-modified Sharp score (85% had no progression) than the control group (67% had no progression) (P < 0.001). The rate of serious infections was 4.7 events/100 patient-years of exposure in the TCZ groups. A greater frequency of neutropenia, thrombocytopenia, hyperlipidemia, and transaminitis was observed with TCZ compared with placebo. ConclusionThe short-term efficacy and safety profile of TCZ is promising. Additional long-term safety data are needed to better characterize the risk–benefit profile of this agent.

Comparative safety of infliximab and etanercept on the risk of serious infections: does the association vary by patient characteristics?

Infliximab, a chimeric monoclonal anti-TNFα antibody, has been found to increase the risk of serious infections compared with the TNF receptor fusion protein etanercept in some studies. It is unclear whether the risk varies by patient characteristics. We conducted a study to address this question. We identified members of Kaiser Permanente Northern California who initiated infliximab (n = 793) or etanercept (n = 2692) in 1997-2007. Using a Cox model, we estimated the propensity-score-adjusted hazard ratio (HR) and 95% confidence interval (CI) of serious infections requiring hospitalization or opportunistic infections comparing infliximab initiators to etanercept initiators. We tested whether the adjusted HR differed by age, sex, race/ethnicity, body mass index, and smoking status. The crude incidence rate of serious infections per 100 person-years was 5.4 (95%CI: 3.8, 7.5) in patients <65 years and 16.0 (95%CI: 10.4, 23.4) in patients ≥ 65 years during the first 3 months following treatment initiation. Compared with etanercept, the adjusted HR during this period was elevated for infliximab in patients <65 years (HR: 3.01; 95%CI: 1.49, 6.07), but not in those ≥ 65 years (HR 0.94; 95%CI: 0.41, 2.13). Findings did not suggest that the HR varied by the other patient characteristics examined. An increased risk of serious infections associated with infliximab relative to etanercept did not appear to be modified by patients' sex, race/ethnicity, body mass index, or smoking status. There was an indication that the increased risk might be limited to patients <65 years. Additional studies are warranted to verify or refute this finding.

Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial

ObjectiveTo determine the efficacy and safety of ocrelizumab (OCR) with methotrexate (MTX) in MTX-naive rheumatoid arthritis (RA) patients.MethodsIn a randomised, double-blind, controlled trial, patients received placebo+MTX (MTX; n=210), OCR 200...

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a forty‐eight–week randomized, double‐blind, placebo‐controlled, parallel‐group phase III trial

To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX. STAGE was a phase III randomized, double-blind, parallel-group international study to evaluate the safety and efficacy of ocrelizumab compared with placebo in patients with active RA continuing MTX treatment. Patients receiving stable doses of MTX were randomized to receive 2 infusions of placebo (n = 320), ocrelizumab 200 mg (n = 343), or ocrelizumab 500 mg (n = 343) on days 1 and 15 as well as weeks 24 and 26. Coprimary end points were the proportion of patients with an American College of Rheumatology 20% improvement criteria (ACR20) response at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. The ACR20 response rates were 35.7% in the placebo group, 56.9% in the ocrelizumab 200 mg group, and 54.5% in the ocrelizumab 500 mg group at 24 weeks, and 27.6%, 58.3%, and 62.1%, respectively, at 48 weeks (P < 0.0001 versus placebo for each dose at both time points). At week 48, both of the ocrelizumab doses improved the ACR50 and ACR70 response rates 3-fold as compared with placebo and showed a statistically significant (P < 0.0001) reduction in joint damage progression relative to placebo (mean change in SHS reduced by 85% and 100% for the 200-mg and 500-mg doses, respectively). Rates of serious infection were comparable in the placebo (3.48 per 100 patient-years) and ocrelizumab 200 mg (3.54 per 100 patient-years) groups but were elevated in the ocrelizumab 500 mg group (8.66 per 100 patient-years). With both ocrelizumab doses, the primary end point was met, and the signs and symptoms of RA were significantly improved at weeks 24 and 48. Ocrelizumab also significantly inhibited the progression of joint damage. A higher rate of serious infections was observed with 500 mg of ocrelizumab as compared with ocrelizumab 200 mg or placebo.

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: Results of a forty‐eight–week randomized, double‐blind, placebo‐controlled, parallel‐group phase III trial

To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors. This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%). Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

Is Anti-TNF Therapy Safer Than Previously Thought?

ANTI–TUMOR NECROSIS FACTOR (TNF) THERAPY HAS revolutionized the treatment of rheumatoid arthritis (RA) and other inflammatory diseases over the last decade. However, because TNF has important physiological roles such as host defense and tumor surveillance, anti-TNF therapy has been subject to rigorous postmarketing safety assessment. In this issue of JAMA, Grijalva and colleagues report results from an analysis of data combined from 4 large US administrative databases within the Safety Assessment of Biologic Therapy (SABER) project that question the accepted notion that anti-TNF therapy confers an increased risk of serious infection. Early randomized controlled trials (RCTs) of anti-TNF therapy did not report a significantly increased rate of serious infections, although there were early signals of concern such as a case of tuberculosis in the first infliximab trial. Subsequent RCTs led to the first meta-analysis of infection risk with anti-TNF therapy, which reported a 2-fold increased risk of serious infection. The strength of the trials was randomization, such that any observed difference should be due to the treatment under investigation, not confounders. Despite some differential loss to follow-up in the individual trials, this signal was nonetheless concerning. The inability of individual RCTs to address the safety of rare or long-term outcomes led to the establishment of European drug registers at the launch of anti-TNF therapy, along with other international studies. An analysis from the German biologics register reinforced the meta-analysis results by reporting a 2-fold increased risk of serious infection. However, subsequent studies reported risks ranging from no increased risk to a greater than 4-fold increased risk. Datathat initiallyappearedconflictingslowlyrevealedamore coherent pattern. A time-dependent risk of serious infection was consistent across studies, with an initially high rate of infection thatdeclinedwithprolongeduseofbiologic therapies. Subsequentstudieshavereplicatedthetime-dependentpattern, suggesting the pattern is largely explained by changes in glucocorticoiduse, improvements indiseaseseverity, andadepletion of susceptible patients (whereby high-risk patients have their infections early and discontinue treatment, thus leaving a cohort that is at lower risk of infections). In previous studies, the rate of serious infection was initially higher among patients treated with anti-TNF than the rate in the comparison group (ie, not taking anti-TNF medications), and the rate ratio declined with time. Grijalva et al present the infection rates in the treated and comparison cohorts from 4 large, US automated databases (Figure 2 of their article). Unlike the time-dependent association observed in other studies, the infection rate was comparable throughout the year of follow-up. This finding raises the question of why the time-dependent risk was not observed. The answer may lie in either the infection rates in the cohort receiving anti-TNF treatment or, importantly, the rates in the comparison group. Different rates of infection in comparison groups across studies have accounted for discrepancies in other anti-TNF studies. For their comparison group Grijalva et al selected new users of nonbiologic therapy who did not benefit from methotrexate in the RA cohort, the largest user subgroup in their study. This approach differs from other studies that derived comparison cohorts from prevalent users of diseasemodifying antirheumatic drugs (DMARDs). From a new user comparison cohort, the comparative risks of starting one treatment vs another can be examined. The clinical issue is whether the infection risk would be higher, for example, for a patient starting anti-TNF therapy compared with starting a DMARD such as leflunomide. In the study by Grijalva et al, the absolute rate of infection in the comparison cohort was much higher than in other studies of patients using DMARDs, perhaps reinforcing that the difference may be driven by differences in the comparator. This is possible because the comparison group, like the treatment group in this study, consisted of underserved, vulnerable patients, a population typically excluded from clinical trials. The next issue to consider is whether the observed relative risk is due solely to the difference in medication exposure, or whether the cohorts also differ in other characteristics that may influence their risk of infection. Selection or channeling bias is inevitable in pharmacoepidemiology, as physicians prescribe a particular treatment for a reason. For

Monoclonal gammopathy after liver transplantation: a risk factor for long-term medical complications other than malignancies

The aims of the study were to evaluate (i) the prevalence of MGUS in patients after liver transplantation (LT), (ii) the role of MGUS as a risk factor for malignancy and other medical complications after LT. One hundred and fifty consecutive patients were included in the study and followed prospectively after LT for more than 18 months. Eighteen patients had MGUS before LT, whereas 49 patients developed MGUS after LT ('de novo' MGUS). Thirty-six of these patients showed a MGUS along all the follow up after LT ('permanent' MGUS). In 31 patients, MGUS disappeared after LT ('transient' MGUS). No patient with MGUS developed B-malignant lymphoproliferative disorder and only one patient developed a myeloma after LT. Comparing patients with 'permanent' MGUS to patients with 'transient' MGUS or without MGUS after LT, the former group showed a higher rate of serious infections (30% versus 13%, P = 0.01), chronic kidney disease (CKD) (75% versus 44%, P = 0.001) and mortality (33% versus 17%, P = 0.04). Permanent MGUS was confirmed as an independent risk factor for serious infections and CKD by multivariate analysis. Permanent MGUS after LT does not entail a significant risk of malignancy, but it is associated with a higher risk of serious infections and CKD.

Long-term safety experience of ustekinumab in patients with moderate to severe psoriasis (Part II of II): Results from analyses of infections and malignancy from pooled phase II and III clinical trials

Ustekinumab targets interleukin (IL)-12 and IL-23 in the treatment of moderate to severe psoriasis. We sought to evaluate the impact of ustekinumab on infections and malignancies, both theoretical risks of blocking IL-12 and IL-23, in patients exposed up to 3 years. Rates of infections and malignancies were evaluated in cumulative safety data from 3117 ustekinumab-treated patients across 4 studies. During the placebo-controlled periods, rates of overall infections per 100 patient-years were similar among placebo (121.0), ustekinumab 45-mg (145.7), and ustekinumab 90-mg (132.2) groups, with overlapping confidence intervals, and remained stable through 3 years in ustekinumab groups. Rates of serious infections during the placebo-controlled periods were similar between placebo (1.70) and 90-mg (1.97) groups, yet lower in the 45-mg group (0.49). Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database. Rates of malignancies during the placebo-controlled periods were comparable among groups (placebo: 1.70; 45 mg: 0.99; 90 mg: 0.98) and remained stable over time in ustekinumab groups. Rates of malignancies, excluding nonmelanoma skin cancer, were comparable with rates expected in the general US population based on the Surveillance, Epidemiology, and End Results database. Controlled periods do not extend beyond 12 to 20 weeks. Only 1247 patients were treated for at least 2 years, to date. Comparator database populations may not fully represent the clinical trial population. The emerging safety profile of ustekinumab remains favorable and does not suggest increased rates of infection or malignancy through 3 years.

Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study

ObjectiveTo evaluate efficacy of tocilizumab in US patients with moderate to severe active rheumatoid arthritis (RA) and inadequate clinical response to disease-modifying antirheumatic drugs (DMARD). Safety-related outcomes were also analysed.MethodsThe...

Treatment benefit or survival of the fittest: what drives the time-dependent decrease in serious infection rates under TNF inhibition and what does this imply for the individual patient?

ObjectiveTo examine the risk of serious infection conveyed by tumour necrosis factor α (TNFα) inhibitors in the treatment of rheumatoid arthritis (RA).MethodsData from patients with RA enrolled in the German...

Association of Thymectomy With Infection Following Congenital Heart Surgery

Congenital absence of the thymus can lead to profound immunodeficiency, suggesting that thymic function during fetal development is essential to normal lymphocyte development. How vital the thymus after birth is to human immune competence and regulation is not known. Routine thymectomy, especially at an early age, may influence immunity, and therefore the risk of infection, autoimmunity, or malignancy. A retrospective review of cardiac surgery patients followed at Seattle Children's Hospital was performed. The primary outcome was rate of serious infections requiring hospitalization. Secondary analyses included age, type of infection, cardiac diagnosis, surgical procedure, and comorbidities. Patients fell into 2 groups: 60 with complete thymectomy and 35 with partial or no thymectomy. There was no statistical difference between groups in the overall prevalence of serious infections (16.7% vs 17.2%, P = 1.0). There was a nonsignificant trend toward reduced time between surgery and onset of first infection in patients in the total thymectomy group versus those without thymectomy (1.7 years vs 4.6 years, P = .07). Total thymectomy before 6 months of age also tended to increase infection rate, but the effect was not significant (0.09/year vs 0.02, P = .14). Gastroesophageal reflux in patients with total thymectomy increased the risk of infection (P = .013), suggesting a cumulative effect. Though infections occurred frequently in the childhood cardiac surgery population, total thymectomy was not associated with increased risk of serious infection. Comorbid conditions may be more important contributing factors increasing the risk of infection in this complex and vulnerable population.

Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: A meta-analysis of randomized controlled trials

To conduct a meta-analysis of the rates of serious infection and malignancy in patients with early rheumatoid arthritis (RA) who have started anti-tumor necrosis factor (anti-TNF) therapy and had not received treatment with disease-modifying antirheumatic drugs (DMARDs) or methotrexate (MTX). A systematic literature search was conducted through the summer of 2009. All studies included were randomized, double-blind, placebo-controlled trials involving patients with early RA who were started on anti-TNF therapy without prior DMARD/MTX use. Six trials met the inclusion criteria for the meta-analysis, comprising a total of 2,183 patients receiving biologic therapy and 1,236 patients receiving MTX. The data extracted were from published trials. A pooled odds ratio (OR) (determined using Mantel-Haenszel methods, with a continuity correction designed for sparse data) was calculated for serious infections (requiring hospitalization) and malignancies, comparing anti-TNF therapy to MTX control. The pooled OR for serious infections was 1.28 (95% confidence interval [95% CI] 0.82-2.00) and that for malignancies was 1.08 (95% CI 0.50-2.32). There was no significant difference in either the rate of serious infections or the rate of malignancies between the anti-TNF therapy group and the control group. Whereas other meta-analyses have shown an increased risk of serious infection and malignancy in patients receiving anti-TNF therapy, the results of the present meta-analysis show that there is not an increased risk when the patients have early disease and have not previously been treated with DMARDs and/or MTX.

Cytomegalovirus Viremia, Pneumonitis, and Tocilizumab Therapy

Cytomegalovirus Viremia, Pneumonitis, and Tocilizumab Therapy

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID).

IntroductionEvidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.MethodsPatients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.ResultsA total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).ConclusionsData from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Updated Results of Combination Cytokine Immunotherapy In the Treatment of Aplastic Anemia and Myelodysplastic Syndrome (MDS)

AbstractAbstract 2920Immunosuppressive therapy using antithymocyte globulin (ATG) and cyclosporine has been successfully used in the treatment of cytopenias in patients (pts) with severe aplastic anemia (AA). Laboratory and clinical data suggest that dysregulated immune mechanisms may also contribute to the pathogenesis of ineffective hematopoiesis in some subsets of early MDS and result in cytopenias. Rabbit ATG (rATG) is active and well tolerated in pts have recurrent/persistent disease after treatment with equine ATG. Here we present our updated results with a combination of rATG, cyclosporine, prednisone, and G-CSF in pts with aplastic anemia or myelodysplastic syndrome.This is a single-arm phase II study evaluating the efficacy and safety of the following combination in pts with aplastic anemia and low or intermediate-1 risk MDS (by the international prognostic scoring system) : rATG 3.5 mg/kg/day (or 2.5 mg/kg/day for age ≥ 55 yrs) intravenously (IV) for 5 days, methylprednisone 1mg/kg/day IV daily for 5 days (given prior to each dose of ATG), followed by oral prednisone tapered off over 1 month, G-CSF (filgrastim daily or pegfilgrastim every 2 weeks) subcutaneously for up to 3 months, and cyclosporine (5 mg/kg) daily for up to 6 months. Dose reductions or interruptions for toxicities were allowed at the discretion of the treating physician. Responses were assessed at 3 months after initiating therapy.Of the 51 pts enrolled, 46 have received treatment including 23 (50%) pts with AA and 23 (50%) pts with MDS. The median age overall was 60 yrs (range, 19–82), 54 (19-82) in the AA and 63 (48-79) in the MDS cohorts respectively. Of the 43 pts evaluable for response (21 AA, 22 MDS), there were 13 (62%) responders (4 CR, 8 PR, 1 HI) in AA cohort and 6 (27%) responders (2 CR, 4 HI) in the MDS cohort. Median age of responders was 59 (19-79). The median time to response (TTR) was 3.2 months. Of the 46 pts who received treatment, 20 pts (43%) were HLA-DR15 positive, 22 (48%) were negative, and 4 (9%) were not checked. In the MDS cohort, 9 (39%) pts were HLA-DR15 positive and none responded. In the AA cohort, 11 (48%) were HLA-DR15 positive, out of which 6 (55%) responded. Among the 19 responding pts described above, 6 (32%) were HLA-DR15 positive and all had AA. The median disease free survival for responders (CR & PR) is 26 months. The median overall survival of responders has not been reached, compared to 20 months for nonresponders (p<0.001). Overall the treatment was tolerable. The most common grade 3/4 toxicities were thrombocytopenia (43%), neutropenia (41%), transaminase elevation (13%), hyperbilirubinemia (7%), infection/fever (7%), and hyperglycemia (4%). Grade 3/4 dyspnea, abdominal pain, and hypertension occurred in 1 patient each. Twenty pts (43%) had infusion related reactions including fever, chills, and dyspnea that was manageable with supportive care.The combination of rATG, cyclosporine, steroids, and G-CSF is a well tolerated, effective regimen in the treatment of aplastic anemia and also has activity in a subset of pts with MDS. The rate of serious infections was relatively low, but infusion reactions were common and should be managed with premedication and supportive care. HLA-DR15 positivity correlated with response in patients with AA, but not in MDS. Responses were slow to occur, but durable, and associated with improved survival. Disclosures:Kadia:Genzyme: Research Funding. Ravandi:Genzyme: Honoraria.

Long-term effectiveness and safety of TNF-blocking agents in daily clinical practice: results from the Dutch Rheumatoid Arthritis Monitoring register

Experience with anti-TNF agents for a decade can be used to research the safety and effectiveness of anti-TNF agents in the long term. The objective of this article is to describe drug survival, disease activity, daily functioning, quality of life and adverse events of TNF-blocking agents in daily clinical practice after 5 years of follow-up. Data from the Dutch Rheumatoid Arthritis Monitoring (DREAM) register of 1560 RA patients were used for analyses (5-year follow-up, n=174). Drug survival and time to first serious infection or malignancy were analysed by Kaplan-Meier analysis. Several outcome measures at several follow-up moments were analysed per intention to treat and per protocol. The 5-year drug survival of the first anti-TNF was 45%, and 60% for total use of TNF-blocking agents. Baseline 28-joint DAS (DAS-28) was 5.1 (s.d. 1.3). After 5 years, the mean DAS-28 was 3.2 (s.d. 1.3) in all patients who had started with TNF-blocking agents and 2.9 (s.d. 1.1) in patients who were still on TNF-blocking agents. In the latter group, the HAQ score was 0.88 (s.d. 0.7) and the EuroQol five dimensions (EQ-5D) utility score was 0.7 (s.d. 0.2). Incidence rates of serious infections and malignancies were 2.9 and 0.6 per 100 patient-years, respectively. Five-year follow-up of RA patients treated with TNF-blocking agents showed a 60% drug survival accompanied by sustained low disease activity, normalized function and quality of life similar to that in the general population. The benefit to risk ratio for long-term TNF-blocking therapy remains favourable.

Severity of infection following the introduction of new infection control measures for medical abortion

Background In response to concerns about serious infections following medical abortion, in early 2006 the Planned Parenthood Federation of America changed the route of misoprostol administration from vaginal to buccal and required either routine antibiotic coverage or universal screening and treatment for chlamydia; in July 2007, the Planned Parenthood Federation of America began requiring routine antibiotic coverage for all medical abortions. We previously reported a pronounced drop in the rate of serious infections following the adoption of these new infection control measures. Our objective in this study was to assess whether the degree of severity of the serious infections differed in the three infection control groups (vaginal misoprostol and no antibiotics; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, to assess whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories. Of particular importance is whether the new infection control measures selectively reduced the least severe serious infections but did not diminish the rate of the most severe infections. Methods We performed a retrospective analysis assessing the degree of severity of infections before infection controls were implemented and after each of the two new measures was adopted: buccal administration of antibiotics with either screen-and-treat method or routine antibiotic coverage. We ranked the severity of infection from 1 (when treatment occurred in an emergency department) to 4 (when death occurred). We compared the distributions of the severity of serious infections in the three infection control groups (none; buccal misoprostol and screen-and-treat method; buccal misoprostol and routine antibiotics) or, equivalently, assessed whether the declines in rates of serious infections after the adoption of new infection control measures differed across the degree of severity categories using the Jonckheere–Terpstra test for a doubly ordered 4×3 table. Results The distribution of infection by severity was the same for all three infection control groups. Likewise, when the two new infection control groups — buccal misoprostol plus either screen-and-treat method or routine antibiotics — were combined, the distribution of infection by severity was the same before and after the new measures were implemented. Conclusion The pronounced decline in the rate of serious infections occurred in each category of severity.

Concomitant Use of Adalimumab and Immunomodulators or Corticosteroids Compared with Adalimumab Alone: Pooled Safety Analysis: 2010 Presidential Poster

Purpose: To assess the incidence of serious infections in patients with Crohn's disease (CD) using adalimumab in combination with immunomodulators and/or corticosteroids. Methods: The proportion of patients with treatment-emergent serious infections was determined from the cumulative adverse event data in lead-in and long-term studies of adalimumab in CD (CLASSIC I and II, CHARM, GAIN, and ADHERE) among patients who received at least 1 dose. Proportions and rates of serious infection were assessed across treatment groups according to receipt of immunomodulators (IMM, i.e., 6-MP, AZA, and methotrexate) and/or corticosteroids at lead-in study baseline. Proportions were compared using Fisher's exact test. Results: In the pooled analysis, serious infection occurred in 10.0% (64/638) of patients using IMM in combination with adalimumab compared with 7.2% (59/821) of patients using adalimumab without IMM (p=0.058). In both groups, baseline use of corticosteroid was associated with increased serious infections (see Table). Within the subgroup receiving adalimumab without IMM, corticosteroid use was associated with a significantly increased proportion of patients with serious infections compared with adalimumab alone (p=0.034). Serious infections were observed most commonly in patients receiving adalimumab plus both IMM and corticosteroids (p=0.005, compared with adalimumab alone). Conclusion: Patients with Crohn's disease treated with corticosteroids and IMMs in combination with adalimumab are at the highest risk of experiencing treatment-emergent serious infections. Disclosure: Dr Sandborn - Consultant, research support: Abbott Dr Colombel - Consultant: Abbott Dr Lewis - Consultant: Abbott Dr Osterman - Consultant: Abbott Dr Robinson - Employee, Abbott Dr Huang - Employee, Abbott Dr Pollack - Employee, Abbott Dr Thakkar - Employee, Abbott.Table: Treatment-emergent serious infections by baseline concomitant therapy