Abstract
Goals:
Compare the relative safety of administering iron infusions on the same day as IV biologic therapy to the administration of these treatments on different days in patients with inflammatory bowel disease (IBD).
Background:
Intravenous (IV) iron therapy is often required in patients with IBD. Many patients with IBD who receive IV iron therapy in the outpatient setting also receive biologic infusion therapy for treatment of their IBD.
Study:
Patients with IBD who received IV iron therapy at a single infusion center were included. We compared documented infusion-related reactions in patients with patients receiving an iron infusion on the same day as their biologic infusion to those who received their iron infusion on a different day.
Results:
Among 481 patients, 129 received an iron infusion on the same day as a biologic infusion. There was no significant difference in the incidence of infusion reaction when comparing patients who received biologic infusion therapy in the same session as the iron infusion to those patients who received a biologic infusion on a different day (5% vs. 7%, p=0.246) or any IBD-related therapy (5% vs. 8%, p=0.206).
Conclusions:
The frequency and type of infusion reactions in patients receiving IV iron therapy on the same day after IV therapy with biologics was not increased compared to patients who received a biologic infusion on a different day. A sequential infusion of biologic therapy followed by IV iron therapy may be a safe and cost-effective approach.
Keywords: anemia, Crohn’s disease, ulcerative colitis, iron-deficiency anemia, infusion
Introduction
Anemia is a common complication of inflammatory bowel diseases (IBDs).1,2,3 While the etiology of anemia in Crohn’s disease (CD) and ulcerative colitis (UC) is often multifactorial, the most common cause of anemia in IBD is due to iron deficiency.2 The prevalence of iron deficiency anemia amongst patients with IBD can range from 20% among outpatients to up to 70% among hospitalized patients.4 Given the high prevalence of iron deficiency anemia among patients with IBD, iron supplementation is recommended in all patients with iron deficiency anemia. Oral iron is convenient and inexpensive, however its efficacy is limited by poor absorption, intolerance, and frequent adverse effects.4,5 Given the potential limitations of oral iron therapy, intravenous (IV) iron replacement is commonly used as a treatment of iron deficiency and iron deficiency anemia in patients with IBD.4 Recent European Crohn’s and Colitis Organization (ECCO) guidelines indicate several clinical scenarios where intravenous iron should be considered as first-line therapy, including in patients with clinically active disease, previous intolerance to oral iron, significantly decreased anemia (below 10 g/dL), or in those patients requiring erythropoiesis-stimulating agents.5
Many adverse reactions have also been described with IV iron therapy,6 however most of these are mild in nature and do not preclude completion of the infusion or delay future infusions. Although serious adverse reactions with IV iron have been noted including hypotension and anaphylaxis, the prevalence of these adverse events are approximately 1-2%.4,6,7 Therefore, providers are encouraged to use IV iron according to recommended guidelines for iron replacement among IBD patients with anemia.
In the current treatment era, many patients with IBD who receive IV iron therapy in the outpatient setting also receive biologic infusion therapy for treatment of their IBD. The relative safety of administering iron infusions on the same day of IV biologic therapy in IBD patients is not well established. One pilot study in 2015 showed no adverse reactions amongst 33 patients who received ferric carboxymaltose immediately after their infliximab infusion (single-session treatment group).8 Another study with 335 patients evaluating the safety on consecutive vedolizumab and iron infusions showed no significant difference in the number of delayed infusion reactions between those who received IV iron at the same visit and those who did not.9
Given existing gaps in our understanding of the safety of this approach, the aim of this study is to evaluate the safety of administering iron infusions on the same day as biologic infusions at a tertiary care IBD center. We hypothesized that those patients receiving a biologic infusion on the same day as their IV iron therapy would demonstrate no greater frequency of iron-therapy related infusion reaction than those patients receiving biologic therapy on a different day.
Material and Methods
Study Design
We performed a retrospective cohort study evaluating patients with a diagnosis of CD or UC who received outpatient IV iron infusions between January 1, 2012 and April 30, 2020.
Patient Selection
All patients, age 18 or older, with a diagnosis of IBD (CD, UC or inflammatory bowel disease unclassified [IBDU]) who received IV iron therapy at a tertiary care outpatient infusion center were included. Patients younger than 18 years of age, without an official diagnosis of IBD, or who received iron infusions in an inpatient setting only, were excluded.
Eligible patients were identified for inclusion using International Classification of Diseases 9th and 10th Clinical Modification (ICD-9-CM and ICD-10-CM) coding for CD (555.xx and K50.xx) and UC (551.xx and K51.xx). Additionally, all eligible patients were required to have a Healthcare Common Procedure Coding System (HCPCS) code for the administration of IV iron therapy. To identify eligible patients with these codes, we utilized the Informatics for Integrating Biology and the Bedside (i2b2) platform through the Carolina Data Warehouse for Health. The i2b2 platform has been described in detail previously,10,11 and was developed by the i2b2 Center, a National Institutes of Health (NIH) funded National Center for Biomedical Computing based at Partners HealthCare System.
Exposure Assessment
Data from the patient’s first documented outpatient IV iron infusion or the first outpatient IV iron infusion on the same-day as biologic therapy was used. Patients received ferumoxitol, ferric carboxymaltose injections, iron dextran, or sodium ferric gluconate infusions. Patients who received IV iron therapy with same-day infliximab, ustekinumab, or vedolizumab or patients receiving IV iron therapy and biologic therapy on different days were included. Iron infusions were given at least 30 minutes after the end of the application of the biologic. Additionally, patients who received IV iron therapy while on other IBD-related therapies were also reviewed.
Outcome Assessment
Patients with infusion-related reactions that occurred acutely (during the infusion) or delayed (within 7 days of the iron infusion) were identified. Reactions documented included anaphylaxis, itching, shortness of breath, chest pain or tightness, flushing or lightheadedness, nausea or vomiting, diarrhea, gastrointestinal bleeding, arthralgias or myalgias, hypotension, bronchospasm, palpitations, and periorbital edema. We then compared the number of documented infusion-related reactions in patients receiving iron infusion on the same day as their biologic infusion versus those who received their biologic therapies on a different day. Additionally, iron infusion-related reactions documented while on other IBD-related therapies were also reviewed.
Covariates
Patient demographics including age, sex, body mass index (BMI), race, and ethnicity were recorded. IBD characteristics including type of IBD (CD, UC, or IBDU), age of diagnosis, duration of disease, and Montreal Classification (location, behavior, and age) were also extracted.
Statistical Analysis
Continuous variables are summarized using median and interquartile range (IQR) and were compared using Wilcoxon-rank-sum testing. Raw values with corresponding percentages are used to express categorical variables, which were analyzed using Fisher exact and chi-square testing as appropriate. Bivariate and multivariable logistic regression models were utilized to evaluate the relationship between same-day administration of a biologic infusion and an iron infusion-related reaction, adjusting for potential confounders. All covariates included in the multivariable analyses were identified a priori based on the potential to affect the likelihood of developing an infusion-related reaction. All analyses were performed using SAS (version 9.4) statistical software (SAS Institute, Cary, NC, USA). The study protocol was approved by the Institutional Review Board at UNC-Chapel Hill.
Results
Demographics and Clinical Characteristics
Between January 2012 and April 2020, we identified 481 patients with IBD who received IV iron therapy at an UNC outpatient infusion center (Table 1). Among all patients receiving IV iron therapy, 417 (86%) received ferumoxitol, 53 (11%) received iron dextran, 7 (2%) received sodium ferric gluconate, and 4 (1%) received ferric carboxymaltose. Among 306 total patients receiving biologic treatments, 174 (57%) received a biologic infusion. Of the patients receiving a biologic infusion, 129 (74%) patients received an iron infusion on the same day as their biologic infusion (Figure 1).
Table 1.
Demographics and Clinical Characteristics of Patients with Inflammatory Bowel Disease Receiving Iron Infusions
| Patients with IBD who received Iron Infusions (n = 481) |
||
|---|---|---|
| n | % | |
| Age | ||
| 18-39 | 203 | 42 |
| 40-50 | 109 | 23 |
| 50-65 | 102 | 21 |
| >65 | 67 | 14 |
| Gender | ||
| Female | 296 | 62 |
| Male | 185 | 38 |
| Race | ||
| White | 343 | 71 |
| Black or African-American | 97 | 20 |
| Asian | 14 | 3 |
| Other | 27 | 6 |
| BMI | ||
| <18.5 | 50 | 11 |
| 18.5 – 24.9 | 213 | 44 |
| 25 – 29.9 | 116 | 24 |
| 30 or greater | 102 | 21 |
| Tobacco use | ||
| Never | 328 | 68 |
| Former | 118 | 25 |
| Current | 19 | 4 |
| IBD Diagnosis | ||
| Crohn’s disease | 327 | 68 |
| Ulcerative colitis | 135 | 28 |
| Indeterminate Colitis | 17 | 4 |
| Duration of disease (median, IQR) | 14 | 7-23 |
| Location of Crohn’s disease | ||
| Ileal | 66 | 14 |
| Colonic | 56 | 12 |
| Ileocolonic | 166 | 35 |
| Upper GI Tract | 40 | 8 |
| Behavior of Crohn’s disease | ||
| Inflammatory | 101 | 21 |
| Stricturing | 126 | 26 |
| Penetrating | 97 | 20 |
| Age at Diagnosis of Crohn’s disease | ||
| ≤ 16 | 79 | 16 |
| 17-39 | 206 | 43 |
| ≥ 40 | 37 | 8 |
| Received methylprednisolone during infusion | 92 | 19 |
| Received acetaminophen during infusion | 419 | 87 |
| Monotherapy with an immunomodulator (methotrexate or a thiopurine) | 111 | 23 |
| Biologic therapy that was administered in the same session as the iron infusion | ||
| Infliximab | 74 | 15 |
| Vedolizumab | 39 | 8 |
| Ustekinumab | 16 | 3 |
| Biologic therapy that was administered on a different day than the iron infusion | ||
| Infliximab | 19 | 4 |
| Vedolizumab | 22 | 5 |
| Adalimumab | 79 | 16 |
| Certolizumab | 14 | 3 |
| Golimumab | 9 | 2 |
| Ustekinumab infusion | 4 | 1 |
| Ustekinumab injection | 30 | 6 |
| Iron dose (mean, SD) | 586 | 281.5 |
Figure 1.
Patients with Inflammatory Bowel Disease Receiving Intravenous Iron Therapy
Infusion Reactions among Patients Receiving Biologic Therapy
In patients receiving biologic infusion therapy (n=174), 9 patients had an infusion reaction (5%). There was no significant difference in the frequency of iron infusion-related reaction when comparing patients who received a biologic infusion on the same day as their iron infusion compared to patients who received the biologic infusion on different days (5% vs. 7%, p=0.246), with the most common of reaction being flushing and/or lightheadedness (Table 2). Similarly, there was no significant difference in iron-related infusion reactions when comparing patients who received same day biologic infusions, compared to the patients receiving injectable biologic therapy or biologic infusions on a different day (5% vs. 8%, p=0.234).
Table 2.
Comparison of Infusion Reactions among Patients Treated with a Biologic Infusion on the Same Day as an Iron Infusion and Patients Receiving a Biologic Infusion and Iron Infusions on a Different Day
| Patients Receiving Same-Day Biologic Infusion n=6 |
Patients Receiving Biologic Infusion on a Different Day n=3 |
All Patients Receiving Biologic Infusions n=9 |
||||
|---|---|---|---|---|---|---|
| n | % | n | % | |||
| Timing of reaction | ||||||
| Acute | 6 | 100 | 3 | 100 | 9 | 100 |
| Type of Reaction | ||||||
| Anaphylaxis | 2 | 33 | 1 | 33 | 3 | 33 |
| Dyspnea | 1 | 17 | 0 | 0 | 1 | 11 |
| Flushing or lightheadedness | 2 | 33 | 2 | 67 | 4 | 44 |
| Nausea/Vomiting | 1 | 17 | 0 | 0 | 1 | 11 |
Note: No significant difference in comparing type of reaction, p=1.00
Administration of pre-medication with acetaminophen was not significantly different in patients with infusion reactions compared to those without reaction (85% vs. 87%, p=0.721), however there was a significant different in administration of pre-medication with methylprednisolone in patients with infusions reactions compared to those without reaction (35% vs. 18%, p=0.014).
Comparison to Infusion Reactions among Total Inflammatory Bowel Disease Population
In a comparison of infusion reactions among patients who received an iron infusion on the same day as their biologic infusion and all patients with IBD who received an iron infusion, there was no significant difference in the proportion of patients developing an infusion reaction (5% vs. 8%, p=0.206). The proportion of infusion reactions experienced by patients in each group were also similar (Table 3).
Table 3.
Comparison of Infusion Reactions among Patients Treated with a Biologic Infusion on the Same Day as an Iron Infusion and the General Inflammatory Bowel Disease Population Receiving Iron Infusions
| Patients Receiving Same-Day Biologic Infusion n=6 |
Patients Receiving Other Inflammatory Bowel Disease- Related Therapy n=28 |
p-value | |||
|---|---|---|---|---|---|
| n | % | n | % | ||
| Timing of reaction | 0.258 | ||||
| Acute | 6 | 100 | 26 | 82 | |
| Type of Reaction | 0.638 | ||||
| Anaphylaxis | 2 | 33 | 8 | 29 | |
| Itching | 0 | 0 | 1 | 4 | |
| Dyspnea | 1 | 17 | 1 | 4 | |
| Chest pain/tightness | 0 | 0 | 7 | 25 | |
| Flushing or lightheadedness | 2 | 33 | 7 | 25 | |
| Nausea/Vomiting | 1 | 17 | 2 | 7 | |
| Diarrhea | 0 | 0 | 1 | 4 | |
| Arthralgias/Myalgias | 0 | 0 | 1 | 4 | |
Discussion
In this retrospective evaluation of over 400 patients with IBD, we demonstrated that patients receiving an iron infusion on the same day as a biologic infusion were at no greater risk for an infusion-related reaction than patients receiving biologic therapies on different days. Our overall rate of iron infusion-related reactions was also low, confirming prior studies, 4,6,7,12-14 and demonstrating the relative safety of this approach. Biologics are the mainstay of treatment for IBD in patients with moderate to severe activity, with many of these therapies being administered via infusion. Given that iron deficiency anemia is common among patients with IBD and that IV iron therapy is effective in treating this condition, these data should provide new reassurance to providers managing iron deficiency anemia in patients with CD and UC on biologic therapy.
Among all patients receiving a biologic therapy and an iron infusion, <10% developed any infusion related reaction. As in the larger population of patients with IBD evaluated in this study, the majority of infusion reactions were mild and transient immediate infusion reactions, which resolved with temporary attenuation of the infusion rate. Perhaps most importantly, patients receiving a biologic infusion on the same day as their iron infusion demonstrated no increased risk for developing an infusion-related reaction. These findings suggest that biologic infusions and IV iron therapies can be administered safely in the same infusion session, potentially leading to significant time savings for patients and limiting the disruptions in work and other activities of daily living. Given that iron replacement has been associated with significant improvements in quality of life among patients with IBD,15,16 the earlier correction of iron-deficiency anemia in conjunction with biologic therapy for disease control may significantly improve clinical outcomes in this population.
Amongst the patients who had an infusion reaction, administration of pre-medication with acetaminophen was not significantly different in patient with infusion reactions compared to those without reaction. However, patients who received pre-medication with methylprednisolone were more likely to experience an infusion-related reaction. These findings likely indicate the more widespread use of corticosteroid pre-medications among at risk patients. Pre-medications with methylprednisolone and an H2 blocker prior to IV iron infusions are typically reserved for those patients who suspected to be at an increased risk of an allergic or infusion reaction, including patients with asthma or more than one drug allergy.17, 18 A prior retrospective study of patients with inflammatory arthritis demonstrated that pre-medication with methylprednisolone is effective in reducing the rates of arthralgia-myalgia syndrome after an iron dextran infusion.18 Additionally, Barton et al. found that 87% of 135 patients with iron-deficiency anemia unresponsive to oral supplementation, had no reaction to iron dextran infusion when pre-medicated with diphenhydramine, cimetidine, and dexamethasone.19 Whether pre-medication is helpful in the prevention of iron infusion-related reactions remains an ongoing area of study, and will likely require further prospective evaluations.
Our study has multiple strengths including the large sample size and the long time period analyzed, allowing for the evaluation of multiple biologic infusions. However, our study has limitations. This remains a retrospective cohort study from one outpatient infusion center at an academic institution. Whether this is representative of larger populations of patients with IBD is unknown, however we would not expect patients in other settings to have a differential risk for infusion-related reactions. Additionally, given the retrospective nature of our study, we were not able to assess the potential impact of IV iron on the bioavailability of biologic therapy. Future prospective studies may be considered to assess both these impacts and the potential for long-term differences in clinical response between each treatment group. Lastly, many of the patients received methylprednisolone, acetaminophen, or diphenhydramine before their biologic infusion per our standard protocol, which may have reduced our ability to assess for adverse reactions to iron infusions in particular. However, this represents a real-world evaluation and thus reflects real-world practice patterns with respect to iron and biologic infusions.
In our assessment, patients receiving IV iron immediately following a biologic infusion did not appear to be at an increased risk of adverse reactions when compared to those patients receiving an iron infusion on a different day. Administration of IV iron therapy on the same day as a biologic infusion can have many benefits in terms of time, cost and convenience to the patient and staff. Given these findings, we believe that the same-day infusion of biologic therapy followed by IV iron therapy may be a safe and cost-effective approach to the treatment of refractory iron deficiency anemia in patients with IBD, and these findings should be evaluated in external populations.
Acknowledgements:
i2b2 software was used in conducting this study. i2b2 is the flagship tool developed by the i2b2 (Informatics for Integrating Biology and the Bedside) Center, an NIH funded National Center for Biomedical Computing based at Partners HealthCare System. The i2b2 instance at the University of North Carolina is supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002489. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Funders and Grant Support:
This research was supported by the National Institutes of Health [K23DK127157-01 (ELB)].
Footnotes
Disclosure of Financial Arrangements and Conflicts of Interest:
Edward L. Barnes has served as a consultant for AbbVie, Gilead, Pfizer, and Target RWE. Hans H. Herfarth has served as a consultant for Alivio, AMAG, Finch, Gilead, Lycera, Merck, Otsuka, Pfizer, PureTech, Seres and research support from Pfizer and Artizan Biosciences. Sumana Reddy, Brandon Shore, and Lior Abramson have no relevant disclosures.
REFERENCES
- 1.Koutroubakis IE, Ramos-Rivers C, Regueiro M, et al. Five-Year Period Prevalence and Characteristics of Anemia in a Large US Inflammatory Bowel Disease Cohort. J Clin Gastroenterol. 2016;50(8):638–643. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Filmann N, Rey J, Schneeweiss S, et al. Prevalence of Anemia in Inflammatory Bowel Diseases in European Countries: A Systematic Review and Individual Patient Data Meta-analysis. Inflamm Bowel Dis. 2014;20(5):936–945. [DOI] [PubMed] [Google Scholar]
- 3.Wilson A, Reyes E, Ofman J. Prevalence and outcomes of anemia in inflammatory bowel disease: a systematic review of the literature. Am. J. Med 2004;116(7):44–49. [DOI] [PubMed] [Google Scholar]
- 4.Bonovas S, Fiorino G, Allocca M, et al. Intravenous Versus Oral Iron for the Treatment of Anemia in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Medicine (Baltimore). 2016;95(2):e2308. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Dignass AU, Gasche C, Bettenworth D, et al. European Consensus on the Diagnosis and Management of Iron Deficiency and Anaemia in Inflammatory Bowel Diseases. J Crohns Colitis. 2015;9(3):211–222. [DOI] [PubMed] [Google Scholar]
- 6.Akhuemonkhan E, Parian A, Carson KA, et al. Adverse Reactions After Intravenous Iron Infusion Among Inflammatory Bowel Disease Patients in the United States, 2010–2014. Inflamm Bowel Dis. 2018;24(8):1801–1807. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.DeLoughery TG. Safety of Oral and Intravenous Iron. Acta Haematol. 2019;142(1):8–12. [DOI] [PubMed] [Google Scholar]
- 8.Cortes X, Borrás-Blasco J, Molés JR, et al. Safety of Ferric Carboxymaltose Immediately after Infliximab Administration, in a Single Session, in Inflammatory Bowel Disease Patients with Iron Deficiency: A Pilot Study. PLoS ONE. 2015;10(5):e0128156. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Gold SL, Schneider Y, Cohen-Mekelburg S, Scherl E, Steinlauf A. Safety of Consecutive Vedolizumab and Iron Infusions: a Retrospective Cohort Study. Am J Gastroenterol. 113;S344. [Google Scholar]
- 10.Murphy SN, Weber G, Mendis M, et al. Serving the enterprise and beyond with informatics for integrating biology and the bedside (i2b2). J Am Med Inform Assoc. 2010;17(2):124–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Murphy SN, Wilcox A. Mission and Sustainability of Informatics for Integrating Biology and the Bedside (i2b2). eGEMs. 2014;2(2):7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.D’Haens G Risks and benefits of biologic therapy for inflammatory bowel diseases. Gut. 2007;56(5):725–732. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Checkley LA, Kristofek L, Kile S, Bolgar W. Incidence and Management of Infusion Reactions to Infliximab in an Alternate Care Setting. Dig Dis Sci. 2019;64(3):855–862. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Spencer EA, Kinnucan J, Wang J, Dubinsky MC. Real-World Experience With Acute Infusion Reactions to Ustekinumab at 2 Large Tertiary Care Centers. J Crohns Colitis. 2020;2(2):otaa022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Szymanska E, Dadalski M, Sieczkowska-Golub J, et al. Premedication Does Not Influence the Incidence of Infliximab Infusion Reactions in Pediatric Patients with Inflammatory Bowel Disease—A Single Center Case–Control Study. J Clin Med. 2021;10(14):3177. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Auerbach M, Chaudhry M, Goldman H, Ballard H. Value of methylprednisolone in prevention of the arthralgia-myalgia syndrome associated with the total dose infusion of iron dextran: A double blind randomized trial. J Lab Clin Med. 1998;131(3):257–260. [DOI] [PubMed] [Google Scholar]
- 17.Barton JC, Barton EH, Bertoli LF, Gothard CH, Sherrer JS. Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation. Am. J. Med 2000;109(1):27–32. [DOI] [PubMed] [Google Scholar]
- 18.Van Wassenaer EA, Meester VL, Kindermann A, et al. Premedication with intravenous steroids does not influence the incidence of infusion reactions following infliximab infusions in pediatric inflammatory bowel disease patients—a case-control study. Eur J Clin Pharmacol. 2019;75(10):1445–1450. [DOI] [PubMed] [Google Scholar]
- 19.Fumery M, Tilmant M, Yzet C, et al. Premedication as primary prophylaxis does not influence the risk of acute infliximab infusion reactions in immune-mediated inflammatory diseases: A systematic review and meta-analysis. Dig and Liver Dis. 2019;51(4):484–488. [DOI] [PubMed] [Google Scholar]