Evolution of treatment patterns and survival outcomes in patients with advanced non-small cell lung cancer treated at Frankfurt University Hospital in 2012-2018.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with advanced non-small cell lung cancer (NSCLC) versus chemotherapy in clinical trials. In Germany, ICIs have been used clinically since 2015 for patients with advanced/metastatic NSCLC without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) aberrations. As part of I-O Optimise, a multinational research program utilizing real-world data on thoracic malignancies, we describe real-world treatment patterns and survival following reimbursement of ICIs for advanced NSCLC in Germany. METHODS: This retrospective cohort study included patients with locally advanced/metastatic NSCLC without known EGFR/ALK aberrations who received a first line of therapy at Frankfurt University Hospital between January 2012 and December 2018, with follow-up to December 2019 or death, whichever occurred first. Using electronic medical records, treatment patterns and survival outcomes were described by histology (squamous cell [SQ]; non-squamous cell [NSQ]/other) and time period (pre- and post-ICI approval). RESULTS: Among eligible patients who started first-line treatment, 136 (pre-ICI) and 126 (post-ICI) had NSQ/other histology, and 32 (pre-ICI) and 38 (post-ICI) had SQ histology. Use of an ICI in the NSQ/other cohort increased from 5.9% (all second- or third-line) in the pre-ICI period to 57.1% (22.2% in first-line, including 13.5% as monotherapy and 8.7% combined with chemotherapy) in the post-ICI period. This was paralleled by a significant (P < 0.0001) prolongation of median (95% CI) OS from 9.4 (7.1-11.1) to 14.8 (12.7-20.5) months between the pre-ICI and post-ICI periods. A similar increase in the uptake of ICI was observed for the SQ cohort (from 3.1% pre-ICI [fourth-line] to 52.6% post-ICI [28.9% as first-line, including 15.8% as monotherapy and 13.2% combined with chemotherapy]); however, analysis of survival outcomes was limited by small group sizes. CONCLUSION: These real-world data complement clinical trial evidence on the effectiveness of ICIs in patients with advanced NSCLC and NSQ/other histology in Germany.

Trends in treatment patterns and survival outcomes in advanced non-small cell lung cancer: a Canadian population-based real-world analysis.

BACKGROUND: As part of the multi-country I-O Optimise research initiative, this population-based study evaluated real-world treatment patterns and overall survival (OS) in patients treated for advanced non-small cell lung cancer (NSCLC) before and after public reimbursement of immuno-oncology (I-O) therapies in Alberta province, Canada. METHODS: This study used data from the Oncology Outcomes (O2) database, which holds information for ~ 4.5 million residents of Alberta. Eligible patients were adults newly diagnosed with NSCLC between January 2010 and December 2017 and receiving first-line therapy for advanced NSCLC (stage IIIB or IV) either in January 2010-March 2016 (pre-I-O period) or April 2016-June 2019 (post-I-O period). Time periods were based on the first public reimbursement of I-O therapy in Alberta (April 2017), with a built-in 1-year lag time before this date to allow progression to second-line therapy, for which the I-O therapy was indicated. Kaplan-Meier methods were used to estimate OS. RESULTS: Of 2244 analyzed patients, 1501 (66.9%) and 743 (33.1%) received first-line treatment in the pre-I-O and post-I-O periods, respectively. Between the pre-I-O and post-I-O periods, proportions of patients receiving chemotherapy decreased, with parallel increases in proportions receiving I-O therapies in both the first-line (from < 0.5% to 17%) and second-line (from 8% to 47%) settings. Increased use of I-O therapies in the post-I-O period was observed in subgroups with non-squamous (first line, 15%; second line, 39%) and squamous (first line, 25%; second line, 65%) histology. First-line use of tyrosine kinase inhibitors also increased among patients with non-squamous histology (from 26% to 30%). In parallel with these evolving treatment patterns, median OS increased from 10.2 to 12.1 months for all patients (P < 0.001), from 11.8 to 13.7 months for patients with non-squamous histology (P = 0.022) and from 7.8 to 9.4 months for patients with squamous histology (P = 0.215). CONCLUSIONS: Following public reimbursement, there was a rapid and profound adoption of I-O therapies for advanced NSCLC in Alberta, Canada. In addition, OS outcomes were significantly improved for patients treated in the post-I-O versus pre-I-O periods. These data lend support to the emerging body of evidence for the potential real-world benefits of I-O therapies for treatment of patients with advanced NSCLC.

Treatment and outcomes for early non-small-cell lung cancer: a retrospective analysis of a Portuguese hospital database.

AIM: This observational study evaluated treatment patterns and survival for patients with stage I-IIIA non-small-cell lung cancer (NSCLC). MATERIALS & METHODS: Adults newly diagnosed with NSCLC in 2012-2016 at IPO-Porto hospital were included. Treatment data were available for patients diagnosed in 2015-2016. RESULTS: 495 patients were included (median age: 67 years). The most common treatments were surgery alone or with another therapy (stage I: 66%) and systemic anticancer therapy plus radiotherapy (stage II: 54%; stage IIIA: 59%). One-year OS (95% CI) for patients with stage I, II and IIIA NSCLC (diagnosed 2012-2016) were 92% (88-96), 71% (62-82) and 69% (63-75), respectively; one-year OS (95% CI) for treated patients with stage I-II or stage IIIA NSCLC (diagnosed 2015-2016) were 89% (81-97) and 86% (75-98) for non-squamous cell and 76% (60-95) and 49% (34-70) for squamous cell NSCLC. CONCLUSION: Treatment advances are strongly needed for stage I-IIIA NSCLC, especially for patients with squamous cell histology.

Real-world treatment patterns and survival outcomes for advanced non-small cell lung cancer in the pre-immunotherapy era in Portugal: a retrospective analysis from the I-O Optimise initiative.

BACKGROUND: As part of the multinational I-O Optimise research initiative, this retrospective cohort study of patients with advanced non-small cell lung cancer (NSCLC) evaluated real-world treatment patterns and survival prior to immunotherapy reimbursement in Portugal. METHODS: This study utilized a database held by IPO-Porto, Portugal's largest oncology hospital. Adult patients diagnosed with stage IIIB or IV NSCLC from January 2012 to December 2016 at IPO-Porto, with follow-up to June 2017, were included. Treatment analyses were performed from 2015 onwards. Kaplan-Meier methods were used for overall survival (OS). Factors associated with OS and systemic anti-cancer therapy (SACT) treatment were assessed using multivariate statistical models. RESULTS: Of 1524 patients diagnosed with NSCLC at IPO-Porto, 1008 patients had advanced disease (stage IIIB: 10.1%, 154/1524, stage IV: 56.0%, 854/1524). For those with advanced disease, median age was 65 years (range: 21-92) and 75.6% (762/1008) were male. Median OS (interquartile range [IQR]) was 11.4 (5.2-26.9) months for stage IIIB and 6.3 (2.4-15.0) months for stage IV. Factors associated with decreased risk of death included female sex and epidermal growth factor receptor gene (EGFR)/anaplastic lymphoma kinase gene (ALK) mutations/rearrangements; factors associated with increased risk of death included older age and stage IV disease. Among patients diagnosed in 2015 or 2016, 75.8% (297/392) received ≥1 line of SACT. Platinum-based chemotherapy was the most common first-line therapy (non-squamous cell carcinoma [NSQ]: 72.9%; squamous cell carcinoma [SQ] 87.3%, 55/63; patients with EGFR/ALK mutations/rearrangements primarily received tyrosine kinase inhibitors). The likelihood of receiving SACT was lower in older patients and those diagnosed with stage IV disease. Patients not receiving SACT had poor survival outcomes (median OS [IQR]: NSQ, 1.8 [1.1-3.1] months; SQ, 2.3 (1.3-3.4) months), while median OS (IQR) in SACT-treated patients was 12.6 (6.1-24.5) months for NSQ and 10.3 (5.7-15.9) months for SQ. CONCLUSIONS: This real-world data analysis from a large Portuguese oncology hospital demonstrates a high disease burden for advanced NSCLC in the pre-immunotherapy era, with nearly one-quarter of patients not receiving SACT. Even in patients receiving SACT, median survival was only about 1 year.

I-O Optimise: a novel multinational real-world research platform in thoracic malignancies.

Aim: To describe I-O Optimise, a multinational program providing real-world insights into lung cancer management. Materials & methods: Real-world data source selection for I-O Optimise followed a structured approach focused on population coverage, key variable capture, continuous/consistent data availability, record duration and data latency, and database expertise. Results: As of 31 October 2018, seven real-world data sources were included in I-O Optimise, providing data on characteristics, treatment patterns and clinical outcomes from more than 45,000 patients/year with non-small-cell lung cancer, small-cell lung cancer and mesothelioma across Denmark, Norway, Portugal, Spain, Sweden and the UK. Conclusion: The ongoing I-O Optimise initiative has the potential to provide a broad, robust and dynamic research platform to continually address numerous research objectives in the lung cancer arena.

Reasonable adjustments to provide equitable and inclusive assessment, screening and treatment of osteoporosis for adults with intellectual disabilities: A feasibility study.

BACKGROUND: People with intellectual disabilities are a high risk population for developing osteoporosis and fragility fractures, yet they experience barriers to accessing dual-energy x-ray absorptiometry (DXA) bone mineral density (BMD) screening and fracture assessment. Reasonable adjustments are a statutory requirement in the UK, but there is a paucity of evidence-based examples to assist their identification, implementation and evaluation. METHOD: Thirty adults with intellectual disabilities underwent DXA BMD screening and fracture risk assessment. Reasonable adjustments were identified and implemented. RESULTS: The presence of osteopenia or osteoporosis was detected in 23 out of 29 (79%) participants. Osteoporosis professionals report that 17 of 18 reasonable adjustments identified and implemented are both important and easy to implement. CONCLUSION: Adults across all levels of intellectual disabilities can complete DXA BMD screening with reasonable adjustments. Widely implementing these reasonable adjustments would contribute to reducing inequalities in health care for adults with intellectual disabilities.

The Scottish Early Rheumatoid Arthritis (SERA) Study: an inception cohort and biobank.

BACKGROUND: The Scottish Early Rheumatoid Arthritis (SERA) study is an inception cohort of rheumatoid (RA) and undifferentiated arthritis (UA) patients that aims to provide a contemporary description of phenotype and outcome and facilitate discovery of phenotypic and prognostic biomarkers METHODS: Demographic and clinical outcome data are collected from newly diagnosed RA/UA patients every 6 months from around Scotland. Health service utilization data is acquired from Information Services Division, NHS National Services Scotland. Plain radiographs of hands and feet are collected at baseline and 12 months. Additional samples of whole blood, plasma, serum and filtered urine are collected at baseline, 6 and 12 months RESULTS: Results are available for 1073 patients; at baseline, 76 % were classified as RA and 24 % as UA. Median time from onset to first review was 163 days (IQR97-323). Methotrexate was first-line DMARD for 75 % patients. Disease activity, functional ability and health-related quality of life improved significantly between baseline and 24 months, however the proportion in any employment fell (51 to 38 %, p = 0.0005). 24 % patients reported symptoms of anxiety and/or depression at baseline. 35/391 (9 %) patients exhibited rapid radiographic progression after 12 months. The SERA Biobank has accrued 60,612 samples CONCLUSIONS: In routine care, newly diagnosed RA/UA patients experience significant improvements in disease activity, functional ability and health-related quality of life but have high rates of psychiatric symptoms and declining employment rates. The co-existence of a multi-domain description of phenotype and a comprehensive biobank will facilitate multi-platform translational research to identify predictive markers of phenotype and prognosis.

Tumour necrosis factor inhibition versus rituximab for patients with rheumatoid arthritis who require biological treatment (ORBIT): an open-label, randomised controlled, non-inferiority, trial.

BACKGROUND: Tumour necrosis factor (TNF) inhibition and B-cell depletion are highly effective treatments for active rheumatoid arthritis, but so far no randomised controlled trials have directly compared their safety, efficacy, and cost-effectiveness. This study was done to test the hypothesis that using rituximab would be clinically non-inferior and cheaper compared with TNF inhibitor treatment in biological-treatment naive patients with rheumatoid arthritis. METHODS: This open-label, randomised controlled, non-inferiority trial enrolled patients with active, seropositive rheumatoid arthritis and an inadequate response to synthetic disease modifying anti-rheumatic drugs (DMARDs) from 35 rheumatology departments in the UK. Patients were randomly assigned 1:1 to the rituximab or TNF inhibitor groups with minimisation to account for methotrexate intolerance using a web-based randomisation system. Patients were given intravenous rituximab 1 g on days 1 and 15, and after 26 weeks if they responded to treatment but had persistent disease activity (28 joint count disease activity score [DAS28-ESR] >3.2; rituximab group) or a TNF inhibitor-adalimumab (40 mg subcutaneously every other week) or etanercept (50 mg per week subcutaneously) according to the patient's and rheumatologist's choice (TNF inhibitor group). Patients could switch treatment in the case of drug-related toxic effects or absence or loss of response. The primary outcome measure was the change in DAS28-ESR between 0 and 12 months in the per-protocol population of patients who were assigned to treatment and remained in follow-up to 1 year. We assessed safety in all patients who received at least one dose of study drug. We also assessed the cost-effectiveness of each strategy. The non-inferiority margin was specified as 0.6 DAS28-ESR units. This study is registered with ClinicalTrials.gov, number NCT01021735. FINDINGS: Between April 6, 2009, and Nov 11, 2013, 295 patients were randomly assigned and given either rituximab (n=144) or TNF inhibitor (n=151) treatment. After 12 months, the change in DAS28-ESR for patients assigned to rituximab was -2.6 (SD 1.4) and TNF inhibitor was -2.4 (SD 1.5), with a difference within the prespecified non-inferiority margin of -0.19 (95% CI -0.51 to 0.13; p=0.24). The health-related costs associated with the rituximab strategy were lower than the TNF inhibitor strategy (£9,405 vs £11,523 per patient, p<0.0001). 137 (95%) of 144 patients in the rituximab group and 143 (95%) of 151 patients in the TNF inhibitor group had adverse events. 37 serious adverse events occurred in patients receiving rituximab compared with 26 in patients receiving TNF inhibitors, of which 27 were deemed to be possibly, probably, or definitely related to the treatment (15 vs 12, p=0.5462). One patient in each group died during the study. INTERPRETATION: Initial treatment with rituximab is non-inferior to initial TNF inhibitor treatment in patients seropositive for rheumatoid arthritis and naive to treatment with biologicals, and is cost saving over 12 months. FUNDING: Arthritis Research UK, Roche.

Brief Report: Predicting Functional Disability: One-Year Results From the Scottish Early Rheumatoid Arthritis Inception Cohort.

OBJECTIVE: To identify baseline prognostic indicators of disability at 1 year within a contemporary early inflammatory arthritis inception cohort and then develop a clinically useful tool to support early patient education and decision-making. METHODS: The Scottish Early Rheumatoid Arthritis (SERA) inception cohort is a multicenter, prospective study of patients with newly presenting RA or undifferentiated arthritis. SERA data were analyzed to determine baseline predictors of disability (defined as a Health Assessment Questionnaire [HAQ] score of ≥1) at 1 year. Clinical and psychosocial baseline exposures were entered into a forward stepwise logistic regression model. The model was externally validated using newly accrued SERA data and subsequently converted into a prediction tool. RESULTS: Of the 578 participants (64.5% female), 36.7% (n = 212) reported functional disability at 1 year. Functional disability was independently predicted by baseline disability (odds ratio [OR] 2.67 [95% confidence interval (95% CI) 1.98, 3.59]), depression (OR 2.52 [95% CI 1.18, 5.37]), anxiety (OR 2.37 [95% CI 1.33, 4.21]), being in paid employment with absenteeism during the last week (OR 1.19 [95% CI 0.63, 2.23]), not being in paid employment (OR 2.36 [95% CI 1.38, 4.03]), and being overweight (OR 1.61 [95% CI 1.04, 2.50]). External validation (using 113 newly acquired patients) evidenced good discriminative performance with a C statistic of 0.74, and the calibration slope showed no evidence of model overfit (P = 0.31). CONCLUSION: In the context of modern early inflammatory arthritis treatment paradigms, predictors of disability at 1 year appear to be dominated by psychosocial rather than more traditional clinical measures. This indicates the potential benefit of early access to nonpharmacologic interventions targeting key psychosocial factors, such as mental health and work disability.

The ForeSee (4C) approach for integrative analysis in gene discovery.

The development of high-throughput experimental techniques has made measurements for virtually all kinds of cellular components possible. Effective integration and analysis of this diverged information to produce insightful knowledge is central to biological study today. In this chapter, we present a methodology for building integrative analytical workbenches using the workflow technology. We focus on the field of gene discovery through the combined study of transcriptomics, genomics and epigenomics, although the methodology is generally applicable to any omics-data analysis for biomarker discovery. We illustrate the application of the methodology by presenting our study on the identification of aberrant genomic regions, genes and/or their regulatory elements with their implications for breast cancer research. We also discuss the challenges and opportunities brought by the latest development of the next generation sequencing technology.

Solutions for complex, multi data type and multi tool analysis: principles and applications of using workflow and pipelining methods.

Analytical workflow technology, sometimes also called data pipelining, is the fundamental component that provides the scalable analytical middleware that can be used to enable the rapid building and deployment of an analytical application. Analytical workflows enable researchers, analysts and informaticians to integrate and access data and tools from structured and non-structured data sources so that analytics can bridge different silos of information; compose multiple analytical methods and data transformations without coding; rapidly develop applications and solutions by visually constructing analytical workflows that are easy to revise should the requirements change; access domain-specific extensions for specific projects or areas, for example, text extraction, visualisation, reporting, genetics, cheminformatics, bioinformatics and patient-based analytics; automatically deploy workflows directly into web portals and as web services to be part of a service-oriented architecture (SOA). By performing workflow building, using a middleware layer for data integration, it is a relatively simple exercise to visually design an analytical process for data analysis and then publish this as a service to a web browser. All this is encapsulated into what can be referred to as an 'Embedded Analytics' methodology which will be described here with examples covering different scientifically focused data analysis problems.

Addressing informatics challenges in Translational Research with workflow technology.

Interest in Translational Research has been growing rapidly in recent years. In this collision of different data, technologies and cultures lie tremendous opportunities for the advancement of science and business for organisations that are able to integrate, analyse and deliver this information effectively to users. Workflow-based integration and analysis systems are becoming recognised as a fast and flexible way to build applications that are tailored to scientific areas, yet are built on a common platform. Workflow systems are allowing organisations to meet the key informatics challenges in Translational Research and improve disease understanding and patient care.

Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study.

BACKGROUND: Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. AIM: To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP. METHODS: A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) > or =2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS. RESULTS: At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy. CONCLUSIONS: In this "true-to-life" study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies.

Closing the osteoporosis management gap in primary care: a secondary prevention of fracture programme.

BACKGROUND: Effective treatments are available to reduce fracture risk in patients with osteoporosis. Prioritisation of assessment and treatment for those patients at highest risk of fracture will and treatment for those patients at highest risk of fracture will will ensure the optimal utilisation of healthcare resources. OBJECTIVES: To confirm prior fracture to be a strong predictor of osteoporosis, evaluate a simple means of identifying patients with osteoporosis, assess the current management gap in this high risk patient group and to enable initiation of treatment where appropriate. RESEARCH DESIGN AND METHODS: All women >/=65 years of age living at home and registered with a general practitioner (GP) in Coatbridge, Lanarkshire, Scotland (4045) were mailed an osteoporosis questionnaire. Participants were from an area of generally low socioeconomic background, where 16% of the population are over >/=65 years and >/=99% are Caucasian. Those who had sustained a fracture or had >/=2 osteoporosis risk factors and had not previously been screened for osteoporosis were invited for a Dual energy X-ray Absorptiometry scan. A second group of women at high risk of osteoporosis were referred by their GP for a scan. Bone mineral density (BMD) was determined and treatment was reviewed and prescribed according to national guidelines. RESULTS: 2386/4045 women returned the questionnaire (response rate 59%); 2286 were correctly completed and made up the sample size. Eight hundred and fifty two had sustained >/=1 fracture(s), of whom 43 (5%) had previously had BMD testing and 80 (9.4%) were receiving treatment. There were 1434 women with no history of fracture that had >/=2 risk factors for osteoporosis. Of 395 women referred by their GP, 113 had sustained fractures. Following the audit, 1054 women were scanned, including 463 women who had not sustained fractures that had >/=2 osteoporosis risk factors. Of the 1054, 591 women had sustained 763 fractures: 46 (6.0%) hip, 284 (37.2%) wrist, 37 (4.8%) humerus and 396 (51.9%) other bones (mainly ankle or rib). Eighty (13.5%) women with a fracture history had normal BMD, 204 (34.5%) were osteopenic and 307 (51.9%) were osteoporotic. Older women were more likely to have osteoporosis: overall, 12.8%, 46.8% and 63.0% of women were osteoporotic in age groups <65 years, 65-75 years and >75 years, respectively. Treatment was prescribed according to Lanarkshire's osteoporosis guidelines for 670 (63.6%) patients: 90.0% received bisphosphonate + calcium/vitamin D and 10% received calcium/vitamin D. CONCLUSIONS: A simple scan identified patients with prior fracture and with osteoporosis. Prior fracture was confirmed to be a strong predictor of osteoporosis; 86.4% of women with a fracture history had low BMD and 51.9% had osteoporosis. Similar disease management programmes elsewhere in primary care to identify high risk patients and ensure appropriate prescribing would, in addition to implementing national guidelines, be pharmaco-economically prudent and improve management of patients with fragility fracture across the UK.

Ab initio modelling of the N-terminal domain of the secretin receptors.

G protein coupled receptors of the secretin family are activated by peptide hormones of about 30 residues in length. There is considerable sequence homology within both the hormone and receptor families. The receptors possess in addition to the integral membrane domain a characteristic extracellular domain of about 120 residues in length, having conserved cysteine residues, which are involved in disulphide bridge formation, and tryptophanes, which have been shown to be critical for hormone binding. This extracellular domain does not have detectable homology to any known protein fold. In order to be able to propose a structure for this domain we have used ab initio prediction methods combined with constraints based on experimental results for the disulphide connectivity. The results of computational tools for predicting secondary structure and accessibility, together with ligand binding and mutational data and other structural considerations were used in the ab initio protein folding programs DRAGON and GADGET and also the simpler program RAMBLE, which was able to explore different permutations of disulphide bond connectivity, tryptophan side chain orientation and chain topology. The methods generated a limited number of plausible models but no single unique solution was found under the constraints. One of these was refined into a full atomic model that contained a possible peptide binding site comprising the most conserved residues.

Erythroblast iron metabolism and serum soluble transferrin receptor values in the anemia of rheumatoid arthritis.

OBJECTIVES: We have investigated in vitro erythroblast iron metabolism in the anemia of rheumatoid arthritis (RA). We also have examined the results in relation to bone marrow iron status in an attempt to explain the reported difference between serum soluble transferrin receptor (sTfR) values in anemia of chronic disease (ACD) and iron deficiency anemia (IDA) in patients with RA. METHODS: Bone marrow was examined in 29 anemic patients with RA, 9 healthy volunteers, and 6 patients with simple IDA. High purity erythroblast fractions were prepared from these bone marrow samples. Erythroblast surface TfR expression and iron uptake was assessed in vitro using (125)I-transferrin (Tf) and (59)Fe-Tf, respectively. The efficiency of erythroblast surface TfR function for Tf-iron uptake was determined by relating total iron uptake at 4 hours to surface TfR number. Serum sTfR values were measured for the RA anemia group, which was subdivided as RA-ACD (marrow iron present) or RA-IDA (marrow iron absent) on the basis of visible reticuloendothelial (RE) marrow iron stores. RESULTS: High purity (87 +/- 5%) erythroblast fractions were obtained from 35 of the 44 marrow samples. Erythroblasts obtained from patients with simple IDA showed a significant increase in surface TfR expression (P = 0.0003) and Tf-iron uptake (P = 0.001). RA anemia also led to a significant increase in erythroblast Tf-iron uptake (P = 0.016). This increase was not associated with an increase in surface TfR expression (P = 0.5), but was seen to occur as a result of a significant increase in the efficiency of surface TfR for Tf-iron uptake (P = 0.027). Within the RA anemia group, the increase in erythroblast Tf- iron uptake at 4 hours was more evident for RA-IDA (3.96 +/- 1.73 versus 1.66 +/- 0.66; P = 0.03) than for RA-ACD (2.69 +/- 1.18 versus 1.66 +/- 0.66; P = 0.057). This additional erythroblast response to absent RE iron stores led to a highly significant difference in serum sTfR values between RA-IDA and RA-ACD (40.2 +/- 14.0 versus 23.9 +/- 5.3 nmoles/liter; P = 0.001) CONCLUSIONS: An increase in erythroblast surface TfR efficiency for Tf-iron uptake compensates for the low plasma iron levels associated with anemia in RA and helps to maintain RA erythroblast iron uptake. With adequate RE iron stores, this increased efficiency limits intracellular iron deprivation and consequently reduces the need to increase surface TfR expression. As a result, serum sTfR levels in RA-ACD remain within the normal range. RA erythroblasts, however, are still able to respond to any additional worsening of the iron supply caused by absent RE iron stores. This additional response causes the highly significant increase in serum sTfR values seen between RA-IDA and RA-ACD.