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Objective To evaluate the effect of antitumor necrosis factor-alpha monoclonal antibody infliximab treatment on anemia in patients with rheumatoid arthritis (RA). Methods Data from patients with RA who received infliximab or placebo in the multicenter, placebo-controlled, double-blind, randomized ATTRACT, ASPIRE, and START studies were included in this post-hoc, pooled analysis. Infliximab (3 to 10 mg/kg) was administered every 4 or 8 weeks, and all patients received stable doses of methotrexate (MTX). We determined the percentage of anemic patients (baseline hemoglobin level <12 g/dL) who had an increase from baseline in hemoglobin level greater than or equal to 1 or 2 g/dL or achieved normal hemoglobin level at week 22. The association of improvement in anemia with improvement in clinical parameters was also evaluated. Results Among patients with anemia at baseline, infliximab plus MTX treatment produced a significantly greater mean (standard deviation) increase in hemoglobin level from baseline to week 22 (0.74 [1.12], P < 0.0001) than placebo plus MTX (0.30 [0.92]). Significantly (P < 0.001) greater proportions of anemic patients treated with infliximab plus MTX had either at least a 1 g/dL (40%) or at least a 2 g/dL (12%) increase in hemoglobin level from baseline to week 22 or achieved normal hemoglobin level (43%) when compared with placebo plus MTX (19, 5, and 28%, respectively). Greater improvement in hemoglobin level among infliximab plus MTX-treated patients was consistently observed across subgroups and in patients without clinical response (American College of Rheumatology 20% response criteria) at week 22. Multiple regression analysis indicated that the effect of infliximab plus MTX on anemia was independent of improvement in disease activity. Conclusion Treatment with infliximab plus MTX significantly improved hemoglobin level among anemic RA patients when compared with treatment with placebo plus MTX, even after adjusting for improvement in disease activity. © 2008 Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis (RA). METHODS: MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1). RESULTS: An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P = 0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P = 0.049) and between group 3 (40.5%; P = 0.038) but not group 4 (36.5%; P = 0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound -5.2%; predefined delta value for noninferiority -10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively. CONCLUSION: Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns. [ABSTRACT FROM AUTHOR]

Background: Tumour necrosis factor alpha (TNFalpha) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFalpha inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors.Methods: 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimumab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov, number NCT00299546.Findings: Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14.0 (IQR 9.0-22.0) swollen and 26.0 (16.0-41.0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2.5 [95% CI 1.5-4.2], p=0.0006), and 58 (38%) patients on 100 mg golimumab (2.8 [1.6-4.7], p=0.0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1-16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1-24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab.Interpretation: Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors.Funding: Centocor Research and Development and Schering-Plough Research Institute. [ABSTRACT FROM AUTHOR]

The Project Optimus initiative from the FDA introduced a new dose optimization and selection paradigm in oncology drug development. The FDA has outlined approaches to dose optimization for single agents, but multiple oncology drugs are being developed for use in combination with other therapies. Dose optimization in the context of combination drug development is complex and requires a case-by-case approach. It necessitates commitment to the totality of available evidence, leveraging all relevant data on mechanism of action, nonclinical and clinical pharmacology, safety, and principles of model-informed drug development. In this article, we outline key considerations for sponsors and investigators pursuing dose optimization with combinatorial regimens. We illustrate important strategies for dose optimization in the combination setting using a range of hypothetical case examples that represent typical drug development scenarios. Close discussions and collaboration with regulators regarding the optimal approaches to these scenarios will continue to be critical., (©2024 American Association for Cancer Research.)

Background: Hereditary angioedema is associated with dysregulation of the kallikrein-kinin system. Factor XII (FXII) is a key initiator of the kallikrein-kinin system, which produces bradykinin, a central mediator of angioedema. Garadacimab (CSL Behring) is a first-in-class, fully human, immunoglobulin G4 monoclonal antibody targeting activated FXII, intended to prevent attacks in patients with C1-esterase inhibitor-deficient hereditary angioedema (HAE-C1-INH). We aimed to investigate garadacimab as a treatment every 4 weeks for patients with HAE-C1-INH., Methods: In this double-blind, placebo-controlled, phase 2 study, patients with HAE-C1-INH were recruited from 12 research centres in Canada, Germany, Israel, and the USA. Eligible patients were aged 18-65 years and must have had at least four attacks of any severity over a consecutive 2-month period during the 3 months before screening or initiation of previous hereditary angioedema prophylaxis. After a run-in period of 4-8 weeks, patients were randomly assigned (1:1:1:1), using an interactive response technology via block randomisation (block sizes of 1-4), to either placebo or 75 mg, 200 mg, or 600 mg garadacimab. Patients were given an initial intravenous loading dose, and then, on day 6 and every 4 weeks for 12 weeks, they were given a subcutaneous dose of their allocated treatment. The primary endpoint was the number of monthly attacks in the intention-to-treat population (defined as all patients who underwent screening, provided consent, and were assigned to treatment) during the 12-week subcutaneous administration period assessed in the 200 mg and 600 mg garadacimab groups versus placebo. Safety was assessed in all patients who received at least one dose or partial dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03712228., Findings: Between Oct 29, 2018, and Aug 28, 2019, 54 patients were screened, of whom 32 were randomly assigned to either placebo (n=8) or 75 mg (n=9), 200 mg (n=8), or 600 mg (n=7) garadacimab. The median age was 39·5 years (28·0-52·5) and 18 (56%) of 32 patients were female and 14 (34%) were male. The median number of monthly attacks during the 12-week subcutaneous treatment period was 4·6 (IQR 3·1-5·0) with placebo, 0·0 (0·0-0·4) with 75 mg garadacimab, 0·0 (0·0-0·0) with 200 mg garadacimab, and 0·3 (0·0-0·7) with 600 mg garadacimab. Compared with placebo, the rate of attacks was significantly reduced with garadacimab at 200 mg (reduced by 100% [95% CI 98-101]; p=0·0002) and 600 mg (reduced by 93% [54-110]; p=0·0003). No serious adverse events, deaths, or adverse events of special interest (anaphylaxis, thromboembolic events, and bleeding events) were observed., Interpretation: Garadacimab 200 mg and 600 mg every 4 weeks significantly reduced the number of monthly attacks versus placebo and was well tolerated during the study. Garadacimab is an efficacious, subcutaneous prophylaxis in patients with HAE-C1-INH and warrants phase 3 evaluation., Funding: CSL Behring., Competing Interests: Declaration of interests TC is a speaker for Pharming, CSL Behring, Takeda, Fresenius Kabi, and Grifols; has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, Spark, BioMarin, Fresenius Kabi, and Grifols; and is on the medical advisory board for the US Hereditary Angioedema Association, the Board of Directors for the Mid-Atlantic American Lung Association, and the Board of Directors for the American Academy of Allergy, Asthma and Immunology. EA-P has received honoraria as a speaker or advisor from Adverum Biotechnologies, BioCryst, BioMarin, Centogene, CSL Behring, KalVista, Pharming, Pharvaris, and Shire/Takeda; and has received grants or clinical trial investigator support from BioCryst, CSL Behring, KalVista, Pharvaris, and Shire/Takeda. PB has consulted for CSL Behring, Takeda, Pharming, Pearl Therapeutics, BioCryst, CVS Health, Novartis, AstraZeneca and GlaxoSmithKline; and has received clinical trial support from CSL Behring, Takeda, BioCryst, and Novartis. MKD and DP are former full-time employees of CSL Behring and own stocks in CSL Behring. HF, IJ, and IP are full-time employees of CSL Behring and own stocks in CSL Behring. JSJ is a speaker for Takeda/Shire, CSL Behring, Teva, AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Regeneron; and has received research funding or consultancy fees from CSL Behring, Takeda/Shire, BioCryst, Novartis, Genentech, AstraZeneca, Allakos, Fresenius Kabi, GlaxoSmithKline, and Regeneron. PKK is or recently was a speaker or an advisor for ALK Pharma, AstraZeneca, CSL Behring, GlaxoSmithKline, Kaleo, Merck, Mylan, Novartis, Pediapharm/Medexus, Sanofi and Takeda/Shire; and has received research funding from CSL Behring, Green Cross, and Takeda/Shire. DSL is a speaker, researcher, and consultant for CSL Behring, Takeda, Pharming, BioCryst, and Grifols. WRL is a speaker for CSL Behring, Pharming, AstraZeneca, Sanofi/Regeneron, GlaxoSmithKline, and Shire/Takeda; has served as a consultant for BioCryst, BioMarin, CSL Behring, Fresenius Kabi, Intellia, KalVista, Pharming, Pharvarius, and Shire/Takeda; is a board member of the US Hereditary Angioedema Association Medical Advisory Board; and has received grants or research support from ALK, BioCryst, CSL Behring, Ionis, Gossamer, KalVista, Kedrion, Therapure, and Takeda/Shire. MM has received financial support from CSL Behring for acting as a study centre investigator during the conduct of the study, and personal fees from CSL Behring, Shire/Takeda, Pharming, BioCryst, Novartis, Octapharma, and KalVista. IM-S has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire. IM-S served as a consultant for BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire; and participated in advisory boards for BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire. AR is a speaker, researcher, and advisor for CSL Behring, Takeda/Shire, BioCryst, Pharming, and Shulov Innovative Science. BR has been a speaker and advisory board member for CSL Behring and Takeda and has not received personal reimbursement for these activities; has participated in multiple clinical trials involving investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, and Pharming and he does not hold patents or investments with these companies or involving this product; and he serves as a volunteer medical scientific advisor to the patient organisation Hereditary Angioedema Canada. WHY has received fees for consulting services from CSL Behring, Takeda/Shire, Novartis, Sanofi Genzyme, and Merck, and research grants from CSL Behring, Takeda/Shire, BioCryst, Pharming, AstraZeneca, Novartis, Sanofi Genzyme, Regeneron, Galderma, AnaptysBio, Glenmark, ALK Pharma, and Dermira., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry., (Copyright © 2020. Published by Elsevier Inc.)

The need for providers and patients to exchange and share imaging has never been more apparent, yet many organizations are only now, as a part of a larger enterprise imaging initiative, taking steps to streamline an important process that has historically been facilitated with the use of CDs or insecure methods of communication. This paper will provide an introduction to concepts and common-use cases for image exchange, outline challenges that have hindered adoption to date, and describe standards for image exchange that show increasing promise of being adopted by vendors and providers.

Objective: Evaluate golimumab in patients with active rheumatoid arthritis (RA) and previous tumour necrosis factor-α (TNF) inhibitor use., Methods: Patients (n=461) previously receiving ≥1 TNF inhibitor were randomised to subcutaneous injections of placebo, golimumab 50 mg or golimumab 100 mg q4 weeks. Primary endpoint (≥20% improvement in American College of Rheumatology (ACR20) criteria at week 14) findings have been reported for all patients in the trial. Reported herein are further assessments of efficacy/safety among patients receiving golimumab+methotrexate (MTX)., Results: Among efficacy-evaluable patients who received MTX at baseline, more receiving golimumab+MTX (n=201) than placebo+MTX (n=103) achieved ACR20 (40.8% vs 14.6%), ACR50 (20.9% vs 3.9%), and ACR70 (11.4% vs 2.9%) responses at week 24. Among the 137 patients who had received only one prior TNF inhibitor (adalimumab, n=33; etanercept, n=47; and infliximab, n=57), week 24 ACR20 rates were 30.3%, 46.8% and 50.9%, respectively, and thus lowest among those who previously used adalimumab. ACR20 response rates were 44.5% (61/137), 36.2% (17/47) and 23.5% (4/17) among patients who had received one, two or three TNF inhibitors, respectively. Adverse event (AE) rates were comparable across type/number of prior anti-TNF agents, but appeared somewhat higher among patients who discontinued previous TNF inhibitor(s) due to intolerance (37/49, 75.5%) versus lack of efficacy (LOE, 113/191, 59.2%)., Conclusions: Patients with active RA previously treated with ≥1 TNF inhibitor had clinically relevant improvement with golimumab+MTX, which appeared somewhat enhanced among those who received only etanercept or infliximab as their prior TNF inhibitor. Golimumab+MTX safety appeared similar across patients, regardless of TNF inhibitor(s) previously used, with fewer AEs occurring among patients who discontinued prior therapy for LOE., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents., Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients., Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change -0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change -0.13). No unexpected adverse events were observed through week 60., Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients.

Systemic sclerosis (SSc) is a disease of unknown causative factor that manifests as a heterogenous group of multiorgan system manifestations and is characterized by vasculopathy and fibrosis of the skin and internal organs, with mortality related to pulmonary, cardiac, renal or gastrointestinal involvement. The prevalence of SSc may be underestimated in the general population. Cases are often undiagnosed or misdiagnosed, particularly cases with mild or no skin manifestations. Because of late referrals to rheumatologic care, many moderate-to-severe cases progress to irreversible end-organ damage that might have been prevented by early diagnosis. Early diagnosis of SSc with initiation of appropriate treatment is essential, with great impact on morbidity and mortality. This review examines presenting features, ensuing complications and treatment providing a focus on SSc as a treatable disease. Primary care providers play a pivotal role in recognizing initial symptoms associated with SSc and securing early diagnosis through early referral to specialists.

Objective: To assess 2-year golimumab efficacy/safety in patients with active rheumatoid arthritis (RA) who had never taken methotrexate (MTX)., Methods: RA patients who had never taken MTX (n = 637) were randomized (1:1:1:1) to placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4) every 4 weeks. Nonresponders based on week 28 swollen/tender joint counts changed treatment as follows: group 1 added golimumab 50 mg, group 2 added MTX, group 3 increased golimumab to 100 mg, and group 4 had no change. Most group 1 patients (85%) initiated golimumab 50 mg + MTX at week 28 or subsequently at week 52. After the last patient completed week 52 and blinding was broken, the investigator could escalate golimumab to 100 mg and/or adjust MTX. The co–primary end points (week 24 American College of Rheumatology criteria for 50% improvement [ACR50] response and week 52 change in Sharp/van der Heijde score [SHS]) have been published previously. We now detail week 52 major secondary end points (Health Assessment Questionnaire [HAQ] disability index [DI] scores and SHS among patients with a baseline C-reactive protein [CRP] level >1.0 mg/dl) and week 104 findings., Results: At week 52 for combined groups 3 and 4 versus group 1, the respective proportions of patients achieving ACR20 and ACR50 responses were 63.2% versus 51.9% (P = 0.017) and 45.3% versus 35.6% (P = 0.044). Respective week 52 mean HAQ DI improvements were 0.70 versus 0.58 (P = 0.053); mean SHS changes were 0.41 versus 1.37 (P = 0.006) among all patients and 0.74 versus 2.16 (P = 0.003) in patients with a CRP level >1.0 mg/dl. Improvements were maintained through week 104. Golimumab + MTX for 2 years yielded statistically less radiographic progression than initial MTX or golimumab 100 mg monotherapy. Golimumab safety profiles through weeks 24, 52, and 104 were generally consistent with those observed in other golimumab studies., Conclusion: In RA patients who had never taken MTX, up to 2 years of golimumab + MTX yielded sustained improvements in clinical signs/symptoms, physical function, and radiographic progression.

Objective: To evaluate the effect of golimumab on haemoglobin levels in patients with RA, PsA or AS., Methods: Secondary analysis was performed on integrated data from five randomized controlled studies: three RA, one PsA and one AS (2303 patients total). Golimumab 50 or 100 mg was injected s.c. every 4 weeks with or without MTX. Control groups received placebo injections plus MTX or background therapy. Patients with haemoglobin levels below the age- and sex-specific normal ranges were considered to have anaemia. Ferritin levels were used to distinguish anaemia of mixed aetiology (≥ 15 and <60 ng/ml) and anaemia of inflammation (≥ 60 ng/ml). Changes from baseline to weeks 14 and 24 in haemoglobin level were compared between treatment groups using an analysis of variance on the van der Waerden normal scores., Results: At baseline, 21% of RA patients, 9% of PsA patients and 15% of AS patients had anaemia. Of these, 24%, 57% and 25%, respectively, had anaemia of inflammation. The median increase from baseline to week 14 in the haemoglobin level of anaemic patients was 0.3 g/dl in the control group and 0.9 g/dl in the golimumab group (P < 0.001). Haemoglobin levels improved within the subgroups of patients with anaemia of mixed aetiology (control, 0.4 g/dl vs golimumab, 0.7 g/dl) (P = 0.305) and with anaemia of inflammation (0.2 vs 1.4 g/dl, respectively) (P < 0.001)., Conclusion: Compared with the control group, patients receiving golimumab treatment had significantly improved haemoglobin levels, particularly among patients with anaemia of inflammation.

Background: Many patients with psoriasis develop psoriatic arthritis, a chronic inflammatory disease that afflicts peripheral synovial, axial, and entheseal structures. The fully human monoclonal antibody ustekinumab is an efficacious treatment for moderate-to-severe plaque psoriasis. We did a randomised, placebo-controlled, phase 3 trial to assess the safety and efficacy of ustekinumab in patients with active psoriatic arthritis., Methods: In this phase 3, multicentre, double-blind, placebo-controlled trial at 104 sites in Europe, North America, and Asia-Pacific, adults with active psoriatic arthritis (≥5 tender and ≥5 swollen joints, C-reactive protein ≥3·0 mg/L) were randomly assigned (1:1:1, by dynamic central randomisation based on an algorithm implemented by an interactive voice-web response system) to 45 mg ustekinumab, 90 mg ustekinumab, or placebo at week 0, week 4, and every 12 weeks thereafter. At week 16, patients with less than 5% improvement in both tender and swollen joint counts entered masked early-escape and were given 45 mg ustekinumab (if in the placebo group) or 90 mg ustekinumab (if in the 45 mg group). At week 24, all remaining patients in the placebo group received ustekinumab 45 mg, which they continued at week 28 and every 12 weeks thereafter. Our primary endpoint was 20% or greater improvement in American College of Rheumatology (ACR20) criteria at week 24. This trial is registered with ClinicalTrials.gov (NCT01009086) and EudraCT (2009-012264-14)., Findings: Between Nov 30, 2009, and March 30, 2011, 615 patients were randomly assigned-206 to placebo, 205 to 45 mg ustekinumab, and 204 to 90 mg ustekinumab. More ustekinumab-treated (87 of 205 [42·4%] in the 45 mg group and 101 of 204 [49·5%] in the 90 mg group) than placebo-treated (47 of 206 [22·8%]) patients achieved ACR20 at week 24 (p<0·0001 for both comparisons); responses were maintained at week 52. At week 16, proportions of patients with adverse events were similar in the ustekinumab and placebo groups (171 of 409 [41·8%] vs 86 of 205 [42·0%])., Interpretation: Ustekinumab significantly improved active psoriatic arthritis compared with placebo, and might offer an alternative therapeutic mechanism of action to approved biological treatments., Funding: Janssen Research & Development., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To evaluate the effects of the anti-TNF-α monoclonal antibody golimumab, administered by s.c. injection or i.v. infusion, on markers of inflammation in patients with RA., Methods: In this phase 1, open-label study, patients with active RA were randomized to receive s.c. golimumab 100 mg at baseline and every 4 weeks through week 20 (n = 33; group 1) or i.v. golimumab 2 mg/kg at baseline and week 12 (n = 16; group 2). Serum levels of CRP, IL-6, serum amyloid A (SAA), TNF receptor II (TNFRII), MMP-3, hyaluronic acid, haptoglobin, ferritin and haemoglobin and serum/urine hepcidin were measured at various time points. Associations between the biomarkers were assessed with Spearman's correlations., Results: In both groups 1 and 2, decreases in mean serum levels of CRP, IL-6, SAA, TNFRII, MMP-3, haptoglobin, ferritin and hepcidin, and mean urine levels of hepcidin occurred within 1 week and were sustained through week 8. Decreases in concentrations of serum CRP, IL-6, SAA, MMP-3, hepcidin, ferritin and haptoglobin and urine hepcidin were maintained through week 24 in group 1, but began to reverse after week 8 in group 2. Among all patients, decreases in serum hepcidin correlated significantly with decreases in serum CRP and ferritin., Conclusion: Decreases in serum and urine concentrations of markers of inflammation occurred as early as 24 h after treatment with golimumab, and most of these improvements were sustained through week 24 in group 1.

Objective: Reactivation of Mycobacterium tuberculosis infection is a major complication in patients treated with anti-tumor necrosis factor (anti-TNF) agents. We report on the 5 cases of active tuberculosis (TB) that developed in the Golimumab Phase III Program (3 with rheumatoid arthritis, 1 with psoriatic arthritis, and 1 with ankylosing spondylitis) through 1 year among 2,210 patients receiving golimumab., Methods: Data from global studies were used for an in-depth evaluation of the 5 cases of TB through week 52. Integrated safety data were evaluated for potential hepatotoxicity in patients treated with anti-TB therapy., Results: No active TB developed among 317 patients receiving golimumab and treated for latent TB with isoniazid. Active TB occurred in 5 patients not treated with isoniazid by week 52 (in 2 patients by week 24); all of the patients had negative TB screening tests (per the local guidelines) and resided in countries with high background rates of TB. No deaths were due to TB. Across all of the groups (placebo and golimumab), alanine aminotransferase and aspartate aminotransferase elevations occurred in greater proportions of patients treated for latent TB infection versus not treated; elevations were largely mild (<3 times the upper limit of normal)., Conclusion: Comprehensive TB screening kept the number of active TB cases relatively low despite conducting the studies in TB-endemic regions. Treatment for latent TB infection appeared effective, since no patients treated for latent TB had TB reactivation. Concurrent treatment with golimumab and anti-TB medication was generally well tolerated. Clinicians should remain vigilant for development of active TB after initiation of TNF inhibitors, since prompt diagnosis and treatment can improve outcomes., (Copyright © 2013 by the American College of Rheumatology.)

Objective: The aim of this study was to assess long-term golimumab therapy in patients with rheumatoid arthritis (RA) who discontinued previous tumour necrosis factor alpha (TNFα) inhibitor(s) for any reason., Methods: Results through week 24 of this multicentre, randomised, double-blind, placebo-controlled study of active RA (≥4 tender, ≥4 swollen joints) were previously reported. Patients received placebo (Group 1), 50 mg golimumab (Group 2) or 100 mg golimumab (Group 3) subcutaneous injections every 4 weeks. Patients from Groups 1 and 2 with <20% improvement in tender/swollen joints at week 16 early escaped to golimumab 50 mg and 100 mg, respectively. At week 24, Group 1 patients crossed over to golimumab 50 mg, Group 2 continued golimumab 50/100 mg per escape status and Group 3 maintained dosing. Data through week 160 are reported., Results: 459 of the 461 randomised patients were treated; 236/459 (51%) continued treatment through week 160. From week 24 to week 100, ACR20 (≥20% improvement in American College of Rheumatology criteria) response and ≥0.25 unit HAQ (Health Assessment Questionnaire) improvement were sustained in 70-73% and 75-81% of responding patients, respectively. Overall at week 160, 63%, 67% and 57% of patients achieved ACR20 response and 59%, 65% and 64% had HAQ improvement ≥0.25 unit in Groups 1, 2 and 3, respectively. Adjusted for follow-up duration, adverse event incidences (95% CI) per 100 patient-years among patients treated with golimumab 50 mg and 100 mg were 4.70 (2.63 to 7.75) and 8.07 (6.02 to 10.58) for serious infection, 0.95 (0.20 to 2.77) and 2.04 (1.09 to 3.49) for malignancy and 0.00 (0.00 to 0.94) and 0.62 (0.17 to 1.59) for death, respectively., Conclusion: In patients with active RA who discontinued previous TNF-antagonist treatment, golimumab 50 and 100 mg injections every 4 weeks yielded sustained improvements in signs/symptoms and physical function in ∼57-67% of patients who continued treatment. Golimumab safety was consistent with other anti-TNF agents, although definitive conclusions regarding long-term safety require further monitoring.

Objective: To evaluate the performance of an interferon-γ release assay (IGRA) versus the standard tuberculin skin test (TST) as a screening tool for latent tuberculosis (TB) infection prior to the initiation of anti-tumor necrosis factor therapy in patients with autoimmune inflammatory diseases., Methods: This integrated analysis involved screening of patients with rheumatoid arthritis, those with psoriatic arthritis, and those with ankylosing spondylitis from phase III trials of golimumab. The IGRA used to screen for latent TB was the QuantiFERON-TB Gold In-Tube test., Results: In this pooled analysis, 2,282 patients underwent both IGRA and TST screening prior to golimumab treatment. Among these patients, 13.8% had at least one test yielding positive findings for latent TB, including 9.4% with positive results by TST, 7.0% with positive results by IGRA, and 2.6% with positive results on both tests. The rate of indeterminate results for TB on IGRA was 1.8%. Agreement between the TST and IGRA results, measured by the kappa coefficient, was 0.22 (95% confidence interval 0.157-0.279; P=0.021). Among the patients with positive IGRA findings, 36.9% had positive TST findings. Among the patients with positive TST findings, 27.4% had positive IGRA findings. Overall, 781 (34.2%) of the 2,282 patients had previously received the bacillus Calmette-Guérin (BCG) vaccine; among this vaccinated group, the rate of positivity for latent TB by TST was 15.2% (119 of 781), compared to a rate of positivity of 9.1% (71 of 781) by IGRA (P=0.0002). Among patients who had not received the BCG vaccine, the rate of positivity by TST was 5.0% (62 of 1,248) and the rate of positivity by IGRA was 5.8% (72 of 1,248) (P=0.3745). When the IGRA was repeated in patients whose results were initially indeterminate, the rate of indeterminate IGRA findings for latent TB was much lower than has been previously reported., Conclusion: In the absence of a true gold standard test for latent TB infection, results of this comparison of IGRA and TST in a large cohort of patients with rheumatic diseases suggest that the IGRA provides greater specificity and possibly greater sensitivity than the TST., (Copyright © 2012 by the American College of Rheumatology.)

Background: The pharmacokinetics of golimumab, a human monoclonal antibody that inhibits the activity of tumor necrosis factor α, after a single subcutaneous (SC) or intravenous (IV) administration have been previously studied., Objectives: The purpose of this study was to assess the pharmacokinetics of golimumab after multiple SC or IV administrations in patients with active rheumatoid arthritis (RA). The effect of concomitant methotrexate (MTX) use on golimumab pharmacokinetics was evaluated., Methods: In this open-label, randomized, Phase I study, 49 adult patients with RA received SC golimumab 100 mg (n = 33) every 4 weeks through week 20 or IV golimumab 2 mg/kg (n = 16) at weeks 0 and 12. Serial blood samples were collected, and serum golimumab concentration was measured with an electrochemiluminescent immunoassay. Golimumab pharmacokinetic parameters were derived with the use of a noncompartmental analysis. Adverse events were monitored at every visit., Results: The population was predominantly Caucasian (84%) and female (76%), and the median age was 57 years. After SC golimumab administration, the serum golimumab concentration achieved steady state by ∼12 weeks with mean trough serum concentrations ranging from 1.15 to 1.24 μg/mL. After the final 30-minute IV infusion of golimumab 2 mg/kg, the mean (SD) clearance (CL) was 7.5 (2.6) mL/d/kg. The mean terminal half-life after SC and IV administrations was ∼13 days. The mean absolute bioavailability for SC golimumab was estimated to be 53%. The geometric mean of golimumab CL/F in patients with and without concomitant MTX use was 13.9 and 21.2 mL/d/kg, respectively, and the geometric mean ratio of CL/F was 65.5% (90% CI: 45.2%-94.9%, P = 0.06). Golimumab was generally well tolerated. No malignancies or deaths occurred during the study., Conclusions: Pharmacokinetics of golimumab were consistent after SC or IV administration in this population of patients with RA. Golimumab was well tolerated and no unexpected adverse events were observed in this trial., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Objective: To evaluate changes in baseline patient characteristics and entry criteria of randomised, controlled studies of tumour necrosis factor alpha (TNFα) inhibitors in rheumatoid arthritis (RA) patients., Methods: A systematic literature review was performed using predefined inclusion criteria to identify randomised, double-blind, controlled trials that evaluated TNFα inhibitors in adult RA patients. Entry criteria and baseline clinical characteristics were evaluated over time for methotrexate-experienced and methotrexate-naive study populations. Enrolment start date for each trial was the time metric. The anchor time was the study with the earliest identifiable enrolment start date., Results: 44 primary publications (reporting the primary study endpoint) from 1993 to 2008 met the inclusion criteria. Enrolment start dates of August 1993 and May 1997 were identified as time anchors for the 37 methotrexate-experienced studies and the seven methotrexate-naive studies, respectively. In methotrexate-experienced trials, no significant change was observed over the years included in this study in any inclusion criteria (including swollen joint counts and C-reactive protein (CRP)), but a significant decrease over time was observed in the baseline swollen joint count, CRP and total Sharp or van der Heijde modified Sharp score, but not in baseline tender joint counts. In the methotrexate-naive studies, significant decreases over the years were observed in swollen joint and tender joint inclusion criteria, but not in baseline tender joint count, baseline CRP, CRP inclusion criteria or baseline total Sharp or van der Heijde modified Sharp score., Conclusion: Inclusion criteria and baseline characteristics of RA patients enrolled in studies of TNFα inhibitors have changed, with more recent trials enrolling cohorts with lower disease activity, especially in methotrexate-experienced trials.

Objectives: Ischaemic digital ulcers (DUs) are common in patients with systemic sclerosis (SSc) and are a cause of disease-related morbidity. In an earlier trial, treatment with bosentan, an oral endothelin receptor antagonist, reduced the occurrence of new DUs by 48%. The present study (RAPIDS-2, for 'RAndomized, double-blind, Placebo-controlled study with bosentan on healing and prevention of Ischemic Digital ulcers in patients with systemic Sclerosis') was conducted to more fully evaluate the effects of bosentan treatment on DUs associated with SSc., Methods: This double-blind, placebo-controlled trial conducted at 41 centres in Europe and North America randomised 188 patients with SSc with at least 1 active DU ('cardinal ulcer') to bosentan 62.5 mg twice daily for 4 weeks and 125 mg twice daily thereafter for 20 weeks (n=98) or matching placebo (n=90; total 24 weeks). The two primary end points were the number of new DUs and the time to healing of the cardinal ulcer. Secondary end points included pain, disability and safety., Results: Over 24 weeks, bosentan treatment was associated with a 30% reduction in the number of new DUs compared with placebo (mean ± standard error: 1.9±0.2 vs 2.7±0.3 new ulcers; p=0.04). This effect was greater in patients who entered the trial with more DUs. There was no difference between treatments in healing rate of the cardinal ulcer or secondary end points of pain and disability. Peripheral oedema and elevated aminotransferases were associated with bosentan treatment., Conclusions: Bosentan treatment reduced the occurrence of new DUs in patients with SSc but had no effect on DU healing. Bosentan was well tolerated and may be a useful adjunct in the management of patients with SSc with recurrent DUs.

Objective: Studies suggest that serum uric acid (SUA) is significantly associated with cardiovascular disease (CVD) mortality among women and blacks. CVD rates are higher among patients with rheumatoid arthritis (RA) than the normal population. The objective of this study was to determine if there was an association between SUA levels and self-reported RA in a multiethnic female population in the United States., Methods: This cross-sectional study was conducted using data for 7374 women above 20 years of age in the Third National Health and Nutrition Examination Survey. Multiple and logistic regression methods were used to determine an association between SUA levels and self-reported RA., Results: Women self-reporting RA had significantly higher SUA levels (p < 0.0001) compared to women not self-reporting RA, also when adjusted for age and race (p < 0.0001). In a regression analysis, significant predictors of SUA levels were: self-reporting RA, race/ethnicity, being married, smoking, use of alcohol, high body mass index, high C-Reactive protein, elevated diastolic or systolic blood pressure, and increased glomerular filtration rate. Education and age were removed from the model. The model explained 24.0% of the variability seen in SUA levels (F = 208.62, p < 0.0001) in this multiethnic female population. When the analyses were repeated stratified by race, self-reporting RA was retained in the model as associated with SUA in white and Mexican American, but not in black women., Conclusion: Despite the limitations imposed by self-reporting of RA on self-administered questionnaires and in-person interviews, practitioners should be aware that women self-reporting RA are at risk of having high SUA levels as well as more traditional CVD risk factors. These women should be offered appropriate preventive interventions related to their increased risk for CVD events.

Objective: Anemia is a common complication in patients with inflammatory diseases such as ankylosing spondylitis (AS). This post hoc analysis of a large, randomized, placebo-controlled trial examined the effect of infliximab on hemoglobin levels, physical function, and fatigue in patients with AS., Methods: Patients received infliximab 5 mg/kg (n = 188) or placebo (n = 68) at weeks 0, 2, 6, 12, and 18. Hemoglobin, interleukin-6 (IL-6), and C-reactive protein (CRP) levels, fatigue (visual analog scale [VAS]), physical function (Bath Ankylosing Spondylitis Functional Index [BASFI]), and disease activity were evaluated at baseline and week 24. Anemia was defined as a hemoglobin level <12 gm/dl for women and <13 gm/dl for men., Results: At baseline, 11 placebo group patients (16.2%) and 37 infliximab group patients (19.7%) had anemia. Of these, more infliximab-treated patients achieved normal hemoglobin levels at week 24 compared with patients receiving placebo (70.3% versus 27.3%; P = 0.0155). Infliximab-treated patients had significant improvements in mean hemoglobin concentration (0.7 gm/dl versus -0.3 gm/dl), BASFI score (-2.1 versus -0.2), and fatigue VAS score (-2.4 versus -0.4) compared with placebo patients (P < 0.001). Multiple regression analyses showed that improvements in hemoglobin level were significantly and independently associated with improvements in physical function and fatigue. Infliximab-treated patients with elevated CRP or IL-6 levels at baseline were more likely than those with low levels to have improvement in hemoglobin levels., Conclusion: Infliximab treatment significantly decreased the proportion of AS patients with anemia and improved hemoglobin levels compared with placebo. Improvement in hemoglobin level was independently associated with improvements in physical function and fatigue.

Objective: The objective of this study was to estimate the prevalence of anaemia and its impact on healthcare utilisation in patients with rheumatoid arthritis (RA)., Methods: Patients with claims for moderate-to-severe RA (ICD-9 code 714.x) treated with disease-modifying antirheumatic drugs as well as controls without RA matched for age, gender and time in plan were selected from the MarketScan Research Database. Anaemia was identified by ICD-9 codes 280.x, 285.2x, 281.9, 285.9 and 284.8. The prevalence ratio and 95% confidence interval (CI) for anaemia among RA patients versus controls were estimated. Overall disease burden was measured using the Elixhauser Comorbidity Index (ECI)., Results: The prevalence ratio for anaemia in RA patients was 2.2 (95% CI 2.1-2.4). Mean ECI was higher in RA (2.26) compared with control (1.02) patients (p<0.001), and RA patients with anaemia had a higher ECI compared with those without anaemia (3.95 vs. 2.08; p<0.001). Total healthcare costs in RA patients with anaemia were approximately twice those of RA patients without anaemia., Conclusions: The prevalence of clinically diagnosed anaemia in RA patients in the claims database was 2.2 times higher than that in the comparable non-RA control group. RA patients with anaemia had significantly higher levels of co-morbidity and healthcare costs than RA patients without anaemia.

Objective: To evaluate the relationship between hemoglobin concentration and physical disability in patients with rheumatoid arthritis (RA)., Methods: Data were derived from 2495 patients with RA enrolled in 3 clinical trials (ATTRACT, ASPIRE, and START) and treated with infliximab (3 to 10 mg/kg) plus methotrexate (MTX), or MTX plus placebo. The association of hemoglobin and the Health Assessment Questionnaire (HAQ) score was assessed at baseline (n = 2471) and Week 22 (n = 2458) by Spearman correlation, and multivariate linear regression models were employed to control for confounding effects from demographic and other clinical variables. A logistic regression model was used to estimate the odds ratio (OR) for a clinically meaningful improvement (> or = 0.25 point increase) in HAQ associated with a > or = 1 g/dl improvement in hemoglobin from baseline at Week 22., Results: About 37% of patients with RA had anemia based on World Health Organization criteria: hemoglobin < 12 g/dl in women (39%) and < 13 g/dl in men (32%). Low hemoglobin level was significantly associated with more severe physical disability at baseline (p < 0.001), and both male and female patients with anemia had more severe disability at baseline. Improvement in hemoglobin after treatment at Week 22 was an independent contributor to improvement in HAQ, and a > or = 1 g/dl improvement in hemoglobin after treatment was associated with a clinically meaningful improvement in the HAQ score at Week 22 (OR 1.43, 95% CI 1.10-1.86; p < 0.01)., Conclusion: Anemia is one of the independent factors contributing to physical disability in patients with RA. Improvement in anemia following effective RA treatment may play an independent role in improving physical function.

Vasculitis associated with connective tissue disorders is an important cause of secondary vasculitis about which little is written. When vasculitis occurs in the setting of a preexisting connective tissue disorder, it often correlates with disease severity and portends a poorer prognosis. It may involve virtually any organ system and present in a myriad of ways. Prompt recognition and treatment of vasculitis can dramatically improve the outcome for the patient. This review focuses on recent insights into the clinical presentation and pathogenic mechanisms that may be involved.

Therapeutic agents from virtually every pharmacological class have been implicated in the development of drug-induced vasculitis. Clinical manifestations range from small vessel hypersensitivity vasculitis and leukocytoclastic vasculitis to clinical syndromes indistinguishable from classical systemic forms of vasculitis such as Wegener's granulomatosis, polyarteritis nodosa and Churg-Strauss syndrome (CSS). The exact pathogenic mechanisms involved remain to be elucidated; but both cell-mediated and humoral immunity appear to play important roles. Affected individuals may present with cutaneous involvement alone or life-threatening systemic involvement, which may result in severe and sometimes fatal illness. Since clinical presentation as well as serological and pathological parameters is identical to idiopathic forms of vasculitis, a high index of suspicion is necessary to accurately and expeditiously diagnose drug-induced vasculitis. Withdrawal of the offending agent alone is often sufficient to induce prompt resolution of clinical manifestations, obviating the need for systemic corticosteroids or more powerful forms of immunosuppression.

Objective: Heterotopic ossification (HO) is a disorder characterized by the formation of new bone in tissue that does not ossify under normal conditions. We report a series of 6 cases in which HO occurred in the setting of adult respiratory distress syndrome (ARDS). We wished to show that HO can occur after neuromuscular blockade and that these cases might provide additional evidence that HO is influenced by neural mechanisms., Methods: Cases of HO were selected from the consultation services at the Massachusetts General Hospital and the Brigham and Women's Hospital. Affected patients all had ARDS and had been treated with a neuromuscular blocking agent. Patients with a history of stroke, burn, head trauma, spinal cord injury, or joint replacement were excluded from this study., Results: Heterotopic bone appeared around large joints in a pattern identical to that seen in patients with paralysis, traumatic brain injury, severe burns, or trauma. New bone formation was self-limited over a period of 1-2 years. Alkaline phosphatase and technetium bone scan were sensitive ways of detecting early disease and monitoring disease activity. Medical therapies had limited benefit. Surgical excision of mature new bone appeared to be the only definitive therapy., Conclusion: Neuromuscular blockade in the setting of ARDS appears to be an important risk factor for the development of HO. The similarity of these cases of HO occurring in patients with brain or spinal cord injury raises the possibility that neural mechanisms may be important in the pathogenesis of this disease. Whether the type of neuromuscular blocking agent and the duration of use are important determinants of disease severity remains to be determined.

The purpose of this study was to determine whether the ventilatory response to CO2 is depressed in term infants after halothane and N2O anesthesia. Ventilatory response to CO2 was determined by using a maskless CO2 response test in which a ventilation ratio is calculated from measurements of transcutaneous PCO2 (PtcCO2). Ventilation ratio represents the fractional increase in ventilation that occurs in response to inspired CO2. Eight infants were studied who were at least 36 wk gestational age and 12 +/- 4 wk postnatal age, did not have apnea in the perioperative period (values are means +/- SD). Ventilation ratio measured with a 4%-inspired-CO2 stimulus increased significantly after anesthesia (3.5 +/- 0.8 vs 3.0 +/- 0.5, P = 0.02). Baseline PtcCO2 was significantly lower after anesthesia than before anesthesia (37 +/- 4 vs 42 +/- 3, P < 0.01) which may reflect the development of a relative metabolic acidosis. (The occurrence of postoperative metabolic acidosis was in fact documented in another group of eight infants.) Ventilatory response to CO2 was not depressed after halothane and nitrous oxide anesthesia in these term and near-term infants.

A preliminary Phase I evaluation of macrophage activating factor (MAF) derived from the partially purified supernatant of human RPMI-1788 lymphoblastoid cell line was performed in 4 parts in 39 patients with advanced cancer. The first two parts used subcutaneous routes of administration and the second two parts used a 4-h intravenous infusion method. Individual doses ranged from 0.1 ml (1.7 mg protein) to 100 ml (1,700 mg protein). Subcutaneous dose was limited by the volume of administered material, and an attempt to use a concentrate of the supernatant resulted in severe local skin reactions. Larger doses given intravenously were well tolerated. Resultant toxicity was mild and consisted of transient fever and chills. One patient with malignant melanoma had a complete response of a 3-cm skin metastasis; one patient with breast cancer had disappearance of a skin nodule while visceral disease progressed; and one patient with histiocytic lymphoma had resolution of a conjunctival lesion. Treatment in many patients was associated with an increase in absolute peripheral lymphocytes. In the high-dose intravenous group, a statistically significant increase in the phagocytic index of peripheral blood leukocytes was noted. Lymphoblastoid MAF appears to be relatively safe to administer and has promise both as an antitumor agent and in the treatment of other altered immune conditions.

The diet manual is an important tool for dietitians, particularly because of regulatory pressures for accountability. The revision of a community diet manual has been described. The use of computer analysis to determine the nutrient content of each diet saved time over manual calculation; however, some difficulties were encountered.