Cost and Cost-effectiveness of Large-scale Screening for Type 1 Diabetes in Colorado.

OBJECTIVE: To assess the costs and project the potential lifetime cost-effectiveness of the ongoing Autoimmunity Screening for Kids (ASK) program, a large-scale, presymptomatic type 1 diabetes screening program for children and adolescents in the metropolitan Denver region. RESEARCH DESIGN AND METHODS: We report the resource utilization, costs, and effectiveness measures from the ongoing ASK program compared with usual care (i.e., no screening). Additionally, we report a practical screening scenario by including utilization and costs relevant to routine screening in clinical practice. Finally, we project the potential cost-effectiveness of ASK and routine screening by identifying clinical benchmarks (i.e., diabetic ketoacidosis [DKA] events avoided, HbA1c improvements vs. no screening) needed to meet value thresholds of $50,000-$150,000 per quality-adjusted life-year (QALY) gained over a lifetime horizon. RESULTS: Cost per case detected was $4,700 for ASK screening and $14,000 for routine screening. To achieve value thresholds of $50,000-$150,000 per QALY gained, screening costs would need to be offset by cost savings through 20% reductions in DKA events at diagnosis in addition to 0.1% (1.1 mmol/mol) improvements in HbA1c over a lifetime compared with no screening for patients who develop type 1 diabetes. Value thresholds were not met from avoiding DKA events alone in either scenario. CONCLUSIONS: Presymptomatic type 1 diabetes screening may be cost-effective in areas with a high prevalence of DKA and an infrastructure facilitating screening and monitoring if the benefits of avoiding DKA events and improved HbA1c persist over long-run time horizons. As more data are collected from ASK, the model will be updated with direct evidence on screening effects.

Cost-effective Tapering Algorithm in Patients with Rheumatoid Arthritis: Combination of Multibiomarker Disease Activity Score and Autoantibody Status.

OBJECTIVE: To analyze the effect of a risk-stratified disease-modifying antirheumatic drug (DMARD)-tapering algorithm based on multibiomarker disease activity (MBDA) score and anticitrullinated protein antibodies (ACPA) on direct treatment costs for patients with rheumatoid arthritis (RA) in sustained remission. METHODS: The study was a posthoc retrospective analysis of direct treatment costs for 146 patients with RA in sustained remission tapering and stopping DMARD treatment, in the prospective randomized RETRO study. MBDA scores and ACPA status were determined in baseline samples of patients continuing DMARD (arm 1), tapering their dose by 50% (arm 2), or stopping after tapering (arm 3). Patients were followed over 1 year, and direct treatment costs were evaluated every 3 months. MBDA and ACPA status were used as predictors creating a risk-stratified tapering algorithm based on relapse rates. RESULTS: RA patients with a low MBDA score (< 30 units) and negative ACPA showed the lowest relapse risk (19%), while double-positive patients showed high relapse risk (61%). In ACPA-negative and MBDA-negative (< 30 units), and ACPA or MBDA single-positive (> 30 units) groups, DMARD tapering appears feasible. Considering only patients without flare, direct costs for synthetic and biologic DMARD in the ACPA/MBDA-negative and single positive groups (n = 41) would have been €372,245.16 for full-dose treatment over 1 year. Tapering and stopping DMARD in this low-risk relapse group allowed a reduction of €219,712.03 of DMARD costs. Average reduction of DMARD costs per patient was €5358.83. CONCLUSION: Combining MBDA score and ACPA status at baseline may allow risk stratification for successful DMARD tapering and cost-effective use of biologic DMARD in patients in deep remission as defined by the 28-joint count Disease Activity Score using erythrocyte sedimentation rate.

The Utilization of Autoantibodies in Approaches to Precision Health.

Precision health (PH) applied to autoimmune disease will need paradigm shifts in the use and application of autoantibodies and other biomarkers. For example, autoantibodies combined with other multi-analyte "omic" profiles will form the basis of disease prediction allowing for earlier intervention linked to disease prevention strategies, as well as earlier, effective and personalized interventions for established disease. As medical intervention moves to disease prediction and a model of "intent to PREVENT," diagnostics will include an early symptom/risk-based, as opposed to a disease-based approach. Newer diagnostic platforms that utilize emerging megatrends such as deep learning and artificial intelligence and close the gaps in autoantibody diagnostics will benefit from paradigm shifts thereby facilitating the PH agenda.

Cost-effectiveness of an autoantibody test (EarlyCDT-Lung) as an aid to early diagnosis of lung cancer in patients with incidentally detected pulmonary nodules.

OBJECTIVE: Patients who have incidentally detected pulmonary nodules and an estimated intermediate risk (5-60%) of lung cancer frequently are followed via computed tomography (CT) surveillance to detect nodule growth, despite guidelines for a more aggressive diagnostic strategy. We examined the cost-effectiveness of an autoantibody test (AABT)-Early Cancer Detection Test-Lung (EarlyCDT-LungTM)-as an aid to early diagnosis of lung cancer among such patients. METHODS: We developed a decision-analytic model to evaluate use of the AABT versus CT surveillance alone. In the model, patients with a positive AABT-because they are at substantially enhanced risk of lung cancer-are assumed to go directly to biopsy, resulting in diagnosis of lung cancer in earlier stages than under current guidelines (a beneficial stage shift). Patients with a negative AABT, and those scheduled for CT surveillance alone, are assumed to have periodic CT screenings to detect rapid growth and thus to have their lung cancers diagnosed-on average-at more advanced stages. RESULTS: Among 1,000 patients who have incidentally detected nodules 8-30 mm, have an intermediate-risk of lung cancer, and are evaluated by CT surveillance alone, 95 (9.5%) are assumed to have lung cancer (local, 73.6%; regional, 22.0%; distant, 4.4%). With use of the AABT set at a sensitivity/specificity of 41%/93% (stage shift = 10.8%), although expected costs would be higher by $949,442 ($949 per person), life years would be higher by 53 (0.05 per person), resulting in a cost per life-year gained of $18,029 and a cost per quality-adjusted life year (QALY) gained of $24,330. With use of the AABT set at a sensitivity/specificity of 28%/98% (stage shift = 7.4%), corresponding cost-effectiveness ratios would be $18,454 and $24,833. CONCLUSIONS: Under our base-case assumptions, and reasonable variations thereof, using AABT as an aid in the early diagnosis of lung cancer in patients with incidentally detected pulmonary nodules who are estimated to be at intermediate risk of lung cancer and are scheduled for CT surveillance alone is likely to be a cost-effective use of healthcare resources.

Assessment of antisperm antibodies in a sample of Egyptian patients with hepatitis C virus infection.

Association of hepatitis C virus (HCV) with autoimmune phenomena and impaired semen parameters has been previously reported. The aim of this study was to investigate the influence of HCV infection on the development of antisperm antibodies (ASAs) in HCV-positive males. The study was conducted on 30 HCV-infected individuals and 30 healthy control subjects. In both patients and control groups, liver enzymes and reproductive hormones were measured; computer-assisted semen analysis (CASA) was performed; HCV-RNA in serum was measured and IgG and IgA ASAs in semen were determined. Free testosterone, sperm concentration, progressive and total motility were significantly lower in HCV patients than in the control group, whereas ASAs of the IgG and IgA classes were significantly higher in HCV patients. However, correlations between viral load and the examined semen parameters and ASAs were nonsignificant. In conclusion, HCV may be responsible for the increased ASAs detected in HCV patients in the present study, possibly providing another plausible explanation for the decreased sperm motility reported in HCV patients. These findings could be of value in fertility management of HCV patients.

Ultrasound and magnetic resonance imaging assessment of joint disease in symptomatic patients with cystic fibrosis arthropathy.

OBJECTIVES: Cystic fibrosis arthropathy (CFA) is a term commonly used for joint pain with and without swelling seen in some patients with CF. Early studies into CFA focused on the presence of rheumatoid factor and immunological changes on synovial biopsy, with parallels drawn between respiratory and joint activity. Identification of anti-cyclic citrullinated peptide antibodies (anti-CCP) as a marker of rheumatoid arthritis (RA), along with increased access to sensitive imaging techniques including ultrasound (US) and magnetic resonance imaging (MRI), offer great potential to investigate and more accurately understand the type(s) of inflammatory arthritis that may underlie CFA. The aim of this study was to phenotype an active CFA cohort using serology and imaging, as a basis for further work in this understudied area. METHODS: This was a prospective observational cohort study of symptomatic CFA patients presenting with joint pain. Participants underwent serological testing, clinical and US joint and entheseal assessment, as well as MRI of the most symptomatic joint/joint area. RESULTS: Ten symptomatic patients were studied with 9/10 having positive clinical findings. Inflammatory changes on US were seen in 8/10 cases. Five patients had positive findings on MRI (3 of whom had received IV gadolinium contrast). This included patients with significant erosive changes. One patient was anti-CCP positive suggestive of RA, and two were anti-nuclear antibody positive. CONCLUSION: Imaging, and to a lesser extent serology, identified inflammatory joint pathology in a proportion of cases, providing important data to explore in a large CFA cohort examining the clinical and imaging phenotype of this group.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS, AMERICAN COLLEGE OF ENDOCRINOLOGY DISEASE STATE CLINICAL REVIEW: CLINICAL RELEVANCE OF MACROPROLACTIN IN THE ABSENCE OR PRESENCE OF TRUE HYPERPROLACTINEMIA.

OBJECTIVE: To review the current literature regarding the prevalence of macroprolactin (macroPRL) in hyperprolactinemic patients and determine recommendations for testing. METHODS: An electronic United States National Library of Medicine PubMed search (through October, 2014) was conducted for search term "macroprolactin." Only English-language articles were considered. RESULTS: MacroPRL is an under-recognized cause of elevated prolactin (PRL) and is present in approximately 4% to 40% of hyperprolactinemic patients depending on the referral population. Clinical findings which could be due to hyperprolactinemia are the impetus for testing for PRL. Because of this there is significant overlap in the clinical presentation of patients with true hyperprolactinemia and those with macroPRL, differentiation cannot always be made on the basis of symptoms. A lack of recognition of the presence of macroPRL can lead to unnecessary laboratory investigations, imaging, and pharmacologic or surgical treatment. CONCLUSION: Until there is a commercially available PRL assay that is not subject to interference by macroPRL, clinicians should consider the possibility of macroPRL, especially if the clinical presentation, imaging findings, and/or response to therapy reveal inconsistencies.

Assessment of bullous pemphigoid disease area index during treatment: a prospective study of 30 patients.

BACKGROUND: Recently, a consensus Bullous Pemphigoid Disease Area Index (BPDAI) was proposed to measure therapeutic outcomes in bullous pemphigoid (BP). OBJECTIVE: To compare BPDAI with other clinical parameters of disease activity at baseline and to describe the variations of BPDAI during the initial phase of treatment. METHODS: Thirty BP patients were included and followed for 1 year. BPDAI was assessed at baseline and on days 30, 90 and 360 by the same investigator. Concomitantly, the number of daily new blisters, the skin surface area of erythematous/eczematous/urticarial plaques and blisters/erosions, total lesion area (TLA), pruritus score and mucosal involvement were recorded. RESULTS: At baseline, BPDAI was 46.7 ± 25 (mean ± SD); it was well correlated with erythematous/eczematous/urticarial skin surface (r = 0.63), TLA (r = 0.83), number of daily new blisters (r = 0.7; p ≤ 0.0002) and anti-BP180 autoantibodies (r = 0.49; p = 0.006), but not with anti-BP230 autoantibodies. For the 8 patients with severe BP at baseline, the mean BPDAI was 76.5, versus 35.9 for moderate BP (p = 0.0007). A value of 56 was proposed as a cut-off value for severe BP. BPDAI decreased to 11.9 ± 8.7, 10.7 ± 12.7 and 2.5 ± 4.1 on days 30, 90 and 360, respectively. CONCLUSION: BPDAI rapidly decreased during the early treatment stage of BP with variations almost totally conditioned by the skin activity component.

Avaliacao comparativa entre os metodos objetivo e subjetivo em laminas coradas pela imuno-histoquimica / Comparative assessment between objective and subjective methods in slides stained by immunohistochemistry

Métodos objetivos de avaliação são frequentemente cobrados em estudos científicos. Exames histológicos com coloração imuno-histoquímica podem ser avaliados por meio de fotometria. OBJETIVO: Comparar este método objetivo com a avaliação subjetiva realizada por três observadores independentes, utilizando lâminas de colesteatoma adquirido da orelha média. MÉTODO: Foram selecionadas um total de 54 imagens de colesteatomas imuno-histoquimicamente coradas pelos anticorpos anti-TNF-R2 (32 lâminas) e anti-TGF-α; (22 lâminas). O anticorpo secundário utilizado nos dois grupos foi o Max Polimer Detection System (Kit Novo Link, Novocastra®, UK). As amostras foram processadas por um scanner digital de lâminas (modelo ScanScope - Aperio). As áreas selecionadas foram submetidas à análise por fotometria. RESULTADOS: A avaliação objetiva por fotometria foi comparada com a avaliação subjetiva por três observadores e submetidas à análise estatística. A análise estatística revelou reprodutibilidade moderada (K valores entre 0,41 e 0,60) para os dois grupos. CONCLUSÃO: O presente estudo demonstrou que as características irregulares das lâminas de colesteatoma da orelha média coradas pela imuno-histoquímica impossibilita a sua adequada avaliação objetiva, enquanto a avaliação subjetiva por observadores experientes se mostrou mais confiável. .

Objective methods of assessment are often required in scientific studies. Histological tests with immunohistochemical staining can be assessed by photometry. OBJECTIVE: To compare this objective method with the subjective evaluation performed by three independent examiners, using slides of acquired middle ear cholesteatomas. METHOD: We selected a total of 54 cholesteatoma images, immunohistochemically stained by anti-TNF-R2 (32 slides) and anti-TGF-α, (22 slides). The secondary antibody used in the two groups was the Max Polymer Detection System (Novo Link Kit, Novocastra®, UK). The samples were processed by a digital slide scanner (ScanScope - Aperio). The selected sites were analyzed by photometry. RESULTS: The objective assessment by photometry was compared with the subjective evaluation by three examiners and subjected to statistical analysis. The Statistical analysis revealed moderate reproducibility (K values between 0.41 and 0.60) for both groups. CONCLUSION: Our study showed that the irregular characteristics of middle ear cholesteatoma slides stained by immunohistochemistry prevents its proper objective evaluation, while the subjective assessment by experienced examiners was more reliable. .

Comparative assessment between objective and subjective methods in slides stained by immunohistochemistry.

UNLABELLED: Objective methods of assessment are often required in scientific studies. Histological tests with immunohistochemical staining can be assessed by photometry. OBJECTIVE: To compare this objective method with the subjective evaluation performed by three independent examiners, using slides of acquired middle ear cholesteatomas. METHOD: We selected a total of 54 cholesteatoma images, immunohistochemically stained by anti-TNF-R2 (32 slides) and anti-TGF-α, (22 slides). The secondary antibody used in the two groups was the Max Polymer Detection System (Novo Link Kit, Novocastra®, UK). The samples were processed by a digital slide scanner (ScanScope - Aperio). The selected sites were analyzed by photometry. RESULTS: The objective assessment by photometry was compared with the subjective evaluation by three examiners and subjected to statistical analysis. The Statistical analysis revealed moderate reproducibility (K values between 0.41 and 0.60) for both groups. CONCLUSION: Our study showed that the irregular characteristics of middle ear cholesteatoma slides stained by immunohistochemistry prevents its proper objective evaluation, while the subjective assessment by experienced examiners was more reliable.

Assessment of cross-reactive host-pathogen antibodies in patients with different stages of chronic Chagas disease.

INTRODUCTION AND OBJECTIVES: Trypanosoma cruzi infection has been shown to induce humoral autoimmune responses against host antigens tissues. Particularly, antibodies cross-reacting with myocardial antigens may play a role in the development of the severe forms of chronic Chagas disease. The aim of this study was to determine the association between clinical stage of the disease and the presence of autoantibodies in patients with chronic Chagasic disease. METHODS: We performed a cross-sectional study in T. cruzi-seropositive patients divided into 3 groups according to the classic classification of chronic Chagas heart of Storino et al. All participants underwent complete clinical examination and their sera were used to measure autoantibody levels. RESULTS: All patients had detectable levels of anti-p2ß and anti-B13 autoantibodies but none had anti-Na-K-ATPase antibodies. No association was observed between electrocardiographic conduction disturbances and autoantibody levels. Patients with chronic Chagas disease stage III had the highest levels of anti-B13 antibodies and a high risk of mortality score, showing a clear association between disease stage and this score. CONCLUSIONS: Anti-B13 antibodies were significantly higher in chronic Chagas disease stage III patients, suggesting that these antibodies may be involved in disease progression and that they might be a useful marker of poor prognosis in terms of heart compromise. Our results also reveal an important correlation between the level of anti-B13 autoantibodies and symptomatic heart failure and/or dilated cardiomyopathy.

Multiplex assessment of non-organ-specific autoantibodies with a novel microbead-based immunoassay.

Advances in immunofluorescence assay development paved the way for the simultaneous detection of several antibodies in one sample, for the serological diagnosis of systemic rheumatic diseases. Standardized automated screening of such antibodies can be achieved by HEp-2 cell-based indirect immunofluorescence (IIF) using a multicolor fluorescence imaging technical platform. To create a common platform for both screening and specific antibody assessment, multiplex measurement of antibodies using fluorescence-coded immobilized microbeads was employed on the same platform. The multicolor fluorescence detection system VideoScan (AKLIDES®) was used for the fluorescence analysis of a multiplex microbead-based immunoassay (MIA). First, immunoglobulin G (IgG) was covalently coupled to one microbead population in duplicate and in three independent experiments. The coupled IgG was detected by a Cy™5-conjugated secondary antibody. Thus, intra- and interassay coefficients of variation (CV) were obtained. Second, a multiplex determination of antinuclear autoantibodies (ANA) to Scl-70, Sm, dsDNA, SS-A (Ro60), CENP-B, and La/SS-B by solid-phase MIA was investigated, using 72 sera from patients with autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis (SS). The reproducibility study revealed intra-assay CVs ranging from 3.2% to 9.9%, and interassay CVs ranging from 9.6% to 14.7%. The detection of Scl-70-, Sm-, CENP-B-, and La/SS-B-ANA with MIA showed very good agreement with the ELISA results (kappa = 1.0). The resulting relative sensitivities and specificities for Scl-70-, Sm-, CENP-B-, dsDNA-, and La/SS-B-ANA were 100%, respectively, with the exception of dsDNA (specificity 97%). Multiplex detection by immobilized fluorescence-coded microbeads using multicolor fluorescence is a reliable method for the assessment of rheumatic-disease-specific antibodies. Multicolor fluorescence analyses with pattern detection algorithms provide a common platform technique for both the screening of ANA by cell-based IIF and specific antibody assessment by multiplex detection.

Proteomic analyses lead to a better understanding of celiac disease: focus on epitope recognition and autoantibodies.

Proteomic technologies are being used with increasing frequency in the scientific community. In this review, we have highlighted their use in celiac disease (CD). The available techniques, which include two-dimensional (2D) gel electrophoresis, mass spectrometry, and antibody and tissue arrays, have been used to identify proteins or changes in protein expression specific to gut tissue from patients with CD. A number of studies have employed proteomic methodologies to determine the diagnostic biomarkers in body fluids or to examine changes in protein expression and posttranslational modifications during signaling. A fast technological development of these methods, along with the combination of classic techniques with proteomics, will lead to new discoveries, which will consent a better understanding of the pathogenesis of CD.

Are anti-citrulline autoantibodies better serum markers for rheumatoid arthritis than rheumatoid factor in Thai population?

The aim of the study is to evaluate the prevalence of anti-citrulline antibodies (anti-CCP) versus rheumatoid factor (RF) in a cohort of Thai patients with rheumatoid arthritis (RA), a variety of rheumatic diseases other than RA and healthy controls. The association between anti-CCP and RA disease activity was also examined. Serum from 125 RA patients, 60 from other rheumatic diseases (non-RA) and 60 from healthy controls were tested for IgM RF and second generation anti-CCP. The association between anti-CCP, RF, the Disease Activity Score (DAS 28) and other relevant laboratory tests (CBC, ESR and CRP) were assessed. The sensitivity and specificity of anti-CCP antibody were 58.7 and 100% when compared with 63.5 and 98.3% for RF. These differences were not statistically significant. The anti-CCP outperformed RF in terms of the positive-predictive values (100 vs. 97.6%); however, the negative-predictive values were 72.4% for RF and 69.6% for anti-CCP. The sensitivity when either anti-CCP or RF was positive increased to 71.2%. Nine out of 45 RF-negative patients had a positive anti-CCP test. Anti-CCP was significantly correlated with parameters of inflammation, but not with DAS 28. In conclusion, although anti-CCP is better than RF in distinguishing RA from other rheumatic diseases, its cost, which is 3.3 times higher than the RF test precludes it from replacing RF as a serum marker for Thai patients with RA. The treatment decisions cannot be based on the test alone, as it has no correlation with DAS 28. Its usefulness is in patients with suspected RA who have had a negative RF test.

Review of the classification and assessment of the cutaneous manifestations of the idiopathic inflammatory myopathies.

Adult and juvenile dermatomyositis, polymyositis and myositis overlapping with another connective tissue disease are rare systemic autoimmune diseases with a primary feature of weakness and muscle inflammation. Cutaneous findings specific to the underlying condition are present in many patients with these disorders. Some lesions are highly characteristic of the idiopathic inflammatory myopathies (IIM), especially in dermatomyositis. Some cutaneous findings are common but not specific to the IIM and others are less frequently observed in patients with these illnesses. Many of these manifestations also have different grades of disease activity or damage. This photoessay reviews the classification and assessment of the cutaneous manifestations of the IIM and presents example photographs of many of the lesions of adult and juvenile IIM accumulated from the clinical experience of international experts in these conditions. The purpose of this work is to facilitate better recognition of the diverse cutaneous manifestations associated with these inflammatory myopathies.

The between-laboratory variation of factor VIII inhibitor testing: the experience of the external quality assessment program of the ECAT foundation.

The detection and quantification of factor VIII (FVIII) inhibitors is clinically important both for the identification of hemophilia A patients with inhibitors and for the management of immune tolerance treatment. Only limited data are available on the between-laboratory variation of FVIII inhibitor testing. This report describes the evaluation of the results of the large-scale external quality assessment program of the European Concerted Action on Thrombosis Foundation. This study includes the results of six different surveys for the period 2006 to 2008 with 100 to 170 participating laboratories. The overall between-laboratory variation ranged from 28% to 52% with a slightly lower variation for the Nijmegen assay (approximately 39%) on average than for the Bethesda assay (approximately 45%). The use of buffered normal pooled plasma as FVIII source showed better performance compared with the use of nonbuffered pooled plasma; likewise the use of FVIII-deficient plasma compared with the use of imidazole buffer. However, the combination of both was essential for lowest between-laboratory variation. The Nijmegen assay also showed better performance with respect to specificity and sensitivity than the Bethesda assay, although the results for neither were entirely satisfactory. In general, it can be concluded that the measurement of FVIII inhibitory antibodies with the Nijmegen assay should be favored over the use of the Bethesda assay. However, further improvement of the laboratory test for FVIII inhibitors is urgently needed.

[Clinical and immunological assessment of efficacy of mexidol in the treatment of lumbosacral radiculopathy].

Efficacy of mexidol in the complex treatment of lumbosacral radiculopathy has been analyzed. Comparing to the traditional treatment using clinical and immunological methods, this method proved to be superior.

[National external quality assessment in auto-immunity: auto-antibodies against thyroid constituents]. / Contrôle national de qualité en auto-immunité: anticorps anti-thyroïdiens.

The French Health Products Safety Agency organized in 2005, for the scheme of the national external quality assessment, a survey on antibodies against thyroid constituents which included for the first time the quantitative assay. The purpose of this survey was to assess the quality of the different methods of these assays. The overall qualitative results are satisfactory. However, this survey pointed out a lower performance for immunodot which appeared to have been misused. Concerning the titer of antibodies, results show a broad dispersion between reagents. This confirms the lack of a real standardisation despite of the existence of the international MRC standards.