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OBJECTIVE: Classification criteria for calcium pyrophosphate deposition disease (CPPD) will facilitate clinical research on this common crystalline arthritis. We report on the first two phases of a four-phase process for developing CPPD classification criteria. METHODS: CPPD classification criteria development is overseen by a 12-member Steering Committee. Item generation (Phase I) included a scoping literature review of five literature databases and contributions from a 35-member Combined Expert Committee and two Patient Research Partners. Item reduction and refinement (Phase II) involved a Combined Expert Committee meeting, discussions among Clinical, Imaging, and Laboratory Advisory Groups, and an item rating exercise to assess the influence of individual items toward classification. The Steering Committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development. RESULTS: Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The Advisory Groups eliminated items they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases. As numerous imaging items were rated +3, the Steering Committee recommended focusing on imaging of the knee, wrist, and one additional affected joint for calcification suggestive of CPP crystal deposition. CONCLUSION: A data- and expert-driven process is underway to develop CPPD classification criteria. Candidate items comprise clinical, imaging, and laboratory features.

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined.

Background Supported by both the ACR and EULAR, the EULAR/ACR 2019 Classification Criteria for SLE employ positive ANA (ever) as an entry criterion and use a weighted scheme with values ranging from 2 to 10, for a classification cut-off of 10. Criteria items are attributed to SLE only if there is no more likely alternative diagnosis in the individual patients. Items are organized in domains, and only the highest ranking item within a domain is counted. These criteria have been validated in a cohort of 696 SLE patients and 574 non-SLE patients from a total of 21 centers, reaching an overall sensitivity of 96.1% and a specificity of 93.4%. To at least estimate the performance in groups underrepresented in the validation cohort of this transatlantic project, we analyzed this cohort for patient subsets with regard to sex, ethnicity, and disease duration. Methods The full EULAR/ACR 2019 classification criteria validation cohort was analyzed for female (n=1,098) and male (n=172) patients, Asian (n=118), Black (n=68), Hispanic (n=124) and White (n=941) patients, and patients with an SLE duration of less than 1 year (n=34), one to less than 3 years (n=196), 3 to less than 5 years (n=157), and 5 or more years (n=879). Sensitivity and specificity were calculated for the EULAR/ACR 2019 criteria, the SLICC 2012 criteria and the ACR 1997 criteria each. Results As shown in table 1, most of the point estimates for sensitivity and specificity in subsets lay within the 95% confidence intervals of the sensitivity and specificity of the EULAR/ACR 2019 criteria validation. In particular, sensitivity and specificity for all ethnic groups were within the confidence intervals or even higher. Formally, the sensitivity was slightly lower for male patients, corresponding to a higher specificity, but the male 95% confidence intervals (0.86–0.98 for sensitivity, 0.90–0.99 for specificity) overlapped. While sensitivity appeared independent of disease duration from year 1 on, sensitivity was only 89% in the first year of disease, identical to the SLICC criteria (89%) and numerically higher than the ACR criteria (56%), but all confidence intervals overlapped. Conclusion While not all subgroups of SLE patients in the validation cohort are of adequate size to fully explore the sensitivity and specificity of the EULAR/ACR 2019 SLE classification criteria in the respective subsets, the point estimates of sensitivity and specificity suggest that the new criteria perform at least reasonably well in all ethnic groups, in men and in early disease. Nevertheless, sensitivity and specificity should be independently validated in larger groups of Asian, Black and Hispanic patients, male patients and in early disease.

Background:Classification criteria for calcium pyrophosphate deposition disease (CPPD) will facilitate clinical research on this common crystalline arthritis. ACR/EULAR are jointly sponsoring development of CPPD classification criteria using a multi-phase process.Objectives:To report preliminary results from the first two phases of a four-phase process for developing CPPD classification criteria.Methods:CPPD classification criteria development is overseen by a 12-member Steering Committee. Item generation (Phase I) included a scoping literature review of five literature databases and contributions from a 35-member Combined Expert Committee and two Patient Research Partners. Item reduction and refinement (Phase II) involved a Combined Expert Committee meeting, discussions among Clinical, Imaging, and Laboratory Advisory Groups, and an item rating exercise to assess the influence of individual items toward classification. The Steering Committee reviewed the modal rating score for each item (range -3 [strongly pushes away from CPPD] to +3 [strongly pushes toward CPPD]) to determine items to retain for future phases of criteria development.Results:Item generation yielded 420 items (312 from the literature, 108 from experts/patients). The Advisory Groups eliminated items they agreed were unlikely to distinguish between CPPD and other forms of arthritis, yielding 127 items for the item rating exercise. Fifty-six items, most of which had a modal rating of +/- 2 or 3, were retained for future phases (see Table 1). As numerous imaging items were rated +3, the Steering Committee recommended focusing on imaging of the knee, wrist, and one additional affected joint for calcification suggestive of CPP crystal deposition.Conclusion:The ACR/EULAR CPPD classification criteria working group has adopted both data- and expert-driven approaches, leading to 56 candidate items broadly categorized as clinical, imaging, and laboratory features. Remaining steps for criteria development include domain establishment, item weighting through a multi-criteria decision analysis exercise, threshold score determination, and criteria validation.Table 1.Categories of items retained for future phases of classification criteria developmentAge in decade at symptom onsetAcute inflammatory arthritis (e.g. knee, wrist, 1st MTP joint*)Recurrence and pattern of joint involvement (e.g. 1 self-limited episode, >1 self-limited episode)Physical findings (e.g. palpable subcutaneous tophus*, psoriasis*)Co-morbidities and family history (e.g. Gitelman disease, hemochromatosis, familial CPPD)Osteoarthritis location and features (e.g. 2nd or 3rd MCP joint, wrist)Synovial fluid findings (e.g. CPP crystals present, CPP crystals absent on 1 occasion* or 2 occasions*, monosodium urate crystals present*)Laboratory findings (e.g. hypomagnesemia, hyperparathyroidism, rheumatoid factor*, anti-CCP*)Plain radiograph: calcification in regions of fibro- or hyaline cartilage+Plain radiograph: calcification of the synovial membrane/capsule/tendon+Conventional CT: calcification in regions of fibro- or hyaline cartilage+Conventional CT: calcification of the synovial membrane/capsule/tendon+Ultrasound: CPP crystal deposition in fibro- or hyaline cartilage+Ultrasound: CPP crystal deposition in synovial membrane/capsule/tendons+Dual-energy CT: CPP crystal deposition in fibro- or hyaline cartilage+Dual-energy CT: CPP crystal deposition in synovial membrane/capsule/tendon+*Potential negative predictor +Assessed in the knee, wrist, and/or 1 additional affected jointDisclosure of Interests:Sara Tedeschi Consultant of: NGM Biopharmaceuticals, Tristan Pascart: None declared, Augustin Latourte Consultant of: Novartis, Cattleya Godsave: None declared, Burak Kundaki: None declared, Raymond Naden: None declared, William Taylor: None declared, Nicola Dalbeth Speakers bureau: Abbvie and Janssen, Consultant of: AstraZeneca, Dyve, Selecta, Horizon, Arthrosi, and Cello Health, Tuhina Neogi: None declared, Fernando Perez-Ruiz: None declared, Ann Rosenthal: None declared, Fabio Becce Consultant of: Horizon Therapeutics, Grant/research support from: Siemens Healthineers, Eliseo Pascual: None declared, Mariano Andrés: None declared, Thomas Bardin: None declared, Michael Doherty: None declared, Hang Korng Ea: None declared, Georgios Filippou: None declared, John FitzGerald: None declared, Marwin Gutierrez: None declared, Annamaria Iagnocco: None declared, Tim Jansen Speakers bureau: Abbvie, Amgen, BMS, Grunenthal, Olatec, Sanofi Genzyme, Consultant of: Abbvie, Amgen, BMS, Grunenthal, Olatec, Sanofi Genzyme, Minna Kohler Speakers bureau: Lilly, Consultant of: Novartis, Frederic Lioté: None declared, Mark Matza: None declared, Geraldine McCarthy Consultant of: PK Med, Roberta Ramonda: None declared, Anthony Reginato: None declared, Pascal Richette: None declared, Jasvinder Singh Speakers bureau: Simply Speaking, Consultant of: Crealta/Horizon, Medisys, Fidia, UBM LLC, Trio health, Medscape, WebMD, Adept Field Solutions, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, Practice Point communications, Francisca Sivera: None declared, Alexander So: None declared, Lisa Stamp: None declared, Janeth Yinh: None declared, Chio Yokose: None declared, Robert Terkeltaub Consultant of: Sobi, Horizon Therapeutics, Astra-Zeneca, Selecta, Grant/research support from: Astra-Zeneca, Hyon Choi: None declared, Abhishek Abhishek Consultant of: NGM Biopharmaceuticals.

Background Chronic nonbacterial osteomyelitis (CNO) is a severe and occult autoinflammatory bone disease of unknown cause. Early diagnosis is challenging, and CNO may debilitate affected children when left untreated. Currently, evidence-based and validated diagnostic and classification criteria for CRMO/CNO are lacking. The insidious disease course, increasing disease incidence, and significant delay in diagnosis highlight the need for the development of classification criteria that leads to more precise and early selection of patients for clinical trials1,2. Objectives To identify candidate items towards developing classification criteria for CNO using anonymous survey and nominal group technique. Methods An international collaborative effort was formed within the pediatric and adult rheumatology communities to conduct the following phases: 1) to generate candidate criteria items by a Delphi survey among international rheumatologists; 2) to reduce candidate criteria items through consensus processes involving physicians managing CNO and patients or caregivers of children with CNO. This study was approved by Seattle Children’s Hospital Institutional Review Board. Results In Phase 1, 259 pediatric rheumatologists (30%, N=865) participated in an online questionnaire about features most relevant to the classification of CNO. Of those, 77 (30%) practiced in Europe, 132 (51%) in North America, and 50 (19%) in other continents. A total of 138 (53%) responders had >10 years of practicing experience and 108 (42%) had managed >10 CNO patients. There were 33 candidate criteria items initially identified. In Phase 2, candidate items were presented to 39 rheumatologists and 7 parents and items were refined or eliminated through item reduction techniques. Seventy-seven (94%, N=82) workgroup members then participated in a second survey to rank the remaining items by their distinguishing power of CNO from mimicking conditions. Figure 1 shows the mean score for the remaining 31 candidate criteria. Multifocal lesions, ruling out malignancy and infection and typical location on imaging had the greatest means. CRP and/or ESR greater than 3x the normal upper limit had the greatest negative means. Discriminatory Score +3/-3 (increases/decreases the likelihood of CRMO the most) +2/-2 (increases/decreases the likelihood of CRMO moderately) +1/-1 (increases/decreases the likelihood of CRMO slightly) 0 (no difference) Conclusion Through surveys and consensus technique, candidate items towards developing classification criteria for CNO were identified. This list of items will guide the design of a feasible patient data collection form towards weighting of each item in the classification criteria. References [1] Roderick MR, Shah R, Rogers V, Finn A, Ramanan AV. Chronic recurrent multifocal osteomyelitis (CRMO)–advancing the diagnosis. Pediatric Rheumatology. 2016 Dec;14(1):47. [2] Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, et al. Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology. 2006 Jun 17;46(1):154-60. Acknowledgement CNO/CRMO Work Group, Childhood Arthritis and Rheumatology Research Alliance Disclosure of Interests Melissa Oliver: None declared, Eveline Wu: None declared, Raymond Naden Speakers bureau: Was a speaker at conferences paid by pharmaceutical companies several times in the past, but not in the last 7 years., Matthew Hollander: None declared, Polly Ferguson: None declared, Fatma Dedeoglu Consultant for: Attended a scientific meeting for Novartis in 2017. Overall monetary amount was less than $5000., Seza Ozen Consultant for: Seza Ozen is receiving consultancy fees from Novartis, Speakers bureau: Roche, Yongdong Zhao Grant/research support from: I have grant support from Bristol-Myer Squibb

Background:An international multi-disciplinary effort is underway to develop rigorous, new, consensus- and evidence-based classification criteria for Antiphospholipid Syndrome (APS). The methodological approach includes four phases; we have previously presented phases I and II (item generation and reduction), which resulted in 27 candidate criteria1organized in laboratory and clinical domains.Objectives:Phase III (item weighting/threshold identification) is currently underway; here we report initial Phase III case collection results.Methods:We used REDCap, a secure data system, for Phase III international case collection. The candidate criteria of 27 items at the end of Phase II was represented in a standardized case collection form. We asked international physicians interested in APS to provide and rate cases using a Likert scale (+3 to -3: highly likely to highly unlikely to be APS). Cases with higher scores (+2 or +3) were categorized as “highly likely” APS, whereas lower scores (+1 to -3) were categorized as “equivocal or unlikely” APS.Results:We collected 314 potential APS cases (mean age 43.8±14.4 years; 79% female; and 77% white) between 6/2019-8/2019 from 17 sites in Europe (47%), North America (41%), and South America (11%). Majority of cases were potential primary APS (64%); 137 were rated as “highly likely” and 177 as “equivocal or unlikely” APS. Lupus anticoagulant, antiβ2glycoprotein-I antibody IgG/M, anticardiolipin antibody IgG, arterial thrombosis, venous thromboembolism, microvascular disease, fetal loss between 16-34 weeks, severe preeclampsia, severe placental insufficiency, cardiac valve disease, and low platelet count occurred with higher frequency in the APS cases categorized as “highly likely” (Table).Conclusion:International collection of cases spanning the spectrum of “highly likely” to “equivocal or unlikely” APS provide “real world” assessment of patients being referred for APS evaluation. In next steps, proposed candidate criteria will be further refined, organized, and weighted, and a preliminary threshold for APS classification will be determined.References:[1]Barbhaiya M et al. Phase II Results [abstract]. Arthritis Rheumatol. 2019;71 (suppl 10).Table.Characteristics of Potential APS Cases Categorized by Physician AssessmentCandidate Relative Criteria, n (%)Total(n=314)Highly Likely APS(n=137)Equivocal or Unlikely APS(n=177)LABORATORYLupus Anticoagulant Test208 (66)117 (85)91 (51)Anticardiolipin Antibody• IgG170 (54)90 (66)80 (45)• IgM138 (44)61 (45)77 (44)Antiβ2glycoprotein-I Antibody• IgG99 (32)66 (48)33 (19)• IgM79 (25)47 (34)32 (18)CLINICALMacrovascular• Superficial Vein Thrombosis15 (5)4 (3)11 (6)• Venous Thromboembolism95 (30)63 (46)32 (18)• Transient Ischemic Attack27 (9)13 (10)14 (8)• Arterial Thrombosis82 (26)58 (42)24 (14)Microvascular*86 (27)62 (45)24 (14)Obstetric**• Embryonic Loss (85 (45)34 (42)51 (48)• Fetal Loss (10w–20 (11)9 (11)11 (10)• Fetal Loss (16w–34w)42 (22)32 (40)19 (18)• Severe Preeclampsia (27 (14)18 (22)9 (8)• Severe Placental Insufficiency (22 (12)13 (16)9 (8)Cardiac Valve Disease***32 (10)21 (15)11 (6)Thrombocytopenia 72 (23)43 (31)29 (16)*Livedo racemosa, livedoid vasculopathy, adrenal hemorrhage, acute ischemic enceophalopathy, cardiac microvascular disease, pulmonary hemorrhage, acute and/or chronic antiphospholipid-related nephropathy; **Total number of patients ever pregnant: 188 (highly likely APS: 81; unlikely APS: 107) ***Valve thickening and/or vegetation.Acknowledgments:The project is supported by ACR/EULARDisclosure of Interests:Medha Barbhaiya: None declared, Doruk Erkan: None declared, Yasaman Ahmadzadeh: None declared, Karen Costenbader Grant/research support from: Merck, GSK, Consultant of: Merck, GSK, Lily, Astra Zeneca, Janssen, Raymond Naden: None declared, Stéphane Zuily: None declared

Background:EULAR/ACR 2019 SLE Classification Criteria were validated in an international cohort.Objectives:To evaluate performance characteristics of SLE classification systems in sex, race/ethnicity, and disease duration subsets.Methods:Sensitivity and specificity of the EULAR/ACR 2019, SLICC 2012 and ACR 1982/1997 criteria were evaluated in the validation cohort.Results:The cohort consisted of female (n=1098), male (n=172), Asian (n=118), Black (n=68), Hispanic (n=124) and White (n=941) patients; and patients with an SLE duration of 1-3 years (n=196), 3-5 years (n=157), and ≥5 years (n=879). Among patients with 1-3 years disease duration, the EULAR/ACR criteria had better sensitivity than the ACR criteria (97% (95%CI 92-99%) vs 81% (95%CI 72-88%). The new criteria performed well in men (sensitivity 93%, specificity 96%) and women (sensitivity 97%, specificity 94%). The new criteria had better sensitivity than the ACR criteria in White (95% vs 83%), Hispanic (100% vs 86%) and Asian patients (97% vs 77%).Conclusion:The EULAR/ACR 2019 criteria perform well in patients with early disease, and across sexes and ethnicities.Disclosure of Interests:Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Ralph Brinks: None declared, Karen Costenbader Grant/research support from: Merck, Consultant of: Astra-Zeneca, David Daikh: None declared, Marta Mosca: None declared, Rosalind Ramsey-Goldman: None declared, Josef S. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, Merck Sharp & Dohme, Pfizer, Roche – grant/research support, Consultant of: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – consultant, Speakers bureau: AbbVie, Amgen Inc., AstraZeneca, Astro, Celgene Corporation, Celtrion, Eli Lilly, Glaxo, ILTOO, Janssen, Medimmune, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Samsung, Sanofi, UCB – speaker, David Wofsy: None declared, Dimitrios Boumpas Grant/research support from: Unrestricted grant support from various pharmaceutical companies, Diane L Kamen Consultant of: Consulted on SLE survey development for Lilly and consulted on SLE trial protocol development for EMD Serono in 2019, David Jayne Grant/research support from: ChemoCentryx, GSK, Roche/Genentech, Sanofi-Genzyme, Consultant of: Astra-Zeneca, ChemoCentryx, GSK, InflaRx, Takeda, Insmed, Chugai, Boehringer-Ingelheim, Ricard Cervera: None declared, Nathalie Costedoat-Chalumeau Grant/research support from: UCB to my institution, Betty Diamond: None declared, Dafna D Gladman Grant/research support from: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – grant/research support, Consultant of: AbbVie, Amgen Inc., BMS, Celgene Corporation, Janssen, Novartis, Pfizer, UCB – consultant, Bevra H. Hahn Grant/research support from: Janssen Research & Development, LLC, Falk Hiepe: None declared, Soren Jacobsen: None declared, Dinesh Khanna Shareholder of: Eicos Sciences, Inc./Civi Biopharma, Inc., Grant/research support from: Dr Khanna was supported by NIH/NIAMS K24AR063120, Consultant of: Acceleron, Actelion, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Corbus Pharmaceuticals, Horizon Therapeutic, Galapagos, Roche/Genentech, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme, UCB, Kirsten Lerstrom: None declared, Elena Massarotti: None declared, William Joseph McCune: None declared, Guillermo Ruiz-Irastorza: None declared, Jorge Sanchez-Guerrero: None declared, Matthias Schneider: None declared, Murray B Urowitz: None declared, George Bertsias Grant/research support from: GSK, Consultant of: Novartis, Bimba F. Hoyer: None declared, Nicolai Leuchten: None declared, Chiara Tani: None declared, Sara Tedeschi: None declared, Zahi Touma: None declared, Gabriela Schmajuk Grant/research support from: Pfizer, Branimir Anic: None declared, Florence Assan: None declared, Tak Chan: None declared, Ann E Clarke: None declared, Mary K. Crow: None declared, László Czirják Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Andrea Doria Consultant of: GSK, Pfizer, Abbvie, Novartis, Ely Lilly, Speakers bureau: UCB pharma, GSK, Pfizer, Janssen, Abbvie, Novartis, Ely Lilly, BMS, Winfried Graninger: None declared, Bernadett Halda-Kiss: None declared, Sarfaraz Hasni: None declared, Peter Izmirly: None declared, Michelle Jung: None declared, Gabor Kumanovics Consultant of: Boehringer, Teva, Speakers bureau: Roche, Lilly, Novartis, Xavier Mariette: None declared, Ivan Padjen: None declared, Jose M Pego-Reigosa: None declared, Juanita Romero-Diaz Consultant of: Biogen, Iñigo Rua-Figueroa: None declared, Raphaèle Seror Consultant of: BMS, Medimmune, Novartis, Pfizer, GSK, Lilly, Georg Stummvoll: None declared, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Maria Tektonidou Grant/research support from: AbbVie, MSD, Novartis and Pfizer, Consultant of: AbbVie, MSD, Novartis and Pfizer, Carlos Vasconcelos: None declared, Edward Vital Grant/research support from: AstraZeneca, Roche/Genentech, and Sandoz, Consultant of: AstraZeneca, GSK, Roche/Genentech, and Sandoz, Speakers bureau: Becton Dickinson and GSK, Daniel J Wallace: None declared, Sule Yavuz: None declared, Pier Luigi Meroni: None declared, Marvin Fritzler: None declared, Raymond Naden: None declared, Thomas Dörner Grant/research support from: Janssen, Novartis, Roche, UCB, Consultant of: Abbvie, Celgene, Eli Lilly, Roche, Janssen, EMD, Speakers bureau: Eli Lilly, Roche, Samsung, Janssen, Martin Aringer Consultant of: Boehringer Ingelheim, Roche, Speakers bureau: Boehringer Ingelheim, Roche

Objective Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. Methods An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multicriterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. Results The entry criterion for the new classification criteria requires the occurrence of at least 1 episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (i.e., synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy computed tomography, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). Conclusion The new classification criteria, developed using a data-driven and decision analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout.

Background EULAR and ACR are supporting multi-phase development of SLE classification criteria based on weighted criteria and a continuous probability scale. Prior steps included criteria generation, criteria reduction through Delphi and Nominal Group Technique exercises, literature review for sensitivity/specificity of candidate criteria, and organization of candidate criteria into seven clinical and three immunologic domains. Objectives To refine definitions of candidate criteria, determine relative weights using multicriteria decision analysis, and determine a threshold score for SLE classification. Methods An SLE Expert Panel (9 North American, 8 European) submitted 167 unique cases with a range of SLE probability. Experts scored 20 representative cases using the candidate criteria and rank-ordered them. In a 2-day meeting, experts reviewed inter-rater reliability of scoring, refined criteria definitions, and participated in a multicriteria decision analysis (MCDA) exercise using 1000Minds TM software. Experts were presented a series of decisions between two cases, each with different criteria from two domains (e.g. oral ulcers [cutaneous] and acute pericarditis [serositis] vs. alopecia [cutaneous] and pleural effusion [serositis]) and anonymously voted for the case more likely to be classified as SLE. Votes were discussed until consensus was reached for each decision. Using the consensus decisions, 1000Minds™ calculated criteria weights, assigned a total score to each of remaining 147 cases and rank-ordered the cases. Experts voted on whether each case should be classified as SLE. MCDA was repeated for criteria whose calculated weights were inconsistent with expert opinion until group consensus was achieved. 1000Minds TM then re-calculated criteria weights and re-ranked cases once. The score of the last case for which expert consensus was achieved was the threshold score. Results Inter-rater reliability was good; human data entry error, not following instructions, and differing interpretations of criteria definitions accounted for discrepancies. Arthritis and pericarditis definitions were modified through group discussion. The MCDA involved 74 pairwise decisions. Cranial neuropathy and Class VI lupus nephritis were removed as they added little to SLE classification. MCDA was repeated for the arthritis and cutaneous domains as initial weights did not match expert opinion. After criteria weights and scores were re-calculated once, experts reached consensus for SLE classification for case score >83. Conclusions Using an iterative process, the expert panel refined definitions, weighted candidate criteria and determined a threshold score of >83 for SLE classification, which will undergo validation. Acknowledgements Joint support from EULAR and ACR Disclosure of Interest None declared

OBJECTIVE: To define candidate criteria within multiphase development of systemic lupus erythematosus (SLE) classification criteria, jointly supported by the American College of Rheumatology and the European League Against Rheumatism. Prior steps included item generation and reduction by Delphi exercise, further narrowed to 21 items in a nominal group technique exercise. Our objectives were to apply an evidence-based approach to the 21 candidate criteria, and to develop hierarchical organization of criteria within domains. METHODS: A literature review identified the sensitivity and specificity of the 21 candidate criteria. Data on the performance of antinuclear antibody (ANA) as an entry criterion and operating characteristics of the candidate criteria in early SLE patients were evaluated. Candidate criteria were hierarchically organized into clinical and immunologic domains, and definitions were refined in an iterative process. RESULTS: Based on the data, consensus was reached to use a positive ANA of ≥1:80 titer (HEp-2 cells immunofluorescence) as an entry criterion and to have 7 clinical and 3 immunologic domains, with hierarchical organization of criteria within domains. Definitions of the candidate criteria were specified. CONCLUSION: Using a data-driven process, consensus was reached on new, refined criteria definitions and organization based on operating characteristics. This work will be followed by a multicriteria decision analysis exercise to weight criteria and to identify a threshold score for classification on a continuous probability scale.

Contains fulltext : 137489.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc. STUDY DESIGN AND SETTING: A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs). RESULTS: Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90). CONCLUSIONS: Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.

OBJECTIVE: The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS: Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS: It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION: The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Summary: Doppler studies of the arcuate and umbilical arteries were performed longitudinally commencing at 24 weeks or less, in 29 pregnant women with chronic hypertension. The hypothesis was that pregnant women with chronic hypertension who develop superimposed gestational proteinuric hypertension and/or deliver small for gestational age babies are those who have abnormal arcuate and/or umbilical flow velocity waveforms. Abnormal arcuate waveforms occurred in 7 women and abnormal umbilical waveforms in 12. Nine babies were small for gestational age, and 6 of them had abnormal arcuate waveforms. Abnormal arcuate waveforms were significantly associated with the delivery of a small for gestational age baby (p = .001) and identified those babies where early delivery was necessary for fetal reasons. All small for gestational age babies had abnormal umbilical waveforms. Superadded gestational proteinuria (or preeclampsia) occurred in 8 pregnancies, however only 3 had abnormal arcuate waveforms. An abnormal arcuate waveform did not predict the later development of gestational proteinuria. An abnormal umbilical waveform however, was associated with the subsequent development of gestational proteinuria. We consider that these findings need to be confirmed in a larger study.

Contains fulltext : 152283.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Existing criteria for the classification of gout have suboptimal sensitivity and/or specificity, and were developed at a time when advanced imaging was not available. The current effort was undertaken to develop new classification criteria for gout. METHODS: An international group of investigators, supported by the American College of Rheumatology and the European League Against Rheumatism, conducted a systematic review of the literature on advanced imaging of gout, a diagnostic study in which the presence of monosodium urate monohydrate (MSU) crystals in synovial fluid or tophus was the gold standard, a ranking exercise of paper patient cases, and a multicriterion decision analysis exercise. These data formed the basis for developing the classification criteria, which were tested in an independent data set. RESULTS: The entry criterion for the new classification criteria requires the occurrence of at least 1 episode of peripheral joint or bursal swelling, pain, or tenderness. The presence of MSU crystals in a symptomatic joint/bursa (i.e., synovial fluid) or in a tophus is a sufficient criterion for classification of the subject as having gout, and does not require further scoring. The domains of the new classification criteria include clinical (pattern of joint/bursa involvement, characteristics and time course of symptomatic episodes), laboratory (serum urate, MSU-negative synovial fluid aspirate), and imaging (double-contour sign on ultrasound or urate on dual-energy computed tomography, radiographic gout-related erosion). The sensitivity and specificity of the criteria are high (92% and 89%, respectively). CONCLUSION: The new classification criteria, developed using a data-driven and decision analytic approach, have excellent performance characteristics and incorporate current state-of-the-art evidence regarding gout. 01 oktober 2015

Objective The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. Methods Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. Results It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. Conclusion The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease. Copyright © 2013 by the American College of Rheumatology.

Background The existing 1980 classification criteria for systemic sclerosis (SSc) are suboptimal for patients with early SSc and some patients with limited cutaneous SSc (lcSSc) where an important subset do not meet those criteria. Objectives To develop and test new classification criteria for SSc by a joint EULAR and ACR committee. Methods Delphi exercises and a nominal group technique were used to create a set of potential items for classification of SSc. Twenty cases were prospectively collected to represent the spectrum of SSc (low probability to high probability) which were ranked by SSc experts and conjoint analysis (1000 Minds®) was used to assign weights to the items and reduce the number of items. Experts agreed that all patients with sclerodactyly and scleroderma skin involvement proximal to the MCPs were considered SSc; patients with skin involvement due another scleroderma-like disorder (e.g. scleromyxedema) or skin thickening sparing the fingers were not regarded to have SSc. The provisional classification system was tested in a random sample of SSc cases and controls of 100 from North America and 100 from Europe (derivation sample). The system was simplified and calibrated to real cases. The classification system was re-analyzed in another sample of SSc cases and controls (validation set; n=405). Results The table provides the final items with the proposed weights. Only the maximum score in each domain is counted. A cut-off of >= 9 (out of 19) had a sensitivity of 91% and specificity of 92% in the validation cohort (n=405). The sensitivity and specificity of the former 1980 ARA criteria in this database were 75% and 72%, respectively. These results are preliminary and not yet approved by the organizational sponsors. Conclusions The preliminary results of the classification criteria for SSc performed better than 1980 Preliminary ARA Criteria for SSc. These criteria can be endorsed for epidemiological studies and clinical trials after approval by ACR and EULAR. Disclosure of Interest None Declared

Indomethacin administration has produced decreases in uteroplacental blood flow in several animal studies; therefore, it has been suggested that the maintenance of uterine blood flow is critically dependent on the continued synthesis of vasodilating prostaglandins. However, vasoconstriction following indomethacin administration may be due to mechanisms other than reduced prostaglandin synthesis. We administered indomethacin (2, 5, or 10 mg/kg) intravenously to seven unanesthetized sheep in late pregnancy and determined the time courses of the uteroplacental and systemic hemodynamic responses, comparing these to the concurrent changes in circulating prostaglandins. Indomethacin administration resulted in rapid increases in systemic and uteroplacental vascular resistance (80% to 100%) and mean arterial pressure (approximately 30%) and in decreases in systemic (approximately 30%) and uteroplacental (0% to 30%) blood flows within 5 minutes. Vasoconstriction was transient, however, and after 60 minutes there was no evidence of uterine or systemic vasoconstriction, although systemic and uterine plasma prostaglandin levels remained reduced for 180 minutes. Thus substantial inhibition of prostaglandin synthesis existed without evidence of concurrent systemic or uteroplacental vasoconstriction, suggesting that uterine blood flow is not directly dependent on maintained prostaglandin synthesis in unstressed pregnant sheep. Furthermore, the transient indomethacin-induced vasoconstriction may not be due to inhibition of prostaglandin synthesis.

This review addresses the following questions: When is drug treatment indicated? What are the adverse consequences of hypertension? What are the possible benefits of antihypertension drug treatment and what is the evidence that these can be achieved? Are these benefits outweighed by the adverse effects of treatment? What are the drugs of choice, and how can they be best used?

The response of uteroplacental blood flow (UBF) to angiotensin II is controversial. Moreover, the relationship of the uterine and systemic responses to infused angiotensin II is not well understood. Thus, in eight chronically instrumented, near-term pregnant sheep, we have determined the relationships between the dose and duration of constant systemic infusions of angiotensin II ([Val5] ANG II) and changes in UBF, uterine vascular resistance (UVR), mean arterial pressure (MAP), and systemic vascular resistance (SVR). [Val5] ANG II caused dose-dependent increases in UVR and MAP at all doses studied (P less than 0.05). The response in UBF was bidirectional, with increases at doses less than or equal to 1.15 microgram/min and decreases at greater than or equal to 2.29 micrograms/min (P less than 0.05). Increases in UBP occurred when the relative rise (delta) in MAP greater than delta UVR, whereas UBF was unchanged when delta MAP = delta UVR and decreased when delta MAP less than delta UVR. SVR also rose in a dose-dependent fashion (P less than 0.05); delta SVR was greater than delta UVR at doses less than or equal to 2.29 micrograms [Val5] ANG II/min (P less than 0.01). In studies of the effect of duration of [Val5] ANG II infusions, UBF increased at all doses during the 1st min, followed by stabilization at 4--5 min, with eventual decreases at doses greater than or equal to 2.29 micrograms/min and increases at doses less than 2.29 micrograms/min. The relationship between the changes in MAP and UVR to the response of UBF was as noted above. It is evident that (a) [Val5] NAG II is uterine vasoconstrictor, (b) changes in UBF are dependent upon relative changes in perfusion pressure and UVR, which in turn are dependent upon both the dose and duration of a [Val5] ANG II infusion, and (c) the uteroplacental vasculature is relatively refractory to the vasoconstricting effects of low doses of [Val5] ANG II.

It is unclear whether the fetus is affected by maternal infusions of angiotensin II; therefore we studied maternal and fetal responses (n = 9) to angiotensin II (1.15, 2.29, 11.5 micrograms/min) infused 5 minutes into the vena cava of chronically instrumented sheep (129 to 137 days of gestation) while monitoring PO2, PCO2, pH, heart rate, uterine blood flow, and arterial and umbilical venous pressures. Pregnant sheep demonstrated expected dose-related increases in mean arterial pressure and decreases in uterine blood flow (p less than 0.05). Increases in fetal mean arterial pressure also correlated with the maternal dose of angiotensin II (r = 0.77, p less than 0.001). Fetal heart rate appeared to increase with 2.29 micrograms/min; however, bradycardia was observed with 11.5 micrograms/min (p less than 0.05) and was associated with decreased PaO2, 19.0 +/- 1.0 to 14.3 +/- 1.4 mm Hg (p less than 0.05), increased PaO2 (p less than 0.05), and decreased umbilical venous PO2, 31.4 +/- 2.3 to 27.0 +/- 1.9 mm Hg. The decreases in PO2 correlated with decreases in uterine blood flow (r = 0.60, p less than 0.002, and r = 0.75, p less than 0.005, respectively). Nevertheless, changes in fetal mean arterial pressure also occurred in the absence of altered fetal oxygenation; thus decreased uterine blood flow and fetal oxygenation alone cannot explain the fetal cardiovascular responses. It is suggested that angiotensin II or an active metabolite may cross the ovine placenta.

Reduced vascular responsiveness to infused angiotensin II (ANG II) has been observed during pregnancy. It has been proposed that infusions produce lower circulating concentrations of ANG II in pregnancy, due to an increase in the metabolic clearance rate of ANG II (MCRangii). We have evaluated the MCRangii and the arterial plasma concentrations of ANG II during constant infusions of 1.15 micrograms ANG II/min into chronically instrumented pregnant (n = 6) and nonpregnant (n = 9) sheep. Although the pressor responses were significantly less in the pregnant than in the nonpregnant sheep (17.5 +/- 0.5 vs. 34.9 +/- 3.2 mmHg, P less than 0.001), the values for MCRangii were not different: 56.2 +/- 6.3 ml X min-1 X kg-1 in nonpregnant and 55.9 +/- 4.3 ml X min-1 X kg-1 in pregnant sheep. The steady-state plasma ANG II concentrations during the infusions were slightly less in pregnant than in nonpregnant sheep (388 +/- 36 vs. 454 +/- 36 pg/ml); however, this difference would be responsible for only a 2-mmHg reduction in the pressor response. We conclude that the reduced pressor response to infused ANG II in pregnancy is not due to an increase in MCRangii nor to lower plasma ANG II concentrations.

A reduced pressor response to infused angiotensin II has been observed in pregnancy. Although this has been considered to reflect reduced sensitivity of the peripheral vasculature to angiotensin II, it has also been suggested that the reduced pressor response is due to a fall in cardiac output during infusion of angiotensin II in pregnancy. In the present study we investigated the hemodynamic responses to infused angiotensin II in chronically instrumented, pregnant and nonpregnant sheep. We measured changes in cardiac output and systemic vascular resistance and related these changes to the increase in mean arterial pressure. The response in systemic vascular resistance to angiotensin II was substantially reduced in pregnant sheep. During angiotensin II infusion cardiac output fell in both groups, but the effect of the fall in cardiac output in reducing the pressor response was greater in nonpregnant animals. Thus, it appears that the reduced pressor response to angiotensin II in pregnant sheep is due to reduced systemic vascular responsiveness and not to differences in cardiac output responses.

Increased fetal secretion of arginine vasopressin (AVP) occurs in association with complicated pregnancies, asphyxia, and meconium-stained amniotic fluid (AF); yet, the role of AVP in fetal homeostasis remains unclear. Using chronically instrumented, near-term lamb fetuses (n = 8), we have ascertained the cardiovascular responses to doses of AVP ranging from 1.94 to 8.73 mU/min, the clearance of AVP from plasma, and the occurrence of meconium release into AF during AVP infusions. AVP administration resulted in a dose-related rise in arterial pressure; although heart rate fell, the decline was not dose-related and occurred before the pressor response. Clearance of plasma AVP was 60 +/- 8.7 ml X kg-1 X min-1, and the half-time in plasma was 2.8 min. AVP was not cleared across the fetal placenta nor by fetal-maternal transport. However, the AF concentration of AVP rose fourfold after the infusion of AVP was stopped. Meconium release into AF occurred in fetuses infused with AVP at rates greater than or equal to 7.76 mU/min. AVP has hemodynamic effects that mimic fetal responses to intrauterine "stress" and may be causally associated with the fetal release of meconium into AF. Furthermore, plasma AVP is cleared in part by the fetal kidney.

Refractoriness to infused angiotensin II is characteristic or normal human and ovine pregnancy; the mechanisms responsible are unclear. In this study, we sought to ascertain in gravid sheep whether hypertonic saline solution alters the vascular responses to angiotensin II, as in gravid women, and to compare the responses of the systemic and uteroplacental vasculature. Dose-response curves were determined. Mean arterial pressure and systemic vascular resistance increased in a dose-dependent fashion before and after hypertonic saline solution; responses were greater after hypertonic saline solution (p less than 0.01). Responses of cardiac output, heart rate, uterine vascular resistance, and uterine blood flow also were dose-dependent, but were unchanged after hypertonic saline solution. Plasma renin activity fell 45% after hypertonic saline solution. Treatment with hypertonic saline solution results in increased pressor responses to angiotensin II that are not a reflection of altered baroreceptor or chemoreceptor reflexes or of the response in the uteroplacental vascular bed. Rather, the increased systemic vascular responsiveness to angiotensin II after hypertonic saline solution appears to be a reflection of other mechanisms, such as alterations in vessel wall dynamics or receptor affinity.

Vascular refractoriness to infused angiotensin II (AII) characterizes normal human and ovine pregnancy. To ascertain whether the refractoriness in the gravid ewe is mediated by either endogenous plasma concentrations of renin and AII or vasomotor reflexes, effects of acute volume expansion (VE) on the pressor response to AII were studied in chronically instrumented nonpregnant and near-term pregnant sheep. Dose-response curves describing the pressor response (delta BP) were determined before and after infusions of 1.0 1 of isotonic saline (NS) or 0.5 1 of 10% dextran (D). In nonpregnant sheep, hematocrit (Hct) and plasma renin activity (PRA) fell in all animals after NS (n = 7) and D (n = 6) (P less than 0.005). After VE with NS and D, delta BP increased at each dose of AII (P less than 0.05). The pressor response to AII in pregnant sheep was not altered by NS although decreases in Hct and PRA were comparable to those in nonpregnant sheep. Baroreceptor responses were not altered. Vascular refractoriness to infused AII in pregnant sheep is not due primarily to changes in plasma concentrations of renin-AII but more likely to another factor, vessel wall refractoriness. In this respect, the ewe is similar to the human.

Summary: Maternal and fetal plasma concentrations of arginine vasopressin (AVP) during asphyxial and hypoxemic episodes were ascertained between 130 and 140 days of gestation in chronically catheterized sheep. During an acute asphyxial stress, i.e., decreased PaO2 and pHa and increased PaCO2, maternal AVP in plasma was unaltered, whereas fetal arterial plasma concentrations rose from 1.6–2.2 μ/ml to 34–385 μ/ml and were associated with massive expulsion of meconium into the amniotic fluid. Mild hypoxemia, induced while the mother breathed a gas mixture consisting of 85% nitrogen and 15% oxygen, did not affect either maternal or fetal plasma AVP concentrations. The use of 10% inspired oxygen resulted in 60% and 50% reductions in maternal and fetal PaO2, respectively (P < 0.05). In this instance, the maternal plasma AVP levels were unchanged, whereas the fetal plasma AVP concentration rose from a mean of 2.61 ± 0.14 (SE) to 10.2 ± 2.59 μ/ml (P < 0.025) within 30 min. Expulsion of meconium into the amniotic fluid did not occur. No evidence of either fetal-maternal placental transfer or fetal-placental clearance of plasma AVP was obtained. Although hypoxemic stress resulted in an elevation of fetal plasma AVP concentration, it does not appear to be the sole factor responsible for AVP release during intrauterine stress. It is suggested that substantial elevations in fetal plasma AVP concentrations may play an integral role in the fetal expulsion of meconium into the amniotic fluid. Speculation: Elevations in fetal plasma concentrations of arginine vasopressin are reflective of intrauterine stress and may be representative of an adaptive mechanism whereby the fetus responds to hypoxemia and asphyxia. Measurement of fetal plasma arginine vasopressin, i.e., cord plasma levels, may serve as an indicator of the degree or severity of intrauterine stress. Moreover, increases in arginine vasopressin during fetal asphyxia could be important in the fetal expulsion of meconium into the amniotic sac, thereby establishing the situation necessary for meconium aspiration.

The uteroplacental vasculature is more refractory to angiotensin II (ANG II) than the systemic vasculature as a whole. To ascertain the differences in responses between reproductive and nonreproductive tissues that account for this, we infused ANG II (0.573, 5.73, and 11.5 micrograms/min) in pregnant sheep (137 +/- 5 days of gestation) and monitored arterial pressure (MAP), heart rate, and uterine blood flow (UBF); cardiac output and regional blood flows were measured with radiolabeled microspheres. Dose-dependent changes in MAP, UBF, and systemic (SVR) and uterine (UVR) vascular resistance occurred (P less than 0.05); systemic responses exceeded uterine (P less than 0.05), except with 11.5 micrograms/min, when % delta UVR = % delta SVR, % delta UVR greater than % delta MAP, and UBF fell 29%. Although a dose-dependent rise in placental resistance occurred, blood flow was unaffected except at 11.5 micrograms ANG II/min, falling 16.8 +/- 3.5% (P = 0.059). In contrast, endometrial perfusion decreased 68 +/- 4.2 and 81 +/- 1.8% (P less than 0.01) with 5.73 and 11.5 micrograms ANG II/min, respectively. Myometrial responses were intermediate, thus placental flow increased from 75 to greater than 90% of total UBF. Adipose, renal, and adrenal glands were extremely sensitive to ANG II, with blood flows decreasing maximally at 0.573 micrograms/min (P less than 0.05). Maximum adipose vascular resistance occurred at 0.573 micrograms/min, greater than 400% (P less than 0.001), exceeding responses in all tissues (P less than 0.05). The placenta is less responsive to ANG II than other uterine and most nonreproductive tissues, resulting in preferential maintenance of uteroplacental perfusion and protecting the fetus from the effects of this vasoconstrictor.

Pregnancy is associated with uterine and systemic vasodilation and reduced vascular reactivity to angiotensin II and perhaps norepinephrine. The uteroplacental vasculature is relatively refractory to angiotensin II but very sensitive to norepinephrine. To investigate the possible role of the high levels of estrogen in pregnancy mediating these hemodynamic changes, we examined systemic and uterine vascular responsiveness to angiotensin II and norepinephrine in eight chronically instrumented nonpregnant sheep treated with 17 beta-estradiol. In these animals, 17 beta-estradiol produced significant systemic and uterine vasodilation without changing arterial pressure; cardiac output increased from 5.3 +/- 0.3 to 6.7 +/- 0.4 L/min, and uterine blood flow increased from 26 +/- 3 to 218 +/- 13 ml/min (mean +/- SE). Treatment with 17 beta-estradiol reduced the increases in systemic vascular resistance produced by angiotensin II and norepinephrine by 25% and 35%, respectively. After 17 beta-estradiol treatment, the uterine vascular responses were compared to the systemic vascular responses; the uterine responses to angiotensin II were only half the systemic responses, whereas the uterine responses to norepinephrine were six times greater than the systemic responses and were associated with decreases in uterine blood flow of 35% to 40%. These hemodynamic features of nonpregnant sheep treated with estrogen are strikingly similar to previous observations in sheep during pregnancy.

Estradiol-17 beta (E2) produces vasodilation in several systemic vascular beds, but most extensively in the nonpregnant uterus. It has been postulated that E2 induces this vasodilation via blockade of vascular alpha-adrenergic receptors. This hypothesis was tested in six chronically instrumented, nonpregnant sheep by comparing the systemic and uterine hemodynamic responses to intravenous E2, to an alpha-adrenergic receptor blocker, phentolamine, and to both agents given together. Uterine blood flow (UBF) increased significantly after E2 administration, from 20 +/- 7 to 233 +/- 37 (SE) ml/min. In contrast, phentolamine had no detectable effect on UBF or on the UBF response to E2 when both were given together. Similar contrasting responses were observed in the effects of E2 and/or phentolamine on the systemic vasculature. When responses to alpha-agonists were evaluated, there was no evidence of alpha-blockade following E2 despite the substantial vasodilation; in contrast, alpha-blockade was present during phentolamine administration when no vasodilation was noted. Therefore, we conclude that E2-induced vasodilation in chronically instrumented sheep is not mediated through blockade of vascular alpha-adrenergic receptors.

The concentration of AVP has been shown by us to be elevated in the human and lamb fetus during perinatal stress, especially hypoxia and asphyxia, with levels being greatest in association with meconium in the amniotic fluid (AF). The role of AVP in these instances is unclear; thus, we studied in fetal lambs the cardiovascular effects and clearance of infused AVP. AVP was infused into the vena cava of fetal lambs, 129-137 days gestation, at doses of 1.94, 3.88, and 7.76 mU/min for 75 min (n=5) while monitoring fetal and maternal mean arterial pressure (MAP), heart rate (HR), and umbilical and uterine blood flows. Samples were obtained for serial determinations of fetal plasma and AF AVP in 3 studies. Fetal plasma AVP rose from 2.0 ± .02 μU/ml (Mean ± SE) to 12 to 67 μU/ml at 60 min without changes in arterial blood gases. AF AVP increased at 60 and 120 min post-infusion, but did not correlate with plasma levels. Fetal MAP at 60 min rose 16 to 24%* while HR fell 9 to 43%*; both responses were dose dependent. Umbilical and uterine blood flows and maternal MAP and HR did not change. Of note, meconium stained AF occurred in association with intermediate and high rates of AVP infusions. The T1/2 of AVP in fetal plasma was 14 ± 2.5 min and the clearance was 51 ± 10 ml/min.kg. We conclude that AVP 1) causes a rise in MAP and fall in HR that relates to circulating levels of AVP, suggesting AVP may mediate these changes during episodes of fetal stress, and 2) may be responsible for the expulsion of meconium into the AF during such episodes. *p < .01