The prevalence and treatment outcomes of antineuronal antibody-positive patients admitted with first episode of psychosis.

BACKGROUND: Antineuronal antibodies are associated with psychosis, although their clinical significance in first episode of psychosis (FEP) is undetermined. AIMS: To examine all patients admitted for treatment of FEP for antineuronal antibodies and describe clinical presentations and treatment outcomes in those who were antibody positive. METHOD: Individuals admitted for FEP to six mental health units in Queensland, Australia, were prospectively tested for serum antineuronal antibodies. Antibody-positive patients were referred for neurological and immunological assessment and therapy. RESULTS: Of 113 consenting participants, six had antineuronal antibodies (anti-N-methyl-D-aspartate receptor antibodies [n = 4], voltage-gated potassium channel antibodies [n = 1] and antibodies against uncharacterised antigen [n = 1]). Five received immunotherapy, which prompted resolution of psychosis in four. CONCLUSIONS: A small subgroup of patients admitted to hospital with FEP have antineuronal antibodies detectable in serum and are responsive to immunotherapy. Early diagnosis and treatment is critical to optimise recovery. DECLARATION OF INTEREST: None.

Antiphospholipid antibody testing for the antiphospholipid syndrome: a comprehensive practical review including a synopsis of challenges and recent guidelines.

The antiphospholipid (antibody) syndrome (APS) is an autoimmune condition characterised by a wide range of clinical features, but primarily identified as thrombotic and/or obstetric related adverse events. APS is associated with the presence of antiphospholipid antibodies (aPL), including the so-called lupus anticoagulant (LA). These aPL are heterogeneous in nature, detected with varying sensitivity and specificity by a diverse range of laboratory tests. All these tests are unfortunately imperfect, suffer from poor assay reproducibility (inter-method and inter-laboratory) and a lack of standardisation and harmonisation. Clinicians and laboratory personnel may struggle to keep abreast of these factors, as well as the expanding range of available aPL tests, and consequent result interpretation. Therefore, APS remains a significant diagnostic challenge for many clinicians across a wide range of clinical specialities, due to these issues related to laboratory testing as well as the ever-expanding range of reported clinical manifestations. This review is primarily focussed on issues related to laboratory testing for APS in regards to the currently available assays, and summarises recent international consensus guidelines for aPL testing, both for the liquid phase functional LA assays and the solid phase assays (anticardiolipin and anti-beta-2-Glycoprotein-I).

Diagnostic value of distinguishing and reporting different perinuclear ANCA (P-ANCA) immunofluorescence patterns: a prospective study.

OBJECTIVES: To investigate whether discriminating the classic perinuclear antineutrophil cytoplasmic antibody (P-ANCA) pattern from atypical P-ANCA and uninterpretable patterns improves the diagnostic utility of ANCA testing. METHODS: All ANCA requests (n = 3,544) referred to Pathology Queensland were analyzed prospectively over 4 months for P-ANCA pattern subtypes and myeloperoxidase (MPO)-ANCA/PR3-ANCA results and correlated with clinical, laboratory, and radiologic evidence of necrotizing small vessel vasculitis. RESULTS: Of the 436 perinuclear immunofluorescence-positive samples, 45 were classic P-ANCA, 163 were atypical P-ANCA, and 228 were antinuclear antibodies/uninterpretable. The classic P-ANCA pattern had a significantly stronger association with vasculitis (30/45) than atypical P-ANCA (2/163) (P <.0001) or ANA/uninterpretable patterns (8/228) (P <.0001). The combination of a classic P-ANCA pattern and positive MPO-ANCA/PR3-ANCA result was also more strongly associated with vasculitis than a positive MPO-ANCA/PR3-ANCA result in isolation (P = .003). CONCLUSIONS: This study demonstrates that reporting different P-ANCA patterns (including ANA/uninterpretable patterns) provides additional diagnostic information to MPO-ANCA/PR3-ANCA results.

Internal quality control and external quality assurance in testing for antiphospholipid antibodies: Part I--Anticardiolipin and anti-ß2-glycoprotein I antibodies.

Over 30 years since it was first described as a discrete clinical entity, the antiphospholipid antibody syndrome (APS) remains a challenge for both laboratory workers and clinicians in a wide range of specialties. In addition to the presence of appropriate clinical features, the diagnosis of APS also fundamentally requires the finding of positive antiphospholipid antibody (aPL) test result(s), which comprise clot-based assays for the identification of lupus anticoagulant (LA) and immunologic ("solid-phase") assays such as anticardiolipin antibodies (aCL) and anti-ß2-glycoprotein I antibodies (aß2GPI). This article is the first of two that review the process for, and provides recommendations to improve, internal quality control (IQC) and external quality assurance (EQA; or proficiency testing) for aPL assays. These processes are critical for ensuring the quality of laboratory test results and thence the appropriate clinical diagnosis and management of APS. This article covers aCL and aß2GPI testing. In brief, IQC is a process that helps control the quality of laboratory test results on a test-by-test basis; IQC should include samples that provide values around the assay critical cut-off values, and there is added value in the inclusion of non-kit assay controls. EQA is a process that helps laboratories assess their performance against those of their peers. For aCL and aß2GPI testing, we provide some updated findings from the Royal College of Pathologists of Australasia Immunology Quality Assurance Program, and covering testing for the past 3 years (2009 to 2011 inclusive). Findings show similar trends to past years, indicating limited improvement in cross-laboratory test results and interpretations. In summary: (1) EQA participants reported greatly varying numerical test data for both aCL and aß2GPI, with interlaboratory coefficients of variation > 50% with most test challenges; (2) there was considerable overlap in the interpretation (negative, positive, low positive, moderate positive, strong positive) that different participants ascribed to identical numerical test results; and (3) there was limited consensus among participants as to whether test results for individual EQA specimens were either positive or negative for aCL and/or aß2GPI.

Rarer clinical associations of antiphospholipid antibodies.

Detection of antiphospholipid antibodies (aPL) are central to the definition of the antiphospholipid (antibody) syndrome (APS). Thrombosis in certain vascular beds, such as the cerebral circulation, the veins of the lower legs and cutaneous vessels, and/or fetal loss, are common manifestations of APS. However, aPL have been found in association with a large range of other clinical conditions-these conditions constitute a rather heterogeneous group and are the subject of this review. Thus, aPL may rarely be found in association with thromboses of vascular beds other than those commonly associated with APS. The combination of thrombosis and aPL still satisfies the criteria for APS, and management of this group of patients is the same as that of APS associated with the more common manifestations of the disease. Alternatively, aPL may be detected in a range of conditions where thrombosis cannot be clearly demonstrated, such as duodenal ulcer or transverse myelopathy. The approach to management of patients who have aPL in association with these conditions is less clear, although in some cases interventions to remove the associated antibody have been associated with amelioration of the condition. Finally, in several studies, aPL have been detected in a proportion of patients with conditions occurring commonly in the normal population-these findings have to be treated with caution in view of inconsistent findings between the reported results and methodological limitation of studies purporting to show positive results.

Standards and reference materials for the anticardiolipin and anti-ß2glycoprotein I assays: a report of recommendations from the APL Task Force at the 13th International Congress on Antiphospholipid Antibodies.

BACKGROUND: The confirmation of diagnosis of the Antiphospholipid Syndrome (APS) relies on laboratory tests. Current classification criteria for definite APS mandate the use of three "standardized" laboratory assays to detect antiphospholipid antibodies (aPL) [viz: anticardiolipin (aCL) IgG and IgM, anti-ß(2)glycoprotein I (anti-ß(2)GPI) antibodies IgG and IgM and/or a lupus anticoagulant (LAC)], when at least one of the two major clinical manifestations (thrombosis or pregnancy losses) are present. Several attempts have been made to standardize the aCL and anti-ß(2)GPI tests, though, a considerable degree of inconsistencies still exist, limiting the clinical and diagnostic value of aPL tests. Among the areas of concern are the type and source of calibrant material, the lack of proper validated reference material and of universal units of measurement, particularly for anti-ß(2)GPI antibodies. CONTENT: A Task Force of scientists and leaders in the field from different countries - discussed and analyzed those critical questions in an evidence-based manner and further discussed and made recommendations at a workshop that was conducted during 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13-16, 2010, Galveston, TX). SUMMARY: This concise report summarizes the findings, conclusions and recommendations of the task force and preconference workshop. The group recommended to ensure the availability of properly prepared and validated polyclonal and monoclonal antibody reference materials for both assays, to continue reporting the aCL assay in GPL/MPL units and to establish consensus international units of measurement for anti-ß(2)GPI antibodies.

Laboratory testing for the antiphospholipid syndrome: making sense of antiphospholipid antibody assays.

The antiphospholipid syndrome (APS) is an autoimmune condition characterised by a wide range of clinical features (primarily thrombosis and/or obstetric related), associated with the presence of antiphospholipid antibodies (aPL) as detected by a diverse range of laboratory tests. APS remains a significant diagnostic challenge for clinicians across a wide range of specialities, largely due to issues related to laboratory testing as well as the expanding range of reported clinical manifestations of APS. The laboratory issues include limitations in detailed knowledge by both clinical and laboratory personnel regarding the 'complete' range of available aPL tests, as well as ongoing problems with assay reproducibility and standardisation. aPL are identified using diverse laboratory procedures based on one of two distinct test processes, namely solid phase and liquid phase assays. The former includes anticardiolipin antibodies (aCL) and anti-ß(2)-glycoprotein I antibodies (aß(2)GPI). The latter are centred on clot-based tests that are used to identify the so-called lupus anticoagulant (LA). This article will discuss: (i) issues related to laboratory testing for APS in terms of the currently available solid-phase and liquid-phase assays, and identifiable biases resulting from these tests usually being performed in different laboratories; (ii) current problems with calibration, standardisation and reproducibility of these assays; (iii) pre-analytical, analytical and post-analytical considerations and ongoing initiatives for improvement; (iv) issues related to potential combinations/panels of available aPL tests; and (v) the entities of seropositive APS, seronegative APS and non-APS aPL-positivity. In doing so, this review will hopefully help bridge the two disciplines of haematology and immunology ('representing' liquid-phase and solid-phase aPL testing, respectively), by improving the understanding of those working in each of these disciplines of the merits and limitations of the assays performed in the other discipline, and encouraging inter-discipline cooperation in the reporting of aPL test results.

The antiphospholipid syndrome: a large elephant with many parts or an elusive chameleon disguised by many colours?

The antiphospholipid syndrome (APS) is characterized by a range of clinical features (primarily thrombosis and/or obstetric-related), together with the presence of antiphospholipid antibody (aPL) as detected by a diverse range of laboratory tests. APS remains a significant diagnostic and management challenge for clinicians across a wide range of specialties, some 30 years after APS was first described as a discrete clinical entity. This is due to ongoing issues regarding nomenclature, the diagnosis of APS in individual patients, the expanding range of recognized clinical manifestations and of APS-related laboratory tests, and management issues in particular APS patient subgroups (including obstetric and catastrophic APS). In addition to the presence of appropriate clinical features, the diagnosis of APS fundamentally requires the finding of positive aPL test result(s), which is hampered by ongoing problems with assay reproducibility and standardization. This review focuses on ongoing dilemmas and issues related to clinical and laboratory aspects of APS including: (1) diagnostic challenges posed by the protean clinical manifestations of APS; (2) current nomenclature and recent proposals for revision of the 2006 international classification criteria; (3) an overview of some key issues related to aPL testing; (4) potential pitfalls of applying the APS classification criteria as diagnostic criteria; and (5) the controversial subgroups of seronegative APS and non-APS aPL positivity.

Current clinical and laboratory practice for the investigation of the antiphospholipid syndrome: findings from the 2008 Australasian antiphospholipid antibody survey.

BACKGROUND: The antiphospholipid syndrome (APS) is an autoimmune condition characterised by vascular thromboses and/or pregnancy morbidity, and its diagnosis currently requires laboratory evidence for the presence of antiphospholipid antibodies (aPL). aPL are identified using a large number of laboratory procedures based on one of two distinct test processes, namely 'solid' or 'liquid' phase assays. The former include anticardiolipin antibodies (aCL) and anti-beta-2-glycoprotein-I antibodies (aB2GPI), while the latter are centred on clot-based tests used to identify the lupus anticoagulant (LA). Depending on their clinical presentation, affected individuals might be seen by a variety of clinical specialties including general physicians and general practionners, with a potentially wide variation in the aPL assays requested. METHODS: The current report summarises findings from the '2008 Australasian antiphospholipid antibody survey', a simple 5-step survey that assessed current clinical and laboratory practice in the investigation of APS. The survey was despatched via various clinical and scientific professional bodies. RESULTS: Responses were received from 130 scientific and clinical personnel, primarily haematology based (94/130; 72%) or immunology based (34/130; 26%). Most respondents (97/130; 75%) ordered or recommended tests for solid phase aPL testing, and most also attempted to grade these tests and their isotypes. Most were familiar with aCL and aB2GPI testing, and tended to request primarily IgG and IgM isotypes of these antibodies. Only a small number of respondents requested/recommended IgA isotype testing of these antibodies or the other solid phase aPL assays (e.g., anti-prothrombin). A similar number of respondents (104/130; 80%) also ordered or recommended tests for LA, and most also attempted to grade these tests and their isotypes. Some discipline-related biases were also evident, in that 32/34 (94%) of immunology-based respondents identified that they ordered or recommended specific solid phase tests for aPL, whereas only 62/94 (66%) of haematology-based respondents did so. In contrast, 83/94 (88%) of haematology-based respondents identified that they ordered or recommended specific LA test procedures, whereas only 18/34 (53%) of immunology-based respondents did so. CONCLUSION: To our knowledge, this report represents the first ever attempt to survey a wide range of clinical and scientific personnel regarding ordering and recommending practices for aPL testing, and provides a snapshot of current clinical and laboratory practice for the investigation of APS in Australia and New Zealand. Most respondents to our survey still consider the immunoglobulin G (IgG) aCL test to be a useful first-line solid phase aPL test, and the dilute Russell's viper venom time (dRVVT) assay to be the most useful LA test.

A consensus approach to the formulation of guidelines for laboratory testing and reporting of antiphospholipid antibody assays.

Despite numerous past and ongoing efforts, there remains significant variation in results from assays for the major antiphospholipid antibodies (aPL), namely anticardiolipin (aCL), anti-beta2 glycoprotein I (anti-beta2GPI), and lupus anticoagulant (LA). There is therefore a need to produce comprehensive guidelines on laboratory testing and reporting of aPL assays. However, because of the paucity of good-quality published evidence, there is a heavy reliance on expert opinion, and thus the existing consensus guidelines for aPL testing and reporting are largely eminence based rather than evidence based. This may potentially bias recommendations to reflect the personal preferences of those who have the greatest influence during the guideline formulation process. This article largely details the experience of the Australasian Anticardiolipin Working Party in undertaking a consensus approach to formulation of guidelines on aCL and anti-beta2GPI testing and reporting, including measures taken to minimize these issues. Despite the time-consuming nature of the process, given the paucity of good-quality published evidence, formulation of guidelines by the consensus process remains an important initiative to improve the standardization of aPL testing and reporting.

Laboratory testing and identification of antiphospholipid antibodies and the antiphospholipid syndrome: a potpourri of problems, a compilation of possible solutions.

The antiphospholipid syndrome (APS) is an autoimmune condition characterized by vascular thromboses and/or pregnancy morbidity, and its diagnosis currently requires laboratory evidence of the presence of antiphospholipid antibodies (aPL). aPL are in turn identified using a large number of laboratory procedures based on one of two distinct test processes, namely solid-phase assays and liquid-phase assays. The former includes anticardiolipin antibodies and anti-beta2 glycoprotein I antibodies, and the latter are centered on clot-based tests that are used to identify the so-called lupus anticoagulant. The current article provides an overview of the laboratory testing and identification of aPL, and in particular the limitations, standardization, and clinical utility of such testing. We also review preanalytical, analytical, and postanalytical issues that compromise the clinical utility of these tests. Finally, we provide a list of recommendations aimed to foster broader international cooperation to assist in the preparation of integrated guidelines, for both solid-phase and liquid-phase assays, and for laboratory testing, clinical ordering, and interpretation.

Clinical features, diagnosis, and management of the antiphospholipid syndrome.

Almost 30 years after it was first described as a discrete clinical entity, the antiphospholipid syndrome (APS) remains a challenge for clinicians in a wide range of specialities. There remain ongoing issues regarding nomenclature, the expanding range of clinical manifestations, and management of certain APS patient subgroups. In addition to the presence of appropriate clinical features, the diagnosis of APS also fundamentally requires the finding of positive antiphospholipid antibody test result(s), and unfortunately much still has to be done to improve the robustness, reproducibility, and standardization of these assays. This article discusses ongoing dilemmas and issues related to clinical aspects of APS including (i) the derivation of the current nomenclature and the implications of recent proposals for its revision; (ii) the problems that the protean clinical manifestations pose for many clinicians, in particular those not intimately familiar with APS; (iii) the potential pitfalls of applying the APS classification criteria as diagnostic criteria (although no doubt tempting for nonspecialist clinicians); (iv) the concept of seronegative APS and the effect that recent proposed changes in antiphospholipid antibody testing strategies may have on this diagnosis; and finally (v) an overview of key developments in the clinical management of APS patients over the past 30 years.

Specific testing for "isolated" anti-52 kDa SSA/Ro antibodies during standard anti-extractable nuclear antigen testing is of limited clinical value.

AIM: To ascertain whether specific testing for "isolated" anti-52 kDa SSA/Ro antibodies (a-SSA/Ro52) during standard anti-extractable nuclear antigen (ENA) testing is clinically useful. METHODS: 1438 consecutive sera submitted for anti-ENA testing over 1 year were evaluated for a-SSA/Ro52 using various assays. RESULTS: 7 of 1438 (0.48%) patients were found to have a-SSA/Ro52 without SSA/Ro60 antibodies. Subsequent testing detected a further five patients. Clinical follow-up was possible in 10/12 patients. 2 of these 10 patients had evidence of primary Sjögren's syndrome (SS) and one had systemic lupus erythematosus (SLE), with sicca symptoms and abnormal Schirmer's tests. Five other patients had sicca symptoms, of which four had abnormal Schirmer's tests. CONCLUSIONS: "Isolated" anti-52 kDa SSA/Ro antibodies were detected in approximately 0.5% of standard anti-ENA requests, in which their presence was generally not associated with underlying SS or SLE. In view of the increased testing complexity and costs in detecting and confirming these antibodies, specific testing for isolated a-SSA Ro52 antibodies during standard anti-ENA testing seems to be of limited clinical value in a non-obstetric population.

A Review of beta2 -glycoprotein-l antibody testing results from a peer-driven multilaboratory quality assurance program.

We evaluated the results of lgG beta2-glycoprotein-I (B2GPI) antibody assays in a multilaboratory setting by analyzing data from an external quality assurance program for the 2003 through 2005 cycles for 27 serum samples, including quantitative IgG-B2GPI values and qualitative interpretation and grading (ie, negative or positive; grade of positivity), according to method type and in conjunction with clinical data. We report high interlaboratory variation in numeric IgG-B2GPI results, comparable to that reported for IgG anticardiolipin antibody (aCL) testing, and some method-based variation. For example, interlaboratory coefficients of variation for IgG-B2GPI were more than 50% in 19 samples (70%). For qualitative reporting, there was generally better consensus than previously reported for semiquantitative IgG-aCL testing; although 100% consensus occurred for only 11 samples (41%), more than 90% of laboratories agreed for 19 samples (70%). In some cases, laboratory findings (negative or positive IgG-B2GPI) did not agree with clinical information. Despite the lack of formal standardization for IgG-B2GPI testing compared with IgG-aCL, there seems to be better cross-laboratory consensus. Improvement in standardization of these assays is still required to improve interlaboratory and intermethod concordance of results and interpretation between laboratories and the clinical usefulness of IgG-B2GPI testing.