Review
The relevance of “non-criteria” clinical manifestations of antiphospholipid syndrome: 14th International Congress on Antiphospholipid Antibodies Technical Task Force Report on Antiphospholipid Syndrome Clinical Features

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Abstract

The purpose of this task force was to critically analyze nine non-criteria manifestations of APS to support their inclusion as APS classification criteria. The Task Force Members selected the non-criteria clinical manifestations according to their clinical relevance, that is, the patient-important outcome from clinician perspective. They included superficial vein thrombosis, thrombocytopenia, renal microangiopathy, heart valve disease, livedo reticularis, migraine, chorea, seizures and myelitis, which were reviewed by this International Task Force collaboration, in addition to the seronegative APS (SN-APS). GRADE system was used to evaluate the quality of evidence of medical literature of each selected item. This critical appraisal exercise aimed to support the debate regarding the clinical picture of APS. We found that the overall GRADE analysis was very low for migraine and seizures, low for superficial venous thrombosis, thrombocytopenia, chorea, longitudinal myelitis and the so-called seronegative APS and moderate for APS nephropathy, heart valve lesions and livedo reticularis. The next step can be a critical redefinition of an APS gold standard, for instance derived from the APS ACTION registry that will include not only current APS patients but also those with antiphospholipid antibodies not meeting current classification criteria.

Introduction

Antiphospholipid syndrome (APS) classification process is characterized by the presence of antiphospholipid antibodies (aPL), namely anticardiolipin antibodies (aCL), anti-beta 2 glycoprotein I (anti-b2GPI), or lupus anticoagulant (LA) associated with thrombosis of arteries or veins or the microcirculation and/or well defined obstetrical manifestations. However, to date there are no accepted criteria for diagnosis of this condition, although classification criteria tend to be used for definition and for diagnostic purposes. Current classification criteria for definite APS were established in a workshop, preceding the 11th International Congress on aPL in Sydney. These criteria derived from the Sapporo preliminary classification criteria for APS [1].

Several clinical manifestations associated with aPL are not included in the revised classification criteria [1]. Since the Congress in Sydney, a significant body of basic research and clinical studies on APS has appeared, bringing new data and an opportunity to revise clinical as well as laboratory manifestations. Considering these new data, the main goal of this task force was to examine the body of evidence related to the set of clinical manifestations that are not included in the current criteria and their association with aPL.

In this context, the Antiphospholipid Antibodies Task Force on Clinical Manifestations was carried out from January to September, 2013 to examine data, the quality of evidence according to GRADE system and develop recommendations in order to carefully suggest a revision of the current classification criteria [2]. A workshop held in Rio de Janeiro at the 14th International Antiphospholipid Congress discussed the findings [3], [4]. We examined all potential clinical criteria and selected the most relevant ones, we did not discuss the obstetrical manifestations, the future trends in treatment and the catastrophic APS which were evaluated by other groups [5], [6], [7].

Section snippets

Objectives

The objectives of this task force were: (1) to assess the patient-important outcomes that have been considered as non-criteria APS manifestations, and (2) to assess the body of evidence of each outcome to support the recommendation to be included on APS classification criteria.

Methodology

The PICO question was formulated as: “In patients with APS (P), are non-criteria APS manifestations (I) associated with APS classification, leading to earlier and most adequate treatment intervention to improve the patient-important outcomes (O)”?

We aimed to define and assess the outcomes that may be related to each non-criteria manifestation. An international group of APS experts of different specialties suggested non-criteria APS manifestations that were considered relevant. Some of the

Superficial vein thrombosis

PICO specific question: “In patients with APS, is superficial vein thrombosis associated with recurrent events, and would this criterion lead to earlier and most adequate treatment intervention to prevent the occurrence of recurrent thrombotic events, including serious life threatening events”?

PICO: P — APS; I/C — superficial vein thrombosis manifestations; O — the occurrence of recurrent thrombotic events, including serious life threatening event.

Discussion

A series of clinical features, that are not included in the classification criteria, but are recognized to be related to APS have been named non-classical or non-criteria clinical manifestations. An International Task Force reviewed those that were considered more clinically relevant, in addition to SN-APS, that although it is not consensus among the task force members, some considered it important to be investigated. We used the GRADE system to evaluate the medical literature on the relevance

Conclusion

The purpose of this task force was to critically analyze the so-called non-criteria manifestations of APS to support their inclusion as APS classification criteria. Classification criteria are important for including homogeneous groups of patients in observational as well as in therapeutic studies. The case has been made for including thrombocytopenia, renal microangiopathy, heart valve disease and two neurological manifestations (chorea and longitudinal myelitis) as classification criteria.

Take-home messages

  • The purpose of this task force was to critically analyze the so-called non-criteria manifestations of APS to support their inclusion as APS classification criteria.

  • Using GRADE system, we found that overall quality of evidence was very low for migraine and seizures,;low for superficial venous thrombosis, thrombocytopenia, chorea, longitudinal myelitis and the so-called seronegative APS, and moderate for APS nephropathy, heart valve lesions and livedo reticularis.

  • A critical redefinition of an APS

Acknowledgment

This work was supported by the Brazilian Foundation for Higher Education Personnel Training Coordination (CAPES paep 2240/2013-40) & the Rio de Janeiro Research Foundation (FAPERJ: APQ2 110.023/2013).

References (93)

  • S.V. Seshan et al.

    Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies

    Blood

    (2009)
  • L.H. Wu et al.

    Inclusion of renal vascular lesions in the 2003 ISN/RPS system for classifying lupus nephritis improves renal outcome predictions

    Kidney Int

    (2013)
  • I. Hollan et al.

    Cardiovascular disease in autoimmune rheumatic diseases

    Autoimmun Rev

    (2013)
  • O. Bouillanne et al.

    Prevalence and clinical significance of antiphospholipid antibodies in heart valve disease: a case–control study

    Am Heart J

    (1996)
  • C. Kampolis et al.

    Evolution of cardiac dysfunction in patients with antiphospholipid antibodies and/or antiphospholipid syndrome: a 10-year follow-up study

    Semin Arthritis Rheum

    (2014)
  • R.A. Asherson et al.

    Chorea in systemic lupus erythematosus and “lupus-like” disease: association with antiphospholipid antibodies

    Semin Arthritis Rheum

    (1987)
  • D. Verrot et al.

    Prevalence and signification of antinuclear and anticardiolipin antibodies in patients with epilepsy

    Am J Med

    (1997)
  • J.T. Peltola et al.

    Antiphospholipid and antinuclear antibodies in patients with epilepsy or new-onset seizure disorders

    Am J Med

    (2000)
  • E. Toubi et al.

    Association of antiphospholipid antibodies with central nervous system disease in systemic lupus erythematosus

    Am J Med

    (1995)
  • V. Pengo et al.

    Correct laboratory approach to APS diagnosis and monitoring

    Autoimmun Rev

    (2013)
  • D. Roggenbuck et al.

    Antiphospholipid antibody profiling: time for a new technical approach?

    Autoimmun Rev

    (2012)
  • M. Mahler et al.

    Autoantibodies to domain 1 of beta 2 glycoprotein 1: a promising candidate biomarker for risk management in antiphospholipid syndrome

    Autoimmun Rev

    (2012)
  • H. Meijide et al.

    The clinical relevance of IgA anticardiolipin and IgA anti-β2 glycoprotein I antiphospholipid antibodies: a systematic review

    Autoimmun Rev

    (2013)
  • M.L. Bertolaccini et al.

    14th International Congress on Antiphospholipid Antibodies Task Force. Report on antiphospholipid syndrome laboratory diagnostics and trends

    Autoimmun Rev

    (2014)
  • R. Cervera et al.

    Does seronegative antiphospholipid syndrome really exist?

    Autoimmun Rev

    (2012)
  • W.A. Wilson et al.

    International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop

    Arthritis Rheum

    (1999)
  • G.H. Guyatt et al.

    GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

    BMJ

    (2008)
  • M. Mendes de Abreu et al.

    The use of GRADE system on autoimmune diseases: challenges for shared decision-making

    Lupus

    (2014)
  • L. Arnaud et al.

    Patient-level analysis of five international cohorts further confirms the efficacy of aspirin for the primary prevention of thrombosis in patients with antiphospholipid antibodies

    Autoimmun Rev

    (2014 Oct)
  • R. Cervera et al.

    Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients

    Arthritis Rheum

    (2002)
  • Y.J. Yang et al.

    Clinical implications of elevated antiphospholipid antibodies in adult patients with primary immune thrombocytopenia

    Korean J Intern Med

    (2011)
  • K.J. Kim et al.

    Thrombotic risk in patients with immune thrombocytopenia and its association with antiphospholipid antibodies

    Br J Haematol

    (2013)
  • C.A. Dasanu et al.

    Isolated thrombocytopenia: should we routinely screen for antiphospholipid antibodies?

    Conn Med

    (2011)
  • R. Cervera et al.

    The Euro-Phospholipid project: epidemiology of the antiphospholipid syndrome in Europe

    Lupus

    (2009)
  • Italian Registry of Antiphospholipid Antibodies (IR-APA)

    Thrombosis and thrombocytopenia in antiphospholipid syndrome (idiopathic and secondary to SLE): first report from the Italian Registry

    Haematologica

    (1993)
  • M.J. Cuadrado et al.

    Thrombocytopenia in the antiphospholipid syndrome

    Ann Rheum Dis

    (1997)
  • L. 1 Stojanovich et al.

    Association between systemic non-criteria APS manifestations and antibody type and level: results from the Serbian national cohort study

    Clin Exp Rheumatol

    (2013)
  • L. Comellas-Kirkerup et al.

    Antiphospholipid-associated thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary antiphospholipid syndrome according to the Sapporo revised classification criteria: a 6-year follow-up study

    Blood

    (2010)
  • D. Erkan et al.

    APS ACTION — AntiPhospholipid Syndrome Alliance For Clinical Trials and International Networking

    Lupus

    (2012)
  • R.A. Levy et al.

    APS ACTION in Brazil

    Braz J Rheumatol

    (2012)
  • R. Cervera et al.

    Task Force on Catastrophic Antiphospholipid Syndrome (APS) and Non-criteria APS Manifestations (I): catastrophic APS, APS nephropathy and heart valve lesions

    Lupus

    (2011)
  • M. Nangaku et al.

    CD59 protects glomerular endothelial cells from immune-mediated thrombotic microangiopathy in rats

    J Am Soc Nephrol

    (1998)
  • M.C. Amigo et al.

    Renal involvement in primary antiphospholipid syndrome

    J Rheumatol

    (1992)
  • D. Nochy et al.

    The intrarenal vascular lesions associated with primary antiphospholipid syndrome

    J Am Soc Nephrol

    (1999)
  • E. Daugas et al.

    Antiphospholipid syndrome nephropathy in systemic lupus erythematosus

    J Am Soc Nephrol

    (2002)
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    Dedication: The authors would like to dedicate this manuscript to the memory of Silvia Pierangeli.

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