Lupus (2003) 12, 530– 534 www.lupus-journal.com
Catastrophic antiphospholipid syndrome: international consensus statement on classi cation criteria and treatment guidelines 1
RA Asherson1, R Cervera2*, PG de Groot3, D Erkan4, M-C Boffa5, J-C Piette5, MA Khamashta6 and Y Shoenfeld7 for the Catastrophic Antiphospholipid Syndrome Registry Project Group†
Rheumatic Diseases Unit, University of Cape Town School of Medicine, Cape Town, South Africa; 2Department of Autoimmune Diseases, Institut Cl´nic d’Infeccions i Immunologia, Hospital Cl´nic, Barcelona, Catalonia, Spain; 3Thrombosis and Haemostasis Laboratory, Department of Haematology, University Medical Center Utrecht, Utrecht, The Netherlands; 4Hospital for Special Surgery, Weill Medical College of Cornell University, New York, USA; 5Department of Internal Medicine, Hoˆpital Pitie´-Salpeˆtrie`re, Paris, France; 6Lupus Unit, The Rayne Institute, St. Thomas’ Hospital, London, UK; 7 Center for Autoimmune Diseases, Chaim Sheba Medical Center, Tel-Hashomer, Israel
The term ‘catastrophic’ antiphospholipid syndrome (APS) is used to de ne an accelerated form of APS resulting in multiorgan failure. Although catastrophic APS patients represent less than 1% of all patients with APS, they are usually in a life-threatening medical situation that requires high clinical awareness. The careful and open discussion of several proposals by all participants in the presymposium workshop on APS consensus, held in Taormina on occasion of the 10th International Congress on aPL and chaired by Munther A Khamashta and Yehuda Shoenfeld (29 September 2002), has allowed the acceptation of a preliminary set of classi cation criteria. On the other hand, the optimal management of catastrophic APS must have three clear aims: to treat any precipitating factors (prompt use of antibiotics if infection is suspected, amputation for any necrotic organ, high awareness in patients with APS who undergo an operation or an invasive procedure), to prevent and to treat the ongoing thrombotic events and to suppress the excessive cytokine ‘storm’. Anticoagulation (usually intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus are, cyclophosphamide,are the most commonly used treatments for catastrophic APS patients. Lupus (2003) 12, 530–534. Key words: anticardiolipin antibodies; antiphospholipid antibodies; catastrophic antiphospholipid syndrome; lupus anticoagulant; plasma exchange
De nition The term ‘catastrophic’ antiphospholipid syndrome (APS) is used to de ne an accelerated form of APS resulting in multiorgan failure. These patients have in common: a) clinical evidence of multiple organ involvement developed in a very short period of time; b) histopathological evidence of multiple small vessel occlusion (a minority also have large vessel thrombosis); and c) laboratory con rmation of the presence of antiphospholipid antibodies (aPL), usually in high titre. 1 Furthermore, most of the catastrophic APS
*Correspondence: R Cervera, Servei de Malalties Autoimmunes, Hospital Cl´nic, Villarroel 170, 08036 Barcelona, Catalonia, Spain. E-mail:
[email protected] † See the names of the members at the end of the article (Appendix A). ©Arnold2003
episodes are preceded by a precipitating event, mainly infections. Although catastrophic APS patients represent less than 1% of all patients with APS,2 they are usually in a life-threatening medical situation that requires high clinical awareness. The classi cation and treatment of this debilitating syndrome are challenging as: a) catastrophic APS patients can present in an evolving manner; b) the mortality rate is approximately 50% despite treatment;3,4 c) the optimal treatment regimen is unknown; and d) catastrophic APS is rare, which makes the syndrome dif cult to study.
Criteria for classi cation The need to develop consensus criteria for de nition and classi cation of the catastrophic APS has been 10.1191/0961203303lu394oa
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Table 1
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Preliminary criteria for the classi cation of catastrophic APS
1) Evidence of involvement of three or more organs, systems and/or tissuesa 2) Development of manifestations simultaneously or in less than a week 3) Con rmation by histopathology of small vessel occlusion in at least one organ or tissueb 4) Laboratory con rmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies)c De nite catastrophic APS · All four criteria Probable catastrophic APS · All four criteria, except for only two organs, systems and/or tissues involvement · All four criteria, except for the absence of laboratory con rmation at least six weeks apart due to the early death of a patient never tested for aPL before the catastrophic APS · 1, 2 and 4 · 1, 3 and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation a
Usually, clinical evidence of vessel occlusions, con rmed by imaging techniques when appropriate. Renal involvement is de ned by a 50% rise in serum creatinine, severe systemic hypertension (> 180/100mm Hg) and/or proteinuria (> 500mg/24hours). b For histopathological con rmation, signi cant evidence of thrombosis must be present, although vasculitis may coexist occasionally. c If the patient had not been previously diagnosed as having an APS, the laboratory con rmation requires that presence of antiphospholipid antibodies must be detected on two or more occasions at least six weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classi cation of de nite APS.9
heightened by the diversity of the clinical and serological presentations that have been reported under this term.3,4 A review of this topic with proposed guidelines for diagnosis and treatment has been published recently.5 The careful and open discussion of these proposals by all participants in the pre-symposium workshop on APS consensus, held in Taormina on occasion of the 10th International Congress on aPL and chaired by Munther A. Khamashta and Yehuda Shoenfeld (29 September 2002), has allowed the acceptation of the preliminary
classi cation criteria presented in Table 1, which slightly differ from the previous proposal.5 De nite catastrophic APS is considered to be present in a given patient when all four criteria are met. It requires the involvement of three or more organs, systems and/or tissues. Probable catastrophic APS is considered if only two targets are affected, if small vessel occlusion cannot be con rmed by histopathology, if the third event develops in more than a week but less than a month despite anticoagulation, or if a patient never tested before has positive aPL at the onset of the catastrophic
Figure 1 Classi cation algorithm of catastrophic APS (see Table 1 for the details). In the presence of more than three organs/systems/ tissues involvement and the con rmation of small vessel occlusion, probable catastrophicAPS should be diagnosed:*If the development of a third event occurs in more than a week but less than a month, despite anticoagulation;**If the presence of aPL at least six weeks apart cannot be con rmed due to the early death of a patient never tested for aPL before catastrophic APS. Lupus
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APS that cannot be con rmed six weeks apart due to early death. Figure 1 shows a sequential algorithm to classify patients as having a catastrophic APS. According to these criteria, 51% of the previously compiled catastrophic APS patients3,4 could be classi ed as having de nite and 35% as having probable catastrophic APS. It is hoped that these preliminary classi cation criteria will be tested in prospective multicentre studies, and modi cations or additions to the criteria will be made at subsequent workshops, especially with regards to differential diagnosis, mainly heparin-induced thrombocytopenia/thrombosis and thrombotic thrombocytopenic purpura. It should be emphasized that these criteria are mostly empirical and have been accepted for classi cation purposes and are not intended to be used as strict diagnostic criteria in a given patient.
Guidelines for treatment The optimal management of catastrophic APS is not known,6 but must have three clear aims: to treat any precipitating factors (Table 2)3,4 (prompt use of antibiotics if infection is suspected, amputation for any necrotic organ;7 high awareness in patients with APS who undergo an operation or an invasive procedure); and to prevent and to treat the ongoing thrombotic events and to suppress the excessive cytokine ‘storm’.8 The literature describing treatment of catastrophic APS is confusing since there have been no prospective studies because of the rarity of the condition.3,4 Therefore, treatment of catastrophic APS is not currently standardized. Anticoagulation (usually
Table 2 Most common precipitating factors in patients with catastrophic APSa Precipitating factor
%
Infections Respiratory tract Cutaneous Urinary tract Sepsis Other Surgery, trauma and invasive procedures Neoplasia Anticoagulation withdrawal/low INR Obstetric complications Lupus ares Oral contraceptives No factor identi ed
35% 15% 8% 6% 3% 10% 13%
a
Percentages from a series of 80 patients.4
Lupus
8% 8% 6% 5% 3% 35%
intravenous heparin followed by oral anticoagulants), corticosteroids, plasma exchange, intravenous gammaglobulins and, if associated with lupus are, cyclophosphamide, are the most commonly used treatments for catastrophic APS patients. Other reported management options include brinolytics, prostacyclin, de brotide, danazol, cyclosporine, azathioprine, haemodialysis and splenectomy.3,4 Analysis of 130 reported catastrophic APS patients demonstrates that older age and higher number of involved organs are associated with death. In this series, there was no difference regarding the number of treatments each patient received when survivors were compared with non-survivors (2.2 + 1.3 vs 2.6 + 1.2; P 0.1). However, patients received an average of more than two treatments. When each treatment was analysed individually, only anticoagulation had a signi cant effect against death. As there were only a few patients in the series who had received anticoagulation only, it is dif cult to recommend anticoagulation as a solitary therapy because most received it in conjunction with other treatments. When the combination regimens were analysed, the highest survival rate (70%) was achieved with the combination of anticoagulation, corticosteroids and plasma exchange or intravenous gammaglobulins in the rst series,3 but this was not con rmed in the second.4 Therefore, when there is a high clinical suspicion of catastrophic APS (i.e., presence of two classi cation criteria), the consensus adopted in an empirical manner was to follow the treatment algorithm described in Figure 2. As laboratory markers of the APS can take time to be obtained and even occasionally can be negative at the time of the thrombotic event, it is essential to start treatment as soon as the syndrome is suspected. A life-threatening condition must be considered when a vital organ (brain, heart, lungs, kidneys, adrenal glands) is involved and develops an organ failure. Plasma exchange with fresh frozen plasma should be especially indicated if features of microangiopathic haemolytic anaemia (i.e., schistocytes) appear. In addition to these therapies, intensive care measures play an essential role in the survival of patients with catastrophic APS.
Acknowledgements The authors wish to thank Gerard Espinosa, Josep Font and Joan Carles Reverter for their comments and suggestions on the preliminary set of criteria, Jose´ Alfredo Go´mez, Jorge Mariano Cucho, Fabia´n Ram´rez and Mar´a Teresa Campoamor for their assistance in the
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Figure 2 Treatment algorithm of catastrophic APS. *Consider exclusion of other microangiopathic syndromes (mainly thrombotic thrombocytopenic purpura and heparin-induced thrombosis/thrombocytopenia).5 **With fresh frozen plasma and specially indicated if schistocytes are present.
data-base processing work, and Margaret G Peterson for her statistical assistance.
References 1 Asherson RA. The catastrophic antiphospholipid antibody syndrome. [Editorial.] J Rheumatol 1992; 19: 508– 512. 2 Cervera R, Piette JC, Font J et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46: 1019– 1027. 3 Asherson RA, Cervera R, Piette JC et al. Catastrophic antibody syndrome. Clinical and laboratory features of 50 patients. Medicine (Baltimore) 1998; 77: 195– 207. 4 Asherson RA, Cervera R, Piette JC et al. Catastrophic antiphospholipid syndrome: clues to the pathogenesis from a series of 80 patients. Medicine (Baltimore) 2001; 80: 355– 376. 5 Asherson RA, Espinosa G, Cervera R, Font J, Reverter JC. Catastrophic antiphospholipid syndrome. Proposed guidelines for diagnosis and treatment. J Clin Rheumatol 2002; 8: 157– 165. 6 Asherson RA, Cervera R. The catastrophic antiphospholipid antibody syndrome: a review of pathogenesis, clinical features and treatment. IMAJ 2000; 2: 268– 273. 7 Amital H, Levy Y, Davidson C et al. Catastrophic antiphospholipid syndrome: remission following leg amputation in 2 cases. Semin Arthritis Rheum 2001; 31: 127– 132.
8 Kitchens CS. Thrombotic storm: when thrombosis begets thrombosis. Am J Med 1998; 104: 381– 384. 9 Wilson WA, Gharavi AE, Koike T et al. International consensus statement on preliminary classi cation criteria for de nite antiphospholipid syndrome. Report of an international workshop. Arthritis Rheum 1999; 42: 1309– 1311.
Appendix A: the Catastrophic Antiphospholipid Syndrome Registry Project Group The ‘Catastrophic APS Registry Project Group’ is a consortium created in 2001 as part of the network promoted by the ‘European Forum on aPL’, a study group devoted to the development of multicentre projects with large populations of APS patients. Coordinators: Ricard Cervera, Jean-Charles Piette, Yehuda Shoenfeld, Josep Font and Ronald A Asherson. Contributors (in alphabetical order): Paulo Barbosa, Showkat Bashir, Jean-Jacques Boffa, Franc¸ois Boue´, Arsinur Burcoglu, Hanna ChwalinskaSadowska, Christopher Davidson, Alex E Denes, Lupus
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Lupus
Ronald HWM Derksen, JF Diaz Coto, Robin Dibner, Patrick Disdier, Rita M Egan, R Enriquez, Doruk Erkan, Gerard Espinosa, Fernanfa Falcini, Leslie S Fang, Mario Garc´a-Carrasco, John T Grandone, Anagha Gurjal, Gilles Hayem, Graham RV Hughes, Sohail Inam, Miguel Ingelmo, Anna Jedryka-Go´ral, K Shashi Kant, Craig S Kitchens, Michael J Kupferminc, Tang Ching Lau, Roger A Levy, Eugene Lim, Ken Lim, Michael D Lockshin, Siu Fai Lui, Peter J
Maddison, Yoseph A Mekori, Takako Miyamae, John Moore, Haralampos M Moutsopoulos, Francisco J Mun˜oz-Rodr´guez, Jacek Musial, Ayako Nakajima, Michael C Neuwelt, Ann L Parke, Michelle A Petri, Manuel Ramos-Casals, Bernardino Roca, Jorge Rojas-Rodr´guez, Je´roˆme Rossert, Allen D Sawitzke, Cees G Schaar, Alex C Spyropoulos, Katsu Takabayashi, Maria Tektonidou, Carlos Vasconcelos and Margaret Wislowska.
