All about Antiphospholipid Syndrome. M.B. Agarwal, MD Prof & Head, Dept of Haematology, Bombay Hospital Institute of Medical Sciences, Mumbai, India

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1 All about Antiphospholipid Syndrome M.B. Agarwal, MD Prof & Head, Dept of Haematology, Bombay Hospital Institute of Medical Sciences, Mumbai, India 1

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7 Antiphospholipid syndrome A study of 192 patients over 31 yrs ( ) 7

8 Antiphospholipid syndrome : 192 cases APS-subtype Number Percentage Primary Secondary SLE SLE-like

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15 Ischemic lesions on leg 15

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17 MRI brain showing multiple ischemic lesions 17

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20 Venous thrombosis 20

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22 Arterial thrombosis 22

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28 APS & Pregnancy Maternal complications Thrombosis-venous, arterial or small vessels Pre-eclampsia / eclampsia HELLP syndrome Fetal complication Recurrent fetal loss IUGR/Intrauterine foetal death / still birth Pre term delivery 28

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30 Anticoagulant 30

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32 Anticardiolipin antibodies Antiphospholipid antibodies Anti β2gp1 antibodies 32

33 APS: Diagnosis 33

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35 Laboratory tests: Myths & realities ACA-IgG & β2gp1-igg are more significant then IgM IgA are not important LA + is the strong risk factor for thrombosis Triple positivity causes the worst of clinical problems, both thrombosis & pregnancy morbidity DE Groot et al, 2005; Galli et al, 2003, Pengo et al, 2005, 2007; Reynaud et al,

36 Significance of >1 lab test positivity 36

37 Non-criteria antibodies APA-IgG, APA-IgM All IgA antibodies Antibodies against Annexin Antibodies against FXII Rodriguez-Garcia et al,

38 Certain observations Triple positivity has best co-relation with both thrombosis and pregnancy morbidity With triple positivity, risk of recurrent thrombosis was 30% over a 6-year follow-up LA positivity has higher incidence of thrombosis then positivity for ELISA based tests Venous thrombosis was related to LA & ACA Arterial thrombosis was related to Anti-β2GPA or triple positivity Reynaud et al, 2014; Pengo et al, 2010; Banzato et al

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41 Secondary APS 41

42 Secondary APS SLE & other immunological disorders Infections: HIV, Hep C, Varicella, others Drugs: Phenothiazines, Phenytoin, others Lymphoproliferative disorders: Lymphoma, paraproteinemia, others 42

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51 Noncriteria features of APS Livedo reticularis Raynaud phenomena Chorea Migraine Cytopenia Evan s syndrome Cardiac valve involvement APS nephropathy 51

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53 Whom to investigate for APS? Unprovoked VTE in young person Thrombosis at unusual site Recurrent thrombosis Ischemic stroke <50 years age SLE or any other autoimmune disease with thrombosis Recurrent pregnancy losses Adult women with ITP Livedo reticularis 53

54 How common is APS? 54

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56 How common is APS? Pregnancy related morbidity : 06% Young Myocardial infarction : 08% Venous thromboembolism : 15% Young Ischemic Stroke : 30% Andreoli et al. An analysis of 120 full-text papers,

57 How common is APS? Commonest acquired prothrombotic disorder 10% of recurrent pregnancy losses Over 20% of SLE subjects have subclinical APS & over 30% of them develop clinical manifestations 30% of new strokes under the age of 50 years Reynaud et al,

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59 Thrombotic APS: Pathogenesis What causes thrombosis in a case of APS is unclear? There are second hits or triggers that till the balance in favor of thrombosis Genetic constitution of the pt wrt genes controlling inflammatory mediators are of probably critical importance Pengo et al, 2005, 2007; Reynaud et al,

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62 Significance of Anti β2gp1 antibody β2gp1is an apolipoprotein It is a member of the complement control family It is a natural inhibitor of coagulation It has 326 amino acids, arranged in 5 protein domains, designated as I to V In 1990, McNeil identified that β2gp1 is the most important cofactor in pathogenesis of clinical APS Pengo et al,

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64 Anti Domain 1 (D1) antibodies de Laat et al showed that the anti-β2gp1 antibody that recognizes domain 1 causes clinical APS Multiple workers had shown that Anti-D1 strongly co-relates with thrombosis Triple +ve pts also have Anti D1 in very high titre Almost 25% of pts having Anti-β2GP1 antibodies do not have Anti-D1 antibody & such pts are usually free from clinical events De Laat, 2005,Pengo et al,

65 Role of complement activation in thrombotic APS Abnormalities in all 3 complement pathways (classical, alternative & innate) have been repeatedly shown in clinical APS Eculizumab that inhibits C5 complement has been an effective treatment for individual cases not responding to anticoagulation & immunosuppression Shapira et al 2012; Arachchillage et al

66 Activation of classical pathway leading to thrombosis and pregnancy complications 66

67 Role of Anti thrombotic pathways Inhibition of thrombomodulin mediated activation of protein C Upregulation of TF pathway by down regulation of TF pathway inhibitor Upregulation of TF expression on monocytes and endothelial cells associated with inflammatory cytokines & addition molecules Liestol et al, 2007; Willis et al,

68 APS with antibodies against protein C 68

69 mtor pathway activation Microvascular thrombosis is an important manifestation of APS mtor is a kinase that regulates cellular growth, proliferation & survival Activated mtor pathway leading to endothelial proliferation & intimal hyperplasia leads to microthrombi causing peripheral ischemia, skin ulcers, apl nephropathy & diffuse alveolar damage Shapira et al 2012; Arachchillage et al

70 mtor inhibitors for APS nephropathy Sirolimus, an mtor inhibitors when given to pts with APS nephropathy requiring renal transplantation, prevented recurrence of vascular lesions in the transplanted kidney 7/10 (70%) of renal allograft pts on Sirolimus had functional graft after a median of 144 months as against 3/27 (11%) of untreated pts Canaud G et al. NEJM. 2014, 371,

71 Pathogenesis of pregnancy complication APS is the single most recognizable risk factor for recurrent pregnancy losses & late placentamediated obstetric complications Immunopathology of obstetric APS is different from that of thrombotic APS This is specially true for cases of recurrent early miscarriages, where thrombosis is hardly ever documented Branch et al, 2014; Out et al,

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73 Prognosis Predominantly a disease of young women Retrospective studies looking at morbidity, mortality & organ damage have been published for both primary & secondary APS There has been clustering based on initial event i.e. VTE, arterial thrombosis or pregnancy morbidity Branch et al, 2014; Out et al,

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75 Prognosis 25-30% of pts progress to organ damage in a mean time of 10 years Highest morbidity has been attributed to neurological damage This was most commonly seen in those with arterial thrombosis as the initial event Grika EP et al. J Rheumatol. 2012; 39:

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77 Euro-phospholipid project It reported 10-year survival rate of 91% Two most important causes of death: Thrombosis (35%) Infections (25%) We need to increase our efforts in determining optimal prognostic markers and therapeutic measures to prevent these two complications Cervera R et al. Ann Rheum Dis. 2015: 74;

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79 It is all about anticoagulation 79

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84 Warfarin Warfarin or any other VKA is the anticoagulant of choice & it has been time tested 84

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86 Intensity of anticoagulation therapy Low-intensity : INR Moderate-intensity : INR High-intensity : INR >

87 Moderate or high-intensity warfarin INR is the best and safest to prevent recurrent VTE High-intensity warfarin is not superior to moderate-intensity warfarin Crowther et al, 2003; Finazzi et al,

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96 Direct oral anticoagulants (DOACs) 96

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98 Direct oral anticoagulants (DOACs) Advantages of DOACs are well established and need no discussion DOACs are superior therapeutic alternatives to VKAs for prevention and treatment of VTE in pts without APS Experience with DOACs in pts with thrombotic APS is limited Hence DOACs are recommended only for APS pts with VTE who have poor anticoagulation control with VKAs or are allergic to VKAs 98

99 Direct oral anticoagulants (DOACs) DOACs have hardly been used for pts of APS with arterial thrombosis & hence not recommended in this situation DOACs have also been not studied in pts of APS with recurrent venous thrombosis & hence not recommended 99

100 DOACs : Conclusion 15 th International Congress on APS-Task Force on APS Treatment Trends Report (2017) Conclusion: DOACs may be useful in pt with venous thrombosis DOACs should not be used in pt with recurrent venous thrombosis or arterial thrombosis 100

101 Recurrent thrombosis despite warfarin High-intensity warfarin To add anti-platelet agents To switch to LMW heparin including high-intensity To combine anticoagulation with immunosuppresion / immunomodulation /others Hydroxychloroquine Statin Sirolimus Rituximab Eculizumab Sperber et al, 1993; Ruiz-Irastorza et al,

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103 Hydroxychloroquine Anti inflammatory agent Inhibits cytosolic phosphalipase A2 Reduces release of cytokines i.e. IL-6 & TNF Currently used as a base line therapy for SLE Inhibits platelet function Reduces thrombosis in mouse model of APS Protects the Annexin V anticoagulant shield Of course, without any bleeding tendency Ruiz-Irastorza et al, 2010; Espinola et al, 2002; Rand et al, 201; Schmidt-Tanguy et al,

104 Hydroxychloroquine APS consensus guidelines support use of HCQS as an adjuvant to anticoagulation in pts with APS who have recurrent thrombosis despite anticoagulation A phase III multicentre trial exploring the effect of HCQS as primary prophylaxis in APS pts has been completed & the findings are awaited Ruiz-Irastorza et al,

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106 Statins Statins are HMG-CoA reductase inhibitors These have anti-inflammatory & anti thrombotic actions on endothelial cells & monocytes Statins increase fibrinolysis & decrease tissue factor mrna expression Clinical studies in APS have shown reduced incidence of VTE with both primary and secondary prophylaxis using Statins Ferrara et al, 2003; Ridker et al,

107 Statins Fluvastatin in pts with APS was shown to reduce pro-inflammatory & pro-thrombotic biomarkers by Erkan et al, th International congress on APL Task Force Report states that Statins may be used as an adjunct treatment in APS with recurrent thrombosis despite adequate anticoagulation (Erkan et al, 2017) 107

108 Statins & Trophoblast Cells 108

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110 Rituximab An effective treatment for ITP & AIHA in a case of APS (Erkan et al et al, 2013) It also helps some other manifestations associated with APS (skin ulcers, Erkan et al, 2013) Few other non-criteria manifestations have also benefited (Erre et al, 2014) Erkan D et al. Arthritis Rheum. 2013; 65:

111 Rituximab It has been used as a life saving measure in CAPS (over 50 case reports) Berman et al, 2013 reviewed the CAPS registry treated with Rituximab and reported a recovery rate of 75% in acute episodes However, this was in combination with multiple other treatment strategies and hence the exact role of Rituximab cannot be assessed Erkan D et al. Arthritis Rheum. 2013; 65:

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113 Eculizumab (Soliris) There are several case reports regarding efficacy of Eculizumab in CAPS Phase II clinical trial evaluating its use to prevent post transplant thrombotic microangiopathy (TMA) in pts having APS-CAPS is on Over 80 pts have been enrolled Eculizumab was effective in increasing graft survival and kidney function at 1 year Glotz et al,

114 Obstetric APS (OAPS) - Prophylaxis Heparin (LMW) & Low dose aspirin form std of care for treatment of RPL (recurrent pregnancy losses) associated with APS Both should be started as soon as pregnancy is confirmed Post-partum thrombo-prophylaxis for 6 weeks for all women with OAPS without any h/o VTE ACCP guidelines 2012, Mak et al,

115 Obstetric APS - Treatment For those pregnant women with OAPS who have had VTE during pregnancy should be converted to therapeutic dose of LMW for the remaining pregnancy & for at least 6 weeks during post natal period (for a total of at least 3 months) Many of these women may need life-long anticoagulation (oral) ACCP guidelines 2012, Mak et al,

116 Hydroxyquinoline for refractory OAPS Prevents complement activation Prevents placental insufficiency Prevents abnormal fetal brain development In a mouse model, it prevented placental metabolic changes as measured by proton magnetic resonance spectroscopy This prevented fetal death Bertolaccine et al,

117 Hydroxyquinoline for refractory OAPS Mekinian et al, 2015: A European multicentre study of 30 women (35 pregnancies): HCQS led to better outcome Vs previous pregnancy with conventional therapy Sciascia et al, 2016: HCQS led to higher rate of live birth & lower prevalence of APS-related pregnancy morbidity (P=.004) HYPATIA is an ongoing prospective randomized controlled trial of HCQS Vs Placebo 117

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119 Asymptomatic APS A study of 258 asymptomatic APS was reported There was prospective evaluation of incidence of first vascular event After a median follow-up of 3 years, annual incidence of vascular events was 1.9% Vs 0.1% in general population Ruffatti et al,

120 Asymptomatic APS Incidence of thrombotic events was 5.3% per year in triple positive 104 subjects The cumulative incidence after 10 yrs was 37% Risk factors leading to clinical events have been assessed In one study, hypertension & LA (and not ACA / Antiβ2GP), were identified as the independent risk factors for occurrence of thrombosis Pengo et al,

121 GAPSS: Global APS Score for SLE acl-igg/igm : 5 Anti-β2GP1 : 4 LA : 4 APA-IgG/IgM : 3 Hyperlipidemia : 3 Hypertension : 1 GAPSS Score of >10 is risk predictor of thrombosis or pregnancy loss 121

122 Asymptomatic APS: General measures Avoid or treat associated risk factors: HTN, DM, dyslipidemia, smoking, sedentary life style, OC pills Prophylaxis against venous thrombosis for those in bed due to medical disorders, during post operative period & after delivery 122

123 Asymptomatic APS: Questions? Should asymptomatic APS receive low dose aspirin? Should they receive HCQS? Should they receive VKAs? Should triple positive & those with HTN be handled differently? All these questions remain to be answered APLASA study is a double-blind, placebocontrolled trial looking at role of aspirin in asymptomatic APS subjects 123

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125 Controversies Should pt with stroke (arterial thrombosis) be handled differently from those with VTE? Is aspirin or double anti-platelet agents alone sufficient without VKAs? Can those developing thrombosis following an obvious trigger factor (OC pills) be taken off anticoagulation after a while? 125

126 Intensity of anticoagulation following arterial events APASS is a published study confirming nonsuperiority of warfarin over aspirin (325 mg/day) in stroke prevention However, the target INR was low ( ) Laboratory tests for APS were not repeated after 12 weeks (done only at entry point) Levine et al,

127 Intensity of anticoagulation following arterial events Moderate-intensity warfarin (INR: ) was shown to be effective in a study but it had poor representation of arterial thrombosis (Crowther et al, 2003) Another study looked at high-intensity warfarin (INR > 3.0) for both arterial thrombosis & recurrent venous events (Ruiz-Irastorza et al, 2007). The study did not have excessive risk of hemorrhage 127

128 Intensity of anticoagulation following arterial events 15 th International congress on APS recommended INR > 3.0 or combined therapy using single antiplatelet agents + INR after arterial events This was a non-graded recommendation as there was non consensus between the panelists BCSH guidelines: Target INR : 2.5. Dose to be escalated to a higher target INR only if there is recurrence of thrombosis Keeling et al,

129 Paediatric APS Paediatric APS is rare 2.8% of APS pts are under the age of 15 years Median age of presentation is 10.7 years Clinical manifestations differ from those in adults Even pre & postpubertal pts have differences In postpubertal pts; obesity, smoking and use of OC pills play important role Cervera R et al. Arthritis Rheum 2002; 46:

130 Paediatric APS The strong female predominance seen in adults is unusual in pediatric APS Primary APS is far more common than in adults Venous thrombosis is uncommon presentation Arterial events are the chief presenting feature Secondary APS is chiefly seen in older subjects There is higher rate of associated hereditary prothrombotic disorders (up to 40%) Aguiar CL et al. Curr Rheumatol Rep 2015; 17:

131 Paediatric APS Mortality was chiefly due to thrombosis and rarely due to bleeding Hence, it is strongly recommended to have highintensity INR in those with recurrent venous thrombosis & arterial thrombosis Cessation of anticoagulation often led to very high rate of recurrences Aguiar CL et al. Curr Rheumatol Rep 2015; 17:

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133 CAPS This term was first coined in 1992 by Asherson It is a rare, life-threatening disease It affects <1% of pts It is characterized by thrombosis affecting multiple organs & a cytokine storm developing over a very short period (1 wk) together with histopathologic evidence of multiple microthromboses chiefly affecting small vessels Carmi OR et al. Expert review of hematology :

134 CAPS Pathogenesis: Poorly understood A primary, genetic susceptibility exists This leads to increased thrombophilic risk (first hit) Second hit (trigger factors) are infections (45%), surgery (20%), malignancies (15%), withdrawal of anticoagulation (10%), OC pills (7%), obstetric complications, trauma, flair of underlying SLE etc Carmi OR et al. Expert review of hematology :

135 Diagnostic criteria Thrombosis affecting 3 or more organs This should happen simultaneously or within 1 week Histological confirmation of small vessel occlusion in at least one organ Persistent apl positivity RA Asherson et al. Lupus 2003; 12:

136 Treatment Therapeutic anticoagulation heparin High dose corticosteroid Plasmapheresis and/or IVIG Other immunomodulatory agents Recurrent / refractory cases Rituximab Eculizumab Carmi OR et al. Expert review of hematology :

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138 Summary APS is the commonest acquired prothrombotic disorder leading to thrombosis & pregnancy morbidity Pathophysiology is ill understood & probably many processes are involved Distinct role of domain1-specific Anti-Β2gp1 Obstetric APS causing multiple first trimester miscarriages may have entirely different pathogenesis 138

139 Summary Diagnosis is a combination of lab analysis and clinical observation Autoimmune nature of APS is beyond doubt Anticoagulation is the main state of management Immunosuppresion & immunomodulation are not the treatment of choice except in secondary APS 139

140 Summary Paediatric APS is rare & guidelines for management are non-existent CAPS is a rare life threatening variant of APS with over 50% mortality despite multi modality treatment DOACs still have to be studied in APS & hence not routinely recommended There is evolving role of HCQS, Statins, Rituximab, Eculizumab & other experimental therapies 140

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142 Cell : mbagarwal1@gmail.com 142

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