ANTIPHOSPHOLIPID ANTIBODY SYNDROME Rheumatology and Internal Diseases Clinic Central Clinical Hospital in Warsaw Warsaw, 137 Wołoska St, 02-507 POLAND Prof. Małgorzata Wisłowska MD, PhD R

The author has no conflicts of interest to disclose

APS Diagnosis Criteria Pathogenesis Clinical manifestation Treatment Own experience CAPS CAPS own experience 3

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) Diagnosis 4

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) A synonym for APS is Hughes’ syndrome. Diagnosis requires that a patient have both a clinical event (thrombosis or pregnancy morbidity) and the persistent presence of antiphospholipid antibody (aPL) documented by: a solid-phase serum assay (anticardiolipin or anti-beta2-glycoprotein I IgG or IgM), a coagulation assay (inhibitor of phospholipid- dependent clotting – the lupus anticoagulant test), or both. 5

ANTIPHOSPHOLIPID ANTIBODY SYNDROME APS can occur as an isolated diagnosis, known as primary antiphospholipid antibody syndrome (PAPS), or it can be associated with systemic lupus erythematosus (SLE) or another rheumatic disease and is known as secondary APS (SAPS). 6

ANTIPHOSPHOLIPID ANTIBODIES Antiphospholipid antibodies (aPL) can be induced by drugs and by infections. The probability that an asymptomatic person with positive tests for aPL, discovered incidentally, will eventually develop the syndrome is low. 7

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) Criteria 8

REVISED SAPPORO CLASSIFICATION CRITERIA FOR APS Miyakis et al. J Thromb 2006; 4: 295-306 9

ANTIPHOSPHOLIPID ANTIBODIES Low-titer of antiphospholipid antibody (aPL), usually transient, is found in up to 10% of normal blood donors and moderate-to high-titer anticardiolipin antibody or a positive lupus anticoagulant test in less than 1%. The prevalence of positive tests increases with age. 10

ANTIPHOSPHOLIPID ANTIBODIES The main antigen to which aPLs binds is beta2 GPI. Beta2GPI is a phospholipid-binding plasma protein present in serum at a concentration of 200 mg/mL and is a member of the complement control protein family with a domain site that activates platelets. 11

Molecular structure of beta2 glycoprotein I Molecular structure of beta2 glycoprotein I. Domain 5 has a positively charged portion that binds to negatively charged phospholipids of the cellular membrane EULAR Textbook 2014, p.538

ANTIPHOSPHOLIPID ANTIBODIES Beta2GPI binds to phosphatidylserine on activated or apoptotic cell membranes of trophoblasts, platelets, and endothelial cells. Under physiological conditions, beta2GPI may function in the elemination of apoptotic cells and as a natural anticoagulant. 13

ANTIPHOSPHOLIPID ANTIBODIES Other, less relevant antigens targeted by aPLs are prothrombin, annexin V, protein C, protein S, kininogens, tissue plasminogen activator, factor VII, factor XI, factor XII and complement component C4. In experimental animal models, immunization with viral and bacterial peptides induces aPLs Ab and clinical events associated with APS. 14

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) Pathogenesis 15

Proposed mechanism of aPL-related thrombosis and placental injury Kelley’s Texbook of Rheumatology 2012, p. 1333

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Proposed mechanism of thrombosis and placental injury. The process begins with activation or apoptosis of platelets, endothelial cells, or trophoblasts, during which the negatively charged phospholipid phosphatidylserine migrates from the inner to the outer cell membrane, which is normally electrically neutral. Circulating beta2GPI then binds to phos- phatidylserine. APL then binds to a beta2GPI- phosphatidylserine dimer. 17

Willis et al. Int J Clin Rheumatol 2014;9:41-57

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Proposed mechanism of thrombosis and placental injury. Antiphospholipid antibody-beta2 GPI dimer binding activates the extracellular complement cascade; initiates an intracellular signaling cascade, and recruits and activates inflammatory effector cells. These include monocytes, neutrophils and platelets, and leads to the release of proinflammatory products (TNF, oxidans, proteases) and the induction of a prothrombotic phenotype. 19

Willis et al. Int J Clin Rheumatol 2014;9:41-57

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Proposed mechanism of thrombosis and placental injury. In addition, through downregulation of signal transducer and activator of transcription 5 (Stat 5) aPLs inhibit the production of placental prolactin, insulin growth factor binding protein-1, and adversely affect formation of a trophoblast syncytium, placental apoptosis, and trophoblast invasion. 21

Willis et al. Int J Clin Rheumatol 2014;9:41-57

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Proposed mechanism of thrombosis and placental injury. Other possible contributory mechanisms of aPL – mediated thrombosis include activation of circulating procoagulant proteins, inhibition of protein C and S activation, induction of tissue factor expression on monocytes and reduction of fibrynolysis. 23

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) Clinical manifestation 24

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Clinical manifestations of APS range from asymptomatic aPL serological positivity (no history of vascular or pregnancy events) to catastrophic APS (multiple thromboses occuring over days). 25

ANTIPHOSPHOLIPID ANTIBODY SYNDROME APS occurs as a multisystemic disease affecting all organ systems. Its principal manifestations are recurrent venous or arterial thromboses, recurrent pregnancy loss, and catastrophic vascular occlusion Many patients have livedo reticularis. Except for its severity, the young age of affected patients and unusual anatomic locations (Budd- Chiari syndrome and upper extremity thromboses), thromboses in APS do not clinically differ from thromboses attributable to other causes. 26

Other features suggesting the presence of antiphospholipid antibodies Kelley’s Texbook of Rheumatology 2012, p. 1332

Kelley’s Texbook of Rheumatology 2012, p. 1334

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) Treatment 29

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Deep vein thrombosis and stroke are the most common clinical manifestations of APS. Treatment is anticoagulation with heparin or warfarin. 30

TREATMENT RECOMENDATION FOR APS Kelley’s Texbook of Rheumatology 2012, p. 1337

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Immunomodulatory agents such as hydroxychloroquine and complement inhibitors have been found to reduce aPL-mediated thrombosis in in vivo animal models, while there have been promising human pilot studies showing the benefit of statins and rituximab in treating APS patients. 32

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Rivaroxaban a direct factor Xa inhibitor was tested as a treatment of the APS in RAPS trial. It has few drug and dietery interactions due to its mode of action. Frequent monitoring of its anticoagulant effect is not necessary. 33

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Another approach to the reduction of aPL activity in APS patients is the inhibition of the target cell receptors responsible for cell activation such as cell- surface receptors ApoER2’, TLR4, AnnA2 and GPIIb/IIIa in aPL-induced activation of Ecs, monocytes and platelets in APS. 34

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Complement inhibition The preclinical data shows the role of complement activation in the progression of thrombotic and obstetric complications in APS. The inhibition of the complement components C3 and C5 (eculizumab) in in vivo murine models have shown to limit the effects of aPL in both thrombotic and obstretic complications. 35

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) Own experience 36

ANTIPHOSPHOLIPID ANTIBODY SYNDROME In our clinic we assessed the prevalence of SAPS in SLE patients hospitalized within the last 6 months and their quality of life. The study group consisted of 101 people of mean age 54.9±12.6 years, the age of the youngest being 22 and the oldest 76 years. 96.5% of the patients were women. The average disease duration was 7 years, varied from one to 50 years. Rheumatology and Internal Diseases Clinic Central Clinical Hospital in Warsaw, 137 Wołoska St., 02-507 POLAND Prof. Małgorzata Wisłowska MD, PhD 37

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Parameters Group SLE APS+ N=15 (12.7%) Group SLE APS- N=86 (72.9%) P Energy level 54.4 ± 39.4 40.0 ± 35.7 0.1626 Physical pain 26.0 [0 – 100] 12.9 [ 0 – 31.5] 0.2475 Emotional support 50.3 ± 24.5 23.5 ± 21.9 <0.0001 Sleep disturbence 37.8 [22.4 – 72.7] 0 [0 – 22.4] Social isolation 20.1 [0 – 62.0] 0 [0 – 0.0] 0.0028 Decrease mobility 31.3 [0 – 56.6] 11.2 [0 – 32.6] 0.1982 Rheumatology and Internal Diseases Clinic Central Clinical Hospital in Warsaw, 137 Wołoska St., 02-507 POLAND Prof. Małgorzata Wisłowska MD, PhD 38

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Parameters Group SLE APS+ N=15 (12.7%) Group SLE APS- N=86 (72.9%) P Paid employement 14 (93.3%). 60 (71.4%) 0.1061 Household duties 13 (86.7%) 70 (68.0%) 0.1358 Social life 11 (73.3%) 28 (33.3%) 0.0035 Family life 10 (66.7%) 20 (23.8%) 0.0018 Sexual activity 0.0145 Leisure time 7 (46.7%) 18 (21.4%) 0.0532 Interests, hobbies 6 (40%) 18 (21.4%) 0.1869 Rheumatology and Internal Diseases Clinic Central Clinical Hospital in Warsaw, 137 Wołoska St., 02-507 POLAND Prof. Małgorzata Wisłowska MD, PhD 39

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Secondary antiphospholipid syndrome was observed in 15 (12.7%) women, with an average age of 51.9 ± 19.2 years and an average disease duration of 5.5 years. The study showed worse physical and psychosocial status in APS positive patients. Rheumatology and Internal Diseases Clinic Central Clinical Hospital in Warsaw, 137 Wołoska St., 02-507 POLAND Prof. Małgorzata Wisłowska MD, PhD 40

ANTIPHOSPHOLIPID ANTIBODY SYNDROME Adverse conditions such as fatigue, sadness, stress, poor physical capacity and sleep disturbances occured unbiversally in all patients with APS (100%), but in varied severity. The disparity between the two groups in the occurence of fatigue was most significant. Both groups demonstrated comparable economic status. Rheumatology and Internal Diseases Clinic Central Clinical Hospital in Warsaw, 137 Wołoska St., 02-507 POLAND Prof. Małgorzata Wisłowska MD, PhD 41

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) CAPS 42

CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME The catastrophic variant is the most severe form of the APS syndrome. Patients with this variant present the following characteristics: clinical evidence of multiple organ involvement that develops over a very short period of time (usually less than a week); histopathological features of small vessel occlusions; and laboratory confirmation of the presence of antiphospholipid antibodies. 43

CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME Described by Ronald Asherson in 1992, this subset is now reffered to as Asherson’s syndrome. Although less than 1% of patients with APS develop this catastrophic variant, its high mortality (30%) emphasizes its importance in clinical medicine today. The majority of patients with this condition end up in intensive care units with multiorgan failure. 44

PRELIMINARY CRITERIA FOR THE CLASSIFICATION OF CAPS Asherson et al. Lupus 2003;12:530-534

CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME From a histopathological point of view, catastrophic APS is a thrombotic microangiopathic condition. The CAPS should be treated with the combination of anticoagulants and intravenous glucocorticoids in high doses. Attemps at achieving a prompt reduction of aPL titer (i.e. plasma exchange and/or intravenous immunoglobulins) should be taken. CAPS secondary to SLE is also treated with cyclophosphomide. 46

CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME Since CAPS is so rare, collecting a sufficient patient number for epidemiological and clinical research is difficult. Because of this cooperation between clinical centrers is necessary. The international registry for patients with CAPS https://ontocrf.costaisa.com/en/web/caps. Consulting avaible: www.med.ub.es/MIMMUN/FORUM/CAPS.HTM ..We also had a patient with this syndrome. 47

ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS) CAPS own experience 48

CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME In our hospital we observed a case of a 26-year-old women in her 25th week of pregnancy with CAPS and SLE. In the 20th week of pregnancy she rapidly developed left and right sural thrombophlebitis appeared, microembolic pulmonary disease, nephrotic syndrome with 12.0 g proteinuria per day, skin ulcers on her nose and cheeks, and disorientation and hallucinations. She tested positive both ANA and aCL. Rheumatology and Internal Diseases Clinic Central Clinical Hospital in Warsaw, 137 Wołoska St., 02-507 POLAND Prof. Małgorzata Wisłowska MD, PhD 49

CATASTROPHIC ANTIPHOSPHOLIPID ANTIBODY SYNDROME Patient was treated with pulses of Solu-Medrol, Fraxiparine and Cyclophosphomide. We observed miscarriage but the patient recovered. Rheumatology and Internal Diseases Clinic Central Clinical Hospital in Warsaw, 137 Wołoska St., 02-507 POLAND Prof. Małgorzata Wisłowska MD, PhD 50

Gomez-Puerta Ann Rheum Dis 2007;66:740-746