Rheumatology and Internal Diseases ClinicCentral Clinical Hospital in WarsawWarsaw, 137 Wołoska St, 02-507

POLAND

Prof. Małgorzata Wisłowska MD, PhD

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ANTIPHOSPHOLIPID ANTIPHOSPHOLIPID ANTIBODY SYNDROMEANTIBODY SYNDROME

The author has no conflicts of interest to disclose

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DiagnosisCriteriaPathogenesisClinical manifestationTreatmentOwn experienceCAPSCAPS own experience

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Diagnosis

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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.

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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).

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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.

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Criteria

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Miyakis et al. J Thromb 2006; 4: 295-306

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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.

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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.

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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.

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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.

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Pathogenesis

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Kelley’s Texbook of Rheumatology 2012, p. 1333

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.

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

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.

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

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.

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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.

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Clinical manifestation

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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).

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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 occlusionMany 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.

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Kelley’s Texbook of Rheumatology 2012, p. 1332

Treatment

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Deep vein thrombosis and stroke are the most common clinical manifestations of APS.

Treatment is anticoagulation with heparin or warfarin.

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Kelley’s Texbook of Rheumatology 2012, p. 1337

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.

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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.

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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.

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Complement inhibitionThe 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.

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Own experience

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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

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

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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] <0.0001

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

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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 10 (66.7%) 28 (33.3%) 0.0145

Leisure time 7 (46.7%) 18 (21.4%) 0.0532

Interests, hobbies 6 (40%) 18 (21.4%) 0.1869

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

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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

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CAPS

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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.

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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.

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Asherson et al. Lupus 2003;12:530-534

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.

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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 CAPShttps://ontocrf.costaisa.com/en/web/caps.Consulting avaible:www.med.ub.es/MIMMUN/FORUM/CAPS.HTM..We also had a patient with this syndrome.

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CAPS own experience

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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

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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

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