Antiphospholipid syndrome

Salient features

 

·       Livedo reticularis, bland necrosis, retiform purpura, or atrophie blanche-like lesions are typical

 

·       The definite diagnosis of antiphospholipid antibody syndrome requires at least one clinical and one laboratory criterion

 

 

Introduction

 

The antiphospholipid syndrome (APLS) is an autoimmune disease with clinical features of thrombosis (venous, arterial and microvascular) and pregnancy complications, which include recurrent fetal loss, preterm delivery and placental insufficiency. The condition is associated with a spectrum of autoantibodies directed against the cellular phospholipid component (hence the term ‘antiphospholipid antibodies’ or APA); most commonly: lupus anticoagulant, anticardiolipin and anti‐β₂‐glycoprotein I (anti‐B2GPI).

 

APLS is diagnosed in a patient with thrombosis and/or defined pregnancy morbidity in the presence of persistent APA. The term ‘primary APLS’ is used when the condition occurs in the absence of any other related disease. The term ‘secondary APLS’ is used when the condition occurs in the context of other autoimmune diseases, such as systemic lupus erythematosus (SLE).

Antiphospholipid antibody syndrome (APLS): Sapporo–Sydney criteria.

The criteria allow for standardization of patients enrolled in clinical studies. GPL, IgG phospholipid units; MPL, IgM phospholipid units.

ANTIPHOSPHOLIPID ANTIBODY SYNDROME: SAPPORO–SYDNEY CRITERIA

At least one clinical criterion and one laboratory criterion required*

Clinical criteria

1.   Vascular thrombosis      ·       One or more objectively confirmed episodes of arterial, venous, or small vessel thrombosis occurring in any tissue or organ   2.   Pregnancy morbidity      ·       One or more unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation – or –   ·       One or more premature births of morphologically normal neonates at or before the 34th week of gestation because of eclampsia, pre-eclampsia, or placental insufficiency – or –   ·       Three or more unexplained consecutive spontaneous abortions before the 10th week of gestation

Laboratory criteria – present on two or more occasions at least 12 weeks apart*

1.   Anti-cardiolipin antibodies, IgG or IgM [>40 GPL or MPL – or – >99th percentile as measured by a standardized ELISA]   2.   Lupus anticoagulant [detected according to the guidelines of the International Society on Thrombosis and Haemostasis]   3.   Anti-β2-glycoprotein I antibodies, IgG or IgM [>99th percentile as measured by a standardized ELISA]

* Patients who do not meet these criteria may still have antiphospholipid antibody syndrome.

 

Epidemiology

Incidence and prevalence

In the general population, APA can be detected in about one in five patients who have had a stroke (CVA) at less than 50 years of age. About 40% of patients with SLE have APA but less than 40% of them will eventually have thrombotic events. Approximately one in four patients with a venous thromboembolism, exhibit APA. Approximately one in 10 women with recurrent miscarriage is diagnosed with APLS.

 

Age

 

APLS is commonest in young to middle‐aged adults; however, it also manifests in children and elderly people.

Sex

 

As with many autoimmune diseases, APLS is commoner in women than in men.

In a 1000-patient cohort of individuals with antiphospholipid antibody syndrome (APLS), there was a strong female predominance (82% women, 18% men) and the mean age was 42 ± 14 years. Fifty-three percent of the patients had primary APLS; secondary APLS was associated with lupus in 36%, with lupus-like syndromes in 5%, and with other diseases in the remaining 6%. Catastrophic APLS occurred in 0.8% of the cohort. In contrast to primary cases, patients with lupus and APLS had more episodes of arthritis, livedo reticularis, thrombocytopenia, and leukopenia. Female patients had a higher frequency of arthritis, livedo reticularis and migraine, while male patients had a higher incidence of myocardial infarction, epilepsy, and arterial thrombosis in the lower legs and feet. Symptoms usually first developed in young to middle-aged individuals.

 

Associated diseases

 

Secondary APLS is associated with SLE and other autoimmune diseases such as rheumatoid arthritis, Sjögren syndrome and systemic sclerosis. The development of APA can occur with syphilis and hepatitis C.

 

 

Pathophysiology

 

The antibodies are directed against a range of phospholipids, including cardiolipin. The route by which thrombosis is induced remains unclear, but some antiphopholipid antibodies interact with a complex of phospholipid and beta2- gycoprotein 1 to inhibit factor 12 activation, platelet activation and prothrombinase activity.

 

 

 

 

Clinical features

 

 

CUTANEOUS FINDINGS IN PATIENTS WITH THE ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APLS)

·       Livedo reticularis, with or without retiform purpura   ·       Cholesterol embolus-like proximal livedo reticularis with distal retiform purpura   ·       Acral livedo reticularis   ·       Sneddon syndrome   ·       Livedoid vasculopathy or Degos-like lesions   ·       Anetoderma-like lesions with microthrombosis   ·       Raynaud phenomenon   ·       Vasculitis-like lesions   ·       Behçet disease-like lesions   ·       Pyoderma gangrenosum-like ulcers   ·       Nail fold ulcers   ·       Splinter hemorrhages   ·       Widespread cutaneous necrosis, typically as part of catastrophic APLS   ·       Pseudo-Kaposi sarcoma   ·       Superficial thrombophlebitis migrans

 

 

 

Patients have one or more clinical episodes of arterial, venous or small vessel thrombosis. Venous thrombosis in APLS is most commonly lower limb deep‐vein thrombosis or pulmonary embolism but any part of the venous system may be involved, including superficial, portal, renal, mesenteric and intracranial veins. The most frequent site of arterial thrombosis in APLS is in the cerebral arteries resulting in transient cerebral ischemia/stroke. Myocardial infarction is less common, although subclinical myocardial ischemia may be under recognized.

In one large study, the incidences of cutaneous findings were: livedo reticularis, 24%; leg ulcers, 5.5%; pseudovasculitic lesions, 3.9%; digital gangrene, 3.3%; cutaneous necrosis, 2.1%; and splinter hemorrhages, 0.7%. Cutaneous lesions may also develop indirectly, i.e. by embolization from heart valve vegetations. Histologically, non‐inflammatory thrombosis of small dermal blood vessels can be demonstrated, but necrotizing vasculitis is usually not a feature.

In addition to the skin, many other organ systems may be involved, although deep vein thrombosis/pulmonary embolus and CNS disease are the most common extra cutaneous manifestations.

 

 

Complications and co‐morbidities

 

In addition to thrombosis and pregnancy morbidity, thrombocytopenia, occult heart valve disease, chorea, cognitive impairment, hemolyticanemia and nephropathy are potential complications of APLS. Transverse myelopathy occurs in SLE and may be more frequent in those with APLS. Catastrophic APLS is uncommon and precipitating factors include surgical procedures, drugs (e.g. sulfur-containing diuretics, captopril, and oral contraceptives), discontinuation of anticoagulant therapy, and especially infections. These patients often present with multi-organ failure; the majority present with renal involvement as well as evidence of acute respiratory distress syndrome.

 

 

Disease course and prognosis

 

The long‐term prognosis of APLS is largely dictated by the risk and effects of recurrent thrombosis and any underlying autoimmune condition in those with secondary APLS. Those with primary APLS have a poor prognosis, with one‐third having organ damage and one‐fifth unable to perform everyday activities. APLS may contribute to an increased frequency of strokes especially in younger individuals. Strokes may develop secondary to in situ thrombosis or embolization that originates from the valvular lesions of Libman–Sacks (sterile) endocarditis, which may be seen in patients with APLS. Valvular heart disease may be severe enough to require valve replacement. Recurrent pulmonary emboli or thrombosis can lead to life‐threatening pulmonary hypertension.

 

 

Investigations

 

When testing for APLS is indicated, testing for lupus anticoagulant and for immunoglobulin G (IgG) and/or IgM antibodies to cardiolipin and/or B2GPI (via ELISA assays) should be performed. Medium or high titers (especially at or above the 99th percentile) are deemed significant positives. Initial positive tests should be repeated to check for persistence at least 12 weeks later. This is to prevent patients with transient positive tests (due to infection, etc.) being diagnosed as having APLS. Testing for IgA antibodies is not recommended.

Those with lupus anticoagulant typically can be identified by the ability of aPL to cause prolongation of in vitro clotting assays such as the activated partial thromboplastin time (aPTT), the dilute Russell viper venom time (dRVVT), the kaolin clotting time(KCT), or, infrequently, the prothrombin time. This prolongation is not reversed when the patient’s plasma is diluted 1:1 with normal platelet-free plasma.

 

 

Treatment

 

Treatment and prevention of thrombosis is a major goal of therapy. The presence of antibodies without any clinical features of APLS is not deemed to be an indication for long‐term anticoagulation. However, in such patients, attention might be paid to modifiable risk factors such as smoking, obesity and diabetes. The use of low‐dose aspirin in asymptomatic patients (as primary prophylaxis) has been advocated by some.

Anticoagulation is typically instituted in those who have APLS (i.e. those who have definite strong positive APA and have had a thrombosis). Most commonly, in non‐pregnant individuals, APLS is treated with heparin, followed by chronic anticoagulation with oral vitamin K antagonists. Aspirin therapy may be added for arterial events or stroke (after the acute event). For pregnant women with APLS and a history of recurrent fetal loss, consultation with an obstetrician and hematologist is advised. Antenatal administration of heparin combined with low‐dose aspirin throughout pregnancy may be advisable – warfarin is avoided because of teratogenicity. In general, treatment is often begun as soon as pregnancy is confirmed.

In lupus patients with APLS, antimalarial therapy may be protective against thromboses. Recommended treatment of catastrophic APLS includes anticoagulation and usually systemic corticosteroids; if life-threatening, plasma exchange and IVIg may be added. Rituximab, cyclophosphamide, and eculizumab have also been used.