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Dermatologic Therapy, Vol. 14, 2001, 117–125Printed in the United States · All rights reserved
Copyright © Blackwell Science 2001
DERMATOLOGIC THERAPY
ISSN 1396-0296
117
Antiphospholipid antibody syndrome (Hughes’ syndrome)
Camille Francès & Jean-Charles Piette
Service de Médecine Interne, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
ABSTRACT:
A wide variety of dermatologic manifestations have been described in the antiphospholipidsyndrome (APS). The most common is livedo reticularis, which is associated not only with cerebrovascu-lar events but also with systemic hypertension and heart valve abnormalities. Its mechanism remainsunclear and no treatment is effective. Lower limb ulcers may be related to deep vein or skin vessel throm-bosis with clinical features of livedoid vasculitis. The latter frequently persist despite antiplatelet therapy,thus requiring anticoagulation. The pseudovasculitis lesions are frequently misdiagnosed if skin biopsiesare not performed, especially in systemic lupus erythematosus-related APS. Antiplatelet therapy is pre-scribed in the absence of large vessel thrombosis. Widespread cutaneous necrosis and digital gangrenesmay be life threatening. They require full anticoagulation. When these lesions appear concomitantly tomultiple vascular occlusions in the setting of “catastrophic” APS, steroids and therapy which can achievea prompt reduction of antiphospholipid antibodies titers should probably be added to anticoagulation.
KEYWORDS:
anticoagulation, antiphospholipid syndrome, livedo reticularis, skin necrosis, Sneddonsyndrome
The first articles on the antiphospholipid syn-drome (APS) described recurrent arterial andvenous thrombosis and miscarriages (1). Theseremain the leading clinical features of this syn-drome, although its spectrum has broadenedconsiderably over the last 15 years. Among them,a wide variety of dermatologic manifestations(Table 1) have been reported (2). Their clinicalsignificance is highly variable. Their manage-ment depends on their clinical aggressivenessand the presence of other manifestations of APS.
When should antiphospholipid antibodies (aPL) be measuredin dermatology?
Theoretically, all the skin manifestations second-ary to a non inflammatory thrombosis, whatever
the size of cutaneous involved vessels, shouldlead clinicians to look for aPL as for other causesof thrombophilic states. The presence of classicalrisk factors for thrombosis, such as pregnancy,postpartum, smoking, or use of estrogen, shouldnot exclude this research, as these classical riskfactors can act as cofactors for thrombosis in APS(3). Practical experience is in fact different. In-deed, the most common skin lesion observed inAPS is livedo reticularis. Its reported prevalencewas found to be similar in primary or systemic lu-pus erythematosus (SLE)-related APS, rangingfrom 4 to 55% depending on the series (4–7).When livedo reticularis is the sole cutaneousmanifestation, its clinical features, although non-specific, may be suggestive of APS (Fig. 1). It isusually widespread, localized not only on thelimbs but also on the trunk and/or buttocks. Itis noninfiltrated and persistent, although somefluctuations in extent and intensity may occur.Broken circular segments and branching patternsare most frequently irregular (livedo racemosa).However, some patients present a regular andcomplete network. The mechanism of livedo re-
Address correspondence and reprint requests to Camille Francès, MD, Service de Médecine Interne, Groupe Hospitalier Pitié-Salpêtrière, 83 Boulevard de l’Hôpital, 75651 Paris Cedex 13 France, or e-mail: [email protected].
Francès & Piette
118
ticularis in APS remains unclear. Histopathologyfrom skin biopsy specimens do not usually showthrombosis, except in catastrophic APS (8). Vas-cular proliferation (9) or endarteritis obliterans ofarterioles (10,11) have been reported in somecases. These features do not exclude patchy pre-vious thrombosis. An interaction of aPL with en-dothelium or other cellular elements of the ves-sels in a way that alters function and inducesvasoconstriction is another possible mechanismof livedo reticularis (12). When livedo is associ-ated with other skin lesions related to APS, biop-sies should be performed on these other lesionsto show thrombosis.
Lower limb ulcers are also considered as fre-quent skin lesions (13), although they are notmentioned in many series (5). They may be re-lated to deep vein or skin vessel thrombosis as in
livedoid vasculitis-like ulcerations (Fig. 2). Deepvein thrombosis and its consequences are easilydemonstrated by Doppler echography. In biopsyspecimens from the edge of livedoid vasculitis-likeulcerations, skin thrombosis is either obvious ormasked by a marked capillary proliferation with ex-travasated red blood cells, sparse inflammatory cellinfiltrates (14,15). Nonspecific granulomatous tis-sue and epidermal hyperplasia have been reportedin large ulcers resembling pyoderma gangrenosum(16). So aPL should be searched in all cases of skinulceration when a thrombotic mechanism is as-sumed, even if not confirmed histologically.
The pseudovasculitis lesions mimic cutaneousvasculitis and may be misdiagnosed if skin biop-sies are not performed, especially in SLE. Throm-bosis of skin vessels is usually obvious on biopsies,even when a lymphocytic or lymphoplasmacyticinfiltrate is encountered without evidence of vas-culitis (17).
Clinical features of widespread superficial cu-taneous necrosis within APS are similar to thoseobserved in other thrombophilic states such as
Table 1.
Dermatologic manifestations of the antiphospholipid syndrome
Livedo reticularisSkin ulcerations
Livedoid vasculitis-like ulcersLarge ulceration resembling pyoderma gangrenosumPostphlebitic skin ulcers
Pseudovasculitis lesionsPurpuraPalmar or plantar erythemaNodulesPustulesMalignant atrophic papulosis-like lesions
Superficial skin necrosisDigital gangrenesSuperficial phlebitisMultiple subungual splinter hemorrhagesAnetoderma
Fig. 1. Livedo racemosa in SLE-related APS.
Fig. 2. Typical pigmented and atrophic scars of livedoidvasculitis-like ulcers with purpuric necrotic lesions inprimary APS.
Antiphospholipid antibody syndrome
119
protein C and protein S deficiencies, monoclonalcryoglobulinemia, and cryofibrinogenemia (Fig.3). In some cases these biological abnormalities,present in association with aPL, may contributeto the thrombotic process (18,19). APS may beprimary or associated with other disorders suchas SLE, rheumatoid arthritis, mycosis fungoides,and human immunodeficiency virus infection(20–23). Histopathology from early purpuric le-sions demonstrates diffuse skin vessel thrombo-sis. In one case, both focal thrombosis and reac-tive angioendotheliomatosis contributed to theangio-occlusive pathology (24).
Digital gangrene was present in 13 of 70 pa-tients (19%) with cutaneous manifestations andlupus anticoagulant (LA) (13) and in 2 of 70 pa-tients (3%) with primary APS (1). Gangrene may bepreceded by distal erythema (25), cyanotic macules(26), or pseudocellulitis (27). Arterial echo-Doppleror angiography visualized occlusion, and some-times stenosis, of large or medium-sized vessels(27,28). Superficial thrombophlebitis is clinicallyevident or may be confirmed by echo-Doppler orskin biopsy.
Multiple subungual splinter hemorrhages ap-pear as tiny, linear, longitudinally oriented, red-dish-brown to black, distal subungual lesionsthat fail to blanch under pressure (Fig. 4). Theymay be observed in various conditions, especiallyin subacute bacterial endocarditis, and in healthypeople. Their sudden onset on multiple fingers inAPS is usually neglected because it is concomi-tant to other worrying thrombotic events (29).
Primary anetoderma (Fig. 5) is a rare elastolyticdisorder that may be the presenting sign of au-toimmune disorders, especially SLE or APS (30,31).The histologic picture of anetoderma associatedwith APS sometimes differs from the classical ane-toderma by the presence of microthromboses (31).
What aPL should be measured?
Although new tests have become available, deter-mination of LA and measurement of anticardio-lipin antibodies (aCL) by enzyme-linked immun-osorbent assay (ELISA) are still the first choice tobe used in the diagnosis of APS (Table 2). The first
Fig. 3. Widespread superficial skin necrosis in SLE-related APS.
Fig. 4. Multiple subungual splinter hemorrhages con-comitant to pulmonary embolism in APS.
Francès & Piette
120
aCL test was developed in 1983 and subsequentlystandardized (32). Both IgG and IgM isotypes areusually determined. IgG aCL is the most relevantisotype, as isolated IgM aCL are present in only5% of cases. Though an increased prevalence ofIgA aCL was found in African Caribbean or Afri-can American patients with SLE (33), the throm-botic risk of IgA aCL remains less clear. Interna-tional guidelines and criteria for the detection ofLA have been established (34). The basic criteriafor the presence of LA are as follows: prolonga-tion of a phospholipid-dependent coagulationtest, evidence of an inhibitor demonstrated bymixing studies, and confirmation of the phos-pholipid-dependent nature of inhibitor. Taipanand Textarin times may be helpful in patients re-ceiving oral anticoagulants (35). Anti-
�
2
-glyco-protein I (
�
2
GPI) assays have several advantagescompared to conventional aCL assays. The plasmaprotein
�
2
GPI is essential in controlling the assem-bly of endothelial cell surface procoagulant com-plexes responsible for enzymatic acceleration ofclotting, and
�
2
GPI is regarded as the target ofmost of autoimmune aPL. The presence of anti-
�
2
GPI antibodies concomitantly to aCL suggeststhese aCL antibodies are pathogenic. Indeed, inprimary and SLE-related APS, IgG anti-
�
2
GPI an-tibodies were found to be better correlated tothrombotic events than IgG aCL (36,37). The su-periority of IgM anti-
�
2
GPI assays over IgM aCL
assays has yet to be determined. In a recentstudy, IgA anti-
�
2
GPI appeared to be the mostimportant isotype detected (38), but further stud-ies are required to evaluate their clinical signifi-cance. In fact, controversial results have been pub-lished concerning the sensitivity of the detectionof anti-
�
2
GPI antibodies, even of the IgG isotype(37). Commercially available enzyme immunoas-say plates differ greatly regarding the detectabil-ity of anti-
�
2
GPI (39,40). So the lack of standard-ization is still a serious drawback in the clinicalevaluation of anti-
�
2
GPI measurement.The existence of patients who seem to fit the
clinical profile of APS but remain negative for allthe preceding assays has led to the developmentof new tests. At the present time, detection of an-tibodies directed to phosphatidylethanolamineor to a mixture of phospholipids are of possibleinterest. Other tests such as ELISA for prothrom-bin or annexin V antibodies are still under devel-opment and require extensive evaluation (41). Inour experience very few APS patients displaychronic biologically false-positive serology forsyphilis.
Whatever the tests, transient aPL antibodiesare sometimes encountered in the absence ofthrombosis, particularly after diverse infections.It is therefore important to demonstrate the per-sistence of positivity by further testing after atleast 6 weeks.
Table 2.
Preliminary criteria for the classification of antiphospholipid syndrome
Clinical criteria
Vascular thrombosisOne or more clinical episodes of arterial, venous, or small vessel thrombosis in any tissue or organ. Thrombosis
must be confirmed by imaging or Doppler studies or histopathology, with the exception of superficial venous thrombosis. For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.
Pregnancy morbidity
One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or
One or more premature births of a morphologically normal neonate at or before the 34th week of gestation because of severe preeclampsia or eclampsia, or severe placental insufficiency, or
Three more unexplained consecutive spontaneous abortions before the 10th week of gestation with maternal anatomic, or hormonal abnormalities and paternal and maternal chromosomal causes excluded.
Laboratory criteria
Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, on two or more occasions, at least 6 weeks apart, measured by a standard enzyme linked immunosorbent assay for
�
2
-glycoprotein 1-dependent anticardiolipin antibodies.
Lupus anticoagulant present in plasma on two or more occasions at least 6 weeks apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis.
Definite APS is considered to be present if at least one of the clinical and one of the laboratory criteria are met.
Antiphospholipid antibody syndrome
121
What is the relevance of dermatologic manifestationsfor the diagnosis of APS?
In the last international consensus statement fordefinite APS (Table 2), clinical criteria includeskin vessel thrombosis on the strict conditionthat thrombosis is confirmed by histopathology,with the exception of superficial venous throm-bosis (42). As we detailed previously, thrombosisis rarely detected in skin biopsy specimens frompatients with only livedo reticularis. Multiplesubungual hemorrhages are exceptionally biop-sied. On the contrary, thrombosis may be de-tected in biopsies from other skin lesions.
Is there any preferential association between skin lesions and other manifestations of APS?
In a study by Alegre et al. (13), skin lesions werethe first sign of APS in 41% of patients and a mul-tisystem thrombotic phenomena occurred in the37% of them. Among the dermatologic manifes-tations of APS, livedo reticularis was found to bestrongly associated with cerebrovascular events(43–45). In 1965 this association, that is, livedoreticularis and cerebrovascular events, was firstdocumented in otherwise healthy people (46) andwas further individualized as Sneddon’s syndrome.A relationship between APS and Sneddon’s syn-drome was first documented by Hughes (1) andconfirmed later (47–49). The prevalence of aPL inSneddon’s syndrome has been reported to rangefrom 0 to 85% depending on the series (48,49); inour experience, it was 41% (11). The comparison ofaPL-negative versus aPL-positive patients devoidof any manifestation suggestive of SLE showed sig-nificant differences (11). The fishnet of the livedowas clearly larger in aPL-negative patients, whofrequently had obvious and sometimes trouble-some skin involvement. This fact might explainthe low prevalence of aPL in a dermatologic seriesof Sneddon’s syndrome (49). Seizures were morefrequent in aPL-positive (37%) than in aPL-nega-tive patients (11%,
p
�
0.05). In a series of patientswith primary and SLE-related APS, livedo reticu-laris was found to be strongly associated not onlywith cerebrovascular events but with systemic hy-pertension and heart valve abnormalities (50,51).
The onset of multiple subungual splinter hem-orrhages in APS is frequently (86%) coincidentalto worrying thrombotic events of various sites(brain, digits, skin, adrenal glands) (29).
“Catastrophic” APS, characterized by wide-spread vascular occlusions involving multiple or-gans simultaneously, is frequently (70%) associ-ated with skin lesions (52). Livedo reticularis,acrocyanosis, large cutaneous necrosis, palmarerythema, digital gangrene, and ischemic ulcerswere reported in this condition (52–55).
How to treat patients with skin lesions
Treatment of patients with skin lesions must beconsidered according to different dermatologicmanifestations and the clinical situation. Twoquestions should be answered: 1) How shoulddermatologic manifestations be treated? 2) Is anyprophylactic long-term treatment required in suchpatients? In the absence of randomized controlledtrials, therapy of dermatologic lesions remainsempiric.
Widespread cutaneous necrosis and/or digitalgangrene are major thrombotic events that re-quire full anticoagulation with heparin. If exten-sion of these skin lesions persists despite antico-agulation, iloprost and/or plasma exchanges maybe prescribed, as they have been reported to besuccessful in isolated cases (22,56). If plasma ex-changes are used, steroids and/or cytotoxics shouldprobably be added to prevent “aPL rebound” (57).When these lesions appear concomitant to multiplevascular occlusions (catastrophic APS), the rationaleof treatment is to control thrombosis by anticoagu-lation and to prevent the circulation and productionof aPL and of mediators (such as cytokines) whichgenerate the hypercoagulable state. So treatmentmay consist of anticoagulation, immunosuppres-sives, such as corticosteroids or cytotoxics, andplasmapheresis or high-dose intravenous immu-noglobulins. The beneficial effect of this combi-nation was reported in a retrospective study. In-deed, patients treated with anticoagulation inaddition to steroids plus a therapy which canachieve a prompt reduction of aPL titers (eitherplasmapheresis or intravenous immunoglobulins)had the highest survival rate of almost 70% (52). Fa-vorable outcome has been recently reported inother patients treated with plasma exchanges
Francès & Piette
122
(58,59). Local treatment consists of the removalof necrotic eschars and local antiseptic therapy toreduce the risk of secondary infection.
No treatment has been proven to be effectivefor livedo reticularis, which in our experiencemay continue or appear despite anticoagulant orantiplatelet therapy. Livedo reticularis is less visi-ble on suntanned skin, but sun exposure is notrecommended in SLE-related APS.
In isolated skin lesions such as livedoid vascu-litis-like ulcers or pseudovasculitis lesions, low-dose aspirin, and dipyridamole has been reportedas effective in some patients (26,60). If such lesionsrecur or extend despite antiplatelet agents, antico-agulation is usually prescribed. Fibrinolytic agentsand heparin have been successful in one case ofrecalcitrant nonhealing cutaneous ulcer (61).
How to prevent recurrence of skin lesions
Prevention of skin lesion recurrence depends notonly on the severity of the skin lesion, but also onthe other features of the disease. In APS the risk ofrecurrent thrombosis was reported as rangingfrom 22 to 69% (62–68). Retrospective analysis ofpatients with recurrent events showed that a venousthrombosis was followed by another venous throm-bosis in more than 70% of cases, and an arterialthrombosis was followed by another arterial throm-bosis in more than 90% of cases. There are no dataconcerning the frequency of recurrence of skinvessel thrombosis. In the literature only one pa-tient had two separate episodes of widespreadcutaneous necrosis, each precipitated by surgicalmanipulation of the urinary tract in the presence
of urinary tract infection (69). As widespread cu-taneous necrosis and/or digital gangrene are con-sidered as major thrombotic events, the currentrecommendation for such cases is long-term high-intensity warfarin (INR
�
3). Indeed, in retro-spective studies, warfarin was the most effectivetherapeutic option in the secondary preventionof thrombosis (57,62). Some authors advocate anINR of 2.0–3.0 for patients with venous thrombo-sis, reserving intensive anticoagulation (INR 3.0–4.0) for patients with arterial thrombosis or recur-rent venous thrombosis (65,66). Aspirin may beassociated with warfarin in cases of recurrentcerebral ischemia (62). Discontinuation of anti-coagulation is followed by a high risk of recur-rence in the first 6 months (62). The rate of life-threatening bleeding in subjects taking warfarin,based on a prospective study, is at least 0.25%/year (70). This risk increases in elderly patients(71). In the absence of large vessel occlusion, pre-vention of recurrence of “minor dermatologicmanifestations” (i.e., livedoid vasculitis-like ulcers,pseudovasculitis skin lesions, superficial throm-bophlebitis) is unclear. Antiplatelet therapy suchas low-dose aspirin (75 mg/day) is frequently alogical first-choice treatment. Hydroxychloroquinehas well-documented antiplatelet effects and hasbeen shown to reduce the risk of thrombosis inboth SLE patients and animal models of APS(72,73). However, in our experience, these treat-ments are frequently ineffective and long-termanticoagulation is required.
In patients with only livedo reticularis and aPL,low-dose aspirin is frequently prescribed for pre-vention of strokes, although it is probably poorlyeffective. Low-intensity warfarin may also be dis-cussed, especially in the presence of heart valveabnormalities (74). Clopidogrel, a new potent an-tiplatelet agent, should probably be evaluated insuch circumstances.
Whatever the type of skin lesions, it is impor-tant to remove or reduce other risk factors forthrombosis (75). Among others, patients are ad-vised to stop smoking and women are counseledagainst the use of estrogen.
Conclusion
In summary, the dermatologic manifestations ofAPS are extremely diverse and heterogeneous,ranging from minor signs to life-threatening con-ditions such as widespread cutaneous necrosis.
Fig. 5. Diffuse anetoderma in SLE-related APS.
Antiphospholipid antibody syndrome
123
Some of them, mainly livedo reticularis, are stronglyassociated with other manifestations of APS. Scien-tific data are required to determine the optimummanagement of these patients, who might benefitfrom recently developed antithrombotic agents.
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