Are You Confident of the Diagnosis?
What you should be alert for in the history
Aside from livedo reticularis or racemosa, and possibly digital infarcts/limb ischemia, Raynaud phenomenon, or acral cyanosis in some patients, there are no dermatologic findings in the history or physical (Figure 1). The presence of livedo reticularis that is extensive or does not clear with warming should prompt one to check for a history of hypertension (often labile), transient ishemic attacks (TIAs), amaurosis fugax, or (usually minor) cerebrovascular accidents (CVAs). Headache, migraine, dizziness, or vertigo, and cognitive changes are nonspecific but possible prodromal symptoms.
Expected results of diagnostic studies
Antiphospholipid (aPL) antibody, including lupus anticoagulant and b2 glycoprotein I antibody, should be checked in all patients. Patients that are aPL antibody positive may develop this syndrome on the background of, or it may evolve into, systemic lupus erythematosus (SLE), so an antinuclear antibody test is warranted.
Intimal proliferation has been described as diagnostic of at least one subset of patients, but the proliferation is actually of subendothelial smooth muscle or myofibroblastic cells.
Biopsy of livedo in aPL antibody cases is not helpful, but one series of fifteen non-aPLantibody cases from Germany reported a sensitivity of 27%, 53%, and 80% with one, two, or three biopsies respectively, taken by deep punch biopsy technique from the white areas of livedo racemosa. A biopsy was considered positive if there was a subendothelial pad of smooth muscle cells (“intimal proliferation”) with subtotal or total lumenal occlusion in at least one arteriole or small artery.
Other series report a much lower incidence of positive livedo biopsies, including the second reference listed, with a two-biopsy positivity rate of 17% in aPL-negative and 29% in aPL-positive Sneddon syndrome patients.
The diagnosis depends on the constellation of livedo, TIA or CVA, and hypertension. The differential diagnosis of livedo is extensive, and the presence of hypertension in the general population is not uncommon, so the suspicion of Sneddon syndrome may require time, or the history of a TIA or CVA, to confirm.
In a patient with livedo and hypertension, with either SLE or aPL antibody, a high index of suspicion should be maintained on follow-up visits. In aPLantibody-negative patients, a syndrome of digital artery-size vasculitis or proliferative arteriopathy, involving mostly digital or CNS arteries, may be identified through arteriography or magnetic resonance imaging, and electroencephalography may be helpful. As mentioned previously, there may be diagnostic findings from skin biopsies in non-aPL antibody cases.
Who is at Risk for Developing this Disease?
Traditionally, Sneddon syndrome is thought to affect mainly women (80%-85%), and those who are younger (25-35 years of age). An incidence of four cases per million per year has been reported.
What is the Cause of the Disease?
This disease has at least two distinct etiologies, listed in the next section (pathophysiology).
Sneddon syndrome is rare, and probably includes at least two distinct pathophysiologic pathways: an aPL antibody-associated vasculopathic syndrome (reported incidence 0-85%, with most cases probably in North America), and a vasculitis or a subintimal smooth muscle proliferative vasculopathy in the non-aPL antibody form (half or more of some European series).
The understanding of aPL syndrome is still evolving, with some hints emerging as to how aPL antibodies might promote thrombosis or interfere with natural anticoagulant activity. The trigger and pathogenesis for non-aPL disease is unknown.
Systemic Implications and Complications
Two papers offer interesting comparisons of the relationship between primary antiphospholipid antibody syndrome (PAPS) and Sneddon syndrome.
One series of fifty-four patients with PAPS compared those with Sneddon syndrome to those without. The two groups were similar with respect to age, gender, race, weight, height, and body mass index. Patients with PAPS and Sneddon syndrome, when compared to those without Sneddon syndrome, were significantly different in the following ways:
longer disease duration: 96 vs. 52 months
higher stroke incidence: 100% (by definition) vs. 10%
higher incidence of arterial events: 100% vs. 30%
higher incidence of limb ischemia: 28.5% vs. 7.5%
higher incidence of arterial hypertension: 64% vs. 32.5%
lower incidence of venous events: 57% vs. 87.5%
lower incidence of pulmonary embolism: 50% vs. 80%
The second study included forty-six patients with Sneddon syndrome, and compared those with aPL antibody to those without. All but one patient showed a racemosa pattern. Very few patients in either group demonstrated abnormal skin biopsy findings, in contrast to a second series cited here. Patients with Sneddon syndrome without aPL antibody, when compared to those with aPL antibody, differed significantly in the following ways:
livedo noticed before neurologic ischemia: 89% aPL antibody negative vs. 58% aPL antibody positive
circumscribed skin necrosis in 19% in aPL negative vs. 10%.
renal disease was less frequent in the aPL-negative group
interestingly, valvulopathy, known to be a complication of aPL syndrome, was seen in the antibody-negative group in nearly identical numbers
thrombocytopenia was seen only in the aPL antibody-positive group
Therapeutic options for Sneddon syndrome are limited. Control of associated cardiovascular risk factors is important for either subset. The use of acetylsalicylic acid (ASA) and anticoagulation for aPL-associated disease is informed somewhat by experience with thrombotic complications in primary and lupus-associated aPL syndrome (see discussion in antiphosphlipid antibody syndrome).
Some advocate the use of similar therapies in non-aPL-antibody-associated Sneddon, but there is no strong supporting evidence for or against. Insufficient evidence exists to guide the use of antiplatelet agents or corticosteroids, although these are advocated by some. ASA 81mg would seem to be the best dose, but no data exists. While some suggest consideration of corticosteroid use, limited or no efficacy has been repeatedly described following the use of various immunotherapies, including corticosteroids, and their use without antithrombotic agents may be harmful.
Even anticoagulant therapy, for which a stronger rationale might be offered—especially in aPL-antibody-positive patients, has not been proven to be of benefit. If warfarin therapy is contraindicated, antiplatelet therapy with ASA and clopidogrel has been suggested, again without any conclusive evidence. Thrombolytic agents and vasodilators have been used in the acute setting.
Optimal Therapeutic Approach for this Disease
As outlined in the previous section, therapy for this syndrome is limited, focusing on the use of antiplatelet agents or corticosteroids.
The dermatologist’s role in patients with Sneddon syndrome is primarily to consider the diagnosis in patients with persistent or extensive livedo reticularis or racemosa, and to evaluate for hypertension or possible early warning signs of mild TIA or CVA symptoms. Once the diagnosis is strongly suspected or established, care and counseling would seem to be the responsibility of the primary care physician or neurologist.
Unusual Clinical Scenarios to Consider in Patient Management
There is much to learn about the pathophysiology of Sneddon syndrome and of aPL syndrome, and there currently appears to be no clear direction for new avenues of therapeutic intervention.
What is the Evidence?
Caldas, CA, de Carvalho, JF. “Primary antiphospholipid syndrome with and without Sneddon’s syndrome”. Rheumatol Int. vol. 31. 2011. pp. 197-200. (Data on differences in these two subsets of PAPS, summarized in text)
Frances, C, Papo, T, Wechsler, B, Laporte, JL, Biousse, V, Piette, JC. “Sneddon syndrome with or without antiphospholipid antibodies: a comparative study in 46 patients”. Medicine. vol. 78. 1999. pp. 209-19. (Data on differences in these two subsets of Sneddon syndrome, summarized in text)
Cox, NH, Piette, WW, Burns, T, Breathnach, S, Cox, N, Griffiths, C. “Purpura and microvascular occlusion (subsection Sneddon’s syndrome)”. Rook’s textbook of dermatology. 2010. pp. 49.42-4. (Recent brief summary of syndrome, with comments on therapy)
Wohlrab, J, Fischer, M, Wolter, M, Marsch, WC. “Diagnostic impact and sensitivity of skin biopsies in Sneddon’s syndrome. A report of 15 cases”. Br J Dermatol. vol. 145. 2001. pp. 285-8. (Skin biopsy may be helpful in non-aPL antibody cases)
Floel, A, Imai, T, Lohmann, H, Bethke, F, Sunderkotter, C, Droste, DW. “Therapy of Sneddon syndrome”. Eur Neurol. vol. 48. 2002. pp. 126-32. (This case report nicely summarizes the limited information on therapy in this syndrome, and highlights the paucity of data available to guide evidence-based therapeutic decisions.)
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