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case records of the massachusetts general hospital

Founded by Richard C. Cabot Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 5-2009: A 47-Year-Old Woman with a Rash and Numbness and Pain in the Legs
Daniela Kroshinsky, M.D., John H. Stone, M.D., M.P.H., Donald B. Bloch, M.D., and Alireza Sepehr, M.D.

Pr e sen tat ion of C a se

Dr. John H. Stone: A 47-year-old woman was seen in the Rheumatology Clinic of this hospital because of numbness and pain in the legs and a rash. The patient had been well until approximately 2 years earlier, when numbness developed, first on the lateral aspect of the left leg, ankle, and foot, and then in an identical distribution on the right. Approximately 3 months later, pain developed on the medial aspect of the left foot, followed by pain in the same distribution on the right foot. During the next 9 months, the pain spread to involve both lower legs diffusely. One year before presentation, acute swelling of the distal left leg developed after an airplane trip. Ultrasonography of the legs, performed at another hospital, showed no evidence of deep venous thrombosis. The swelling subsided spontaneously during a 2-week period. Six to 8 months before this evaluation, mottled discoloration of the skin developed on the feet, ankles, and lower legs, with isolated, tender nodules up to 1.5 cm in diameter that blanched partially with pressure. Intermittent swelling of the legs and ankles occurred. Results of laboratory tests are shown in Table 1. Approximately 8 weeks before presentation, the patient saw a physician at another facility. Levels of serum electrolytes, albumin, globulin, thyrotropin, ferritin, folate, and vitamin B12 and results of renal- and liver-function tests were normal. Results of other laboratory tests are shown in Table 1. The next day, a dermatologist performed a biopsy of the skin of the left temple. Pathological examination of the specimen reportedly showed perivascular and perifollicular inflammation with telangiectasias, which was thought to be consistent with rosacea-like dermatitis. One week later, pathological examination of a biopsy specimen of a cutaneous nodule on the left ankle reportedly revealed a focal lymphohistiocytic infiltrate around a small muscular artery in the subcutis, with no evidence of vasculitis or erythema nodosum. Three weeks before presentation, the patient saw a rheumatologist at another facility. The patient reported a history of dry eyes (for which she used cyclosporine eye drops) and numbness, tingling, and color changes in her fingers in conditions
From the Departments of Dermatology (D.K.); Rheumatology, Allergy, and Immunology (J.H.S., D.B.B.); and Pathology (A.S.), Massachusetts General Hospital; and the Departments of Dermatology (D.K.), Medicine (J.H.S., D.B.B.), and Pathology (A.S.), Harvard Medical School. N Engl J Med 2009;360:711-20.
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of extreme cold, without digital pallor. The blood pressure was 126/80 mm Hg, the weight 57.8 kg, and the height 163.2 cm. There was mild crepitus on flexion and extension of the knees, without effusions. There were scattered erythematous lesions on the face and anterior portion of the chest that blanched to gentle pressure. There were irregular areas of erythema over the feet and lower legs, which blanched partially with pressure. No nodules were observed. The remainder of the examination was normal. Results of serum and urine protein electrophoresis and immunofixation were normal. Results of other laboratory tests are shown in Table 1. One week later, she returned to the rheumatologist because of 3 to 4 days of increased pain and swelling in the left ankle. Slight warmth and mild tenderness to touch were present around the left lateral malleolus, with a rounded, 1-cm area of erythema. The range of motion in both ankles was normal, and there was no evidence of enthesopathy at the insertion of the Achilles tendon. The plantar fasciae were not tender. There was no sensation to pinprick over either medial malleolus. The erythrocyte sedimentation rate was normal. Two weeks later, she saw a rheumatologist at this hospital. She did not have xerostomia, pain or swelling of the joints, weakness, alopecia, malar rash, oral or tongue ulcers, lymphadenopathy, shortness of breath, chest pain, fevers, night sweats, or a change in weight. She had had varicella in childhood, mild hypertension for 10 years, and a ruptured appendix with peritonitis 15 years earlier. She worked as a consultant, drank alcohol socially, and did not smoke. Her mother had Sjgrens syndrome, autoimmune hepatitis, and interstitial lung disease and had died of interstitial lung disease. Her father had a neuropathy when he was elderly. An older sister had been reported within the previous year to have vasculitis, which did not appear to be a primary form of either cutaneous or systemic vasculitis. A maternal relative had a history of Sjgrens syndrome, but no details were known. The patients medications included vitamins, oral contraceptives, and cyclosporine ophthalmic emulsion. She was allergic to sulfa medications. On examination, the vital signs were normal. Examination of the skin (Fig. 1) disclosed mottled discoloration from the midcalf distally, which was suggestive of livedo reticularis. A tender, erythematous nodule, 3 cm in diameter, was present
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just below the left lateral malleolus; two smaller, less tender lesions were present in the same area. There were small porcelain-colored areas on both lower legs, which the patient said corresponded to the locations of previous nodules. There was decreased sensation to light touch over the medial aspects of both feet. There was no capillary dilatation in the nail beds, Raynauds phenomenon, or joint swelling or deformity. The remainder of the examination was normal. Computed tomographic (CT) scanning of the chest and abdomen showed no lymphadenopathy or pulmonary infiltrates. The white-cell count was 3000 per cubic millimeter, with a normal differential count, hematocrit, hemoglobin level, and platelet count; review of a peripheral-blood smear revealed no abnormalities in the white cells, red cells, or platelets. A diagnostic procedure was performed.

Differ en t i a l Di agnosis
Dr. Daniela Kroshinsky: This patient presents with a rash compatible with livedo reticularis, tender cutaneous nodules, atrophie blanche, mononeuritis multiplex, and peripheral-blood cytopenias. Serologic testing for rheumatologic diseases has been unrevealing.
Livedo reticularis

Our patients clinical picture is compatible with livedo reticularis a netlike, violaceous discoloration of the skin typically on the legs, which is caused by increased prominence of the venous beds in the skin, either from impediments to arterial inflow, venous dilatation, or obstruction to venous outflow. Livedo reticularis has a broad differential diagnosis (Table 2),1 which can be focused by considering the patients personal and family history, the presence or absence of other skin lesions, and laboratory testing. The history should focus on elements that suggest potential autoimmune conditions or thrombotic disorders. This patients mother had severe complications of Sjgrens syndrome, and the asymmetric leg swelling that the patient had several months before presentation may have represented a thrombotic event, although this was not proved. The skin examination should focus on identifying purpura, nodules, ulcers, scars, nail-fold abnormalities, and alterations in skin temperature. In this patient, nodular skin lesions, atrophie blanche, and a rash on the face were presfebruary 12, 2009

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Table 1. Results of Laboratory Tests Performed Elsewhere.* Variable White-cell count (per mm3) Differential count (%) Neutrophils Lymphocytes Monocytes Eosinophils Basophils Platelet count (per mm
3)

Reference Range 4,00010,500

6 to 8 Mo before 6 to 8 Wk before Evaluation Evaluation 2,400 2,000

3 Wk before Evaluation 2,100

4074 1446 413 07 03 140,000415,000 020

50 34 13 2 1 196,000 29

53 26 19 2 0 177,000 6

52 33 12 1 1 161,000 12

Erythrocyte sedimentation rate (mm/hr) Antineutrophil cytoplasmic autoantibody Cytoplasmic Qualitative Quantitative (antibody to proteinase 3) (U/ml) Perinuclear Qualitative Quantitative (antibody to myeloperoxidase) (U/ml) Atypical Antinuclear antibody Direct (U/ml) Anti-RNP antibody (U/ml) Anti-Smith antibody (U/ml) Sjgrens antiSS-A antibody (U/ml) Sjgrens antiSS-B antibody(U/ml) Antidouble-stranded DNA Anticardiolipin antibody (U/ml) IgG (GPL units) IgM (MPL units) IgA (APL units) Complement (mg/dl) C3 C4

<1:20 dilution, negative <21, negative

<1:20 3 3

<1:20 dilution, negative <21, negative <1:20 dilution, negative

<1:20 7 <1:20 4

<100, negative <100, negative <100, negative <100, negative <100, negative <1:10 dilution, negative

26

39 19 14 31 2 <1:10

<11, negative <10, negative <13, negative

<11 <10 18

90180 936

108 23

* APL denotes IgA phospholipid, GPL IgG phospholipid, and MPL IgM phospholipid. Reference values are affected by many variables, including the patient population and the laboratory methods used. They may therefore not be appropriate for all patients. The reference ranges provided are those of the laboratory at which the tests were performed.

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80% of cases of livedo reticularis.2 However, biopsy of a cutaneous nodule would probably have an even higher yield.
Atrophie blanche

The patient had white, porcelain-like regions of scarring at sites of previous cutaneous nodules. This pattern of scarring, known as atrophie blanche, is characterized by ivory-white, stellate areas, often accompanied by atrophy or sclerosis and often surrounded by hyperpigmented borders and telangiectasias. Atrophie blanche is not specific for any pathologic process and can occur in systemic lupus erythematosus (SLE), scleroderma, the antiphospholipid-antibody syndrome, livedoid vasculopathy, and cutaneous polyarteritis nodosa, as well as in areas of venous stasis and varicosities.3
Xerophthalmia

Our patient had been undergoing treatment for chronic xerophthalmia, which results from decreased tear production due to lacrimal-gland dysfunction. Although this symptom is most commonly associated with Sjgrens syndrome, it can be seen in other connective-tissue diseases, sarcoidosis, amyloidosis, hypothyroidism, and vitamin A deficiency and can be caused by medications such as antihistamines and antidepressants. Sjgrens syndrome or SLE would be the most likely cause in this patient.
Mononeuritis multiplex

Figure 1. Photographs of Skin Lesions. There is a reticular pattern of bluish discoloration (livedo reticularis) on the skin of the anterior lower legs RETAKE 1st ICM (Panel A). AUTHOR Kroshinsky An erythematous nodule over the malleolus 2nd REG F FIGURE 1a&b was tender (Panel B). 3rd
CASE

TITLE

4-C Line SIZE Enon ARTIST: mst H/T H/T 16p6 FILL Combo ent, in addition to the livedo pattern; I will discuss

EMail

Revised

AUTHOR, PLEASE NOTE: the implications of these findings later. LaboraFigure has been redrawn and type has been reset. tory investigation shouldcarefully. a comprehensive Please check include hypercoagulability workup and serologic testing ISSUE: 2-12-09 forJOB: 36007 connective-tissue diseases, which were negative in this patient. A skin biopsy could narrow the differential diagnosis further, separating inflammatory from thrombotic processes. Biopsy specimens taken from at least three skin areas, including both the blanched center and the lacy, discolored skin down to the subcutaneous fat, yield a diagnosis in about

The patients numbness and pain indicate involvement of organs beyond the skin namely, peripheral nerves. The sequential nature of these lesions is classic for a mononeuritis multiplex that is, the dysfunction of individual, named peripheral nerves. Most systemic diseases associated with mononeuritis multiplex, including vasculitides, connective-tissue disease, cryoglobulinemia, sarcoidosis, diabetes, amyloidosis, neoplasms, and infections, cause nerve damage by affecting the vasa nervorum. The combination of livedo reticularis, tender cutaneous nodules, atrophie blanche, and mononeuritis multiplex, together with the peripheral-blood cytopenias, suggest connectivetissue disease, most likely SLE (possibly complicated by Sjgrens syndrome, the antiphospholipidantibody syndrome, or both), vasculitis (including cutaneous polyarteritis nodosa), or livedoid vasculopathy. Several of these entities could occur together.
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Systemic lupus erythematosus

Cutaneous changes develop in up to 50% of patients with SLE even before they fulfill the minimum American College of Rheumatology criteria for the classification of SLE.4 This patients livedo reticularis and subcutaneous nodules are within the spectrum of SLE.5 Vasculitis develops in up to one third of patients with SLE.6 Small-vessel vasculitis predominates, but medium-sizedvessel vasculitis also occurs.6 Small-vessel vasculitis is typified by palpable purpura, which this patient does not have; medium-sizedvessel vasculitis, in contrast, can present with livedo reticularis, mononeuritis multiplex, and ulceration.5 This patients clinical findings are most consistent with a medium-sizedvessel vasculitis. Patients with SLE and medium-sizedvessel vasculitis have a higher prevalence of mononeuritis multiplex, visceral vasculitis, and ischemic cutaneous lesions, but they are less likely to have a malar rash or discoid lesions than are patients who have SLE without medium-vessel vasculitis.6 Ninety-nine percent of patients with SLE have a positive antinuclear antibody (ANA) assay.7 True ANA-negative SLE exists but has become rare since the introduction of testing with the HEp-2 cell substrate.8 Patients with ANA-negative SLE often have antibodies to the Ro (SS-A) antigen or secondary antiphospholipid-antibody syndrome. This patient could have ANA-negative SLE.
Sjgrens syndrome

Table 2. Possible Causes of Livedo Reticularis in this Patient.* Hematologic diseases Antiphospholipid-antibody syndrome Sneddons syndrome Cryoglobulinemia Cryofibrinogenemia Multiple myeloma Myeloproliferative disorder (polycythemia vera, essential thrombocythemia) Rheumatologic diseases Vasculitis of medium-sized blood vessels (polyarteritis nodosa, ANCAassociated vasculitis, mixed cryoglobulinemia) Connective-tissue diseases (systemic lupus erythematosus and related conditions) Livedoid vasculopathy Cardiovascular diseases Embolic disease (cholesterol emboli, septic emboli, atrial myxoma) Malignant tumors Renal-cell carcinoma Intravascular lymphoma Mycosis fungoides Endocrine disorders Hypothyroidism, pernicious anemia Pheochromocytoma Carcinoid * ANCA denotes antineutrophil cytoplasmic autoantibody.

This patients keratoconjunctivitis sicca could be a manifestation of Sjgrens syndrome, which is also characterized by peripheral neuropathy (including mononeuritis multiplex) and peripheral-blood cytopenias, among other manifestations.9-11 Classic cases are associated with a positive ANA assay and Ro (SS-A) or La (SS-B) antibodies.10 The patients family history of Sjgrens syndrome increases the likelihood that her clinical findings are due to a connective-tissue disease.12-14
Antiphospholipid-antibody syndrome

leukopenia.17,18 The diagnosis is confirmed by the demonstration of moderate-to-high titers of IgG or IgM anticardiolipin antibodies or lupus anticoagulant that are positive on retesting 12 weeks later.16,17 This patient did not have evidence of anticardiolipin antibodies.
Cutaneous polyarteritis nodosa

Livedo reticularis is the most common cutaneous manifestation of the antiphospholipid-antibody syndrome and can present before the development of thrombi within other organs.15 The antiphospholipid-antibody syndrome can occur either as a primary condition or secondary to a connective-tissue disorder, usually SLE.16,17 The hematologic features of the antiphospholipid-antibody syndrome may include thrombocytopenia and
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This patient has painful dermal nodules on the legs, in the area of the malleoli, accompanied by livedo reticularis and ulcerations that heal with atrophie blanche; this constellation of findings is typical of cutaneous polyarteritis nodosa a medium-sizedvessel vasculitis that is limited largely to the skin.5,19 Peripheral-nerve involvement is also described in some patients,5 and episodes can be accompanied by leg swelling, as in this patient.5,19 The diagnosis is challenging, because cutaneous polyarteritis nodosa has no distinctive autoantibodies and cannot be identified by other laboratory tests. Elevated levels of
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acute-phase reactants and a normochromic anemia are detected frequently during active disease, but in contrast to the findings in our patient, leukopenia and thrombocytopenia are not typical of cutaneous polyarteritis nodosa.19
Livedoid vasculopathy

Livedoid vasculopathy is a segmental, hyalinizing vasculopathy that involves small and mediumsized blood vessels in the lower legs. It can present with livedo changes in the skin, focal purpura, and painful, irregularly shaped lesions around the malleoli. It can be an isolated or a primary condition or can be associated with a variety of hypercoagulable risk factors, including antiphospholipid antibodies, as well as most other serologic and genetic risk factors for either venous or arterial thromboses, and connective-tissue diseases.20 Our patients cutaneous findings could be explained by livedoid vasculopathy occurring in the setting of a connective-tissue disorder, the most likely of which would be SLE.
Summary

Figure 2. Skin-Biopsy Specimens (Hematoxylin and Eosin). A skin-biopsy specimen from the left lateral malleolus (Panel A) shows small vessels in the superficial papillary RETAKE 1st AUTHOR Kroshinsky ICM dermis that have thickened and hyalinized walls and 2nd a REG F FIGURE 2a-c tufted, tortuous appearance. The specimen also shows 3rd CASE TITLE Revised a perivascular lymphocytic infiltrate with areas suggesEMail 4-C Line tiveEnonmicrothrombi, diagnostic of livedoid vasculopaof SIZE ARTIST: mst H/T H/T thy FILL (inset). A skin biopsy from the left ankle performed 16p6 Combo at another hospital 8 weeks before this evaluation (Panel AUTHOR, PLEASE NOTE: B) shows extensive deposition of dermalbeen reset. Figure has been redrawn and type has mucin, highPlease check carefully. lighted by alcian blue stain, and a lymphocytic infiltrate around the middle and deep dermal vessels (inset). JOB: 36007 A skin biopsy from the left temple ISSUE: 2-12-09 othperformed at the er hospital 7 weeks before this evaluation (Panel C) shows an interface dermatitis with vacuolopathy at the dermoepidermal junction; periadnexal and perineural lymphocytic inflammation was also present (inset).

I would review all outside biopsy specimens with a dermatopathologist and, if they are nondiagnostic, repeat the biopsies of both the livedo and a skin nodule. Serologic testing for both connective-tissue disease and antiphospholipid antibodies should be repeated. In addition, I would perform a genetic coagulopathy profile, coagulation tests, serologic testing for hepatitis B and C, and a urinalysis, and I would test for cryoglobulins. Dr. Nancy Lee Harris (Pathology): Dr. Stone, would you tell us your thinking when you saw the patient? Dr. Stone: I considered three major diagnoses: ANA-negative SLE, a hematologic cancer, and cutaneous polyarteritis nodosa. The patient had had two negative ANA assays, as well as negative assays for autoantibodies that are more specific for SLE or related disorders. SLE seemed unlikely in view of these results. The normal peripheral-blood smear and unremarkable CT scan were reassuring with regard to hematopoietic malignant conditions. Polyarteritis nodosa would have explained the tender nodules on her lower extremities and the mononeuritis multiplex but would not have accounted for her neutropenia and lymphopenia. Therefore, we referred her for a skin biopsy of the lesion near the left lateral malleolus and repeated the ANA.
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Livedo reticularis pattern

Epidermis

Venule Dermis Platelet Fibrin Perivascular tissue Arteriole Lymphocyte Neutrophil

Subcutaneous tissue

Venule

Endothelial damage Extravasation of fluid and lymphocytes

Figure 3. Possible Pathophysiology of Livedo Reticularis in Cases of Livedoid Vasculopathy. Livedo reticularis is caused by increased prominence of the venous beds in the skin, either from impediments to arterial inflow, venous COLOR FIGURE dilatation, or obstruction of venous outflow. In livedoid vasculopathy, it is postulated that there is damage to the endothelium, extravasation of fluid and lymphocytes to the perivenular space, and activation of intravascular coagulation pathways with intraluminal thrombi. Rev7 01/08/09 The combination of these processes probably leads to obstruction of venous outflow with consequent venous dilatation and the livedo Author Dr. Kroshinsky reticularis pattern. Fig # 3 Title ME Harris DE phologic picture is diagnostic of livedoid vasculCl inic a l Di agnosis Daniel Muller Artist

Cutaneous polyarteritis nodosa.

Dr . Da niel a K roshinsk y s Di agnosis

ANA-negative SLE with livedoid vasculopathy; secondary antiphospholipid-antibody syndrome cannot be excluded.

Pathol o gic a l Discussion

Dr. Alireza Sepehr: The biopsy from the left lateral malleolus showed thickening and hyalinization of the small vessels in the dermis (Fig. 2A), with foci suggestive of small microthrombi and a perivascular lymphocytic infiltrate (Fig. 2A, inset). No leukocytoclastic vasculitis or fibrinoid necrosis of the vessel walls was seen. This morn engl j med 360;7

opathy. AUTHOR PLEASE NOTE: Figure has histoLivedoid vasculopathy is characterized been redrawn and type has been reset Please check carefully logically by a thin and flattened epidermis, segIssuein the 2-12-2009 date mental hyalinization of small vessels superficial dermis, endothelial swelling, and dilated capillaries with tortuous loops. Extravasation of red cells with or without hemosiderin, microthrombi, and perivascular lymphocytic infiltrates are typical. The absence of fibrinoid necrosis and inflammation of the vessel wall differentiates this condition from the vasculitides.21,22 The pathophysiology of this condition is not fully understood, and hypotheses include formation of fibrin cuffs around small vessels due to fibrin leakage in chronic venous insufficiency, white-cell trapping and activation and subsequent endothelial damage secondary to venous hypertension, and activation of the procoagulant pathway by antiphospholipid antibodies; different combinations of
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these mechanisms may be operative in different clinical settings.3,23 The damage to small cutaneous veins probably produces the clinical picture of livedo reticularis (Fig. 3). Dr. Stone: The diagnosis of livedoid vasculopathy prompted us to reevaluate the coagulation tests. The anticardiolipin antibody (IgG) level was markedly elevated (42.3 IgG phospholipid units; reference range, 0 to 15). The remainder of the hypercoagulation workup was negative, except for a slightly decreased level of protein S, which can be seen in patients using oral contraceptives. We requested repeated ANA testing, and we asked for a review of the outside pathological slides. Dr. Donald B. Bloch: On repeat testing at this hospital, ANAs were detected by indirect immunofluorescence assay (titer, 1:1280), in a speckled pattern. Subsequently, antibody to double-stranded DNA (dsDNA) was detected (titer, 1:40); enzyme immunoassays for antibodies to Ro (SS-A), La (SS-B), Smith, and U1-RNP were negative. A second serum sample from this patient was retested in our laboratory, and the positive ANA result was confirmed. One potential explanation for the conflicting results is that ANAs developed during the 8-week interval between previous testing and the patients presentation here. However, in patients with SLE, the autoantibodies usually develop many months or years before the development of symptoms of SLE.24 Thus, it seems unlikely that ANAs developed during the 8-week interval. Moreover, a subsequent sample sent to the same commercial laboratory was still reported to be negative for ANAs. The most likely explanation for the conflicting ANA results in this case is the use of different screening tests for ANAs. The Clinical Immunology Laboratory at this hospital uses indirect immunofluorescence and a human epidermoid carcinoma cell line (HEp-2) to screen for ANAs. At dilutions of 1:40 and 1:160, indirect immunofluorescence is reported to be positive in 97% and 95% of patients with SLE, respectively.25 The commercial laboratory that tested this patients serum for ANAs uses a flow cytometrybased solid-phase screening assay, in which colored polystyrene beads coated with autoantigens are mixed with the patients serum, incubated with fluoresceinconjugated antihuman IgG, and examined with the use of a dual-laser flow cytometer to detect both the color of the bead and the amount of autoantibody coating the bead. The flow cytometry based kit contains nine different-colored beads
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coated with defined autoantigens: Ro, La, Sm, U1-RNP, Scl-70, Jo-1, Cenp-B, dsDNA, and histones. A 10th bead is coated with material extracted from HEp-2 cell nuclei. A serum sample is reported as having ANAs if it contains autoantibodies directed against at least 1 of the 10 coated beads. The details of how the antigens are produced, purified, linked to the beads, and tested for stability are trade secrets. HEp-2 cells contain many more than the nine autoantigens linked to the fluorescent beads. Whether these other autoantigens are well represented in the HEp-2 nuclear extract on the 10th bead is not known. Important epitopes may be altered or lost during the process of conjugation of the antigens to the beads. This patients experience suggests that the change in testing methods may result in failure to diagnose systemic autoimmune disease. Recent reports suggest that the sensitivity of a positive fluorescent-bead assay for the diagnosis of SLE may be as low as 49 to 58%.26,27 This case illustrates the importance to the clinician of knowing how the laboratory performs the screening test for ANAs. If SLE or another systemic autoimmune disease is suspected but the ANA screening test by means of enzyme-linked immunosorbent assay or fluorescent-beadbased assay is negative, then the test should be repeated using indirect immunofluorescence on HEp-2 cell substrate. Dr. Sepehr: Two skin biopsies performed before the patients evaluation at this hospital were reviewed, and the findings were consistent with a connective-tissue disease. The biopsy specimen from the left ankle showed extensive deposition of dermal mucin and a lymphocytic infiltrate around the middle and deep dermal vessels (Fig. 2B). A biopsy specimen from the temple area also showed deposition of mucin in the dermis, interface dermatitis at the dermoepidermal junction, and periadnexal and perineural lymphocytic inflammation (Fig. 2C). The combination of the findings in the three biopsies, the positive ANA assay, the antibody to dsDNA, and the elevated levels of IgG anticardiolipin antibody supports a diagnosis of livedoid vasculopathy associated with SLE.

Discussion of M a nagemen t
Dr. Stone: The treatment of livedoid vasculopathy remains highly empiric. Habits such as smoking and medications such as oral contraceptives are
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strongly discouraged. This patient discontinued her oral contraceptives. Active interventions generally are designed to interfere with platelet function, interrupt other components of the clotting cascade, or treat an underlying condition such as a known hypercoagulable state28 or SLE. The spectrum of agents targeting blood clotting ranges from baby aspirin to tissue plasminogen activator and includes warfarin, dipyridamole, and heparin.21 When SLE and the antiphospholipid-antibody syndrome are present, hydroxychloroquine and warfarin must be considered. We opted to treat the patient with baby aspirin and hydroxychloroquine and planned to use warfarin if she did not respond to the initial treatment. Four months after presentation, the development of new cutaneous nodules had ceased, the livedoid appearance of the legs had resolved, and both the pain and numbness had improved. Dr. Harris: The patient is here today, and I would like to invite her to comment on her experience. The Patient: By the time I saw Dr. Stone, I was virtually bedridden. It seemed like an eternity. My improvement was very gradual, but after about 3 or 4 weeks of treatment, the swelling and then the pain subsided. When I came to Boston which happens to be my favorite city to see Dr. Stone, I couldnt walk or go to museums. Yesterday, as I walked through the Boston Common, virtually pain-free, I thought, What a miracle! It was a circuitous route to the diagnosis, with false negative laboratory tests and skin biopsies not interpreted correctly, but despite the fact that so many things went wrong, I have had a wonderful result.
References
1. Gibbs MB, English JC III, Zirwas MJ.

Dr. Margaret Seton (Rheumatology): Dr. Stone, how can you be sure this is not Sjgrens syndrome? Dr. Stone: As rheumatologists, we become comfortable with our inability to render precise diagnoses in all patients. In this case, there are two things, the positive dsDNA antibodies and the cutaneous findings, that are consistent with lupus. Although she could have both lupus and Sjgrens syndrome, we do not think a lip biopsy (which, if positive, can confirm a diagnosis of Sjgrens syndrome) is justified at this point. Dr. Dwight Robinson (Rheumatology): Did you consider using corticosteroids? Dr. Stone: In view of the presence of both coagulopathy and livedoid vasculopathy, I thought that the treatment decision was between something on the milder side, such as aspirin and hydroxychloroquine, or full-dose anticoagulation with warfarin. We opted to go with the baby aspirin and the hydroxychloroquine, and the patient has done very well. One year after the diagnosis, the ANA assay was positive at 1:320 and the anti-dsDNA at 1:10, and the IgG anticardiolipin antibody level was 26.9 IgG phospholipid units. The pain and swelling have resolved, and she has residual numbness over both medial malleoli.

A nat omic a l Di agnosis

Lymphocyte-mediated vasculopathy, with fibrin microthrombi and vascular hyalinization (livedoid vasculopathy), secondary to SLE.
Dr. Stone reports receiving consulting fees from Merck and ZymoGenetics. No other potential conflict of interest relevant to this article was reported.

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acteristics in 670 patients. Medicine (Baltimore) 2006;85:95-104. 7. Gill JM, Quisel AM, Rocca PV, Walters DT. Diagnosis of systemic lupus erythematosus. Am Fam Physician 2003;68:2179-86. 8. Cross LS, Aslam A, Misbah SA. Antinuclear antibody-negative lupus as a distinct diagnostic entity does it no longer exist? QJM 2004;97:303-8. 9. Fox RI, Stern M, Michelson P. Update in Sjgren syndrome. Curr Opin Rheumatol 2000;12:391-8. 10. Papiris SA, Tsonis IA, Moutsopoulos HM. Sjgrens syndrome. Semin Respir Crit Care Med 2007;28:459-71. 11. Ramos-Casals M, Brito-Zern P, Font J. The overlap of Sjgrens syndrome with other systemic autoimmune diseases. Semin Arthritis Rheum 2007;36:246-55.

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