|Ahead of print publication
Livedoid vasculopathy with mononeuritis multiplex associated with protein S deficiency mimicking systemic vasculitis
Vikramraj K Jain1, Krishnamurthy Hegde2, Renuka Panchagnula3
1 Department of Clinical Immunology and Rheumatology, ChanRe Diagnostic Laboratory, Bengaluru, Karnataka, India
2 Department of Medicine Bhagwan Mahaveer Jain Hospital, ChanRe Diagnostic Laboratory, Bengaluru, Karnataka, India
3 Department of Pathology, ChanRe Diagnostic Laboratory, Bengaluru, Karnataka, India
Vikramraj K Jain,
Bhagwan Mahaveer Jain Hospital, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
A 34-year-old female presented with recurrent ulcers over the bilateral lower limbs with mononeuritis multiplex. Possibilities considered were small-to-medium vessel vasculitis and vasculopathy. Skin biopsy was suggestive of livedoid vasculopathy (LV). Investigations revealed protein S deficiency. The patient was treated with anticoagulation and immunosuppression after which her symptoms improved. LV can be associated with thrombophilias, fibrinolytic disorders, autoimmune diseases, and malignancy. Polyarteritis nodosa closely mimics the disease and needs a deep dermal biopsy to differentiate.
Keywords: Livedoid, polyarteritis nodosa, protein S deficiency, vasculopathy
|How to cite this URL:|
Jain VK, Hegde K, Panchagnula R. Livedoid vasculopathy with mononeuritis multiplex associated with protein S deficiency mimicking systemic vasculitis. Indian J Rheumatol [Epub ahead of print] [cited 2019 Jan 18]. Available from: http://www.indianjrheumatol.com/preprintarticle.asp?id=246316
| Introduction|| |
Livedoid vasculopathy (LV) is a non inflammatory thrombotic condition, characterized by recurrent painful purpuric ulcerative lesions around ankle and dorsum of feet that heal with stellate porcelain white scars. It can be associated with thrombophilias, fibrinolytic disorders, autoimmune diseases and malignancy. Histopathology reveals segmental vessel wall hyalinization of dermal blood vessels with fibrinoid deposition in lumen and minimal perivascular lymphocytic infiltration. Neurological involvement in LV is rarely described and presents usually as mononeuritis multiplex, months to years after onset of cutaneous lesions. Polyarteritis nodosa (PAN) is a close differential diagnosis. Workup requires a deep skin biopsy to primarily exclude PAN. Rheumatologists should be aware of this entity that can sometimes be managed with anticoagulation alone.
| Case Report|| |
A 34-year-old female, with no comorbidities, presented with recurrent ulcers over the bilateral lower limbs around the ankle and dorsum of the foot for 1 year. Ulcers were painful and healed spontaneously over a few months leaving behind whitish scars, only to recur again over a fresh site. She also had complaints of numbness and burning sensation over her medial two fingers of left hand and medial aspect of the left forearm that started 1 month ago, followed a few days later by difficulty in making a fist. There was no history of fever, weight loss, myalgias, joint pain, Raynaud's phenomenon, or oral ulcers. No history of any other organ system involvement. She had no history of spontaneous recurrent abortions or deep vein thrombosis.
On examination, the patient had livedo racemosa over her left upper limb. Multiple stellate purpuric ulcers with crusting were present behind the right lateral malleolus with surrounding multiple healed porcelain white scars. Similar lesions were present around the left lateral malleolus and dorsum of the left feet. A 3 cm × 1 cm ulcer with crusting was seen around the left medial malleolus [Figure 1]. All peripheral pulses were palpable. Blood pressure was 110/80 mm Hg. Neurological examination revealed decreased touch, pain, and pinprick sensation over the left distal medial forearm, ulnar border of hand, and medial one and half digits. The motor weakness of intrinsic muscles of left hand supplied by ulnar nerve was present. Possibilities considered were livedoid vasculopathy (LV), medium vessel vasculitis – polyarteritis nodosa (PAN), and antiphospholipid antibody syndrome.
|Figure 1: (a) Multiple stellate purpuric ulcers with crusting were present behind the right lateral malleolus with surrounding multiple healed porcelain white scars. Similar lesions were present around the left lateral malleolus and dorsum of the left foot. A 3 cm × 1 cm purpuric ulcer with crusting was seen around the left medial malleolus. (b) One year later, ulcers are completely healed|
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Investigations revealed hemoglobin of 13.7 g%, white blood cell count of 12,500/mm3, and a platelet count of 3.31 lac/mm3. Erythrocyte sedimentation rate of 25 mm/h and C-reactive protein was 11.11 mg/L. Renal and liver function tests, blood sugars, and urine routine were within normal limits. Viral serologies (HIV, hepatitis B surface antigen, and hepatitis C virus) were negative. Venous Doppler bilateral lower limbs were normal. Thrombophilia workup was done before starting anticoagulation therapy. Prothrombin time/international normalized ratio was 0.86, and activated partial thromboplastin time was 38.4 s. Anticardiolipin (IgG and IgM), antiB2GP1 (IgG and IgM), and lupus anticoagulant were negative. Antinuclear antibody and antineutrophilic cytoplasmic antibody by immunofluorescence were negative. Serum homocysteine levels were normal. Protein S functional activity was 28.4% (normal 50%–140%), and free antigen levels were 38% (normal 60.1%–113.6%) were reduced, while protein C and antithrombin III functional activity were normal. Factor V Leiden mutation was negative. Serum cryoglobulins, cryofibrinogens, serum protein, and immunofixation electrophoresis were not done.
Nerve conduction studies revealed decreased amplitude over the bilateral common peroneal nerve and left ulnar nerve, increased latency, and decreased the velocity of left ulnar nerve with absent sensory nerve action potential over the left sural nerve. Skin biopsy from ulcer edge revealed fibrin deposition around the dermal vessels occluding the lumen with sparse chronic inflammatory infiltrate consistent with LV [Figure 2]a and [Figure 2]b. Sural nerve biopsy was planned; however, the patient refused. Computed tomography angiography of the abdomen to rule out the presence of an aneurysm was not done in the absence of abdominal symptoms. Primary diagnosis made was LV with ischemic neuropathy due to underlying procoagulant (i.e., protein S deficiency) state. However, a differential of PAN was still considered as both conditions can coexist. A decision to start both anticoagulation and immunosuppression was made in view of both differentials and patient's refusal for nerve biopsy to further confirm the diagnosis. The patient was initially started on the overlap of low-molecular-weight heparin and warfarin with prednisolone 1 mg/kg and mycophenolate mofetil following which her sensory and motor symptoms improved and skin lesions resolved completely over the next 2 months. Steroids were gradually tapered and stopped, and mycophenolate discontinued after 6 months as the patient had no clinical worsening despite stopping her steroids and there being no available definitive evidence of PAN. At 12 months of follow-up, the patient is presently only on anticoagulation and is doing well with no recurrence of skin lesions. Repeat protein S functional activity (29.3% [normal 50%–140%]) and free antigen levels (38.5% [normal 60.1%–113.6%]) done 1 year later after stopping anticoagulation for 2 weeks were still reduced.
|Figure 2: (a) Biopsy showing thickening and hyalinization of superficial dermal vessels (arrows) with fibrin deposits in the lumen obliterating the lumen but no inflammation around them. (b) The vessels of the deep dermis and subcutis showed perivascular chronic inflammatory cells (arrow) and vascular thrombi (star). The overlying epidermis showed intraepidermal blister formation and denudation|
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| Discussion|| |
LV is a noninflammatory thrombotic condition, associated with hypercoagulable or impaired fibrinolytic states, characterized by recurrent painful purpuric ulcerative lesions around the ankle and dorsum of the feet that heal with stellate porcelain white scars. Histopathology reveals segmental vessel wall hyalinization of dermal blood vessels with fibrinoid deposition in the lumen and usually minimal perivascular lymphocytic infiltration. Direct immunofluorescence (DIF) may show the deposition of immunoglobulin, fibrin, and complement components. Intraluminal thrombosis of dermal blood vessels leads to ischemia of the cutaneous microcirculation and subsequently cutaneous infarction.
LV has an incidence of 1:1,00,000 per year, usually affects the age group of 15–50 years and is more common in females (2.4–3:1). Lesions usually begin as painful macules and/or papules in the lower limb that often ulcerate and heal slowly over weeks or months into atrophic porcelain white scars surrounded by punctate telangiectasia and brownish pigmentation., They may be accompanied by livedo racemosa – bluish-gray broken ring-like macules, caused by reduced cutaneous blood flow.
Neurological involvement in LV is rare and presents usually as mononeuritis multiplex, months to years after the onset of cutaneous lesions. Neuropathy occurs secondary to ischemia from vascular thrombosis of vasa nervorum. Nerve biopsy typically shows the features of axonal loss with vasculopathy.
English articles available on PubMed with no limit on publication date were reviewed on September 23, 2018 using the combination of following search words: “livedoid vasculopathy,” “livedoid vasculitis,” “segmental hyalinizing vasculitis,” and “neuropathy” or “mononeuritis multiplex.” The total number of articles derived from the PubMed search was ten, and a total number of patients described were 29. These were then read, analyzed, and cross-referenced. The reference lists of selected review articles citing the above articles were studied to obtain additional original articles and data obtained compiled [Table 1].
|Table 1: Published cases of livedoid vasculopathy with neurological manifestations|
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Differential diagnosis includes small and medium vessel vasculitis (especially PAN), chronic venous insufficiency, pyoderma gangrenosum, and Degos disease. Conditions associated with LV include inherited and acquired thrombophilias, autoimmune rheumatic diseases, and malignancy [Figure 3]. In a prospective study of 34 patients with LV, 18 (52%) had underlying procoagulant condition with protein C and/or S deficiency in only 3 (8.82%) patients.
Workup requires a skin biopsy specimen for histopathology and DIF. Biopsy features of LV in superficial dermis can coexist with features of PAN in the deep dermis and subcutaneous region, probably secondary to the obliteration of the medium vessels. The biopsy specimen from the marginal skin and eventual ulcer should hence include deep dermis to primarily exclude PAN that is otherwise difficult to differentiate clinically. Laboratory tests to detect abnormalities suggestive of autoimmune connective tissue diseases, thrombophilias, paraproteinemias, and serology for hepatitis B, C, then HIV should be performed [Table 2].,,
The treatment of LV depends on the associated cause. Options include antiplatelet agents, anticoagulants, vasodilators, rheological agents, and rarely corticosteroids - alone or in combination with immunosuppressive medications tailored to the underlying etiology. Supportive measures, such as compression stockings, pain relief, cessation of smoking, and bed rest with leg elevation, may also help in healing of ulcers in certain cases.,,
Our case of LV with mononeuritis multiplexes due to underlying protein S deficiency closely mimics medium vessel vasculitis and represents the typical diagnostic and therapeutic challenges in the management of such lesions. A nerve biopsy and abdominal angiography would be preferable to conclusively rule out PAN; however, typical cutaneous biopsy findings on deep dermal specimen, persistent low protein S, and response to anticoagulation alone after stopping immunosuppression would favor LV.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that name and initial will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]