Digital ulcerations : A case of cutaneous polyarteritis nodosa Alejandro Perez, MD, FSVM, RPVI Providence Heart and Vascular Institute, Vascular Medicine Regional Medical Director for Providence Wound Care and Hyperbaric Program Columbia Wound Care Consortium Quarterly Symposium - 7/26/2014 1

Disclosures None 2

Objectives Understand workup of causes of digital ulcerations Diagnosis of cutaneous polyarteritis nodosa (PAN) Treatment of PAN

Case 44 y/o man c/o toe ulcerations Has had leg skin abnormalities for 9 months. First noted swelling of feet and ankles. Active marathon runner and kept exercising.

Case- Additional History After 6 months developed distal ischemia. Right toe ulcers 2,3 developed first and progressed to eschar by 8 th month of symptoms Left toe ulcers 1-4 at earlier stages of progression with less involvement

Case- Additional History Has had bx to r/o cutaneous PAN. Pathology results of left arm/leg revealing for perivascular inflammatory infiltrate (plasma cells, eosinophils) without definitive vasculitis. Had been started on prednisone with resolution of swelling. Has had no systemic symptoms of fever or fatigue.

Case Past Medical History Iron deficiency anemia Past Surgical History Tonsillectomy Vasectomy Family History Sister- RA, Mother- cancer

Case Social History Never a smoker; no illicit drug use From India, but immigrated 20 yrs prior Works as computer programmer Review of Systems (-) for fevers, weight loss; (+) for leg swelling and toe ulceration, (+) anemia

Case Current Medications: Acetaminophen 650 mg PRN ASA 325 mg daily. Cholecalciferol (Vita D-3) 1,000 U Daily Clopidogrel 75 mg daily Prednisone 30 mg daily Probiotic Allergies: NKDA

Case- On Examination Vital Signs: BP: 122/82 mmHg P: 70, Weight: 128 lbs, Height: 5' 10" | BMI General: Well appearing thin man. No distress. Cardiovascular: Regular rhythm. Normal S1 and S2. No murmurs. Normal carotid pulses. No carotid bruits. Abdominal aorta: Normal aortic impulse. No abdominal bruit. Peripheral pulses: 2+ Radial, Femoral, DP, PT No edema

Case- Toe ulcerations Skin examination: Right toe ulcers 2,3. Left toe ulcers 1-4. Toe ulcers with eschar and no purulence. Livedo pattern to feet Hyperpigmentation of distal legs.

Right foot ulcer

Left foot ulcer

Laboratory Testing Negative: Factor V Leiden mutation, Prothrombin gene mutation, Protein C/S deficiency, AntiThrombin III deficiency, Lupus anticoagulant. Mild elevation of cardiolipin Ig M antibody, beta2 glycoprotein Ig M antibody ESR has been elevated on 2 checks

Laboratory Testing RA negative:RF and anti-CCP ab Normal: ANA, cryoglobulin, Hepatitis B/C, platelet function, ANCA panel( including myeloperoxidase and serine PR3 testing)

Imaging studies Arterial leg study, CTA chest/abdomen/pelvis and TTE without pathology Digital testing: Right 2 nd, 3 rd, 4th digit: ischemia noted. Left 2 nd,3 rd,4 th, 5 th digit: ischemia noted.

Digital ulcers – Multiple Causes Trauma/Thermal Injury/Radiation fibrosis Spider bite Drug induced, Ergotism Atheroembolic Cardioembolic Raynaud’s, Chilblains(pernio) Rheumatologic/Autoimmune Buerger’s(TAO)

Polyarteritis Nodosa Systemic necrotizing vasculitis that affects medium-sized muscular arteries; occasional involvement of small muscular arteries Kidneys, skin, joints, muscles, nerves, and gastrointestinal tract are commonly involved Spares the lungs

Polyarteritis Nodosa Diagnosis usually in middle-aged or older adults Incidence rises with age, with a peak in the sixth decade 1.5:1 male predominance Can affect children Hepatitis B/C virus,and hairy cell leukemia lead to secondary PAN

Diagnosis of PAN –ACR criteria At least three of the following criteria are present: Otherwise unexplained weight loss >4 kg Livedo reticularis Testicular pain or tenderness Myalgias/weakness Mononeuropathy or polyneuropathy New-onset diastolic BP > 90 mmHg Elevated BUN(>40 mg/dL) or creatinine (>1.5 mg/dL) Evidence of HBV infection arteriographic abnormalities not from noninflammatory disease processes A biopsy of small/ medium-sized artery with PMNs

Biopsy Nodules and ulcers: small 2 to 4 mm “punch” biopsies of the skin sample only the epidermis and superficial dermis and unlikely to include muscular arteries. Elliptical surgical skin biopsies that include deeper dermis and subcutaneous fat more helpful

PAN- histology PAN does not involve veins. cellular infiltrate contains PMLs and mononuclear cells. Fragments of WBCs (leukocytoclasis). Fibrinoid necrosis: Necrosis of the arterial wall results in a homogeneous, eosinophilic appearance. Disruption of the internal and external elastic lamina -> aneurysms

Cutaneous PAN Skin manifestations: Tender erythematous nodules Purpura Livedo reticularis Ulcers Bullous/vesicular eruption

Cutaneous PAN Lesions may be focal or diffuse Typically on lower extremities. Limb edema is common. Infarction and gangrene of the fingers, toes, extending into the subcutaneous tissue.

Other possible vasculitis Granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis (Churg-Strauss) Henoch-Schönlein purpura (IgA vasculitis) Cryoglobulinemic vasculitis Drug-induced vasculitis Vasculitis secondary to connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis)

Laboratory studies creatinine, muscle enzymes, LFTs, HBV and HCV, and urinalysis. ESR and CRP Antineutrophil cytoplasmic Ab (ANCA) Antinuclear antibodies (ANA) Complement components (C3 and C4) Cryoglobulins Serum and urine electrophoresis for monoclonal gammopathy Testing for HIV

Treatment of cutaneous PAN Initially glucocorticoids alone Prednisone 1 mg/kg daily (max mg daily) x four weeks Taper to 20 mg daily by month 3 or 4 Taper slowed: -2.5 mg daily every 14 days If not improving can consider azathioprine, methotrexate, mycophenolate

PAN Untreated, 13 percent five-year survival If treated, five-year survival is approximately 80 percent

Followup deeper sections are obtained … at the dermal subcutaneous fatty tissue junction, there is a single medium-sized blood vessel which wall is infiltrated by neutrophils. There is a surrounding inflammatory infiltrate, containing neutrophils, eosinophils, plasma cells, and lymphocytes…most consistent with subtle vasculitis. Similar changes can be seen in POLYARTERITIS NODOSA as well as other vasculitides, affecting medium sized vessels."

Followup – Toe ulcerations Maintained on prednisone and continues to improve. Started on CCB to help with peripheral flow. Left toe ulcers nearly healed Right toe ulcers demarcated Foot pain greatly improved

Summary Suspect vasculitis in setting of digital ulcerations. Biopsy is often necessary for diagnosis of PAN. Steroid therapy helps most for treatment of cutaneous PAN.