Primary Cutaneous Small Vessel Vasculitis Dr.NaveenBasappaMay16

Primary Cutaneous Small Vessel Vasculitis Dr. Naveen Basappa Rheumatology Noon Rounds May 16, 2006 DEFINITION • PCSVV is: •All cutaneous-limited leukocytoclastic vasculitis (LCV) without extracutaneous involvement •idiopathic •also known as “cutaneous leukocytoclastic angiitis” or “leukoctyoclasia” •diagnosis of EXCLUSION •the most common clinical presentation of LCV WHAT IS LEUKOCYTOCLASTIC VASCULITIS? Definition - LCV • Neither a DIAGNOSIS nor a DISEASE! • LCV describes the clinical and pathological manifestations of an entity affecting the small vessels of the skin Histology - LCV • Infiltration of neutrophils perivascularly • Degranulation and fragmentation of neutrophils – production of nuclear dust • Fibrinoid necrosis of damaged vessel walls • Necrosis, swelling, and proliferation of endothelial cells • Extravasation of red blood cells Clinical Presentation: cutaneous lesions • Palpable Purpura • most common presenting form • round, 1-3mm – palpable! • coalesce to form plaques • primarily dependent areas (legs, buttocks) Clinical Presentation: cutaneous lesions • Urticarial Lesion • Annular, Edematous • Last longer than 24 hours • Followed by ecchymosis, purpuric staining • Can occur anywhere on body • Burning/Painful lesion – less pruritic Clinical Presentation: cutaneous lesions • Nodular lesions • Livedo reticularis • Necrotic lesions • Erythematous plaques • Erythema multiforme-like lesions • Ulcerations Other Clinical Features • May be acute (hours) or chronic (weeks) • May have fevers, constitutional symptoms, MILD myalgias and/or arthralgias • Involvement of other internal organs (e.g., kidneys, GI tract, frank joint or nerve) is suggestive of systemic disease Other Clinical Features • Majority of PCSVV is self limited, singly episodic • 8-10% have chronic/recurring episodes • Overall good prognosis (isolated to skin) Subsets of PCSVV • Essential Mixed Cryoglobulinemia (EMC) • Normocomplementemic Urticarial Vasculitis (NUV) • Acute Hemorrhagic Edema of Infancy (AHEI) EMC • Results in deposition of temperature sensitive cryoprecipitate of Ig complexes • Appear as palpable purpura in dependent areas as well as cooler acral sites • Often present with arthralgias/arthritis, nephropathy, neuropathy • Often associated with systemic disease (HCV, CTD, heme malignancies) • Strong association with HCV and cryoglobulinemia (high suspicion for dx!) NUV • Distinct painful, burning urticarial lesions, last >24hrs, with ecchymosis, staining, occurring anywhere but ONLY cutaneous involvement • More chronic relapsing/remitting course • HYPOcomplementemic UV - association with SLE or SLE-like systemic/multiorgan findings (kidney, joints, lung) • Also consider viral hepatitis, EBV, Sjogren’s AHEI • Lesions of face and extremites in infants • Occurs post infection with virus/bacteria but can be idiopathic • Generally self-limiting with excellent prognosis Approach • Since PCSVV is a diagnosis of exclusion, we must RULE OUT other entities to determine the true etiology of the presentation and therefore, appropriately direct treatment • Only 50% of all cases end up with a diagnosis Differential Diagnosis • Idiopathic (~50%) • Infections (~20%) • Drugs (~10%) • Neoplasms (<1%) • Connective tissue diseases (10-15%) • Other systemic diseases • Chemicals Infections • Viral: • HBV, HCV, HIV, CMV • Bacterial • Streptococcus, Staphylococcus, Chlamydia, Mycobacterium • Subacute Bacterial Endocarditis! • Fungal • Yeast • Protozoan • Malaria Drugs (~7 days post exposure) • Penicillins, cephalosporins, erythromycin, clindamycin, • Sulfonamides • Phenytoin • ASA, NSAIDs • Furosemide • Allopurinol Neoplasms • Hematologic • Non-Hodgkin’s Lymphoma • Adult T-cell Lymphoma • Multiple Myeloma • Waldenstrom’s Macroglobulinemia • Solid • Lung • Breast • Colon • Renal • Prostate • Head and Neck Connective Tissue Disease • Systemic Lupus Erythematosus • Behcet’s Disease • Sjogren’s Syndrome • Rheumatoid Arthritis Vasculitis • Churg-Strauss Syndrome • Polyarteritis Nodosa (PAN) • Wegener’s Granulomatosis • Microscopic Polyangiitis Other Diseases • Henoch-Schonlein Purpura (IgA deposition) • Erythema elevatum diutinum • Inflammatory Bowel Disease • Cryoglobulinemia • a 1 antitrypsin deficiency • Pyoderma gangrenosum • Cystic Fibrosis • Atrial Myxoma Chemicals/Substances • Food additives/chemicals • Dyes • Occupational chemical exposures • Nicotine patches Evaluation 1. ANY EVIDENCE OF SYSTEMIC INVOLVEMENT? 2. IS THERE AN ASSOCIATED DISORDER? • History Evaluation • Drug history • Preexisting symptoms/diagnoses • acute or chronic disorder • autoimmune disease • Recent or chronic infection • Systemic symptoms • Travel history • Time frame/pattern of lesion appearance • Physical Exam • General Appearance (toxic, systemic) • Clear characterization of lesion • Comprehensive exam of all systems Investigations • CBC, Lytes, renal and liver profile, ESR, urine analysis with microscopy, stool for occult blood • ANA, ANCA, RF, anti-ds DNA, complement, cryoglobulins, SPEP • Cultures – blood, urine, throat swabs, HBV, HCV, HIV • Chest X-ray  CT Chest • Echocardiogram – SBE, atrial myxoma Investigations • SKIN BIOPSY • Attempt on lesion 18-48 hours old • Depth of involvement – deeper dermis involvement = likely systemic disease • Stain for hematoxylin and eosin • Assess immunofluorescence – IgM (Cryo lymph prolif, post infectious), C3 (HUV, lupus), IgA (HSP, post infectious), IgG (lupus) Finding Clinical High fever Paresthesias Association Infection, severe systemic inflammation Suggestive of deeper, perineural vasculature Vasculitic involvement of gastrointestinal vasculature (HSP) Table 3 High-yield clinical and laboratory findings for significant systemic disease-associated leukocytoclastic vasculitis Abdominal pain Frank arthritis Laboratory evaluation Abnormal creatinine and/or urine analysis Infection, severe systemic inflammation Sensitive for systemic disease (WG, MPA, SLE, HSP, CSS) ESR > 40 mm/h rheumatoid factor, cryoglb, and low complement Infection, heme malignancies, severe systemic inflammation Triad very suggestive of viral hepatitis/HCV Abnormal complete blood count Depressed complement Chest X-ray abnormalities Hematologic malignancies, infection, severe inflammation Sugg SLE or SLE-like disease if assoc w/ urticarial vasculitis Infection, WG, CSS, MPA, malignancy c-ANCA Histological Hematoxylin and eosin Strongly suggestive of Wegener's granulomatosis Vasculitis of deeper/larger vasculature Direct immunofluorescence Suggestive of more severe, systemic disease (PAN) Lupus band (granular IgG, IgM ± C3 at the BMZ) Predominantly IgA vasculature deposition SLE or SLE-like disease associated with urticarial vasculitis Highly suggestive of HSP c-ANCA, cytoplasmic-antineutrophil cytoplasmic antibody; BMZ, basement membrane zone; CSS, Churg–Strauss syndrome; ESR, erythrocyte sedimentation rate; HCV, hepatitis C virus; HSP, Henoch–Schönlein purpura; Ig, immunoglobulin; MPA, microscopic polyangiitis; PAN, polyarteritis nodosa; PR-3, proteinase-3; SLE, systemic lupus erythematosus; WG, Wegener's granulomatosis. Management • Treat underlying cause if known • If drug related, resolution seen within 2 weeks of removal of drug • If no alternate cause can be determined, then can diagnose as PCSVV and manage accordingly Management of PCSVV • Clinically driven as evidence lacking • Case reports, case series, personal experience • Bed rest, warming, leg elevation, NSAIDs, antihistamines, analgesics for symptomatic pain/burning Management of PCSVV • Diet – bland, low antigenic diets • Should have allergy testing first • Colchicine or dapsone can be used for skin manifestations – dapsone well tolerated • Prednisone – most widely used, no good evidence, side effect profile • Hydroxychloroquinine – good for HUV, not for PCSVV Management of PCSVV • If recurrent, chronic, symptomatic PCSVV: • Azathioprine (low dose or combo with Pred) • Mycophenolate mofetil (no evidence in PCSVV) • Cyclosporine – efficacious but limited: • For acute tx only • Serious side effect profile • MTX - ? Effective but can induce LCV • IVIG – selectively effective • Plasmapheresis – good with/without prednisone if refractory to traditional tx. Treat ment Elimi nation diet Colch icine Dapso ne Predn isone Hydro xychlo roquin e Opinion May be helpful in food allergensuspected cases Can be efficacious as monotx or in combo with other mods. Frequently used, good evidence for PCSVV Excellent for single episodic disease Frequently used Useful for HUV, no evidence in PCSVV Good efficacy/evidence for prednisone- sparing agent in PCSVV Dose NA Considerations Ensure proper nutrition Price* NA 0.6 mg 1–3 times daily as tolerated 100–200 mg/ kg/day Frequent GI complaints, watch for heme abnormalities Extra caution in elderly Need prior G6PD testing. Monitor for liver and hematologic changes Slow taper (4–6 weeks) to prevent rebound. Long-term, use: GI prophylaxis, evaluations of blood pressure and glucose Inexpensive. $12/m onth (bid dosing) Inexpensive, $20/ mnth ( 200 mg/d) Inexpensive $21/m (1.0 mg/kg/day) Inexpensive $36/m nth (200 mg bid) Moderate $60 per month (high TPMT, 1.5 mg/kg) 0.5–1.0 mg/ kg/day 200–400 mg/ kg/day Need G6PD and eye examination at baseline; eye examination q 6–12m Need to check TPMT levels Need frequent laboratory monitoring Infection risk Dependent on TPMT levels AZA Myco phen. mofeti l Cyclos porine Metho trexate Helpful in systemic vasculitides No reported cases in PCSVV Good efficacy for acute disease with short-term use Not indicated. Many cases of inducing LCV Benefit in LCV assoc with immunodef, persistent ulcers or chronic infection Up to 2 g total daily Laboratory monitoring for hematologic and liver abnormalities Infection risk Monitor for BP, renal fxn, neurologic changes. Multiple drug–drug interactions Very ex. $500 per month (1.5 g/day) Very ex. $300/ mn (3 mg/kg/day) 2.5–5 mg/ kg/day IVIG Plasm aphere sis 200–1000 mg/kg single dose od x 3–4 days or single doses every 3–4 weeks Cardiovascular risk, anaphylaxis Cardiovascular risk Very ex $50 per gram Very ex $875–950 per treatment Helpful in refractory cases As needed bid, twice daily; G6PD, glucose-6-phosphate dehydrogenase; GI, gastrointestinal; HUV, hypocomplementemic urticarial vasculitis; IVIG, intravenous immunoglobulin; LCV, leukocytoclastic vasculitis; NA, not applicable; TPMT, thiopurine methyltransferase. *Based on a 70-kg patient per month. Prognosis/Follow Up • Majority of patients have limited disease with good prognosis • Short duration and singly episodic • PCSVV often the early pre-clinical manifestation of an occult systemic disease • Need close, long term follow up/observation • Can discover sinister diseases earlier for better outcome • Idiopathic, LCV that is limited to skin, no systemic involvement Summary of PCSVV • Commonly presents as palpable purpura but can vary - type of lesion and location • Diagnosis of exclusion, therefore requires diligent and thorough work up • Usually self limited; Immunosuppression options if chronic/symptomatic • Needs close long term observant follow up as usually precursor presentation to more serious illness FIN