Hematologic Manifestations of Lupus

1. Hematologic Manifestations of Lupus Nicole Cullen AM Report Feb 24, 2010

2. Definition of “Hematological Involvement” • As defined by the American College of Rheumatology for diagnostic purposes… • Leukopenia (WBC <4 x 109) on 2 or more occasions • Lymphopenia (ALC <1500/µL) on 2 or more occasions • Thrombocytopenia (plts <100K) in the absence of offending drugs • Hemolytic anemia • 59% of SLE patients affected by the hematologic manifestations at some point

3. Anemia • Manifests in 50-78% of cases • Usually normocytic, normochromic • Generally mild, reflects disease activity • Only treated if symptomatic or concomitant renal insufficiency with Hgb <11 • First line of treatment generally consists of promoting erythropoiesis (Epo, Aranesp) • Hard to tell true erythropoietin level because autoantibodies interfere with lab testing • If the above unsuccessful or other indications for them, the next step is steroids/immunosuppressants (first step in AIHA, aplasia)

4. Anemia (continued) • Most often due to chronic disease • Can also be autoimmune hemolytic, microangiopathic hemolytic • Blood loss 2 to thrombocytopenia, anti-inflammatories • Hypersplenism • Anemia associated with CKD • Case reports of pure red cell aplasia, aplastic anemia • Autoantibodies to erythroid burst forming units, CFUs, erythroblasts, erythropoetin, bone marrow precursors

5. Leukopenia • Up to 50% of SLE patients • Usually lymphopenia • Autoimmune destruction, drugs, increased apoptosis of Tcells • Neutropenia also seen (ANC <1500) • Autoimmune destruction, marrow suppression, hypersplenism, drugs • Some functional neutrophil defects, possibly secondary to inhibition of complement derived chemotactic factors, immune complexes, meds • Decreased circulating basophils and eos • Increased risk of infection • Even when controlling for immunosuppressive meds • Treat (pred, cyclophos, etc.) only when neutropenic, and/or recurrent pyogenic infection • G-CSF to maintain the ANC >1000, but use minimized due to potential to cause disease flare, leukocytoclastic vasculitis

6. Thrombocytopenia • Mild cases are frequent (25-50% of pts with SLE), but plts <50K in only 10% • Usually autoimmune (different IgG subclass that binds to the plts than in ITP, but otherwise similar) • More common in patients with anticardiolipin Ab • Acute, severe thrombocytopenia usually parallels acuity of the disease, responsive to steroids • More chronic form, while less steroid responsive, rarely causes significant sx • ITP has been found to precede SLE in 3-16% of these patients, up to 10 years before SLE diagnosed • Question of increased plt destruction, but evidence not convincing

7. Treatment of Thrombocytopenia • Very similar to that of ITP • As usual, treat if <50K and symptomatic, <20K even if asx • Steroids are first line treatment • Pred 1mg/kg daily vs dex 40mg qd x4d at intervals of 2-4 wks • Azathioprine may produce additional benefit or a steroid sparing effect • Should see a response in 1-3 weeks. If not… • IVIG • Often used to increase plt count quickly – if severe, needs surgery, etc • Cyclophos (preferred if active nephritis as well), azathioprine • MMF, danazol, vincristine, ritux • Splenectomy in refractory cases • Relapse common

8. Thromobosis • Increased risk in SLE, which is then further increased if anti-phospholipid antibody present • Decreased fibrinolysis due to an increase in levels of tissue plasminogen activator inhibitor • Decreased free protein S • 10% of SLE pts experience thrombotic complications • If aPL + → 50% • Rarely, lupus pts may acquire Abs to clotting factors which lead to bleeding

9. Antiphospholipid Antibody Syndrome • Antiphospholipid antibodies are directed against negatively charged phospholipids (or their attached proteins) • The syndrome is defined by 2 main criteria: • Clinical feature (vascular event or pregnancy morbidity) AND • Presence of one type of autoantibody known as an antiphospholipid Ab (aPL) on lab testing x2, at least 6-12 wks apart and within 5 years of clinical event • Lupus anticoagulant • Anticardiolipin Ab • Anti-ß2 glycoprotein-I • APS can also clinically manifest as many other things not included in the diagnostic criteria (livedo reticularis, thrombocytopenia, valve dz, nephropathy, migraines, Raynad’s, pulm HTN, stroke, ulcers, adrenal insufficiency) • Mechanisms predisposing to clotting: • Disruption of the prostaglandin/thromboxane balance • Up-regulation of plt aggregation • Dysregulation of complement activation • Ill-defined direct effect on placenta

10. APS (con’t) • Associated with lupus (34%), but also in a variety of other clinical conditions as well as in otherwise healthy persons • Some studies have indicated that the frequency of thrombotic events is greater in SLE associated APS than primary APS • ? association with ischemic heart disease • Increased risk of this (seroconversion) in pts treated with cyclosphosphamide • Question evolution of primary APS into SLE • 13% at 9 years in one study • Observational studies have indicated that APS in SLE patients is an independent risk factor for premature death (not always due to thrombotic events) • “Catastrophic APS” – widespread thrombotic disease with multiorgan failure, high mortality. • Only 1% of patients with APS over a seven year study

11. Lupus Anticoagulant • Lupus “anticoagulant” because its presence can create a prolonged PTT, and rarely PT • Actually creates a tendency toward thrombosis • Only 50% of people found to have a lupus anticoagulant actually meet the criteria for lupus (at identification, or later)

12. Anticardiolipin Ab • 44% of SLE patients • Cardiolipin is a negatively charged phospholipid, which when bound by the antibody causes agglutination that results in the false positive VDRL test • May be induced by some infections (CMV), meds (phentyoin, chlorpromazine, cocaine)

13. ß2-glycoprotein-I • AKA apolipoprotein H • Becomes antigenic once it binds to a negatively charged surface • Frequently bind to anticardiolipin, which may account for aCL’s clinical features of APS

14. Obstetric Complications • Recommended to become pregnant once the disease has been quiescent for at least 6 months, with good renal fxn • Patients should be followed by MFM • Common complications • Disease flare (~20% in those who have been in remission those 6 months, otherwise ~65%) • Fetal loss (rates 17-45%), IUGR, preterm delivery, preeclampsia • Neonatal lupus (complication of complete heart block in the infant) • Less common complications include htn, postpartum hemorrhage, VTE, emergency C-section • Pregnancy in women with active lupus nephritis associated with up to 75% rate fetal loss, worsening of renal manifestations in mother • If not able to control the disease sufficiently without glucocorticoids, recommended to continue these through pregnancy

15. Prophylaxis • Antiphospholipid + patient • No thromboembolic prophylaxis in asx pts with no other risk factors and no h/o thrombosis • Pts with SLE, other connective tissue disorder or h/o miscarriage should receive baby asa daily • Anything else is a discussion • Secondary prevention in aPL + pts with lifelong anticoagulation (warfarin or heparin derivative) • Recurrence rate ~25% per year • Some will advocate retesting for aPL after 3 mos of anticoagulation, and if gone, can consider stopping anticoagulationj • If still recurrent VTE despite anticoagulation, recommendation is target INR increased to 3-4 or add low-dose asa (some will do this if it was an arterial event) • Lovenox recommended in pregnant women who are antiphospholipid positive (and/or low dose asa in some studies) • Recommended that any woman with aPL avoid OCPs, particularly those with estrogen

16. Resources • Keeling DM and Isenberg DA. Haematological Manifestations of Systemic Lupus Erythematosus. Blood Reviews 1993; 7: 199-207 • UpToDate. Hematologic manifestations of systemic lupus erythematosus in adults. Last updated June 2009. • Drenkard C, Villa AR, Alarcon-Segovia D et al. Influence of the antiphospholipid syndrome in the survival of patients with systemic lupus erythematosus. Journal of Rheumatology 1994; 21:1067-1072. • Urbanus RT, Derksen RH and de Groot PG. Platelets and the antiphospholiid syndrome. Lupus 2008; 17:888-894. • UpToDate. Clinical manifestations of the antiphospholipid syndrome. Last updated September 2009. • Ames PR, Margarita A and Alves JD. Antiphospholipid Antibodies and Atherosclerosis: Insights from Systemic Lupus Erythematosus and Primary Antiphospholipid Syndrome. Clinical Review of allergy and Immunology 2009; 37: 29-35.