COPYRIGHT. Systemic Lupus Erythematosus. A General Internal Medicine Perspective. George Stojan, MD

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1 Systemic Lupus Erythematosus A General Internal Medicine Perspective George Stojan, MD

2 Disclosures None

3 Case #1 24 year old African American female presents with 6 weeks of stiffness affecting her hands followed by hair loss. She is fatigued and has intermittent low grade fevers. On exam, she has diffuse painless swelling of metacarpal and proximal interphalangeal joints. You confirm dry, brittle hair that breaks easily in a bitemporaldistribution. Her serologies show a positive ANA in a titer of 1:160 (diffuse pattern) and a low complement C4. Does this patient have systemic lupus?

4 Systemic Lupus International Collaborating Clinics (SLICC) 2012 classification criteria (1) Clinical Criteria 1. Acute cutaneous lupus 2. Chronic cutaneous lupus 3. Oral ulcers or nasal ulcers 4. Non-scarring alopecia 5. Synovitis involving two or more joints and at least 30 min of morning stiffness 6. Serositis 7. Renal (urine protein-to-creatinine ratio [or 24 h urine protein]) representing 500 mg protein per 24 h or red blood cell casts 8. Neurological: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral and cranial neuropathy, acute confusional state 9. Hemolytic anaemia 10. Leukopenia (<4000 cells per μl at least once) or lymphopenia (<1000 cells per μl at least once) 11. Thrombocytopenia (< cells per μl) at least once Immunologic Criteria 1. Antinuclear antibody concentration greater than laboratory reference range 2. Anti double-stranded DNA antibody concentration greater than laboratory reference range (or two-fold the reference range if tested by ELISA) 3. Anti-Sm: presence of antibody to Sm nuclear antigen 4. Antiphospholipid antibody positivity as determined by any of the following: positive test result for lupus anticoagulant, false-positive test result for rapid plasma reagin, medium-titre or high-titre anticardiolipin antibody concentration (IgA, IgG, or IgM), or positive test result for anti-b2-glycoprotein I (IgA, IgG, or IgM) 5. Low complement C3, low C4, low CH50 6. Direct Coombs' test in the absence of haemolytic anemia

5 Diagnostic vs Classification Criteria ACR and SLICC classification criteria developed for research purposes only, not for clinical diagnosis Gold standard for diagnosis is still: expert opinion Criteria are historical and cumulative: records are essential for the evaluation of every SLE patient

6 What if patients do not meet criteria? Patients who meet less than four ACR criteria or have other representative, non-criteria SLE manifestations have incomplete lupus erythematosus (2) 50% of patients with an autoimmune diathesis have an unclassifiable profile at the time of disease onset (3) The range of progression to SLE varies from 5.3% to 57%- highest risk in first 4 years (2) Predictors of transition: female sex and young age, malar rash, photosensitivity, oral ulcers, low complements, anti-dsdna, and anticardiolipins (4)

7 Case #2 48 year old Caucasian female with history of chronic back pain for 20 years presents for evaluation of new neck, shoulder, hip, knee, and ankle pain which is disabling. She is extremely fatigued. Sleep is unrefreshing. She has intermittent diarrhea and constipation. Her migraines are worsening. She has intermittent numbness and tingling over her face and extremities. She has a known positive ANA in a titer of 1:80. She fired her previous PCP and rheumatologist because they told her she doesn t have lupus. Her exam is normal with the exception of diffuse soft tissue and joint tenderness to palpation. What is the next step in workup?

8 What does a positive ANA mean? - In a study(5) of healthy adults (age 20 to 60 years), 31.7% had a positive ANA result at a 1:40 dilution, 13.3% at a 1:80 dilution, 5% at a 1:160 dilution, and 3.3% at a 1:320 dilution. - In the same study, 38.5% of patients with noninflammatory soft tissue rheumatism had a positive ANA result at a 1:40 dilution, and 23.1% at a 1:80 dilution. - The false-positive rate for any rheumatic disease was 72% in patients 65 years old or younger, and 90% in patients older than 65 years. - Even ANAs that are positive at a titer of 1:320 or greater are more likely to be falsely positive (55%) than indicative of any rheumatic disease (45%).

9 Case #3 19 year old male brought in by his mother for lupus screening. He is asymptomatic. His mother was diagnosed with lupus at age 21 and has had numerous complications including lupus nephritis and refractory thrombocytopenia. His exam is completely unremarkable. What workup is indicated? Is the patient at higher risk of acquiring SLE?

10 SLE- genetic component High concordance rate (14 to 57 percent) of SLE in monozygotic twins First-degree relatives have a 17-fold increased risk of SLE compared with the general population Twenty-seven percent of 195 children of mothers with lupus had a positive test for anti-nuclear antibodies Screening of asymptomatic patients is not recommended regardless of family history.

11 Case #4 30 year old female with lupus nephritis in remission, presents for evaluation of dyspnea on exertion. For the past few months she has noticed a cough and shortness of breath with walking up 3 flights of stairs at work. Yesterday while on an elliptical in the gym, she noticed a brief chest tightness that resolved after a few seconds. Her exam is significant for a BP of 148/95mmHg and was otherwise normal. Her lupus monitoring labs are stable. Discuss your approach to the case.

12 Cardiovascular Disease in SLE (7) Accelerated atherosclerosis is the major cause of late mortality among patients with SLE. Despite the negative results of the LAPS trial, statins remain the mainstay of treatment of hyperlipidemia ACE inhibitors should be used as first line agents for treatment of hypertension to a goal of less than 120mmHg systolic. Aspirin should be used in any patient with SLE who has a history of CVD, positive antiphospholipid antibodies or lupus anticoagulant, history of hypertension, diabetes mellitus, hypercholesterolemia and a history of smoking. Despite the lack of conclusive benefit, the treatment of vitamin D deficiency and hyperhomocysteinemia is encouraged. The role of immunosuppressives, in treatment of atherosclerosis remains to be elucidated.

13 Case #5 62 year old man with a 20 year history of leukopenia and thrombocytopenia, intermittent fevers, ANA 1:640 in a diffuse pattern, low C4, and lymphadenopathy seen by multiple rheumatologists at BWH, MGH, and BIDMC without a diagnosis of SLE referred for a second opinion. Multiple lymph node excisional biopsies negative for lymphoma over the years. SLE diagnosis established and hydroxychloroquine initiated. 6 months later he develops double quotidian fevers with normal workup. PET scan shows periportal lymphadenopathy-biopsy negative for lymphoma. As his primary care physician, how would you best contribute to his care (and establish the diagnosis!)

14 SLE and Cancer (8) Increased risk of: Hodgkin s and non-hodgkin lymphoma Breast cancer Lung cancer (1.4 times more common than in the general population) Cervical cancer and abnormal PAP tests Endometrial cancer Patients with SLE undergo cancer screening (mammogram, faecal occult blood and cervical smear test) even less frequently than the general population.

15 Case #6 45 year old woman with SLE establishes care with you after firing her previous PCP who insisted on vaccinating her. She read online that flu shots trigger severe lupus flares. She knows her lupus was triggered by a hepatitis vaccine she received 20 years ago while employed as a medical assistant. Her medication regimen consists of hydroxychloroquine and 5mg prednisone daily. What do you advise this patient?

16 SLE and Infections (9) High morbidity and mortality associated with infections Flu vaccination is safe and does not lead to SLE flares Vaccination against Pneumococcus appears safe, although with reduced anti-pneumococcal antibody production Hepatitis B vaccination is safe with no increase in SLE flares Tetanus toxoid administration not associated with disease flares Inactivated live vaccines are contraindicated in patients taking immunosuppressive drugs and/or glucocorticoids at a dose >20mg/day.

17 Case #7 34 year old male who was diagnosed with lupus nephritis class IV three months ago, currently treated with mycophenolate 3000mg daily and prednisone 40mg daily, presents to you for follow up. You notice his rheumatologist has not started any PCP prophylaxis. Is PCP prophylaxis indicated in this patient? If it is, what antibiotic would you prescribe?

18 Lupus and Antibiotics (9) SLE patients are at high inherent risk of infections, unrelated to immunosuppressive therapy Tetracyclines, sulfa, and fluoroquinolones are sun-sensitizing Minocycline increases risk of drug-induced lupus Sulfonamide use in SLE patients is associated with flares: photosensitive rashes and cytopenias Bactrim Please use atovaquoneor dapsone for PCP prophylaxis instead of

19 Case #8 24 year old Asian female in the 2 nd trimester of her first pregnancy, establishes care with you after moving from China. She carries a diagnosis of SLE based on unclear criteria and has been on hydroxychloroquine for a few years. Her last lupus flare was 4 years ago. She is very concerned that hydroxychloroquine will damage her baby and she wants to stop it. She wants to know whether her lupus will affect her baby. Should she stop hydroxychloroquine? Are there any predictive factors of pregnancy outcomes in SLE patients that you could check?

20 Pregnancy in SLE (10) Patients who are clinically stable at conception tend to remain in remission Refer to high risk obstetrician and rheumatologist Hydroxychloroquine should be continued throughout pregnancy Plaquenil does not increase risk of congenital defects, spontaneous abortions, fetal death, prematurity or decreased numbers of live births in patients with autoimmune diseases The cessation of Plaquenil treatment during pregnancy increases the degree of lupus activity There are 2 predictive factors of pregnancy outcomes in SLE patients: presence of antiphospholipid antibodies, especially lupus anticoagulant, and presence of anti-ro/anti-la antibodies

21 Case #9 57 year old with lupus nephritis in remission presents with widespread pain rated as 150/10 affecting her back, neck, shoulder and hip girdle, associated with disabling fatigue, unrefreshed sleep, intermittent diffuse numbness and tingling, diarrhea, and seizures without any EEG correlate. Her pain specialist placed her on fentanyl 800 mcg lollipops q 2 hours which are not helping her pain at all. A lyme specialist pulsed her with solumedrol a total of 24 times over the past 6 months with no improvement in pain and has continued her on daily IV ceftriaxone for chronic Lyme. What is your next step in working up this patient?

22 Fibromyalgia and SLE (9) Up to 30% of SLE patients have fibromyalgia The most common cause of chronic pain and positive ANA is fibromyalgia Arthralgias are common in SLE- described as stiffness and gel phenomenon SLE does not affect the neck, shoulder girdle, back, or trochanteric regionthis is usually fibromyalgia Fatigue is a manifestation of active lupus but resolves with treatmentchronic fatigue is not a manifestation of quiescent SLE - this is usually fibromyalgia Prednisone and opiates have no role in the treatment of fibromyalgia

23 Case #10 44 year old male with SLE presents for his annual exam. He has no complaints. On exam, his blood pressure is 140/95mmHg and otherwise is unremarkable. Urinalysis shows a protein/creatinine ratio of 0.6. On review of his previous labs, you notice his urine protein/creatinine ratio has ranged between over the past 6 months. What is the next step in workup and treatment?

24 Lupus Nephritis (9) All patients with clinical evidence of active lupus nephritis need renal biopsy Refer for renal biopsy every SLE patient with a persistent urine/protein creatinine ratio>0.5gr/day Urine albumin, microalbumin, and spot urine protein underestimate proteinuria and should not be used as screening methods Findings in a spun urine sample do not correlate with histopathology All SLE patients with nephritis must be on hydroxychloroquine, unless there is a contraindication ACE inhibitors can decrease proteinuria by up to 50% and should be prescribed in each case

25 Case #11 30 year old with SLE diagnosed based on malar rash, thrombocytopenia, inflammatory arthritis, ANA, and anti-sm presents for evaluation of persistent daily headaches for the past month. She had migraines previously but current headache is different, keeping her awake at night and not responding to any analgesics. The next step in her workup is

26 Headache in Lupus There is no evidence of an increased prevalence or a unique type of headache in SLE. Exclude aseptic or septic meningitis, sinus thrombosis (especially in patients with antiphospholipid antibodies), cerebral or subarachnoid haemorrhage. In the absence of high-risk features from the medical history and the physical examination (including fever or concomitant infection, immunosuppression, presence of antiphospholipid antibodies, use of anticoagulants, focal neurological signs, altered mental status, meningismus and generalised SLE activity), headache alone in a SLE patient requires no further investigation beyond the evaluation, if any, that would have been performed for non-sle patients

27 Case #12 32 year old female with SLE manifesting with seizures, lupus nephritis, leukopenia, ANA, antiphospholipid antibodies, and low complements on azathioprine 150mg daily and prednisone 10mg daily (allergic to antimalarials), wants to discuss contraceptive options. She is on an OCP estrogen/progesterone combination but her rheumatologist told her she needs to switch to something else. What are your recommendations?

28 SLE and Hormone Replacement Therapy (12) SELENA trial: patients on hormone replacement therapy are more likely to develop mild to moderate flares Always avoid estrogen containing oral contraceptives, selective estrogen receptor modulators, thalidomide, and HRT in patients with antiphospholipid antibodies, especially a lupus anticoagulant For patients who want to use an oral hormonal contraceptive, the estrogen-progestin contraceptives may be used in patients with stable low disease activity and documented negative apls. Progestin-only contraceptives and IUDs are preferable in patients with high disease activity. The use of estrogen-progestin contraceptives are contraindicated in women with apls with or without SLE, due to the increased risk for thrombosis

29 Treatment

30 Lupus Health Insurance : Hydroxychloroquine (13) Treats cutaneous lupus and arthritis Reduces incidence of lupus flares by 50%, Prevents renal and central nervous system involvement and progression, Cardioprotective Lowers total cholesterol in patients receiving steroids Lowers fasting blood glucose concentration Reduces incidence of thrombotic events Improves overall survival in patients with SLE Smoking inhibits the efficacy of hydroxychloroquine

31 Hydroxychloroquine Well tolerated Retinal toxicity risk small with regular monitoring: keep dose below 6.5mg/kg of lean body weight/day Compliance is a major issue Whole blood HCQ levels <200ng/ml are a marker of long term poor adherence Low HCQ concentrations are associated with SLE disease activity and are a strong marker of future flare HCQ level of >1000ng/ml has a negative predictive value of 96% for exacerbation during follow up

32 Alternative Antimalarials (9) Chloroquine: slightly higher risk of retinal toxicity: keep dose below 3mg/kg/day Patients who develop drug allergy to HCQ can usually be safely switched to chloroquine Quinacrine: No cross reactivity with HCQ or CQ Only compounding pharmacies 100mg/day

33 P is for Poison: Prednisone (14) High dose prednisone in SLE is defined as >6mg/day Prednisone>6mg/day increases later organ damage by 50%. At doses>18 mg/day, the risk of later organ damage is increased 2.5 fold Prednisone is an independent risk factor for cardiovascular events in patients with lupus. Doses>10 mg/day increase the risk 2.5 time while doses> 20 mg/day or higher, increase risk 5 fold. profile FLOAT trial: intramuscular triamcinolone leads to a more rapid response compared to medrol dose-pack, with a better side effect

34 NSAID NSAID treatment increases risk of cardiovascular events in SLE NSAID use in SLE increases the risk of worsening glomerular filtration

35 Steroid sparing treatments MycophenolateMofetil Azathioprine Cyclophosphamide Cyclosporine and Tacrolimus Methotrexate Leflunomide

36 Niche Therapies for Lupus Subsets Dapsone Thalidomide Dehydroepiandrosterone

37 Belimumab Human monoclonal antibody that binds soluble BLyS First FDA approved drug for SLE in decades Uncertain efficacy in patients of African American descent No doubt about efficacy, but what is the effect size? Most effective in patients with moderate-to high SLE activity, who have dsdna antibodies and low complements, and who are already on stable standard treatment including prednisone, antimalarial, and immunosuppressive medication.

38 Rituximab EXPLORER trial: not useful in nonrenal generalized lupus LUNAR trial: does not improve outcomes in lupus nephritis Can be considered for patients with lupus nephritis who have failed cyclophosphamide, mycophenolate, or both Off-label use in patients with severe or refractory hematologic lupus Case reports of efficacy in CNS lupus Data is controversial: clinical trials failed, but observational data continues to suggest efficacy

39 References 1. Petri M, Orbai A-M, Alarcón GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and Validation of Systemic Lupus International Collaborating Clinics Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheum Aug;64(8): Stojan G. Incomplete Lupus. In: Systemic Lupus Erythematosus. 1st ed. Elsevier; In print. 3. Alarcón GS, Williams GV, Singer JZ, Steen VD, Clegg DO, Paulus HE, et al. Early undifferentiated connective tissue disease. I. Early clinical manifestation in a large cohort of patients with undifferentiated connective tissue diseases compared with cohorts of well established connective tissue disease. J Rheumatol Sep;18(9): Rúa-Figueroa Í, Richi P, López-Longo FJ, Galindo M, Calvo-Alén J, Olivé-Marqués A, et al. Comprehensive description of clinical characteristics of a large systemic lupus erythematosus cohort from the Spanish Rheumatology Society Lupus Registry (RELESSER) with emphasis on complete versus incomplete lupus differences. Medicine (Baltimore) Jan;94(1):e Tan EM, Feltkamp TE, Smolen JS, Butcher B, Dawkins R, Fritzler MJ, et al. Range of antinuclear antibodies in healthy individuals. Arthritis Rheum Sep;40(9): Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet Lond Engl Nov 22;384(9957):

40 Reference 7. Stojan G, Petri M. Atherosclerosis in systemic lupus erythematosus. J CardiovascPharmacol Sep;62(3): Sultan SM, Ioannou Y, Isenberg DA. Is there an association of malignancy with systemic lupus erythematosus? An analysis of 276 patients under long-term review. RheumatolOxf Engl Oct;39(10): Daniel Wallace, Bevra Hahn. Dubois Lupus Erythematosus and Related Syndromes. 8th ed. Elsevier; Stojan G, Baer AN. Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis and management. Expert Rev Clin Immunol Jul;8(5): Petri M, Bello KJ, Fang H, MagderLS. Vitamin D in systemic lupus erythematosus: modest association with disease activity and the urine protein-to-creatinine ratio. Arthritis Rheum Jul;65(7): Lateef A, Petri M. Hormone replacement and contraceptive therapy in autoimmune diseases. J Autoimmun May;38(2-3):J Petri M. Use of hydroxychloroquine to prevent thrombosis in systemic lupus erythematosus and in antiphospholipid antibody-positive patients. CurrRheumatolRep Feb;13(1): Sawah S Al, Zhang X, Zhu B, MagderLS, Foster SA, IikuniN, et al. Effect of corticosteroid use by dose on the risk of developing organ damage over time in systemic lupus erythematosus-the Hopkins Lupus Cohort. Lupus Sci Med. 2015;2(1):e

41 THANK YOU!