SLE Diagnosis and Management

11. Alopecia (hair loss)

a. Alopecia has also been removed from the criteria for SLE b. Can be a large lesion, or diffuse, which is more common

f. ***Renal and CNS are rarely affected in DI-Lupus

****

19. Classification of Lupus Nephritis

19. Classification of Lupus Nephritis by the International Society of Nephrology (ISN) and the Renal Pathology Society (RPS) changed from the above criteria a. I. Minimal Mesangial Lupus Nephritis b. II. Mesangial Proliferative Lupus Nephritis c. III. Focal Lupus Nephritis d. IV. Diffuse Lupus Nephritis e. V. Membranous Lupus Nephritis f. VI. Advanced Sclerotic Lupus Nephritis i. Scarred kidney, medicines will not work at this point b/c an active lesion in needed for effectiveness

26. Positive ANA

26. Positive ANA (with high titer) further testing may include: a. Anti-dsDNA, or native DNA i. 75% specific*** b. Anti-ENA i. RNP ii. Smith 1. 95% specific*** iii. RO (SS-A) iv. LA (SS-B) c. RPR (VDRL) i. False positive d. Complement (CH50) e. Anti-histone i. Associated with drug-induced lupus, but also true systemic lupus

23. Environmental triggers for SLE

UV Light i. Hence, photosensitivity b. Drugs i. Will go over this at the end c. Smoking i. More prone to develop lupus and exacerbate lupus d. Infections i. Pet dogs 1. Aside: What other neurological disease is involved with pet dogs? a. ALS, Lou-Gehrig disease ii. Lab workers 1. ANA may become positive in lab workers e. Silica f. Mercury - ? Fish

7. Malar rash

a. A repeat image from ~3 weeks ago b. Malar rash crossing the bridge of the nose, sparing the nasolabial folds i. Found in about 40% of Lupus patients ii. If a patient has renal failure, positive ANA, but no malar rash, probably still has Lupus - do not need to have the malar rash for diagnosis a. Malar rash - not a very good image, skipped i. More likely that this rash can be resolved with treatment b. Discoid rash***

8. Photosensitivity

a. After sun exposure, see photosensitivity***, malar rash is exaggerated

21. Epidemiology of SLE

a. Age of Onset i. 15-40 y/o b. Female: Male Ratio i. 9:1 female to male ratio ii. Estrogen may play a role c. Black vs. White i. Blacks are twice as common to develop the disease ii. 1 in 250 black females develop SLE iii. 1 in 500 white females develop SLE iv. 10-15% of the female population in the U.S. will have a positive ANA for various reasons, including lab error, but will not have Lupus d. Incidence i. 1/375 females have Lupus

30. Lab Assessment of Activity of SLE

a. Clinical signs i. Laboratory 1. Anti-dsDNA a. Usually increases 2. Complement a. Usually decreases 3. Hematocrit a. Tends to decrease 4. (UA) 5. (S. Creatinine) 6. (Creatinine clearance)

9. Periungual erythema in image below

a. Erythematous rash that is between*** the joints b. Periungual (around the nails) erythema c. Not found in the criteria for SLE, but a subtle sign of CTD

rash in dermatomyositis

a. Glistening papules b. Seen in pediatrics c. This is to be differentiated from the rash of Lupus d. Papules right over the bony prominences or joints

18. WHO Classification of Renal Lupus

a. I. Normal b. II. Mesangial changes c. III. Focal GN d. IV. Diffuse GN i. Pathologists will look at about 10 glomeruli, if >5 affected it's diffuse, if <5 affected it's local (Dr. Pascucci said this somewhat mockingly) e. V. Membranous f. VI. Sclerosing

32. Management of SLE (He likes this slide)

a. Indications for Steroids i. Renal, CNS, Hematologic, Myositis, and Cardiopulmonary disease ii. Life-threatening ("Crisis") iii. Quality of life 1. Are patients tired, worn out, miserable? 2. Give patients 5-10mg of prednisone (low dose steroids) b. Cytotoxics i. Where steroids fail*** ii. Imuran or Cytoxan iii. IV "Pulse" Cytoxan c. "Pulse" Steroids d. Experimental i. Plasmapheresis ii. TNI iii. Rituxan iv. TNF-α Inhibitors v. DHEA

vi. ESR 25. Antinuclear Antibody (ANA)

a. Indirect immunofluorescence i. The most sensitive screening test for Lupus after a careful history and physical ii. The antibody being positive doesn't meant the patient definitely has the disease b. Positive Titer c. Significant Titer d. Disease Associations

20. Revised Criteria for SLE

a. Malar rash i. Present 40% b. Discoid rash i. Scarring of lesion c. Photosensitivity d. Oral ulcers i. Can be on the soft and hard palates, mucosa, and they are usually painless*** e. Arthritis f. Serositis g. Renal disorder h. Neurologic disorder i. Seizures ii. Psychosis i. Hematologic disorder j. Immunologic disorders k. ANA l. Aside: LE Cell Prep was removed from the criteria because it was a difficult test to do, expensive, and only 75% sensitive, was replaced by the ANA test m. Need 4 of the 11 criteria to make a diagnosis of Lupus***

17. Primary central nervous system involvement in Lupus: Neurologic Signs or Symptoms

a. Meninges*** b. Headaches c. Meningismus d. Cerebrum*** i. Psychosis is in the diagnostic criteria**** e. Dementia i. May be the most common CNS manifestation of Lupus f. Strokes g. Subarachnoid hemorrhage h. Migraine Other headaches i. Seizures*** i. Seizures are in the diagnostic criteria*** j. Cerebellum*** k. Ataxia l. Spine*** m. Paraparesis n. Multiple Sclerosis-like disorder o. Cranial and peripheral nerve*** p. Cranial and peripheral sensory and motor neuropathies q. Mononeuritis multiplex r. Myasthenia gravis s. Guillain-Barre syndrome

33. Other Drugs for Treatment of SLE

a. Methotrexate i. Used to treat skin, Arthritis ii. Keeps the steroid dose down, safer than steroids (less side effects) iii. Recall: DMARD of choice for RA b. Leflunomide i. Arthritis (~1/3 of pts = Marked Benefit) ii. Scratch this one out, not used c. DHEA - Mild Male Hormone i. ↓ Steroid Req & ↓ Flares ii. Not FDA-Approved iii. No Benefit for Osteoporosis iv. Not really used

joint involvement in Lupus

a. Most common joint involved in Lupus is the PIP b. But may affect almost any joint c. How do you differentiate between the arthritis in RA and Lupus?*** i. CCP antibody can help to say it's RA, but more importantly... ii. Radiographically will see erosion/rat bite lesion, the radiographic hallmark of RA, which helps differentiate

28. Helpful Serologies in SLE

a. Most sensitive: ANA*** b. Most specific: Anti-Smith Ab*** c. Subset Markers: i. Anti-dsDNA→Worried about the development of Renal disease*** 1. dsDNA can act as a prognostic indicator ii. Anti-RNP→Overlap (mixed connective tissue disease) syndrome iii. Anti-Ro→Skin, Congenital Heart Block 1. Same a Sjögren's SS-A antibody 2. Anti-Ro associated with congenital complete heart block in the offspring of mothers with Lupus iv. Anti-Histone→Drug induced SLE

35. New Immunosuppressive Approaches for SLE

a. Mycophenolate Mofetil (CellCept) i. Renal Disease and CNS disease, especially*** ii. IV CTX "No Longer DOC" iii. 24% Remission in 6 months b. Biologics*** c. Anti-TNF medications and SLE

31. Management of SLE,

a. NSAIDs are first - helpful for fever and Serositis b. Anti-malarial drugs (Hydroxychloroquine) are very helpful for arthritis c. Bad rashes and mouth sores - Hydroxychloroquine (PLAQUENIL) is the drug of choice d. If muscles are inflamed - steroids e. Lupus pneumonitis - steroids f. Where steroids fail use cytotoxic agents

40. Mortality/Prognosis of SLE

a. Overall survival i. In 1980 about 75% of Lupus patients lived 5 years ii. Today 90% have a 10 year survival b. Infection*** i. Infection and Renal Disease are probably tied for first with most common causes of death in SLE c. Renal Disease*** i. Clinical Diagnosis ii. Biopsy Diagnosis iii. WHO Classification iv. Chronicity Index d. CNS i. Primary vs. secondary ii. Diagnosis established e. Cardiac i. Pericarditis, myocarditis ii. Endocarditis iii. CAD iv. *Offspring f. *Overall survival

3. One of the diagnostic criteria of SLE, image below

a. Pleural effusion with meniscus sign and Pericardial effusion

34. IV pulse Cytotoxan for SLE

a. Reserved for severe renal or CNS disease*** i. Know the above line, but don't need to know the details*** b. Dosage: 500 mg/m2 iv q. 1 month for 6 months c. Hydration and premedication d. Results i. ↑Creatinine clearance ii. ↑Anti-DNA titer iii. ↓ESR iv. ↓T-cells v. ↑Complement levels

2. Connective Tissue Disorders

a. Rheumatoid arthritis i. Recall, RA effects about 1% of the population, or 3 million Americans b. Systemic lupus erythematosus i. Second most common CTD to RA c. Systemic sclerosis d. Poly/dermatomyositis e. Vasculitis f. Sjögren's syndrome g. Overlap (MCTD) h. Undifferentiated CTD

1. Clinical Classification of the Rheumatic Diseases

a. SLE falls under the CTDs b. Crystal-forming - monoarticular, acute onset, intermittent (pain may remit spontaneously) c. When we think about CTDs we look at polyarthritis (5+ joints) or arthralgias (systemic sign of the disease other than the joints)

22. Immunogenetics

a. SLE is an immunologic disorder of unknown etiology which can affect any organ system and is characterized by multiple autoantibodies b. Cellular Immunity is the "proof" that this is an autoimmune disorder i. Suppressor cells are deficient in Lupus, making SLE patients prone to infection (also makes white count lower) c. Familial Tendency i. Tends to run in families d. HLA Typing e. Complement Deficiency f. Laboratory Data (Antibodies) g. Hormonal Influence i. Estrogen? ii. But there are many influences, we assume a virus causes Lupus but this hasn't been proven

37. Anti-Phospholipid Ab Syndrome

a. Sapporo Criteria from UpToDate: Two Clinical and One Laboratory Criterion Present: i. Clinical 1. Vascular Thrombosis - venous, arterial or small vessel Thrombosis 2. Pregnancy Morbity - unexplained fetal death ≥ 10 weeks; one or more premature births (before 34 weeks gestation) due to Eclampsia, PreEclampsia placental insufficiency or 3 or more Embryonic pregnancy losses (< 10 weeks gestation) ii. Laboratory 1. Presence of APL on 2 or more occasions at least 12 weeks apart & no more than 5 years prior to clinical manifestations a. IgG and/or IgM aCL (RPR, VDRL) in moderate or high titer b. Ab to B-2 glycoprotein 1 (Anti-B2 GPI) of IgG or IgM isotype c. Lupus Anticoagulant i. This is simply the PTT test

24. Laboratory screening tests for CTD

a. This slide is a repeat from before, this is the "Big 6" i. CBC ii. Urinalysis 1. Very helpful to cue you in to pay closer attention to patient's kidneys iii. CMP iv. ANA v. RA-Latex vi. ESR

5. Characteristic Features of CTD

a. Triad*** i. Polyarthritis (Arthralgia) ii. Systemic sign(s) of disease other than the joints iii. Multiple autoantibodies in the serum

6. Revised criteria for SLE*************

a. Used to be 14 criteria, now down to 11, these criteria are about 95-97% sensitive, and if used appropriately 95-97% specific for making a diagnosis of SLE - originally devised to put Lupus patients in clinical studies KNOW THESE i. Malar rash ii. Discoid rash iii. Photosensitivity iv. Oral ulcers v. Arthritis vi. Serositis vii. Renal disorder viii. Neurologic disorder ix. Hematologic disorder x. Immunologic disorder xi. ANA

16. Libman-Sacks Endocarditis

a. Wart-like vegetations on both sides of the valve b. This is more of a post-mortem finding, affecting maybe 3% of Lupus patients c. This is nearly a pathognomonic lesion of Lupus

41. SLE and CAD a. Risks

i. Age ii. Duration of steroid treatment 1. Those given steroids may develop premature coronary artery disease (Great board question) iii. Hypertension iv. Cholesterol (? steroids) v. Obesity vi. Hydroxychloroquine may be protective 1. Every Lupus patient should be on this if it can be tolerated by patient 2. Hydroxychloroquine may lower cholesterol by 8.9% (PETRI)

j. Immunologic disorders

i. Anti-Smith 1. Most specific ii. Anti-dsDNA 1. 2nd most specific iii. Anti-cardiolipin 1. Chronic false positive syphilis: RPR+ or VDRL+, present for 6 months, negative FTA (confirmatory test) or ABS tests 2. Patients can present in a myriad of ways iv. Anti-phospholipid Antibody (APA) 1. May not get to this at the end of lecture; Don't think there are any questions on the exam on APA

36. Drug-Induced Lupus c. Drugs implicated (Probable)

i. Anticonvulsants*** 1. Phenytoin ii. Anti-Thyroid Drugs iii. Anti-Microbial agents iv. Beta-blockers v. Lithium vi. Paraaminosalicylate vii. Captopril viii. Interferon Gamma ix. Oral contraceptives?*** x. HCTZ xi. Glyburide xii. SSZ xiii. Terbinafine xiv. Amiodarone xv. Ticlopidine xvi. Hydrazine xvii. Docetaxel

e. Complement Deficiency

i. C2 deficiency is one of the most common deficiencies in SLE ii. As an aside: What recurrent infections may be present with a terminal complement deficiency? 1. Recurrent gonococcemia or meningococcemia

g. Diagnosis of DI-Lupus

i. Dx: A) above Sx noted in patient taking offending agent for > 1 month ii. B) Anti-Histone Ab (in absence of others) iii. C) Spontaneous resolution within 1-7 months (this is the key)*** after offending is discontinued

c. Anti-TNF medications and SLE

i. Embrel, Humira, Remicaide 1. May Induce drug-induced SLE or Lupus-like disease (LLD)*** ii. Anti - ds DNA - May ↑ iii. Anti - Cardiolipin - May ↑ iv. *May benefit arthritis and proteinuria

HLA Typing

i. HLA-D3 and sometimes D2 are highly involved with SLE 1. HLA A1-B8-D3 is considered the "autoimmune locus," involved in: a. Graves Disease b. Addison disease c. Hyperthyroidism d. Hashimoto's thyroiditis e. Sjögren's disease i. Aside: Sjögrens, the dry eyes-dry mouth syndrome, is becoming popular on board exams

i. Hematologic disorder ***Remember the numbers***

i. Leukopenia 1. Low WBC count < 4,000*** a. Lower than on the routine CBC ii. Hemolytic anemic Diagnosed by: 1. Elevated Reticulocyte count 2. Direct or indirect positive Coombs test 3. Decreased Haptoglobin iii. Thrombocytopenia 1. <100,000 platelets*** iv. Lymphopenia 1. <1,500 lymphocytes*** on 2 consecutive slides

36. Drug-Induced Lupus a. Characterisitcs

i. M = F 1. Not 9:1 female ii. 15, 000 - 30,000 cases/year iii. May be genetic predisposition (HLA-D4) iv. Prone in drugs that are slow Acetylators v. Anti-Histone Ab present vi. Anti-ds DNA usually lacking

k. ANA

i. Most sensitive*** test for Lupus (98%) ii. Few false negatives iii. Less expensive than predecessor test (LE Cell Prep)

Serositis

i. Pleuritis Diagnosed by: 1. Pleural effusion on X-Ray or CT 2. Rub auscultated 3. Classical clinical history ii. Pericarditis Diagnosed by: 1. Classical echocardiogram finding 2. EKG changes 3. Rub auscultated 4. Classical clinical history

36. Drug-Induced Lupus

i. Procainamide*** ii. Hydralazine*** 1. Used to treat Hypertension iii. Minocycline*** 1. Used to treat Acne iv. Diltiazem v. Penicillamine vi. INH*** vii. Quinidine*** viii. TNF Alpha Inhibitors*** ix. Interferon-alpha x. Methlydopa*** 1. Used to treat hypertension in Pregnant ladies xi. Chlorpromazine xii. Practolol

g. Renal disorder

i. Proteinuria 1. Diagnosed by 500mg in a 24 hour collection, or 2. 3g or more on two separate urinary analyses ii. Casts of any sort other than the benign casts found in healthy urine 1. White cell, red cell or mixed

b. Biologics***

i. Rituximab (Rituxan)*** 1. Hasn't proven to be truly effective ii. Anti CD40L*** iii. Belimumab (BENLYSTA) 1. Anti - BLyS 2. Inhibits Biologic Activity of BAFF (B-cell Activating Factor) also known as BLYS (B-Lymphocyte Stimulator) 3. Indication: Active SLE despite treatment with NSAIDs, Steroids, Antimalarials or Immunosuppressives 4. No studies in treatment of Renal or CNS Disease a. Why Pascucci is not a fan of this drug 5. Limited Use: Patients requiring 10mg Prednisone daily along with AZA, CellCept or MTX or those who are intolerant 6. Dosage: 10mg/kg IV Days 0, 14, 28 & Q 28 days thereafter. 7. N.B. BLISS-52 and BLISS-76 trials (1684 pts) a. Revealed: Improvement in at least 4 points on SLE b. Disease Activity Index (SLEDAI)

e. Other conditions with positive ANA

i. SLE ii. Other CTD iii. Drugs iv. Age v. Pulmonary Fibrosis vi. COPD vii. CAH viii. Herpes ix. AIDS x. Burns xi. Myasthenia xii. CUC xiii. Malaria

b. Discoid rash***

i. This is disc-like or coin-like scarring*** rash ii. One of the 11 criteria iii. One can't guarantee that this rash will be resolved with treatment 1. Dermatologists inject this rash with steroids which sometime helps 2. Hydroxychloroquine may help discoid rash in Lupus iv. About 10% of patients with just pure discoid lupus will go on to develop true systemic lupus