SLE 1) Epidemiology a. Worldwide b. 15-125 per 100,000 in US c. Especially prevalent in women in reproductive years i.

90% of patients are women, particularly in patients 15-65 yo ii. More common in African-Americans, and Asians as compared to whites 2) Classification criteria a. Need 4 or more of following to make diagnosis of SLE (for clinical studies): b. Malar rash i. Not to be confused with rosacea; referring to rosacea 1. Typically begins as flushing 2. May progress to persistent redness, like sunburn that persists, and inflammatory changes ii. Distinguished from SLE, rosacea: 1. May show papules or pustules, resembling acne, which are rare in SLE 2. Often involves nasolabial folds which are spared in SLE c. Discoid rash i. Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions ii. Very deep lesions- deep bc causes scarring. More superficial lesion typically wont cause scarring. iii. Lupus band test = diagnostic(ish) 1. Deposition of Ig and/or C (complement) at dermoepidermal junction 2. + in DLE and non-lesional, non-sun exposed skin in SLE patients 3. Diagnostic utility debatable 4. Illustrates autoantibodies in SLE

5. Dont do this really anymore due to debatable utility. d. Photosensitivity i. Skin rash as result of unusual reaction to sunlight, by patient history or physician observation ii. Rash induced on the patients back. Initially no rash- applied UV in that distribution and got the rash. UVB worse than UVA. iii. Photosensitivity helps explain malar rash somewhat. e. Oral ulcers i. Oral or nasopharyngeal ulceration, usually painless, observed by a physician f. Arthritis i. Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness, swelling, or effusion ii. can get ulnar deviation; but with xray dont find erosions. (unlike RA) g. Serositis i. Pleuritis: Convincing history of pleuritic chest pain or rub heard by physician or evidence of pleural effusion ii. OR iii. Pericarditis: Documented by ECG, rub, or evidence of pericardial effusion h. Renal disorder i. Persistent proteinuria greater than 0.5 g per day or greater than 3+ if quantitation not performed ii. OR iii. Cellular casts, which may be red cell, hemoglobin, granular, tubular, or mixed iv. Lupus Nephritis 1. WHO Classification

a. Based on kidney biopsy, histology, staining for immunoglobulin and C by immunofluorescence, + electron microscopy b. Revised several times, most recently in 2003 c. Wide range of histological forms of lupus nephritis i. Differences in indications and responses to therapy 1. Diffuse proliferative (type IV) is indication to treat; membranous (type V) generally not aggressively treated [basically not going to get anything out of treatment at that point] d. Activity and chronicity indices may be predictive of response to therapy but controversial

i.

Neurologic disorder i. Seizures: In the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance) ii. OR iii. Psychosis: In the absence of offending drugs or known metabolic derangements (e.g., uremia, ketoacidosis, or electrolyte imbalance) iv. Often referred to as cerebritis (?) v. May also involve peripheral nervous system vi. Much broader spectrum than implied by classification criteria 1. Ranges from stroke to mild cognitive or emotional disturbance

j.

Hematologic disorder i. All of the below are possibilities (not all are necessary) ii. Hemolytic anemia, with reticulocytosis 1. Potentially many different causes which are not part of clinical criteria or typical pathogenesis of SLE a. Anemia of chronic disease b. Renal insufficiency c. Blood loss d. Drugs 2. Most important is autoimmune hemolytic anemia a. One of classification criteria b. Illustrates immune pathogenesis 3. Can sometimes detect complement on the RBCs iii. Leukopenia: Less than 4000/mm3 total on two or more occasions iv. Lymphopenia: Less than 1500/mm3 on two or more occasions 1. (also for leucopenia) Potentially many causes a. Infections

b. Drugs c. Rarely due to inadequate marrow production d. Often due to peripheral destruction, presumably from anti-WBC antibodies v. Thrombocytopenia: Less than 100,000/mm3 in absence of offending drugs 1. Potentially many causes a. Drugs (heparin common in hospital) b. Thrombotic thrombocytopenic purpura (TTP) i. Thrombocytopenia, microangiopathic hemolytic anemia, CNS defects, renal insufficiency ii. Should be distinguished because of different therapy 2. Classic in SLE: Immune thrombocytopenic purpura (ITP) a. Antibody coated platelets vi. Regarding cytopenia 1. May precede other manifestations of SLE, i.e., may be presenting manifestation a. Autoimmune hemolytic anemia b. ITP 2. Presence of antibody coated blood cells is not necessarily associated with destruction k. Immunologic disorder i. Again, not all required just 1 ii. Anti-DNA: Antibody to DNA in abnormal titer iii. Anti-Sm: Presence of antibody to Sm nuclear antigen iv. Positive finding of antiphospholipid antibodies based on: 1. An abnormal serum level of IgG or IgM anti-cardiolipin antibodies; 2. A positive test result for lupus anticoagulant using a standard method; or

3. A false-positive serologic test for syphilis known to be positive for at least 6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test a. i.e., More specific tests for syphilis will be negative but serologic test = positive. v. Other (not sure if these count) 1. Lupus Anticoagulant a. Some SLE patients have abnormal coagulation studies (typically PTT) i. PTT mx a coagulation pathway. Would expect if time is prolonged (takes longer to clot), should have a bleeding problem. If look more carefully, there are antibodies that prolong PTT and not due to coagulation factor deficiency (ex Factor IX deficiency). Distinguish by mixing studies. Hemophilia serum and add normal plasma should correct; means some inhibitor is there b. Associated with +VDRL c. Due to antibodies not coagulation factor deficiencies i. Mixing studies--1:1 mix of patients plasma with control plasma does not correct due to inhibitor d. Antibodies against phospholipids associated with arterial thrombosis not bleeding as suggested by lab abnormalities i. Clinical picture not bleeding, but is thrombosis! So misnomer, anticoagulant implies bleeding problems. The clinical problem = THROMBOSIS. 2. Anti-phospholipid Antibody Syndrome a. Presence of anti-phospholipid antibodies associated with i. Arterial, venous, or small vessel thrombus ii. Recurrent spontaneous abortions, typically before 10th week of gestation b. Can be catastrophic with simultaneous vessel occlusions involving 3 or more organs

i. Stroke, renal problems, lower extremity issues possibly c. Skin manifestations i. Livedo reticularis ii. Retiform purpura l. Antinuclear antibody (ANA) i. An abnormal titer of antinuclear antibody (ANA) by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome ii. History of ANA: Preceded by LE cell, most often seen in BM or fluid collections in SLE patients 1. Before ANAs were actually described, what was described in clinical literature was LE cell most often seen in bone marrow or fluid of SLE pts. Hallmark of lupus few SLE are truly ANA negative. But LE cell is dx, but not very sensitive. May have to look at many slides to see it. 2. See phagocytosis of other cells in LE cell. iii. Hallmark of SLE; few patients if any are truly ANA-negative iv. Also seen in many other diseases--highly non-specific v. Now typically done by indirect immunofluorescence microscopy, similar to ANCA determination vi. Qualitative, previous lack of standardization vii. Useful screening test viii. NOTE: WITH IF, CAN SEE DIFFERENT ANTIGENS ARE RESPONDING FOR ANA. NOT ALL LUPUS IS THE SAME ix. ANA and Dz associations 1. Look for diff components of diff antigens and thats what we should do. dsDNA is quite specific for lupus with 95% specificity but not very sensitive. Dont tend to see dsDNA antibodies with other disorders that have positive ANAs. 2. Sm is also useful test but actual specificity is misstated. Actually pretty high but not very sensitive. Again, if look at specificity and see with other disorders very infrequently.

3. RNP is said to have high specificity. Try to figure out what he meant by typo. 4. Histone antibodies almost all drug induced lupus has antibody against histones. 5. A couple more antibodies to talk about, Ro and La. 6. Found in lupus pts and Sjogrens. 3) Other lupus forms a. Drug-induced SLE i. Many drugs implicated in inducing SLE but few are more than case reports ii. Most convincing (*best established) = quinidine, hydralazine, procainamide iii. Drug-induced +ANA more common than SLE and is not necessarily indication to stop drug iv. Drug-induced lupus tends to be more benign (less kidney and CNS disease) v. Associated with anti-histone ANA vi. Withdrawal of drug generally results in resolution and no recurrence if patient stays off drug 1. Rechallenge is rare b. Neonatal lupus i. Associated with anti-Ro and anti-La autoantibodies in mother ii. Infants may develop complete heart block and/or transient manifestations of SLE 1. Helps establish autoantibodies are important in dz. Transplacental transfer of IgG may lead to this. iii. If not life threatening illness, is transient and can go away. 4) Problems with with classification criteria a. Use to begin thinking about SLE but do not use as absolute guide i. No ANA: SLE highly unlikely b. Does not list exclusion criteria but it is implicit that other diagnoses must be excluded i. Especially infections and malignancy

c. Patients are heterogeneous [so many diff manifestations] d. No mention of other common manifestations i. Constitutional symptoms (fatigue, malaise, anorexia, fever) ii. Raynauds phenomenon iii. GI symptoms (usually non-specific) iv. Lymphadenopathy v. Other rashes vi. Alopecia vii. Keratoconjunctivitis sicca (2 Sjgrens syndrome) viii. Muscle weakness (due to inflammatory myositis) ix. Cardiac (Libmann-Sacks endocarditis) x. Elevated ESR (CRP) xi. Hypocomplementemia 5) Diagnostic Workup a. Suspect diagnosis i. Unexplained constitutional symptoms (fatigue, malaise, weight loss, fever) suggesting inflammation ii. Multi-system disorder iii. Skin rash iv. Arthritis v. Laboratory abnormalities, especially renal dysfunction, cytopenias b. Collect information compatible with diagnosis of SLE--typical signs and symptoms c. Consider other diagnoses and exclude as necessary, particularly infections and malignancy d. The lab evaluation

Laboratory Evaluation
If H & P are normal and suspicion for SLE is low, order panel #1 If H & P are abnormal, and suspicion for SLE is high, or panel #1 suggests SLE, order panel #2

Panel #1
CBC Urinalysis Metabolic panel Liver function tests ESR (erythrocyte sedimentation rate) (Blood and urine cultures) ANA Chest X-ray

Panel #2
dsDNA Ro/La RNP/Sm C3, C4 Coombs PT/PTT VDRL Anti-phospholipid antibody panel ? Cryoglobulins ? Serum protein electrophoresis (SPEP)

e. Kidney bx i. Helpful to establish degree of glomerular involvement, and predict outcome of therapy 1. Usually done in SLE patient with evidence of renal involvement ii. May be helpful (but usually not used) to establish diagnosis of SLE 1. Can usually establish without doing invasive test iii. Note overlapping renal manifestations of the different histologic types 1. Problem = clinical clues all over the map. As mentioned, Membranous GN not treated aggressively. Type Iv do treat aggressively. Problem is just by taking 24 hour urine, wont distinguish you. This is problem had, and why bx may be useful. 6) Pathogenesis a. Pathogenesis of one manifestation may not be applicable to another i. Autoantibodies may explain one case; another may be due to something else. b. Therapy for one manifestation may not be very helpful for another i. Antimalarial drugs not very potent, but still very useful for skin rashes. Not good for kidney problems. c. Evidence for Complement in Pathogenesis of SLE i. Complement consumption in active SLE

1. Low C3, low C4 (classical pathway of complement activation) ii. Complement deposition in lesions 1. Lupus band test (as mentioned earlier under discoid rash) 2. Renal bx IF 3. Complement with Coombs tests (hemolytic anemia) iii. But complement deficiencies predispose to SLE WTF!!!!!!??!?!111 1. It is not protective 2. 35 cases of C1q deficiency 94% have SLE like illness. 3. Complement deficiencies ALSO associated with infection though.

Barilla-LaBarca and Atkinson, Curr Op Rheum 2003

4. GWAS studies based on autoimmunity a. Does lead to things like this implicates every component of immune system. Every aspect of immunity basically.

b. Caveats of GWAS i. Linked genes are common in control populations ii. The Odds Ratios of the linked genes indicate that each contributes little to risk of disease 1. Contribution of multiple genes 2. Heterogeneity of patient population? 3. What about complement deficiencies? Too rare for GWAS? iii. Disease association of marker in a gene does not mean that the gene itself is involved in disease 1. Could implicate the gene itself or genetic elements in surrounding genetic interval, i.e., genes, promoter elements, miRNA, etc. 2. Other evidence must be accumulated to directly implicate the gene in disease pathogenesis iv. Genes implicated in other autoimmune diseases v. Problem more power the more people, but phenotypes are different so the GWAS may lose effectiveness if spread over different forms of SLE c. The results of GWAS i. C8orf 1. High rates of dz allele in control 2. Odds ratio not even that high, either 3. No coding region variants of either C8orf13 or BLK are associated (variants are in intronic segments) d. Summary i. Many theories, each cannot explain multitude of pathologies in SLE as broadly defined ii. Complement activation often associated with active SLE but complement deficiencies predispose to SLE

iii. GWAS provide clues to pathogenesis but studies may be fundamentally flawed, and by definition, cannot account for environmental factors that may be inherent in SLE 7) Therapy

Treatment of SLE
Safer

NSAIDs Antimalarials Dapsone Corticosteroids Azathioprine Methotrexate Mycophenolate mofetil Cyclophosphamide

More potent

a. Considerations i. Consider severity of disease and if manifestations are life-threatening (CNS, renal, cardiac, pulmonary) 1. Certain manifestations are more aggressively treated (diffuse GN versus membranous GN) ii. Corticosteroids mainstay of therapy but have significant side effects, requiring steroid taper iii. Cytotoxic drugs often used as steroid-sparing agents (azathioprine, methotrexate) but may be effective adjuncts (cyclophosphamide) iv. NSAIDs may be helpful for less severe manifestations (arthritis) v. Antimalarials and dapsone helpful for cutaneous LE vi. Need to consider teratogenic risk of medications since most patients are women in child-bearing years

Novel Therapies in Pipeline

Inhibition of B-cell survival Anti-Blys Anti-BAFF

B-cell toleragen

Inhibition of co-stimulatory Interactions

Anti-CD40L CTLA4-Ig

Dendritic cell

Complement blockade? Manzi, 2008

vii. Many drugs being developed target different components of the immune system. Will be interesting to see how this all works. viii. Early data with Anti-CD20 doesnt work.