1. Systemic Lupus Erythematosus
Mohammed A. Omair MBBS, SF Rheum
Consultant Rheumatologist
Assistant Professor
Program Director of the KSU Rheumatology Fellowship
King Khalid University Hospital
King Saud University

2. Objectives Introduction Pathogenesis
When to diagnose SLE and the use of the classification criteria
Auto-antibodies and complement
Important organ involvement
Therapies
Disease related complications
Drug related complications

3. Introduction
SLE is a chronic autoimmune disease that affects almost all body organs.
The pathogenesis rely heavily on autoantibody production and the formation of immune complexes that deposit into the tissue consequently leading to complement activation and damage.
The story starts when you lose self tolerance due to defective clearance.

4. Genetic Background
Mok, C. and Lau, C.J Clin Pathol Jul; 56(7): 481–490.

5. Environmental Trigger
Mok, C. and Lau, C.J Clin Pathol Jul; 56(7): 481–490.

6. Immune System Dysregulation
Mok, C. and Lau, C.J Clin Pathol Jul; 56(7): 481–490.

7. Pathogenesis of SLE
Mok, C. and Lau, C.J Clin Pathol Jul; 56(7): 481–490.

8. 1997 Modified ACR Criteria Criterion Definition 1. Malar Rash
Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds
2. Discoid rash
Erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
3. Photosensitivity
Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
4. Oral ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by physician
5. Nonerosive Arthritis
Involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion
6. Pleuritis or Pericarditis
Pleuritis--convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion OR
Pericarditis--documented by electrocardigram or rub or evidence of pericardial effusion
7. Renal Disorder
Persistent proteinuria > 0.5 grams per day or > than 3+ if quantitation not performed
Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed
8. Neurologic Disorder
Seizures--in the absence of offending drugs or known metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance
Psychosis--in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance
9. Hematologic Disorder
Hemolytic anemia--with reticulocytosis
Leukopenia--< 4,000/mm3 on ≥ 2 occasions
Lyphopenia--< 1,500/ mm3 on ≥ 2 occasions
Thrombocytopenia--<100,000/ mm3 in the absence of offending drugs
10. Immunologic Disorder
Anti-DNA: antibody to native DNA in abnormal titer
Anti-Sm: presence of antibody to Sm nuclear antigen
Positive finding of antiphospholipid antibodies on:
1. an abnormal serum level of IgG or IgM anticardiolipin antibodies,
2. a positive test result for lupus anticoagulant using a standard method, or
3. a false-positive test result for at least 6 months confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test
11. Positive Antinuclear Antibody
An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs

9. 2012 SLICC Criteria

10. What to do When Your Patient Does Not Fit?
Definitive
Probable (useless)
Possible (useless)
When you are not sure call it undifferentiated connective disease!!!

11. Autoantibodies
There are more than 100 identified autoantibody for SLE.
Their presence is not only important for diagnosis but some of them can predict organ involvement.

12. ANA Present in more than 95% of subjects.
ANA negative lupus does not exist in the mind of some rheumatologists.
If present it should exclusively diagnosed by an experienced rheumatologist.
A titer ≥ 1:160 can be considered positive.
Remember only 11-13% of persons with a positive ANA test have lupus and up to 15% of completely healthy people have a positive ANA test (up to 37% in people older than 65 years).

13. Anti-Double Stranded DNA
Anti-dsDNA antibodies are highly specific to SLE: < 0.5 % of healthy people or patients with other autoimmune diseases have anti-dsDNA antibodies, whereas 70 % of SLE patients are positive.
Isenberg DA, et al. Arthr Rheum. 1985; 28(9):999–1007.

14. Anti-Double Stranded DNA
Can be detected in the serum of patients before the onset of the disease.
Correlates well with disease activity.
Decreases with therapy.
It is highly associated with renal involvement

15. Anti-Smith (Sm)
The sensitivity and specifity of anti-Sm are 39.7% and 98.6%, respectively.
Can be present before the onset of SLE.
Does not change with disease activity.
Pan, L. Et al. Ann Acad Med Singapore.1998 Jan;27(1):21-3.

16. Anti-Ro and Anti-La
Anti-Ro/SSA and anti-La/SSB antibodies are present in approximately 30 and 20 percent of patients with SLE, respectively.
Their presence signifies:
Overlap with Sjogren’s syndrome
Risk of cutaneous lupus
Risk of CHB in pregnant mamas with lupus.
ANA negative lupus!!!

17. Complement
The complement system is a humoral component of the innate immune system that contains about 30 proteins.
Complement becomes activated by 3 main pathways: the classical, alternative, and lectin pathways.
All 3 pathways converge on the generation of C3 convertases that result in the production of anaphylatoxins and a proinflammatory cascade.

18. Pathways in Complement Activation

19. Complement in SLE
Deficiencies (of early components C1q, C4) predispose to pediatric SLE.
Activation leads to deposition and organ damage.
Levels decrease with activity and improve with treatment.

20. How to Approach a Patient with SLE
Ask every single question in Nicholas Talley.
It is called the disease with a 1000 faces.
Make sure you look for an overlap (Sjogren’s syndrome, APS, SSc, RA, DM).
Higher prevalence of other autoimmune diseases (hypothyroidism, celiac disease, and vitiligo).

21. Hematological Manifestations
One or more cell line
leucopenia
Anemia
Thrombocytopenia
TTP
Pure red cell aplasia

22. Treatment
Steroids
Azathioprine
MMF
RTX
Splenectomy
TPE for TTP

23. REMEMBER INFECTION AND DRUG INDUCED BONE MARROW SUPPRESSION

24. SEROSITIS
Usually steroid responsive but in some patients needs a steroid sparing agent.

25. Renal Involvement
The most common internal organ involvement affecting up to 75% of patients in their lifetime.
Can be part of the first presentation
Clinical Presentation:
Asymptomatic proteinuria
New onset HTN
Nephrotic syndrome
Rapidly Progressive Glomerulonephritis

26. Renal Involvement Glomerular disease (LN) Tubulointerstitial nephritis
TTP
APS related with
Overlap with AAV

27. Lupus Nephritis
The ISN classification system divides glomerular disorders associated with SLE into 6 different patterns:
Minimal mesangial lupus nephritis (class I) 
Mesangial proliferative lupus nephritis (class II) 
Focal lupus nephritis (class III)
Diffuse IV lupus nephritis (class IV)
Membranous lupus nephritis (class V)
Advanced sclerosing lupus nephritis (class VI)

28. Investigation Creatinine Urinalysis 24 hour protein US kidney
Kidney biopsy
Indications: elevated serum creatinine, 24 hour excretion more > 500 mg/day or active urine sediment.

29. Treatment Class I: no specific treatment (rarely seen)
Class II: no specific directed therapy (maybe increasing corticosteroids and optimizing the immunosuppressive agent)
Class III & IV: Induction (CYC or MMF+ high dose corticosteroids) maintenance (AZA or MMF) (RTX as 3rd line for either induction or maintenance)
Class V: same as proliferative but CsA and tacrolimus may play a role.
Class VI: prepare for dialysis or evaluate for transplant.

30. REMEMBER TO ALWAYS LOOK AT THE MSU OF A LUPUS PATIENT

31. Neuropsychiatric Involvement
Neurologic and psychiatric symptoms occur in 10-80% of patients.
The pathogenesis can involve one or more of the following:
Vasculopathy
Autoantibodies (Ribosomal P antibody, anti-neuronal antibodies)
Other: These include cytokines, neuropeptides, oxidative stress, nitric oxide , and interference with neurotransmission

32. Clinical manifestations
Cognitive dysfunction.
Headache.
Mood disorder.
Cerebrovascular disease.
Seizures.
Polyneuropathy.
Anxiety.
Psychosis

33. Imaging Brain atrophy disproportioned to age is common. Demyelination
Small vessel disease or Stroke
Normal MRI with active lupus cerebritis

34. Treatment Steroids and CYC for inflammatory complications.
Alternatives could be RTX, CsA, and FK506
ASA and/or warfarin for stroke syndromes (always check for APS)
Anti-epileptic for seizures
Pain modulating drugs for neuropathy.
Headache treat the underlying cause

35. REMEMBER CNS INFECTION IS NOT TO BE MISSED

36. Skin Skin is commonly involved in SLE.
There are more than 20 types of rashes in lupus.
In a culture like ours many women live with many of these complications in silence.
It is our job to improve detection and management of these lesions.

37. Photosensitive Rashes
Butterfly and all others can be easily managed by a very novel and advanced strategy called PREVENTION
HCQ plays a major role in the treatment of cutaneous lupus.
Systemic steroids, azathioprine, dapsone.
Topical cream is not our business.

38. Discoid Rash Can be the sole cutaneous manifestation.
The risk of progression to SLE in patients with DLE was demonstrated to be 16.7% progression within 3 years of diagnosis.
Classically presents with erythematous-to violaceous, scaly plaques with prominent follicular plugging that often results in scarring and atrophy.

39. Other Rashes
RP with gangrene
Purpuric rash
Pemphigoid
Psoriaform

40. REMEMBER WHEN YOU ARE NOT SURE REQUEST A SKIN BIOPSY

41. Hydroxychloroquine Standard of care in every SLE patient.
Has a positive effect on: proteinuria, cutaneous, arthritis, thrombotic events, hyperlipidema, hyperglycemia, and improves survival.
Dose is 6.3mg/kg.
Adverse events: GIT, myopathy, and retinopathy.

42. Remember to send them for annual screening for retinal toxicity

43. Azathioprine Steroid sparing agent
Effective as maintenance of LN, myositis, cutaneous lupus, CNS lupus.
Dose is 2-3mg/kg
Adverse events: hypersensitivity reaction, pancytopenia, and hepatitis
Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) can predict AEs

44. Mycophenolate Mofetil
Mainly used as induction and maintenance of LN.
Can be used for myositis, cutaneous or CNS lupus.
Dose is 2-3g/day
Adverse events: GIT, and pancytopenia.

45. CsA and Tacrolimus Used mainly in LN class V.
Maybe used for CNS lupus.
Low dose CsA can be effective in SLE 3mg/kg/day
Tacrolimus dose is 2-3mg/day
Drug level guides the dosing
Adverse events: HTN, ginigival hyperplasia, hypertrichosis, DM, and increase creatinine.

46. Rituximab Almost used in everything
Dose can be calculated with the lymphoma protocol or RA protocol.
Despite it failed the RCTs its efficacy is unshakable in the heads of rheumatologists.
Adverse events: hypersensitivity reaction, fluid retention, and PML.

47. Belimumab Anti-BLyS (B-cell stimulating factor inhibitor).
The first and only biologic approved for SLE.
Approved for seropositive SLE with refractory mucocutaneus and articular manifestations.

48. Disease Related Complications
There have been a major improvement in the outcome of SLE over the last 30 years.
Still a minority die from DAH, RPGN, PHTN, and myocarditis.

49. Treatment Related Complications
Now living longer we discovered that if management is not done systematically (liberally).
Patients develop steroids related complications and die from premature CAD.
If immunosuppressive medications are not tapered when disease is quiescent patients die from infections and drug side effect.
Risk of malignancy is higher in SLE.

50. Remember you can harm more than do good if you do not re-evaluate your patients’ needs

51. Remember you are treating a human with lupus
Remember you are treating a human with lupus! Discuss vaccination, fertility, conception, metabolic syndrome and cancer screening

52. Thank you!!!