Systemic Lupus Erythematosus

Mohammed A. Omair MBBS, SF RheumConsultant Rheumatologist

Assistant ProfessorProgram Director of the KSU Rheumatology

FellowshipKing Khalid University Hospital

King Saud University

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

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.

Genetic Background

Mok, C. and Lau, C.J Clin Pathol. 2003 Jul; 56(7): 481–490.

Environmental Trigger

Mok, C. and Lau, C.J Clin Pathol. 2003 Jul; 56(7): 481–490.

Immune System Dysregulation

Mok, C. and Lau, C.J Clin Pathol. 2003 Jul; 56(7): 481–490.

Pathogenesis of SLE

Mok, C. and Lau, C.J Clin Pathol. 2003 Jul; 56(7): 481–490.

1997 Modified ACR CriteriaCriterion 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 1.Pleuritis--convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusion2.OR2.Pericarditis--documented by electrocardigram or rub or evidence of pericardial effusion 

7. Renal Disorder 1.Persistent proteinuria > 0.5 grams per day or > than 3+ if quantitation not performed2.OR2.Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed 

8. Neurologic Disorder 1.Seizures--in the absence of offending drugs or known metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance2.OR2.Psychosis--in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance 

9. Hematologic Disorder 1.Hemolytic anemia--with reticulocytosis2.OR2.Leukopenia--< 4,000/mm3 on ≥ 2 occasions3.OR3.Lyphopenia--< 1,500/ mm3 on ≥ 2 occasions4.OR4.Thrombocytopenia--<100,000/ mm3 in the absence of offending drugs 

10. Immunologic Disorder 1.Anti-DNA: antibody to native DNA in abnormal titer2.OR2.Anti-Sm: presence of antibody to Sm nuclear antigen3.OR3.Positive finding of antiphospholipid antibodies on:4.1. an abnormal serum level of IgG or IgM anticardiolipin antibodies,5.2. a positive test result for lupus anticoagulant using a standard method, or6.3. 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

2012 SLICC Criteria

What to do When Your Patient Does Not Fit?

• Definitive• Probable (useless)• Possible (useless)• When you are not sure call it

undifferentiated connective disease!!!

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.

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).

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.

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

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.

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!!!

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.

Pathways in Complement Activation

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.

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).

Hematological Manifestations

• One or more cell line• leucopenia• Anemia• Thrombocytopenia• TTP• Pure red cell aplasia

Treatment

• Steroids• Azathioprine• MMF• RTX• Splenectomy• TPE for TTP

REMEMBER INFECTION AND DRUG INDUCED

BONE MARROW SUPPRESSION

SEROSITIS

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

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

Renal Involvement

• Glomerular disease (LN)• Tubulointerstitial nephritis• TTP• APS related with • Overlap with AAV

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)

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.

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.

REMEMBER TO ALWAYS LOOK AT THE MSU OF A

LUPUS PATIENT

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

Clinical manifestations

• Cognitive dysfunction.• Headache.• Mood disorder.• Cerebrovascular disease.• Seizures.• Polyneuropathy.• Anxiety.• Psychosis

Imaging

• Brain atrophy disproportioned to age is common.

• Demyelination• Small vessel disease or Stroke• Normal MRI with active lupus

cerebritis

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

REMEMBER CNS INFECTION IS NOT TO BE

MISSED

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.

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.

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.

Other Rashes

• RP with gangrene• Purpuric rash• Pemphigoid• Psoriaform

REMEMBER WHEN YOU ARE NOT SURE REQUEST A

SKIN BIOPSY

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.

REMEMBER TO SEND THEM FOR ANNUAL

SCREENING FOR RETINAL TOXICITY

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

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.

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.

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.

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.

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.

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.

REMEMBER YOU CAN HARM MORE THAN DO

GOOD IF YOU DO NOT RE-EVALUATE YOUR PATIENTS’ NEEDS

REMEMBER YOU ARE TREATING A HUMAN WITH

LUPUS!DISCUSS VACCINATION, FERTILITY, CONCEPTION, METABOLIC SYNDROME

AND CANCER SCREENING

THANK YOU!!!