Transcript Diapositiva 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
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 Criteria
Criterion
1. Malar Rash
Definition
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 effusion
2.OR
2.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 performed
2.OR
2.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 imbalance
2.OR
2.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 reticulocytosis
2.OR
3
2.Leukopenia--< 4,000/mm on ≥ 2 occasions
1.OR
3
3.Lyphopenia--< 1,500/ mm on ≥ 2 occasions
1.OR
3
4.Thrombocytopenia--<100,000/ mm in the absence of offending drugs
10. Immunologic Disorder
1.Anti-DNA: antibody to native DNA in abnormal titer
2.OR
2.Anti-Sm: presence of antibody to Sm nuclear antigen
1.OR
3.Positive finding of antiphospholipid antibodies on:
1.1. an abnormal serum level of IgG or IgM anticardiolipin antibodies,
2.2. a positive test result for lupus anticoagulant using a standard method, or
3.3. 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 1080% 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 Smethyltransferase (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!!!