- ACRONYMS AND DEFINITIONS
- ACR - American College of Rheumatology
- ANA - Antinuclear antibodies
- CCB - Calcium channel blockers
- DIL - Drug-induced lupus
- EULAR - European League Against Rheumatism
- NMDA - N-methyl-D-aspartate
- RCT - Randomized controlled trial
- SLE - Systemic Lupus Erythematosus
- EPIDEMIOLOGY
- Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect a number of organ systems including the kidneys, brain, skin, lungs, and heart
- In the U.S., the prevalence of SLE is about 52 cases per 100,000 people. Women and African Americans have a much higher risk, and the disease tends to be more severe in children. The peak incidence for women occurs in the 20s to 30s, and men do not have an age predilection.
- The incidence of SLE has been increasing in recent years, a trend that is likely secondary to increased awareness, increased testing, and an increase in the diagnosis of mild cases
- The lupus syndrome can also be precipitated by certain medications in what is referred to as drug-induced lupus [21,31]
- RISK FACTORS
- Known risk factors
- Female sex (9:1 female to male)
- African American (as high as 206/100,000 in African-Caribbean women)
- Asian
- Family history
- Possible risk factors
- Ultraviolet radiation
- Smoking
- Epstein-Barr virus
- Female hormones
- Hormone replacement therapy
- Oral contraceptives
- Occupational exposure: silica, pesticides, mercury [1,2,3,19,21,22]
- DRUG-INDUCED LUPUS (DIL)
- Overview
- Certain medications have been known to cause a lupus-like syndrome that is referred to as "drug-induced lupus"
- Symptoms of drug-induced lupus are similar to the constitutional symptoms seen in SLE and may include joint pain and swelling, muscle pain, fever, rash, weight loss, and blood abnormalities
- Antihistone antibodies are seen in up to 95% of patients with drug-induced lupus. Antichromatin antibodies are also common as are Anti-ssDNA (single-stranded DNA) antibodies. Anti-dsDNA (double-stranded DNA) antibodies are rare in drug-induced lupus and complement levels are usually normal.
- The syndrome typically resolves once the offending drug is stopped, but corticosteroids may be required in severe cases
- Many drugs have been implicated in DIL through case reports, but these do not prove causation. Drugs that have well-documented associations with DIL are listed below.
- Medications associated with drug-induced lupus
- ACE inhibitors
- Anticonvulsants (phenytoin, valproate, carbamazepine)
- Calcium channel blockers (diltiazem)
- Griseofulvin
- Hydralazine (up to 20% risk with chronic use)
- Interferon alpha and beta
- Isoniazid
- Methimazole
- Minocycline
- Minoxidil
- NSAIDs
- Procainamide (up to 20% risk with chronic use)
- Proton pump inhibitors (lansoprazole,omeprazole, pantoprazole, esomeprazole)
- Penicillamine
- Propafenone
- Pyrazinamide
- Quinidine
- Rifabutin
- Terbinafine (Lamisil®)
- Thiazide diuretics
- TNF inhibitors (Humira®, Enbrel®, etc.) [27,28,29]
- PATHOLOGY
- Lupus is believed to be caused by deficiencies in the complement system that lead to defective apoptotic (programmed) cell death and clearance
- During apoptotic cell death, cellular debris are engulfed by phagocytes. Failure of proper and complete phagocytosis can lead to nuclear debris being captured by antigen presenting cells.
- Antigen presenting cells with captured nuclear debris interact with T and B cells, and antinuclear antibodies are produced [21]
- SYMPTOMS
- Overview
- Symptoms of SLE are highly variable and dependent upon the organ system(s) affected
- Skin symptoms
- Malar rash - red rash of nose and cheeks often in shape of a butterfly. Occurs in up to a third of patients.
- Discoid rash - red, raised, disc-shaped patches
- Photosensitivity - sun exposure causes rash or worsens existing rash
- Oral ulcers - sores in mouth
- Joint symptoms
- Arthritis - joint pain and swelling is the presenting symptom in up to half of patients. Joints of the hands, wrists, and knees are typically affected. Joint involvement is usually symmetric and polyarticular (> 4 joints), but it may also be asymmetric. Unlike rheumatoid arthritis, joint disease is rarely erosive or deforming.
- Organ-specific symptoms
- Lungs - inflammation of the lining around the lungs (pleuritis) that causes chest pain which is worse with deep breathing
- Heart - inflammation of the sac surrounding the heart (pericarditis) may occur. Symptomatic pericarditis which is marked by sharp chest pain, shortness of breath, and palpitations is seen in up to 25% of patients. Cardiac tamponade may also be seen, but is rare, occurring in 1 - 2.5% of patients. [26]
- Kidney disorders - persistent protein or cellular casts in the urine
- Neurologic disorders - seizures and psychosis
- Constitutional symptoms
- Fever
- Fatigue
- Weight loss
- Lab findings
- Hemolytic anemia - red blood cell lysis
- Leukopenia - low white blood cell count
- Thrombocytopenia - low platelet count
- Other related syndromes
- Raynaud's syndrome - vasoconstriction in hands when exposed to cold (occurs in about 20% of SLE patients)
- Sicca syndrome - causes dry eyes and mouth (occurs in 10 - 20% of SLE patients) [2,4,5,21,31]
- DIAGNOSIS
- Antinuclear antibodies (ANA)
- ANAs are antibodies directed at various cellular components. The term, "antinuclear," is outdated because ANAs have come to encompass antibodies directed at cellular components that reside both inside and outside the cellular nucleus. ANAs are present in several autoimmune diseases including systemic lupus erythematosus (SLE) and inflammatory myopathies.
- ANA testing is commonly used as a screening tool for SLE because ANAs are present in > 96% of patients with SLE. ANAs are also quite prevalent in healthy individuals without symptoms of SLE. A NHANES study from 2011 - 2012 found that the prevalence of ANAs (at a dilution ≥ 1:80) in the general population was 15.9% which was up from a prevalence of 11% in 1988 - 1991. The table below gives the prevalence of ANAs among healthy individuals at different titers. [30]
- The dilution of sera (titer) with the ANA test indicates the amount of ANAs that are present. The higher the dilution (for example 1:640 is higher than 1:80), the higher the likelihood that the ANAs are associated with autoimmune disease.
Positive ANA serum dilution | % of healthy individuals with positive ANA at this dilution |
---|---|
1:40 | 32% |
1:80 | 13% |
1:160 | 5% |
- ANA subtypes
- ANAs can be subdivided into subtypes based on the antigen they target
- Most labs now have ANA tests that reflex to antibody subtypes if an ANA test is positive. Labs vary by which subtypes their panels include, but some of the more common ones are presented in the table below.
- Despite the name "antinuclear antibodies," some ANAs are antibodies against cellular components that occur outside the cellular nucleus
ANA subtypes | Prevalence in SLE |
---|---|
Anti double-stranded DNA (anti-dsDNA)
|
70 - 80% |
Antichromatin antibodies
|
50 - 90% |
Antihistone antibodies
|
30 - 60% |
Sjögren's Antibody / Anti-SSA (Anti-Ro)
|
30 - 40% |
Anti-Sm antibodies (Smith antibodies)
|
10 - 30% |
Ribonucleoprotein antibodies (RNP antibodies, anti-u1)
|
15 - 25% |
Sjögren's Antibody / Anti-SSB (Anti-La)
|
10 - 15% |
- Antinuclear antibody (ANA) patterns
- If ANAs are present, a test can be performed where the ANAs are combined with cells. The ANAs will attach to antigens in the cells that they have been formed against. Immunofluorescence techniques are then used to illuminate the attached antibodies. Depending on the type of ANAs present, different patterns may be observed that are associated with specific autoimmune diseases.
ANA pattern | Associated condition |
---|---|
Nuclear patterns | |
Homogenous | SLE, drug induced SLE/vasculitis, JIA |
Coarse speckled | MCTD, SLE, Raynaud, SSc, SS, UCTD |
Fine speckled | SLE, SS, SSc, IM, MCTD |
Centromere | SSc (limited), Raynaud’s |
Nucleolar | SSc, Raynaud’s, IM, overlap |
Cytoplasmic patterns | |
Diffuse | SLE, IM |
Fine speckled | IM, DM, PBC, interstitial lung disease |
Other autoantibodies seen in SLE | Prevalence in SLE |
---|---|
N-methyl-D-aspartate receptor antibodies (NMDA receptor antibodies)
|
33 - 50% |
C1q complement antibodies
|
40 - 50% |
Antiphospholipid antibodies (anticardiolipin, anti-Beta 2 glycoprotein I)
|
20 - 30% |
- Complement C3 and C4 levels
- The complement system is a group of about 20 circulating proteins. When complement proteins are activated, they aid in the destruction of foreign pathogens. Two complement proteins, C3 and C4, are activated by antigen-antibody complexes, and during high inflammatory states, they are rapidly consumed. Decreased levels of C3 and/or C4 are a sign of increased lupus disease activity, particularly lupus nephritis. [7]
- Diagnostic criteria
- No formal diagnostic criteria have been published for SLE. Instead, the ACR and EULAR have published what they call "classification criteria." Classification criteria are defined as standardized criteria intended to help form uniform patient cohorts for research purposes.
- While the diagnosis of SLE still remains somewhat subjective, the classification criteria provide a basis for forming a diagnosis
- Classification criteria that were published by the ACR in 1997 are presented in the first table below. Classification criteria that were developed in a joint effort by EULAR and the ACR in 2019 are presented in the second table.
ACR 1997 SLE Classification Criteria |
---|
To establish a classification of SLE, any 4 of the following must be present:
|
ACR / EULAR 2019 SLE Classification Criteria | |
---|---|
Entry criteria
|
|
Clinical domains and criteria | Weight |
Constitutional | |
|
2 |
Cutaneous | |
|
2 |
|
2 |
|
4 |
|
6 |
Arthritis | |
|
6 |
Neurological | |
|
2 |
|
3 |
|
5 |
Serositis | |
|
5 |
|
6 |
Hematological | |
|
3 |
|
4 |
|
4 |
Renal | |
|
4 |
|
8 |
|
10 |
Immunological domains and criteria | Weight |
Antiphospholipid antibodies | |
|
2 |
Complement proteins | |
|
3 |
|
4 |
Highly specific antibodies | |
|
6 |
|
6 |
Features of Different Arthritis Syndromes | |||||||
---|---|---|---|---|---|---|---|
Finding | Psoriatic arthritis | Rheumatoid arthritis | Lupus | Gout | Ankylosing spondylitis | Reactive arthritis | IBD-associated arthritis |
Age of onset Male:Female |
30 - 40s 1:1 |
35 - 50s 1:3 |
20 - 30s 1:9 |
30 - 60s 3:1 |
17 - 30s 3:1 |
20 - 30s 5:1 |
30s 2:1 |
Distal joints |
Fingers and toes including DIP Asymmetric ≤ 4 joints |
Fingers and toes, spares DIP Symmetric > 4 joints |
Hands, wrists, knees Symmetric > 4 joints |
Great toe, foot, ankle, knees, elbow Asymmetric < 4 joints |
Lower limbs (30 - 50%) Asymmetric < 4 joints |
Knees, ankles, hips Asymmetric < 4 joints |
Hands and knees Asymmetric |
Spine disease | Axial joints - 50% Sacroiliitis - 40% |
Uncommon | Uncommon | Absent | 100% | Sacroiliitis - 50% Back pain - 50% |
30% |
Enthesitis | 30 - 50%, Plantar fascia and Achilles's tendon | Absent | Absent | Absent | Common | Common, Achilles tendon and plantar fascia | Uncommon |
Dactylitis | 40 - 50% | Absent | Absent | Uncommon | Uncommon | Common | Absent |
HLA-B27 positive | 40 - 50% | Not associated | Not associated | Not associated | 90 - 95% | 75% | 30% |
Eye disease | Uveitis - 8% | Dry eyes - 20% | Dry eyes - 15% | Absent | Uveitis - up to 30% | Conjunctivitis (common) Anterior uveitis - 25% |
Uveitis - up to 7% |
Other features | Psoriasis - 100% Nail disease - 85% |
Positive RF and Anti-CCP | Positive ANA Joint disease is non-erosive |
Elevated uric acid | Primarily affects the spine and pelvis | ✝Preceding infection Urethritis (common) Self-limited - 80% |
Occurs in 10 - 20% of patients with IBD |
- MANAGEMENT
Systemic lupus erythematosus drugs | |
---|---|
Biologicals
|
Immunosuppressants
|
SLE treatment recommendations |
---|
General recommendations in patients without major organ involvement
|
Lupus Nephritis (LN)
|
Skin disease
|
Neuropsychiatric lupus
|
Other related conditions
|
- DISEASE ACTIVITY INDICES
- A handful of indices have been developed to quantify lupus disease activity
- The indices are often used in trials to measure outcomes. A link to an online calculator for the SLEDAI-2K index is provided below.
- Other indices include The British Isles Lupus Assessment Group (BILAG), European Consensus Lupus Activity Measure (ECLAM), and the Physician Global Assessment (PGA) index
- STUDIES
PubMed abstract]
[- A trial published in the Lancet enrolled 867 patients with active SLE
Main inclusion criteria
- ACR criteria for SLE
- Active disease defined as score ≥ 6 on SELENA-SLEDAI
- ANA (titre ≥ 1:80) or anti-dsDNA antibody (≥ 30 IU/mL)
- Stable treatment regimen defined as prednisone (0–40 mg/day), NSAID, antimalarial, or immunosuppressive drugs for at least 30 days before the first study dose
Main exclusion criteria
- Severe active lupus nephritis
- CNS lupus
- IV cyclophosphamide within 6 months of enrollment
- IVIG or prednisone (> 100 mg/day) within 3 months
Baseline characteristics
- Average age - 36 years
- Female sex - 95%
- Average duration of disease - 5.5 years
- Average SELENA-SLEDAI score - 9.8
- Receiving prednisone - 96%
- Average prednisone dose - 12.5 mg
Randomized treatment groups
- Group 1 (288 patients) Belimumab 1 mg/kg by IV infusion on Day 1, 14, 28, and then every 28 days
- Group 2 (290 patients) Belimumab 10 mg/kg by IV infusion on Day 1, 14, 28, and then every 28 days
- Group 3 (287 patients) Placebo infusion on Day 1, 14, 28, and then every 28 days
- Study drug was added to patient's current regimen
- Changes to standard of care were restricted after 16 weeks of treatment for immunosuppressive drugs and after 24 weeks for antimalarial drugs
- Prednisone dose was not restricted in the first 24 weeks, but required return to within 25% or 5 mg greater than the baseline dose, with no further increases for the remainder of the study
Primary outcome: Response rate at 52 weeks. Response was defined as having all of the following: reduction of at least 4 points
in the SELENA-SLEDAI score (scale 0 [no disease] to 105 [worst disease]); no new BILAG A organ domain score; no more than 1 new BILAG B organ domain score; and no worsening in Physician
Global Assessment (PGA) score
Results
Duration: 52 weeks | ||||
Outcome | Bel 1mg | Bel 10mg | Placebo | Comparisons |
---|---|---|---|---|
Primary outcome (response rate) | 51% | 58% | 44% | 1 vs 3 p=0.012 | 2 vs 3 p=0.0006 |
Time to first disease flare (median days) | 126 | 119 | 84 | 1 vs 3 p=0.002 | 2 vs 3 p=0.003 |
Prednisone dose reduced by ≥ 50% at 52 weeks | 23% | 28% | 18% | 1 vs 3 p=0.16 | 2 vs 3 p=0.012 |
Median decrease in anti-dsDNA levels | 35% | 38% | 12% | 1 or 2 vs 3 p<0.000 |
|
Findings: Belimumab has the potential to be the first targeted biological treatment that is approved specifically for systemic lupus erythematosus, providing a new option for the management of this important prototypic autoimmune disease
- STUDY
- Design: Randomized placebo-controlled trial (N=448 | length = 104 weeks) in adults with biopsy-proven, active lupus nephritis
- Treatment: Belimumab 10 mg/kg every 4 weeks vs Placebo added to standard therapy (cyclophosphamide or mycophenolate)
- Primary outcome: A ratio of urinary protein to creatinine of ≤ 0.7, an GFR that was no worse than 20% below the pre-flare value or at least 60 ml/min, and no use of rescue therapy for treatment failure at week 104
- Results:
- Primary outcome: Belimumab - 43%, Placebo - 32% (p=0.03)
- Findings: In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone.
- The TULIP-2 trial enrolled 362 adults with moderately to severely active SLE.
Main inclusion criteria
- Moderate-to-severe SLE
- Positive ANA, anti-dsDNA, or anti-Smith
- Stable treatment with ≥ 1 of the following: steroid, antimalarial agent, azathioprine, mizoribine, mycophenolate, methotrexate
Main exclusion criteria
- Active severe lupus nephritis
- Neuropsychiatric SLE
- Serum creatinine > 2 mg/dl
Baseline characteristics
- Average age 42 years
- Female - 93%
- BILAG-2004: ≥1 A item - 49%
- BILAG-2004: No A item and ≥2 B items - 47%
- Baseline therapy: Steroids - 80% | Antimalarial - 69% | Immunosuppressant - 48%
Randomized treatment groups
- Group 1 (180 patients): Anifrolumab 300 mg by IV infusion every 4 weeks for 48 weeks
- Group 2 (182 patients): Placebo
- Other treatments were stable throughout the trial except for glucocorticoids. For patients receiving oral prednisone or equivalent at ≥ 10 mg/day, an attempt at tapering to ≤ 7.5 mg/day was required between weeks 8 and 40. Glucocorticoid doses were required to be stable for the last 12 weeks of the trial.
Primary outcome: difference between the two groups in the percentage
of patients who had a BICLA response at week 52, defined as all of the following: a reduction of all severe (BILAG-2004 A) or moderately severe (BILAG-2004 B) disease activity at baseline to lower levels (BILAG-2004 B, C, or D and C or D,
respectively) and no worsening in other organ systems (with worsening defined as ≥ 1 new BILAG-2004 A item or ≥ 2 new BILAG-2004 B items); no worsening in disease activity, as determined by the SLEDAI-2K score (no increase from baseline) and by the PGA score (no increase of ≥ 0.3 points from baseline); no discontinuation of the trial intervention; and no use of restricted
medications beyond protocol-allowed thresholds.
Results
Duration: 52 weeks | |||
Outcome | Anifrolumab | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 47.8% | 31.5% | p=0.001 |
Steroid reduction | 51.5% | 30.2% | p=0.01 |
≥ 50% reduction in swollen/tender joints | 42.2% | 37.5% | p=0.55 |
Annual flare rate | 0.43 | 0.64 | p=0.08 |
SRI(4) response | 55.5% | 37.3% | p<0.001 |
Upper respiratory infection | 21.7% | 9.9% | N/A |
Herpes zoster | 7.2% | 1.1% | N/A |
|
Findings: Monthly administration of anifrolumab resulted in a higher percentage of patients with a
response (as defined by a composite end point) at week 52 than did placebo, in contrast
to the findings of a similar phase 3 trial involving patients with SLE that had a different
primary end point. The frequency of herpes zoster was higher with anifrolumab than with
placebo.
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