5.

SYSTEMIC LUPUS ERYTHEMATOSUS

DEFINITION

Systemic lupus erythematosus is a multisystemic disease of unknown etiology

with protean clinical and laboratory manifestations and a variable course and
prognostic.

EPIDEMIOLOGY

Incidence of lupus is variable depending on:

• Studied population
Age
Genre - women are more affected than men.
Race - The afro-american race is three times more affected than the Caucasian
race.
Ethnic affiliation
Duration of the study
• EC: 3.3-4.8
• USA: 1.8-7.6
The onset of the disease is between 15-40 years old (fertile period).
The F: M ratio is 9:1.
Prevalence of the disease is characterized by:
➢ Variability
➢ Type of report
➢ Social-economical factors
• EC: 12.5-28
• USA: 14.6-50

PATHOGENESIS

1.Apoptosis (inefficient apoptosis)

Autoantigens are released by necrotic as well as apoptotic cells. Defects in the
clearance of apoptotic cells may lead to aberrant uptake by macrophages which
then present the previously intracellular antigens to T and B cells thus driving
the autoimmune process.
2.Cytokine model
Signature of IFN - the over-expression of the type I interferon pathway in
patients with lupus.
Genetic risk factor: Haplotype 5 (IRF5) of IFN
3. Genetic factors - genetic susceptibility to lupus is inherited. An interval on the
long arm of chromosome - cr. 1 – 1q23-24, is linked to lupus.
A single nucleotide polymorphism (SNP) within the programmed cell death 1
gene (PDCD1) is associated with the development of lupus in both European and
Mexican populations.
4. Environmental factors
Sunlight exposure – the most common trigger.
Exposure to mercury, mixing pesticides.
EBV – Epstein Barr virus (90%)
• ↑ cells
• ↑ viral load
5. Hormones
Exogenous estrogens involvement in SLE:
• Risk 1.9 x ↑
• Onset of flares
Contraceptive pills and anticardiolipin antibodies are associated with risk of
thrombosis. The risk is present even if the anticardiolipin antibodies are missing,
in a lupus patient.

CLINICAL MANIFESTATIONS

1. General manifestations – the “B” symptoms

• malaise
• fatigue – active lupus
• fever
 • weight loss
2. Skin manifestations
• lupus- specific lesions
• acute
• days to weeks – photosensitivity
• pruritic or painful
• commonly accompanied by other inflammatory manifestations
➢ malar “butterfly rash” – non transient
➢ generalized erythema
➢ bullous lupus erythematosous – neck, axilla, inguinal
• subacute
• non-fixed, non-scarring, exacerbating, remitting
• occur in sun-exposed area
• may be generalized
➢ annular – polycyclic
➢ psoriasiform – papulosquamous
• chronic lupus
• starts as erythematous papules or plaque with scaling becoming
thick and adherent with a hypopigmented central area
➢ localized discoid – absence of systemic manifestations
➢ generalized discoid associated with systemic features
➢ lupus profundus – panniculitis plus skin lession
• lupus – non-specific lesions
• vasculitis
• livedo reticularis
• oral lesions
• panniculitis – deep, firm nodule
• urticarial lesions – mucous membrane lesions – mouth, vagina,
nasal septal erosions (vasculitis), often chronic
• non-scarring alopecia –common in lupus, may be induced by drugs
such as cytotoxic drugs or corticosteroids
3. Arthritis/arthralgia – the most common presenting manifestations of
SLE
• any joint may be affected
• typically – small joints of the hand, wrists and knees
• asymmetric
• typically not erosive
• mild synovial thikening
• tenosynovitis – early manifestation
• subluxations initially reversible (hands)
• late lupus – hook-like erosions similar with the erosions described
in post-rheumatic fever Jaccoud’s syndrome
• 2 complications: septic arthritis and osteonecrosis (later stages of
lupus)
4. Myositis
• secondary to joint inflammation
• secondary to drugs – corticosteroids, antimalars
• muscle atrophy + mononuclear cell infiltrate
5. Renal disease
• renal failure
• advanced nephrotic syndrome
• always ask for urine analysis and serum creatinine
• renal biopsy – diagnosis and treatment regimens – lupus nephritis
• Lupus nephritis classification:
• First class
• Normal
• Second class
• Mesangial nephritis
• Third class
• Focal proliferative glomerulonephritis
• Forth class
• Diffuse proliferative glomerulonephritis
• Fifth class
 • Membraneous nephropathy
• Sixth class
• Advanced sclerosing glomerulonephritis
6. Neuropsychiatric manifestations
• Neurologic manifestation
• stroke syndrome
• seizures – grand mal, petit mal, focal, temporal lobe
• headache
• transverse myelitis
• cranial neuropathy
• peripheral neuropathy
• movement disorder
• Psychiatric manifestations
• psychosis
• organic brain syndrome
• psychoneurosis
• neurocognitive dysfunction
7. Serositis
• pleuritis – usually small, occasionally massive
• frequently bilateral
• often seen in aged patients or drug induced lupus
• infections must be ruled out
• fluid is an exudate with glucose concentrate normal (pay attention
in RA the levels of glucose are low)
• the wight blood cells are moderately increased:
• acute settings – neutrophils
• chronic settings – lymphocytes
• pericarditis – most common presentation of heart involvement
• pericardial rub plus chest pain – often absent
• cardiac tamponade is rare
 • pericardial fluid pattern: leukocytosis with a high percentage of
neutrophils, complement activity may be present, increased ANA
concentrations, positive LE cells
• large p[ericardial effusions if associated with uremia
8. Pulmonary involvement
• pleuritis
• pneumonitis – acute or chronic
• Acute pneumonitis – fever, dyspnea, cough, occasionally
hemoptysis. The pulmonary infiltrates are associated with other
lupus manifestations.
• Chronic pneumonitis presents as a diffuse interstitial lung disease,
characterized by dyspnea on exertion, non-productive cough and
basilar rales.
• pulmonary hemorrhage – presents with cough and hemoptysis.
It is secondary to pulmonary vasculitis.
• pulmonary embolism
• pulmonary hypertension – dyspnea
• normal chest radiograph
• patients are mildly hypoxic and have a restrictive pattern on
pulmonary function test
• carbon dioxide diffusion capacity is reduce
• Raynaud’s phenomenon is frequently present
• shrinking lung syndrome – unexplained dyspnea, small lung
volumes with restrictive pulmonary function studies and an
elevated diapragm. Responds to acute treatment with
corticosteroids.
9. Cardiac involvement
• myocarditis - suspected if arrhythmias or conduction defects
present with unexplained cardiomegaly with or without
congestive heart failure or an unexplained tachycardia
• endocarditis – non-bacterial vegetations can be found up to 60%
of patients with lupus. Vegetations may vary for small to large.
 Acute and subacute endocarditis may occur so prophylactic
antibiotics for surgical procedures are advisible.
• coronary heart disease – manifestation of atherosclerosis
(generalized).
10. Gastrointestinal involvement
• diffuse abdominal pain
• anorexia
• nausea
• vomiting
• pseudo-obstruction presentation – diffuse peritonitis, bowel
vasculitis, pancreatitis or inflammatory bowel disease
• ascites may become chronic – painless, associated with other lupus
symptoms
• other manifestations: esophageal disease, liver disease (active
hepatitis, hepatomegaly)
11. Reticuloendothelial system involvement
• lymphadenopathy – non-specific feature of lupus, is common. The
nodes are: soft, non-tender and vary in size. The nodes
demonstrated reactive hyperplasia.
• spleen – “onion skin lesions” – periarterial fibrosis –
pathognomonic for lupus. Hypotheses: the hypersaturation of
reticuloendothelial system leads to prolonged circulations of
immune complexes and their tissue deposition. It was found in
lupus patients – spleen atrophy or splenic lymphoma.

The clinical course of the SLE can be divided in five patterns:

1. classic lupus
• at least 4 ACR criteria present
2. drug induced lupus
• no previous history of lupus
• develops after drug exposure
• Drug’s lupus inducers:
 ➢ positive drug’s association: chlorpromazine, methyldopa,
hydralazine, procainamide, isoniazid
➢ possibly drug’s association: dilasntin, penicillamine, minocycline,
quinidine
➢ questionable drug’s association: gold salts, grisofulvin, infliximab,
certain antibiotics
3. late stage lupus
• more than 5 years duration
• prognostic is due to its long term complications, not really the
disease flares
• chronic morbidity: end-stage renal disease, dialysis,
transplantation, osteonecrosis, atherosclerosis, venous syndromes,
pulmonary emboli, neuropsychiatric dysfunction, shrinking lung
syndrome
4. latent lupus
• constellation of clinical manifestations suggestive for SLE
• less than 4 ACR criteria presents
• not a classical pattern for lupus
5. anti-phospolipid syndrome

Predictors of renal disease:

• ethnicity
• histopathological findings:
➢ tubular atrophy
➢ diffuse proliferative glomerulonephritis
• duration of glomerulonephritis signs for more than 6 months before
biopsy
• serum creatinine greater than 140mol/L

LABORATORY FINDINGS

• Hematologic abnormalities
• Cytopenia is pathognomonic in lupus.
• anemia – different etiologies: secondary to chronic inflammatory disease,
renal insufficiency, blood loss, drugs. The most significant is the
autoimmune hemolytic anemia caused by the autoantibodies directed
against RBC antigens, detected by Coombs’ test. Sometimes the test is
negative. EVANS SYNDROME – hemolitic anemia + thrombocytopenia.
• leucopenia
• lymphopenia
• thrombocytopenia
• Serological manifestations
• Ds DNA atb. are associated with:
➢ ↑nefropathy
➢ ↑hemolitic anemia
➢ ↑fever
➢ ↓thrombosis
➢ ↓sicca sdr.
• anti-SM atb.
• anti-SSa, anti-Ro: neonatal lupus, photosensitivity, Sjogren’s syndrome
• anti-SSb, anti-La: neonatal lupus, Sjogren’s syndrome
• anti-RNP: overlap syndrome
• anti-histone antibodies – druged induced lupus
• RF
• aPL IgG, IgM (Cardiolipin/β 2 –GPI) - miscarriage/clots
• LA
• .Complement deficiency – CH50, C3 and C4. Be attentive because the
complement components are not stable at room temperature so due to
improper sample handling low CH50 titers may be found with normal C3
or C4.
• usually in early manifestations of an active lupus disease the C1, C4, C2
and C3 are involved.
• Other findings:
• prolonged partial prothrombine time
• positive Coomb’s test
 • a false-positive Venereal Disease Research Laboratories (VDRL) test for
syphilis
• elevated erythrocyte sedimentation rate
• CRP – usually negative; elevated in infections or in patients with
predisposition to coronary artery disease

IMAGISTIC FINDINGS

There are non specific imagistic findings in SLE.

CLASSIFICATION CRITERIA

New Classification Criteria – SLICC (Systemic Lupus International

Collaborating Clinics group) 2012
Clinical
1.Acute cutaneous
2.Chronic cutaneous
3.Oral ulcers
4.Alopecia
5.Synovitis
6.Serositis
7.Renal involvement
8.Neuralgia
9.Haemolytic anaemia
10.Leukopenia/lymphopenia
11.Thrombocytopenia
Immunological
1.ANA
2.Anti ds-DNA
3.Anti Sm
4.APA
5.Low complement
6.Direct Coombs’ test
LUPUS – at least one clinical and immunologic criteria or biopsy proven lupus
nephritis + anti ds-DNA or ANA

ACR revised Lupus Classification Criteria

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 occurs 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
a physician.
5. Arthritis: Non-erosive arthritis involving two or more peripheral joints,
characterised by tenderness, swelling or effusion.
6. Serositis:
a. Pleuritis: convincing history of pleuritic pain or rub heard by a physician or
evidence of pleural effusion or
b. Pericarditis: documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder
a. Persistent proteinuria >0.5 g per day or >3+ if quantitation is not performed or
b. Cellular casts: may be red cell, haemoglobin, granular tubular, or mixed
8. Neurological disorder
a. Seizures: in the absence of off ending drugs or known metabolic derangements
(eg, uraemia,acidosis, or electrolyte imbalance) or
b. Psychosis: in the absence of off ending drugs or known metabolic
derangements (eg, uraemia, acidosis, or electrolyte imbalance)
9. Hematologic disorder
a. Hemolytic anaemia with reticulocytosis, or
b. Leucopenia: <4000/mm3, or
c. Lymphopenia: <1500/mm3, or
d. Thrombocytopenia: <100 000/mm3 in the absence of off ending drugs
10. Immunologic disorder
a. Anti-DNA: antibody to native DNA in abnormal titre, or
b. Anti-Sm: presence of antibody to Sm nuclear antigen, or
c. Positive finding of antiphospholipid antibodies based on:
(1) an abnormal serum concentration of IgG or IgM anticardiolipin 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 immobilisation or fl uorescent
treponemal antibody absorption test.
11. Antinuclear antibody: An abnormal titre of antinuclear antibody 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.

Lupus- at least 4 criteria should be present.

TREATMENT

The treatment in lupus is aiming:

• remission
• maintaining remission
• management of comorbidities
The management of lupus patient is determined by the clinical manifestations,
the experience of the physiscian and also the co-morbidities associated. Usually
we are dealing with an immunosuppresive pattern.
The most used immunosuppressive therapy pattern is:
Arthritis
Methotrexate
Leflunomide
Renal involvement
Cyclophosphamide
Mycophenolite mofetil
Azathioprine
Rituximab
Cutaneous lupus
Hydroxycloroquine
Methotrexate – second line agent
Mycophenolite mofetil – second line agent
Discoid lupus
Thalidomide – less used due its toxicity: neuropathy, teratogenicity, premature
gonodal failure, thrombosis.
CNS involvement
Methotrexate
Azathioprine – vasculitis
Cyclophosphomide

Corticosteroids, alongside with antimalars are the most common treatment in

lupus. They are used for the induction, the maintenance of remission and in
flares. The doses are different according with the protocols, but in the latest
years using the minimal successful dose of corticosteroids have been a target
(due to side effects).
A low dose of corticosteroids is considered less than 10mg/day, a moderate one
0.2-0.5 mg/kg/day and a high dose is represented by 0.5-1 gm/kg/day.

TAKE HOME MESSAGES

• SLE occurs mostly in women during their reproductive years.

• Lupus can complicate a pregnancy, even if the disease itself is not active.

SLE’s flares Preeclampsia/eclampsia

Any time during pregnanacy Not before the 20th week of gestation
Rash Pathologically brisk reflexes
Arthritis Clonus
Serositis Elevated serum levels of hepatic
transaminases
Fever HELLP syndrome – 3rd trimester
Less common increased serum acid Increased serum uric acid level
levels
Active urine sediment Decreased urine calcium
concentrations

• Most of SLE flares are due to noncompliance.

• Immunosuppressive drug regimens in SLE are selected according to the
organ involved. The treatment in lupus is a patterned one.
• Less GC
• Early switch
• Prevention of cardiovascular disease
• Prevention of other comorbidities
• Prolonged maintenance of immunosupression
• Plaquenil “poisoning”
• Unmasking non-compliance to therapy

References:
1. Stone JH, A Clinician’s Pearls and Myths in Rheumatology, Springer 2009,
493: 23-26
2. Bijlisma WJJ, Eular Compendium on Rheumatic Diseases, BMJ Publishing
Group, 2009, 824: 257-279