Lupus Flare: How to Diagnose and Treat

Lata S Bichile, Vaibhav C Chewoolkar

INTRODUCTION

S ystemic lupus erythematosus (SLE) is a chronic, susceptible individuals. On exposure to environmental

relapsing, often febrile multisystem autoimmune disorder
characterized by immune mediated tissue damage. It has
protean manifestations that evolve over years. The clinical
spectrum of SLE is wide and ranges from benign easily
treated disease with rash, arthritis, fatigue, to a very
severe life threatening illness with progressive irreversible
damage. The course of the disease is variable and is
characterized by flares of rampant inflammation that can
threaten, in an unpredictable manner, almost any organ
in the body, including the brain, kidney, and heart. Flare
can be considered as a reappearance of clinical features
which were earlier quiescent. Subtle abnormalities in
haematological, cardiac and central nervous system (CNS)
clinical, lab parameters and imaging occur either isolated
or in combination which help to diagnose flare at an early
stage. Flare involving renal, cardiovascular and CNS requires
prompt diagnosis and management.
stimulus in the form of ultraviolet light, dietary factors,
infections and to certain drugs,demethylation of DNA occurs
rendering it antigenic. Patients with SLE have poor clearance
mechanisms for the cellular debris and these induce the
immune system. Immune complexes form intravascularly and
are deposited in the glomeruli. Alternatively, auto antibodies
may bind to antigens already located in the glomerular
basement membrane, forming immune complexes in situ.
Immune complexes promote an inflammatory response by
activating complement and attracting inflammatory cells,
including lymphocytes, macrophages, and neutrophils.
SLE flares
For the understanding of SLE flares, it is pertinent to
Table I: Clinical features of SLE (Our own
database-251 patients seen over 3 years)

There are certain easily identifiable and avoidable triggers

for lupus flare. These include:
1. Exposure to sunlight
2. Physical and mental stress
3. Intercurrent infections
4. Pregnancy
5. Non compliance with treatment or sudden withdrawal
of drugs.

PATHOGENESIS
SLE is characterized by abnormal immune response due
to persistence of pathogenic B and T cells in genetically
282 Medicine Update-2011
know the clinical features of SLE (Table I). During flare,
organ system may be involved singly or in combination.
The onset may be acute or insidious. The symptoms may
be non-specific constitutional or specific for the organ
system involved.Arthalgia, fever and rash are the common
presenting features.
Immunological profile in lupus flares
Disease activity can be evaluated with anti-dsDNA,
complement determinations (C3, C4, and CH 50), and
erythrocyte sedimentation rate (ESR) .Generally, an
elevated ESR and anti-dsDNA and low C3, C4 levels are
associated with active disease, especially lupus nephritis.
Table II: SLE disease activity index (SLEDAI) score
Clinically relevant lupus nephritis is associated with a 30%
decrease in creatinine clearance, proteinuria of greater than
1000 mg/d, and renal biopsy findings indicating active lupus
nephritis. Anti-nucleosome antibodies appear early in the
course of the autoimmune response in SLE. They have high
sensitivity and specificity for the diagnosis of SLE, and the
titers correlate with disease activity. Anti-C1q antibodies
are associated with lupus nephritis; higher titers correlate
with active renal disease.
Systemic Lupus Erythematosus Disease Activity Index1
(SLEDAI-Table II) scores correlate with the clinician’s
impression of level of disease activity.

 An increase in SLEDAI > 3 indicates flare.
How to sense lupus flare from symptoms
The following are the clinical features which are can be
considered as a warning of impending flare:
 Increasing fatigue
 Arthralgias and myalgias
 New or worsening rash
 Persistent headache
 Fever
 Abdominal pain.
Renal flare
Patients with active lupus nephritis often have other
symptoms of active SLE, including fatigue, fever, rash,
arthritis, serositis, or CNS disease. These are more common
with focal proliferative and diffuse proliferative lupus
nephritis. Nephritis is characterized by peripheral edema
secondary to hypertension or hypoalbuminemia. Extreme
peripheral edema is common with diffuse proliferative
or membranous lupus nephritis. Headache, dizziness,
visual disturbances, and signs of cardiac decompensation
are commonly related to hypertension. During flare, the
WHO histopathological class changes to a higher level
with additional features of activity or chronicity.Basic
hematological profile reveals anaemia, raised ESR and
thrombocytosis.Urine examination will show proteinuria,
leucocyturia, haematuria and casts. Complement levels fall
and dsDNA leves rise.
Renal biopsy
 Renal biopsy should be considered for any patient with
SLE who has clinical or laboratory evidence of active
nephritis (active urinary sediments, RBCs, albuminuria
with 24 hr urinary protein >500mg) especially with the
first episode of nephritis.
 Renal biopsy may be useful in patients with recurrent
episodes of nephritis, by revealing the histological
pattern and stage of disease (activity and chronicity).
Renal biopsy is useful in determining prognosis and
planning treatment.
The characteristic patients who experience renal flare are:
1. Those who took longer time to remit.
2. Treatment period for remission> 31 months and
maintenance phase of 2 years or more.
3. Median time of first remission >10 months.
Bad renal prognostic markers in renal flare:
1. Onset of hypertension.
Medicine Update-2011 283
2. Low serum albumin.
3. Chronicity index more than 3.
4. Tubular atrophy.
5. Interstitial fibrosis.
Cutaneous flare
In cutaneous flare, the photosensitive rash over face, nose,
auricular area reappears or becomes more severe.UV light
exposure results in an abnormally prolonged erythema of
the skin. This can even be after several weeks of exposure.
In a photo provocation study, UV A triggered lesions in 33%
of patients and UV B in 14-51% patients.
Oral ulcers in flares
These are attributed to necrotizing vasculitis and predict
severe systemic disease flare .Oral lesions occur in 20-25%
of patients with cutaneous lesions in SLE flare.
Hematological flare
Acute immune hemolytic anaemia with a sharp fall in
hemoglobin (>3gm), spherocytes on peripheral smear, raised
bilirubin and reticulocyte count and a positive Coomb’s test
confirm hemolytic process. Leucopenia and lymphopenia
correlate with disease flare.Thrombocytopenia may be
due to antiplatelet or antiphospholipid antibodies(APLA).
Pancytopenia may be due to drugs, infections or
hemophagocytosis.During isolated hematological flare,
complement levels do not decrease and dsDNA titers are
high.
Cardiovascular system flare
Cardiac manifestations are chest pain due to pericarditis
or coronary angitis. Myocarditis presents with unexplained
tachycardia, arrhythmias and cardiomegaly with or without
cardiac failure. Doppler echocardiography may demonstrate
diastolic dysfunction or pericardial effusion.Libman
Sach’s endocarditis, though rare, may be associated with
antiphospholipid syndrome. Coronary vasculitis is associated
with active disease and lupus flare.
Central Nervous System (CNS) flare
Headache: Prevalence is 24-72%. Headache occurs with
other features of active SLE.2
Psychosis, mood disorder and anxiety3: Psychosis is
reported in 8 % and is characterized by delusions or
hallucinations. Lupus psychosis should be distinguished from
steroid induced psychosis.
Seizures: General / focal seizures occur in 6-51% patients
and are due to generalized disease or focal neurologic
284 Medicine Update-2011
events.
Demyelination, transverse myelopathy, chorea: These
are rare manifestations. Incidence is 1-3%. Transverse
myelopathy and chorea present as acute manifestations and
have strong association with APLA. Transverse myeopathy
is almost always secondary to vascular occlusion. Sensory
motor neuropathy has incidence upto 28%.
DIAGNOSTIC IMAGING FOR C.N.S. FLARE
C.T. - Only for acute cerebral hemorrhage.
MRI - T2 weighted images identify edema. Fixed lesions in
paraventricular and sub cortical white matter within the
territory of major cerebral blood vessel may be found.
Diffuse sub cortical white matter lesions and patchy hyper
intensities in gray matter may be found. Other lesions may
be venous thrombosis and increase signals in spinal cord.
MR Spectroscopy - Allows identification and quantification of
brain metabolites. It gives an indirect assessment of cellular
changes. Neurocognitive dysfunction is associated with
reduced N-acetyl levels. Brain lactate levels are increased
indicating ischemic inflammation. Choline compounds are
increased reflecting damaged cell membranes and myelin
destruction.
Biologic markers in CSF
Pleocytosis.
Elevated proteins.
Elevated neurofilament triplet protein- 74% sensitive, 65%
specific.
CSF- Gilal fibrillary acidic protein (GFAP) - 48% sensitive, 87%
specific.GFAP levels are associated with MRI abnormalities
and decreased following therapy with cyclophosphamide.
Every SLE patient may have subclinical CNS involvement
which can flare to any bizarre clinical picture. A clinical
suspicion and appropriate imaging (PET scan, angiography,
MRI) should be instituted early.
Myositis
During lupus exacerbations, myositis with muscle tenderness
and proximal muscle weakness is common. It occurs in
~10% patients. Raised CPK, aldolase and EMG do not help
to differentiate other inflammatory myopathies from lupus
myositis. At times, normal enzymes may be found. A muscle
biopsy is required in such cases.
Effect of pregnancy on SLE flares
The types of flares can be as follows:
 Cutaneous
 Hematological (thrombocytopenia)
 Pericarditis
 Arthritis
 Renal
 Vasculitis
Frequency of flares in pregnancy4
1st trimester-13.3%
2nd trimester-40%
3rd trimester-13.3%
Post partum-33.3%
Pregnancy in patients with SLE should not be regarded as an
unacceptable high risk condition provided that conception is
accurately planned and patients are managed with a careful
multidisciplinary treatment schedule. Flares usually occur
during the last half of pregnancy and within the first few
weeks after delivery .The patients should hence be carefully
monitored during this period (Table III). The presence of
APLA increases the risk for miscarriages.5 Lupus antibodies
can be transferred from the mother to the fetus and result in
neonatal lupus. Problems can also develop in the conducting
system of the heart (congenital heart block). Women
pregnant and known to have the antibodies for anti-Ro (SSA)
or anti-La (SSB) should have frequent echocardiograms to
monitor fetal heart and surrounding vasculature.
Monitoring SLE flare
1. Watch for clinical signs and symptoms
2. Hematological tests
3. Biochemical tests
4. Immunological tests (Table IV)
5. Specific organ system monitoring
6. Imaging
TREATMENT OF S.L.E. FLARE
Arthritis and cutaneous flare
Acute severe joint pain should initially be treated with short
course NSAIDs.Animalarials are particularly useful for arthritis
and cutaneous manifestations of SLE. These agents have
multiple properties: immunosuppressive, anti-inflammatory
and sun-blocking. They are also reported to possess anti-
platelet and cholesterol lowering effects. The drug of
choice is hydroxychloroquine (200 mg BD for 3 months and
then 200 mg daily). The maintenance dose must not exceed
6 mg/kg/day. Although the incidence of retinal toxicity is
very low, annual monitoring of vision is recommended (for
chloroquine, 6-monthly monitoring is desirable). Topical
sunscreens with SPF of atleast >15 should be applied on
exposed parts. In non-responders, low dose corticosteroids

Table III: Laboratory monitoring in pregnancy and antiphospholipid syndrome with lupus flare
Table IV: Immunological tests in SLE flare
or methotrexate or leflunomide should be added.
Renal flare
Reduction of proteinuria with angiotensin converting
enzyme (ACE) inhibitors delays and prevents renal sclerosis.
A combination of ACE inhibitors and angiotensin receptor
blockers reduce proteinuria by ~50%.Spironolactone also
helps to reduce proteinuria.Eplerenone can be used in men
because of its low risk of causing gynaecomastia.
Mycophenolate mofetil is the preferred medication for
induction in active nephritis because of its therapeutic
equivalence with Cyclophosphamide (CYC) and lower
rates of adverse events.6 The standard regimen of CYC
or mycophenolate with corticosteroids still remains the
best option to preserve renal function in patients with
proliferative lupus nephritis.7 Solid evidence shows that
this drug combination administered either traditionally
(corticosteroid and monthly pulse CYC) or in modified
regimen (smaller doses of CYC given at weekly or
fortnightly intervals over a short treatment duration) can
Medicine Update-2011 285
induce a complete or partial remission in more than 80%
of patients with proliferative lupus nephritis.Azathioprine
or mycophenolate with low dose steroids can be used
for maintenance. Rituximab, a B-lymphocyte- depleting
therapy, appears to be effective in SLE and is being used for
SLE and lupus nephritis.8 Statins are indicated in patients
with nephrotic syndrome and patients who have developed
steroid induced hyperlipidemia. Besides lipid lowering,
they have anti inflammatory properties. They are useful in
reducing the incidence of inflammatory and steroid related
atherosclerosis in SLE.
CNS flare
Important step is to determine whether the event can be
convincingly attributed to SLE. Low hemoglobin, high ESR,
low C3, C4 levels, rising titers of dsDNA indicate a flare.
CSF study to rule out infections such as tuberculosis and
India ink preparation for fungi is the next important step.
Methyl prednisolone 1 gm IV daily for 3 days followed by IV
cyclophosphomide 1 gm on 4th day is a standard protocol
286 Medicine Update-2011
to initiate immuno suppression. Oral corticosteroids 1
mg/kg are recommended as maintenance therapy along
with 1 gm CYC monthly for 6 months and 3 monthly for 8
cycles. Maintenance with azathioprine is recommended
on completion of induction with CYC. Anticoagulation is
indicated strongly for focal disease and such a therapy
will be lifelong. Cognitive assessment and intervention is
beneficial on a long term. Plasmapheresis is indicated in CNS
manifestations secondary to thrombotic thrombocytopenia.
IVIg is reserved in non responders to standard protocol or
terminally ill patients. Anticonvulsants, psychotropics and
anxiolytics are given as per indication.
Myositis and hematological flare
Both acute myositis and immune hemolysis warrant
induction with high dose steroids (1mg/kg prednisone). In
life threatening situations, Methyl prednisolone 1 gm IV
daily for 3 days can be used. IVIg or plasmapheresis are
other alternatives.Maintenence with high dose prednisolone
should be continued for 6 weeks to 3 months to prevent
early relapse. Patients should be simultaneously monitored
for steroid induced myopathy.Azathioprine can be used for
maintenance and as a steroid sparing agent.
CVS flare
Addition of aspirin, ACE inhibitors and statins should be
considered in all patients unless contraindicated to standard
steroid and immunosuppressant drug regime. Anticoagulants
should be used in patients with coronary vasculitis,
antiphospholipid syndrome with a previous thrombotic
event and patients with ischemia or infarction. Diuretics
and inotropes should be given as per indication.
REFERENCES
1. Bombardier C, Gladman DD, Urowitz MB et al. Derivation of the SLEDAI.
A disease activity index for lupus patients. The Committee on prognosis
studies in SLE. Arthritis Rheum 1992; 35: 630-40
2. Amit M, Molad Y, Levy O, Wysenbeek AJ: Headache in systemic lupus
erythematosus and its relation to other disease manifestations. Clin
Exp Rheumatol 1999 Jul-Aug; 17(4): 467-70
3. Khoshbin S, Glanz BI, Schur PH: Neuropsychiatric syndromes in systemic
lupus erythematosus: a new look. Clin Exp Rheumatol 1999 Jul-Aug;
17(4): 395-8
4. Ruiz?Irastorza G, Lima F, Alves J et al. Increased rate of lupus flare
during pregnancy and the puerperium. A prospective study of 78
pregnancies. Br J Rheumatol1996; 35:133-8.
5. Loizou S, Byron MA, Englert HJ, David J, Hughes GR, Walport MJ.
Flare in pregnancy
Therapeutic decisions should be based on organ involvement.
Drugs used to control SLE disease activity are potentially
hazardous. Corticosteroids are administered in gradually
escalating doses. Various authors have found no adverse
effects on fetus at low to moderate steroid doses. Acute
and severe flares can be managed by high dose steroids
for a short period with intensive monitoring of patient and
fetus. Standard dose of Azathioprine(less than 2.5mg/kg/
day) does not increase the risk of congenital anomalies
and can be judiciously used with periodic fetal scans for
malformation.9 Drugs like CYC and methotrexate are highly
teratogenic and are absolutely contraindicated. Aspirin
should be given to antiphospholipid positive patients and in
patients with previous pregnancy loss or thrombotic event.
A previous blood clotting event may benefit by continuation
of heparin throughout and after pregnancy for up to six to
12 weeks, at which time the risk of clotting associated with
pregnancy seems to diminish.
How can a lupus patient prevent disease flares?
Most patients with SLE lead full, active, healthy lives.
Periodic increases in disease activity (flares) can usually
be managed by varying medications. Since ultraviolet light
can precipitate and worsen flares, patients with systemic
lupus should avoid sun exposure. Sunscreens and clothing
covering the extremities can be helpful. Abruptly stopping
medications, especially corticosteroids, can also cause flares
and should be avoided. The key to successful management is
regular follow up allowing monitoring of symptoms, disease
activities and treatment related adverse effects.
Association of quantitative anticardiolipin antibody levels with fetal
loss and time of loss in systemic lupus erythematosus. Q J Med1998;
255:523-31.
6. Cross J, Dwomoa A, Andrews P, Burns A, Gordon C. Main J, et al.
Mycophenolate mofetil for remission induction in severe lupus nephritis.
Nephron clin Pract 2005; 100(3):c92-100.
7. Ginzler EM, Dooley MA, Aranow C: Mycophenolate mofetil or intravenous
cyclophosphamide for lupus nephritis. N Engl J Med 2005 Nov 24;
353(21): 2219-28
8. Anolik JH, Campbell D, Felgar R, et al. B lymphocyte depletion in the
treatment of systemic lupus (SLE): phase i/ii trial of rituximab (Rituxan)
in SLE. Arthritis Rheum 2002; 46(9):S717.
9. Ostensen M.Optimisation of antirheumatic drug treatment in pregnancy.
Clin Pharmacokinet 1994; 27:486-503.