Lupus Flare: How to Diagnose and Treat

Lata S Bichile, Vaibhav C Chewoolkar

INTRODUCTION

S ystemic lupus erythematosus (SLE) is a chronic,

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. 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

susceptible individuals. On exposure to environmental 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)

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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.

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 clinicians impression of level of disease activity.

Table II: SLE disease activity index (SLEDAI) score

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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.

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 Coombs 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 Sachs 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

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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 antiplatelet 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

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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

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

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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.

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.

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