Diagnosis and Management of Systematic Lupus Erythematosus (SLE)


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The Egyptian Journal of Hospital Medicine (Apr. 2017) Vol.67 (2), Page 672-678

Diagnosis and Management of Systematic Lupus Erythematosus
(SLE)
Yousef Taleb Gaafar AL-katheri1, Foad Assad M Bukhari2, Murad Muneer Mawlawi3, AL NIHAB ALI NAJI A4, Reem Ahmed B Alanazi5, Bayan Saeed A Alghamdi1, Ahdab Abdulmuti
Alkubaydi1, Nada Talal Ibrahem Bima1, Rayan Marzooq F Almutairi6, Abdullah Salem Z Alghamdi6, Abdurhman Ahmed ALshikhi1, Maram Mutlaq R Altaiary1, Jnadi Mohammed J
Madkhali7, Shaima Mohammed Al-Ghuraybi8, Abdulkareem khaled almotairi1
1ibn Sina College,2King Abdulaziz University,3 King Fahd General Hospital,4 Anak General
Hospital,5 Almaarefa collage ,6Umm Alqura University ,7Jazan University,8Batterje Medical College

ABSTRACT Background: Systemic lupus erythematosus (SLE) is the prototypic multisystem autoimmune disorder with a wide range of clinical presentations impacting almost all organs and tissues, such extreme heterogeneity suggests that SLE represents a syndrome rather than a single disease. Although the precise etiologic mechanism is unknown, genetic, hormonal, and environmental factors, as well as immune abnormalities, have been detected. Associations between lupus onset and age, sex, geography, and race have also been established. Aim of the work: This review will focus on advances in the diagnosis and management of SLE. Conclusion: The diagnosis of SLE must be based on the proper constellation of clinical findings and laboratory evidence. Management of this disease should be individualized and should include both pharmacological and non-pharmacological modalities for symptom relief and resolution as well as improved quality of life. Keywords: Systematic Lupus Erythematosus, connective tissue disorder SLE, NSAID,

INTRODUCTION Systemic lupus erythematosus (SLE) is a
multisystem autoimmune rheumatic disease with a highly variable course.It is most prevalent in females of childbearing age with a female: male ratio of 9:1 in this population. The prevalence of SLE is also higher in certain ethnicities, reflected in prevalence rates of 40/100 000 persons in Northern European cohorts in comparison with rates of 200/100 000 persons in studies of patients of African-American descent 1.
Patients with SLE may present with various systemic manifestations including diverse abnormalities of the skin, kidney, and haematological, pulmonary, and reproductive and musculoskeletal systems. The general symptoms are not specific. Common manifestations may include arthralgias and arthritis, malar and other skin rashes, pleuritis or pericarditis, renal or CNS involvement, hematologic cytopenias and weight changes are the most common symptoms in new cases or recurrent active SLE flares. Fatigue, the most common constitutional symptom associated with SLE, can be due to active SLE, medications, lifestyle habits, or concomitant fibromyalgia or affective disorders. Fatigue due to active SLE generally occurs in concert with other clinical

and laboratory markers. Fever, another common yet nonspecific symptom of SLE, may also result
from many causes, the most common of which include active SLE, infection, and drug fever2. Careful history taking may help to differentiate these. Weight loss may occur in patients with active SLE. Weight gain may also be due to corticosteroid treatment or active disease such as nephrotic syndrome anasarca 3. These symptoms can mimic other autoimmune diseases, infectious diseases, endocrine abnormalities, chronic fatigue, and fibromyalgia 4. SLE significantly increases the risk of cardiovascular disease as well.
SLE a chronic, recurrent, potentially multisystem inflammatory which can be fatal and difficult to diagnose5. The disease has no single diagnostic marker; instead, it is identified through a combination of clinical and laboratory criteria6. Accurate diagnosis of systemic lupus erythematosus is important because treatment can reduce morbidity7 and mortality,12 particularly from lupus nephritis. This article reviews evidence-based recommendations for the diagnosis of systemic lupus erythematosus by primary care physicians. The 1992 Revised

Received: 22 / 03 /2017 Accepted: 30 / 03 /2017

672 DOI : 10.12816/0037820

Diagnosis and Management of Systematic Lupus Erythematosus

American College of Rheumatology (ACR) Classification Criteria however offers developed to aid trial design, offer a useful aide-mémoire to the rheumatologist of some of the more common features of SLE. Management is complex and involves clinicians across many different specialties, with important variations in practice apparent across and within these specialties. For example, prescription of antimalarial drugs and testing for antiphospholipid antibodies are routine among rheumatologists but not among nonrheumatologists8. Prescribed doses for glucocorticoid regimens also differ across specialties 9. SLE is one of a small number of truly multisystem disorders. The heterogeneous nature of the disease can result in delayed diagnosis and cause considerable difficulty in the design of robust clinical trials. There is no diagnostic test specific for SLE and as such the diagnosis remains a clinical one, relying on a combination of clinical and laboratory features. The 1992 Revised American College of Rheumatology (ACR) Classification Criteria, while developed to aid trial design, offer a useful aide-mémoire to the rheumatologist of some of the more common features of SLE 10.
DIAGNOSIS OF SYSTEMATIC LUPUS ERYTHEMATOSUS (SLE) The diagnosis of SLE is mainly done through:
1- Clinical findings: Close observation of the patients’ signs and symptoms.
The 1997 Update of the 1982 American College of Rheumatology (ACR) Revised Criteria for Classification of Systemic Lupus Erythematosus is a valuable resource in the assessment of patients when SLE is suspected. If a patient displays four or more of the 11 criteria (either simultaneously or at different time points), the diagnosis of SLE can be made with 95% specificity and 85% sensitivity11.
When the Systemic Lupus International Collaborating Clinics (SLICC)12 group revised and validated the ACR SLE classification criteria in 2012, they classified a person as having SLE in the presence of biopsy-proven lupus nephritis with ANA or anti-dsDNA antibodies or if 4 of the diagnostic criteria, including at least 1 clinical and 1 immunologic criterion, have been satisfied.

The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic:
Serositis Oral ulcers Arthritis Photosensitivity Blood disorders Renal involvement Antinuclear antibodies Immunologic phenomena (eg, dsDNA; anti-Smith [Sm] antibodies) Neurologic disorder Malar rash Discoid rash 2- Laboratory testing and evidence which is split into stages:

Stage I: routine laboratory tests, which

probably provide first line diagnostically

useful information

i. Complete blood count and differential may

reveal

leukopenia,

mild

anemia, and/or thrombocytopenia

ii. Elevated serum creatinine may be

suggestive of renal dysfunction

iii. Urinalysis with urine sediment may reveal

hematuria,

pyuria,

proteinuria, and/or cellular casts

Stage II: SLE specific tests 1. ANA testing : positive in virtually all
patients with SLE at some time in the course of their disease . If the ANA is positive, one should test for other specific antibodies such as dsDNA, anti-Sm, Ro/SSA, La/SSB, and U1 ribonucleoprotein (RNP). In some labs, a positive ANA test by indirect immunofluorescence will automatically result in testing for such additional antinuclear antibodies that are often present in patients SLE Anti-dsDNA and anti-Sm antibodies are highly specific for SLE, but anti-Sm antibodies lack sensitivity13. AntidsDNA and anti-Sm antibodies are seen in approximately 70 and 30 percent of patients with SLE, respectively. Figure 1 2. Anti-Ro/SSA and anti-La/SSB antibodies are present in approximately 30 and 20 percent of patients with SLE, respectively; however, both antibodies are more commonly associated with Sjögren’s syndrome 14. 3. Anti-U1 RNP antibodies are observed in approximately 25 percent of patients with SLE, but they also occur in patients with other conditions and high levels are almost

673

Yousef AL-Katheri et al.

always present in patients with mixed connective tissue disease (MCTD) 13,14.
4. Antiribosomal P protein antibodies have a
high specificity for SLE, but have low

sensitivity for SLE. They also lack specificity for involvement of a particular organ system or disease manifestation.

ANA Testing

Titer<1.4
Low probability; alternative
explanation for Organ system manifestations

Titer>1.4
Higher probability; Refer to rheumatologist for full evaluation: 1- ACR diagnostics criteria 2- Lab. Tests: CBC+ Serum creatine+
anti dsDNA+ anti phospholipids+

Explanation found
SLE ruled out

No explanation Refer to the
rheumatologist for further investigation

0 to 3 ACR criteria
Incomplete or

4 to more ACR criteria
SLE confirmed

No SLE

Figure 115: An algorithm for the diagnosis of systemic lupus erythematosus (SLE). (ANA = antinuclear
antibody; ACR = American College of Rheumatology; anti dsDNA = antibody to double-stranded DNA antigen; anti-
Sm = antibody to Sm nuclear antigen). Information source (11, 16, 17).

3- Diagnostic testing tailored to each patient such b.

as :

a. Diagnostic imaging: not routinely obtained unless

indicated by the presence of symptoms, clinical

findings, or laboratory abnormalities. Examples

include:

c.

 Plain radiographs of swollen joints. Unlike

affected joints in RA, erosions are observed infrequently in SLE 18. Depending on the stage of d.

disease, deformities may be present on radiograph.

 Renal ultrasonography to assess kidney size and to e.

rule out urinary tract obstruction when there is

evidence of renal impairment.

 Chest radiography (eg, for suspected pleural

effusion, interstitial lung disease, cardiomegaly).

 Echocardiography (eg, for suspected pericardial

involvement, to assess for a source of emboli, or

noninvasive estimation of pulmonary artery

pressure; and for evaluation of suspected valvular

lesions, such as verrucae).

 Computed tomography (CT) (eg, for abdominal

pain, suspected pancreatitis, interstitial lung

disease).

 Magnetic resonance imaging (MRI) (eg, for focal

neurologic deficits or cognitive dysfunction).

674

Biopsy of an involved organ (eg, skin or kidney) is necessary in some cases. Typical histologic findings in various organs in SLE are discussed in topic reviews devoted to the particular sites of involvement. Electrocardiography in the assessment of chest pain that may be due to pericarditis or to myocardial ischemia. Tests to assess for pulmonary embolism in a patient with pleuritic chest pain and dyspnea Diffusing capacity for carbon monoxide (DLCO) to assess for suspected pulmonary hemorrhage and to estimate the severity of interstitial lung disease.
MANGEMENT OF SYSTEMATIC LUPUS ERYTHEMATOSUS (SLE)
The approach to the treatment of signs and symptoms of lupus depends on the type and the severity of disease. General recommendations for all patients include sun protection, proper diet and nutrition, exercise, smoking cessation, appropriate immunizations, and management of comorbid conditions. A. Pharmacotherapy

Diagnosis and Management of Systematic Lupus Erythematosus

Medications used to treat SLE manifestations

include the following:

1. NSAIDs may be used to alleviate

musculoskeletal pain, swelling, and aches. These

drugs possess pain-reducing, anti-inflammatory,

and anticoagulant properties, which are beneficial

in treating common lupus-associated

manifestations; however, the potential for side

effects (see Table 1) must be considered before

clinicians prescribe NSAIDs for a patient with lupus19,20.

2. Steroids: Corticosteroids mimic naturally

occurring hormones excreted by the adrenal gland

and help regulate blood pressure and immune

function. These agents decrease the swelling and

pain associated with inflammation, which can

occur in a lupus flare. Because of their serious

long-term side effects (see Table 1),

corticosteroids should be used at the lowest

possible dose and only for periods necessary to control an active exacerbation of lupus. 19,20

3. Immunosuppressants :are primarily used in more

severe cases of lupus when high-dose

corticosteroids or antimalarial treatments have

failed to control the signs and symptoms of

disease. They are also used when it is necessary to

induce and maintain remission and to reduce flares

or relapses. Immunosuppressants may be given

with high-dose corticosteroids to control flares, to

achieve a lower dose of each medication, or to

reduce the occurrence of adverse events. The most

commonly used agents in this class are

cyclophosphamide (Cytoxan, Bristol-Myers

Squibb) and azathioprine (Azasan, Salix; Imuran,

GlaxoSmithKline). Mycophenolate (CellCept,

Genentech/Roche) has also been used for lupus-

related kidney problems. Side effects of this drug class are listed in (Table 1). 19,20

4. Antimalarial Medication: Some antimalarial

agents have proved effective in treating the

various signs and symptoms of lupus and

preventing subsequent flares. Although the exact

mechanism is unclear (see Table 1), antimalarials

may interfere with T-cell activation and inhibit

cytokine activity. These agents may also inhibit

intra-cellular toll-like receptors, which recognize

and bind foreign materials, thereby contributing to

activation

of

the

immune

system21. Hydroxychloroquine (e.g., Plaquenil,

Sanofi) is the most commonly studied and used

drug in its class, but it has the potential to cause

serious visual and muscle disturbances.

5. Monoclonal Antibodies

 “Belimumab”

In March 2011, the FDA approved the first

human monoclonal antibody for the treatment of

lupus. Belimumab (Benlysta, Human Genome

Sciences/GlaxoSmithKline) is the first agent in

more than 50 years to be approved for patients

with lupus. Belimumab inhibits the activation of B

lymphocytes by interfering with a protein

necessary for B-cell activity (BLyS). Previously

known as LymphoStat-B, belimumab is

recommended for patients with active SLE who

are receiving standard therapy with NSAIDs,

antimalarials,

corticosteroids,

and/or

immunosuppressants. Common adverse effects are presented in Table 122.

 Rituximab

As a genetically engineered chimeric

monoclonal antibody directed against the CD20

antigen, rituximab (Rituxan, Genentech/Roche)

has also shown potential in the treatment of SLE.

It is believed that B cells responsible for the

production of pathogenic autoantibodies, and other

immune-mediated substances associated with

lupus, are depleted by rituximab. During the past

few years, a number of open-label and

retrospective studies have reported promising

results with rituximab (when taken with

corticosteroids and other immunosuppressants in

the management of both pediatric-onset and adult-

onset lupus).

Benefits of rituximab have also been noted in

patients with lupus nephritis, arthralgia, arthritis,

serositis, cutaneous vasculitis, mucositis, rashes,

fatigue, and neurological and refractory

symptoms. Adverse events were generally mild.

Mild-to-moderate infusion reactions were reported most often.23,24

Some randomized controlled studies have

provided mixed results regarding the efficacy and

role of rituximab in the treatment of SLE. In a

study by Terrier et al., clinical responses were

reported in 71% of patients who received

rituximab, demonstrating a significant benefit in

refractory lupus (with or without concomitant

immunosuppressive therapy). Cutaneous, articular,

renal, and hematological improvements were

noted most often, along with an acceptable tolerance profile.25

A systematic review covering 188 SLE patients

treated with various regimens of rituximab, 91%

showed a significant improvement in one or more

systemic manifestations, particularly in patients

with renal involvement (e.g., lupus nephritis).

Adverse events were experienced by 23% of

patients, and infections were reported most often26 .However, two additional randomized,

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Yousef AL-Katheri et al.

placebo-controlled studies, conducted since 2010,
failed to demonstrate significant clinical
improvements with rituximab in patients receiving concomitant steroid therapy27. Despite the

favorable tolerability and safety profile of rituximab, further evaluation of this drug is required for patients with SLE.

Table 1: Commonly Used Medications in the Treatment of Systemic Lupus Erythematosus

Classification
NSAIDs (including salicylates)
Corticosteroid s
Immunosuppressants

Commonly Used Agents and Dosage
relatively wide range of agents and
dosages
Prednisone PO 0.5– 2 mg/kg per day
Methylprednisolon e IV 500–1,000 mg daily for 3 to 6 days
(acute flare)
Cyclophosphamide PO 1–3 mg/kg per
day or 0.5–1 g/m2 IV monthly with or without a
corticosteroid Azathioprine PO 1–
3 mg/kg per day Mycophenolate PO
1–3 g daily

Mechanism of Action
Block prostaglandin synthesis through inhibition of cyclooxygenase
enzymes, producing anti-inflammatory,
analgesic, and antipyretic effects
Multiple effects on immune system (e.g., blocking
cytokine activation and inhibiting interleukins, γ-
interferon and tumor necrosis factor-α)
Multiple suppressive effect on immune system (e.g., reduction of T-cell and B-cell proliferation; DNA
and RNA disruption)

Potential Adverse Effects
Gastrointestinal irritation and bleeding, renal
toxicity, hepatic toxicity,
hypertension
Weight gain, hypertension, hyperglycemia, hyperlipidemia, osteoporosis, cataracts, edema, hypokalemia, muscle weakness, growth suppression, increased risk of infection, glaucoma
Myelosuppression, hepatotoxicity, renal
dysfunction, infertility, increased risk of infection and
cancer

Common Monitoring Parameters
Nausea, vomiting, abdominal pain, dark/tarry stool;
baseline and annual CBC, SCr, LFTs, urinalysis
Baseline blood pressure, bone density, glucose, potassium, lipid panel; glucose
every 3 to 6 months; annual lipid panel and
bone density
Baseline and routine CBC, platelet count, SCr,
LFTs, and urinalysis (depends on individual drug)

Monoclonal antibodies
Antimalarials

Belimumab IV 10 mg/kg (over a
period of 1 hour), every 2 weeks for
the first three doses, then every 4
weeks
Hydroxychloroquin e PO 200–400 mg
daily

Block binding of BLyS to receptors
on B cells, inhibiting survival
of B cells, and reducing B-cell differentiation into immunoglobulinproducing plasma
cells Unclear; may interfere with T-cell activation and inhibit cytokine activity; also thought to inhibit intracellular TLRs

Nausea, diarrhea, pyrexia,
nasopharyngitis, insomnia, extremity
pain, depression, migraine,
gastroenteritis, infection (e.g., pneumonia, UTI, cellulitis, bronchitis)
Macular damage, muscle weakness

Gastrointestinal complaints,
infectious signs and symptoms,
mood or behavioral changes, infusion reactions
Funduscopy and visual field
examination at baseline and every
6 to 12 months

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Diagnosis and Management of Systematic Lupus Erythematosus

BLyS = B-lymphocyte stimulator protein; CBC = complete blood count; DNA = deoxyribonucleic acid; IV = intravenous; LFTs = liver function tests; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth; RNA = ribonucleic acid; SCr = serum creatinine; TLRs = toll-like receptors; UTI = urinary tract infection.

B. Additional Treatment Options Researchers have been particularly interested in the use of stem-cell transplantation to introduce healthy cells into the body in order to help rebuild the immune system. Both DHEA and rituximab have been studied in clinical trials and have provided improvements in patients’ quality of life. DHEA is believed to help in the regulation of sex hormones, whereas rituximab decreases the number of B cells and may be most beneficial in patients who do not respond to the other traditionally used immunusuppressants24,25.
C. Patient Education Stress the importance of adherence to medications and follow-up appointments for detection and control of SLE disease. Instruct patients with SLE to seek medical care for evaluation of new symptoms, including fever. Advise them regarding their heightened risks for infection and cardiovascular disease. Educate patients with SLE regarding aggressive lipid and blood pressure goals to minimize the risk of coronary artery disease. Instruct patients with SLE to avoid exposure to sunlight and ultraviolet light. Also, encourage them to receive nonlive vaccines during stable periods of disease, to quit smoking, and to carefully plan pregnancies.
PREGNANCY Women with SLE are at increased risk for serious medical and pregnancy complications, such as thrombosis, infection, thrombocytopenia, transfusion, pre-eclampsia, and death28. Because of the high risk of miscarriage, stillbirths, premature delivery, and exacerbation of SLE, it is recommended that women not become pregnant if they have active disease or significant organ involvement. Oral contraceptives must be given cautiously because high doses of estrogen can cause SLE exacerbations 28.Pregnancy outcomes are improved if conception is delayed until SLE has been inactive for at least 6 months and if the patient’s medications are adjusted in advance. Baseline and monthly monitoring (e.g., laboratory tests, ultrasonography, fetal surveillance tests, maternal echocardiography, and antibody testing) should be performed for all

pregnant lupus patients, because signs and symptoms of lupus flares may be similar to those typical of pregnancy28. Neonates should be carefully evaluated for placental transfer of maternal antibodies, which could lead to cutaneous or cardiac complications (e.g., congenital heart block and cardiomyopathy). If a woman is pregnant and has active SLE, corticosteroids may be prescribed with caution to manage the disease. Most steroids are Pregnancy Category C drugs. NSAIDs (Pregnancy Category C and D) have also been used, but to a lesser extent, and they should be avoided during early pregnancy and the last trimester. If necessary, hydroxychloroquine may be used, but it is also a Pregnancy Category C drug. Therefore, therapy must be individualized and the drug’s benefits and risks must be carefully considered. Immunosuppressive agents are contraindicated in pregnancy, except for azathioprine, a Pregnancy Category C drug. In women with SLE and antiphospholipid antibodies, prophylaxis with aspirin, lowmolecular-weight heparin, or both, is indicated for the prevention of fetal loss28.
CONCLUSION Although no cure has been discovered for this autoimmune disease, many medications are available to help control flares, to maintain remission, and to manage symptoms. Pharmacists and other health care professionals can play a vital role in treatment by educating patients, monitoring their therapeutic regimens, and identifying preventable drug-associated adverse events. Current research is under way, with the hope that improved quality of life and increased survival can be achieved for the many patients affected by SLE each year.
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Diagnosis and Management of Systematic Lupus Erythematosus (SLE)