Systemic Lupus Erythematosus

Pratap Sagar Tiwari, MD

Pic reference: autoimmunityblog.com

Introduction• SLE is an chronic inflammatory multisystem autoimmune disease

that can affect the skin, joints, kidneys, lungs, nervous system, serous membranes, and/or other organs of the body. • Immunologic abnormalities, especially the production of a

number of antinuclear antibodies, are prominent feature of the disease.• The clinical course of SLE is variable and may be characterized by

periods of remissions and of chronic or acute relapses. • Around 90% of are F, the peak age at onset is betwn 20-30 yrs.

Historical Aspects• The term ‘lupus’ (Latin for ‘wolf’) was first used during the Middle Ages to describe erosive skin lesions

evocative of a ‘wolf’s bite’. • In 1846 the Viennese physician Ferdinand von Hebra (1816–1880) introduced the butterfly metaphor to

describe the malar rash. He also used the term ‘lupus erythematosus’ and published the first illustrations in his Atlas of Skin Diseases in 1856.

• Lupus was first recognised as a systemic disease with visceral manifestations by Moriz Kaposi (1837–1902). • The systemic form was further established by Osler in Baltimore and Jadassohn in Vienna. • 1909: The description of the false positive test for syphilis in SLE by Reinhart and Hauck from Germany

(1909).• 1923: The description of the endocarditis lesions in SLE by Libman and Sacks in New York.• 1935: The description of the glomerular changes by Baehr .• 1941: The use of the term diff use connective tissue disease’ by Klemperer, Pollack and Baehr .• 1948: The beginning of the modern era in SLE was the discovery of the ‘LE’ cell by Hargraves, Richmond and

Morton at the Mayo Clinic ..

Note: An LE cell is a neutrophil or macrophage that has phagocytized the denatured nuclear material of another cell.The denatured material is an absorbed hematoxylin body (also called an LE body)

Natural history and course

Ref: Natural history of systemic lupus erythematosus. SLICC, Systemic Lupus International Collaborating Clinics/American College ofRheumatology damage index. Reprinted with permission from Bertsias GK, Salmon JE, Boumpas DT. Therapeutic opportunities insystemic lupus erythematosus: state of the art and prospects for the new decade. Ann Rheum Dis 2010;69:1603–11.

PathogenesisEnvironmental Factors

Downloaded from http://jcp.bmj.com/ on November 2, 2015 - Published by group.bmj.com

Diagnosis• The diagnosis of SLE is straightforward in a patient who presents with

several compatible c/f and who has supportive laboratory studies. • A good example is a young woman who presents with complaints of

fatigue, arthralgia, and pleuritic chest pain and who is found to have hypertension, a malar rash, a pleural friction rub, mild peripheral edema. Laboratory :leukopenia, anemia, an ↑ S creatinine, hypoalbuminemia, proteinuria, an active urinary sediment, hypocomplementemia, a + Coombs test, and + tests for ANA, including those to ds DNA & Sm.

Laboratory testing Laboratory tests that may provide diagnostically useful information when SLE is suspected include:• Complete blood count and differential• Erythrocyte sedimentation rate and/or C reactive protein• Urinalysis• 24-hour urine collection for calculation of creatinine clearance and for quantitation of proteinuriaAutoantibody testing • Antinuclear antibodies (ANA)• Antiphospholipid antibodies• Antibodies to double stranded DNA (dsDNA)• Anti-Smith (Sm) antibodies• Measurement of serum complement levels C3 and C4 may also be helpful, since hypocomplementemia is a frequent finding in active SLE.

Imaging Diagnostic imaging may be valuable but is not routinely obtained unless indicated by the presence of symptoms, clinical findings, or laboratory abnormalities. Examples include:• Plain radiographs of involved joints• Renal ultrasonography to assess kidney size and to rule out urinary tract obstruction when

there is evidence of renal impairment• Chest radiography• Echocardiography • Computed tomography (CT) (eg, for abdominal pain, suspected pancreatitis, interstitial lung

disease)• Magnetic resonance imaging (eg, for focal neurologic deficits or cognitive dysfunction)• Contrast angiography, which may be valuable if vasculitis affecting medium-sized arteries is

suspected (eg, mesenteric or limb-threatening ischemia)

Others• Biopsy — Biopsy of an involved organ (eg, skin or kidney) is necessary

in some cases. • In the absence of renal abnormalities, renal biopsy has nothing to

offer and should not be performed.

• Renal involvement occurs in 40–70% of all SLE patients and is a major cause of morbidity and hospital admissions. Immune complex formation/deposition in the kidney results in intra-glomerular inflammation with recruitment of leucocytes and activation and proliferation of resident renal cells .

• Proteinuria of various levels is the dominant feature of lupus nephritis (LN) and is usually accompanied by glomerular haematuria.

• Urinalysis is the most important and effective method to detect and monitor disease renal activity.

Autoantibodies• The ANA test is the best diagnostic test for SLE and be performed when SLE

is suspected .• The ANA is positive in significant titer (usually 1:160 or higher) in virtually all

patients with SLE. The probability of having SLE is less than 0.14 % if the ANA test is negative .

Antinuclear antibodies are also present, usually in lower titer, in a variety of other disorders • Sjögren’s syndrome — 68 percent• Scleroderma — 40 to 75 percent• Juvenile idiopathic arthritis — 16 percent• Rheumatoid arthritis — 25 to 50 percent

dsDNA and Sm antibodies• There are two commonly obtained autoantibodies that are highly

specific for SLE: anti-double-stranded DNA (dsDNA) antibodies and anti-Sm antibodies .• Sensitivity — 66-95 percent• Specificity — 75-100 percent• Predictive value — 89-100 percent

ACR criteriaCriterion DefinitionMalar rash Fixed erythema, flat /raised, over malar eminences, sparing the nasolabial folds.Discoid rash Erythematosus raised patches c adherent keratotic scaling and follicular

pluggingPhotosensitivity Skin rash as a result of unusual reaction to sunlight, by patient or physicianOral ulcers Oral/nasopharyngeal ulceration, usually painless, observd by physician (12-45%)Arthritis Nonerosive arthritis involving 2 or more peripheral joints, characterized by

tenderness, swelling, or effusion (53-95%) Serositis Pleuritis –H/O pleuritic pain/rub heard by a physician or evidence of effusion OR

Pericarditis - documented by EKG, rub or evidence of pericardial effusionRenal disorder Persistent proteinuria >0.5 gms/d or >3+ if quantitation not performed OR

Cellular casts - may be red cell, hemoglobin, granular, tubular, or mixed (40-70%)

Note: Mucocutaneous involvement is almost universal in SLE

Skin Rashes in SLE

Malar Rash Discoid Rash

Ref: medscape

Rhupus: Jacoud arhtropathyDeformities in the hands such as ulnar drift at the MCP joints, swan neck and boutonniere deformities, and hyperextension at the interphalangeal joint of the thumb closely resemble those seen in rheumatoid arthritis. The absence of erosions on radiographs and their reducibility distinguish this condition from the deforming arthritis of rheumatoid arthritis. Courtesy of Dr D Vassilopoulos.

ACR criteriaCriterion Definition

Neurologic disorder Seizures OR psychosis - in the absence of offending drugs or known metabolic derangements (uremia, ketoacidosis, or electrolyte imbalance)

Hematologic disorder

Hemolytic anemia - with reticulocytosis ORLeukopenia - <4000/mm 3 total on two or more occasions ORLymphopenia - <1500/mm 3 on two or more occasions ORThrombocytopenia - <100,000/mm 3

Immunologic disorders

Anti-DNA - antibody to native DNA in abnormal titer ORAnti-Sm - presence of antibody to Sm nuclear antigen ORPositive antiphospholipid antibody on: 1. an abnormal serum level of IgG or IgM anticardiolipin antibodies, or 2. a positive test result for lupus anticoagulant using a standard method, or 3. a false-positive test result for at least 6 months confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption teston

Antinuclear antibody An abnormal titer of ANA 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

Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25:1271.

Note:• Although the ACR classification criteria may also be used as a diagnostic aid,

there are several caveats in their use for diagnostic purposes. • These criteria were developed and validated for the classification of patients

with a longstanding established disease and may exclude patients with early disease or disease limited to a few organs. Thus, in spite of their excellent sensitivity (>85%) and specificity (>95%) for patients with established disease, their sensitivity for patients early in the disease may be significantly lower.• Among patients referred for lupus to tertiary care centres, two thirds of

patients fulfil ACR criteria, approximately 10% have clinical lupus but do not fulfil criteria, and 25% have fibromyalgia-like symptoms and positive antinuclear antibody (ANA) but never develop lupus.

CONSTITUTIONAL SYMPTOMS • Fatigue, fever, and weight loss are typically present at some time during the course of the

disease, occurring in 50 to 100 %. • Fatigue is the MC complaint & is occasionally the most debilitating. It occurs in 80-100 % • Myalgia — Myalgia is common in SLE. • Weight changes — Weight changes are frequent in patients with SLE and may be related to

the disease or to its treatment.• Weight loss — Weight loss often occurs prior to the diagnosis of SLE. Unintentional weight

loss may be due to decreased appetite, to the side effects of medications (particularly diuretics or antimalarials), and to gastrointestinal disease (eg, gastroesophageal reflux, abdominal pain, peptic ulcer disease, or pancreatitis).

• Weight gain — Weight gain in SLE is usually due to one of two factors: salt and water retention associated with hypoalbuminemia (eg, due to nephrotic syndrome or protein losing enteropathy) or increased appetite associated with the use of glucocorticoids.

Management• GENERAL TREATMENT CONSIDERATIONS• TREATMENT OF SPECIFIC ORGAN INVOLVEMENT

GENERAL TREATMENT CONSIDERATIONS• Sun protection — Avoid exposure to direct or reflected sunlight and

other sources of ultraviolet (UV) light (eg, fluorescent and halogen lights). A sunscreen with a SPF of 55 or greater is suggested.• Smoking cessation — Cigarette smoking may increase the risk of

developing SLE, and smokers in general have more active disease. Hydroxychloroquine is less effective in smokers .• Immunizations — patients should receive appropriate immunizations

prior to the institution of immunosuppressive therapies.

Others• Avoidance of specific medications : Drugs induce SLE• Pregnancy and contraception — Pregnancy should be avoided during active disease

due to the high risk of miscarriage and exacerbation. Women with SLE should be counseled not to become pregnant until the disease has been quiescent for at least six months.• Oral contraceptives can cause exacerbations of SLE.• Pregnant patients with active lupus are generally managed with glucocorticoids.

Other drugs used during pregnancy include nonsteroidal antiinflammatory drugs (avoided during early pregnancy and in the third trimester) and hydroxychloroquine (probably safe). • Cyclophosphamide , cyclosporine , mycophenolate mofetil, and methotrexate are

contraindicated, while azathioprine can be cautiously used.

TREATMENT OF SPECIFIC ORGAN INVOLVEMENT

Medications• Nonsteroidal antiinflammatory drugs (NSAIDs) • Antimalarials: hydroxychloroquine • Glucocorticoids• Immunosuppressive agents: cyclophosphamide , cyclosporine , tacrolimus , leflunomide ,methotrexate , azathioprine , mycophenolate and belimumab.

Medications• NSAIDs are generally effective for musculoskeletal complaints, fever,

headaches, and mild serositis. Naproxen may have greater relative cardiovascular safety than other NSAIDs.• Antimalarials are most useful for skin manifestations and for

musculoskeletal complaints. In addition, in long-term studies, the use of antimalarials, such as hydroxychloroquine , prevented major damage to the kidneys and central nervous system . Their use may also reduce the risk of disease flares, though this is less clear for renal and central nervous system (CNS) manifestations

Glucocorticoids• Systemic glucocorticoids (eg, high doses of

1-2mg/kg/d of prednisone or equivalent used alone or in combination with immunosuppressive agents are generally reserved for patients with significant organ involvement, particularly renal and CNS disease. • Patients with whereas non-organ-threatening disease (eg, cutaneous,

musculoskeletal, constitutional) patients usually respond to 5 to 15 mg of prednisone (or equivalent) daily until a glucocorticoid-sparing agent or antimalarial can take effect.

Medications• Immunosuppressive medications other than glucocorticoids

(eg, methotrexate , cyclophosphamide , azathioprine , mycophenolate or rituximab ) are generally reserved for patients with significant organ involvement and/or for patients who have had an inadequate response to glucocorticoids.

Prognosis• The overall 5-year survival of SLE is over 90%. • Mortality within 5 years of diagnosis is usually due to organ failure or

overwhelming sepsis, both of which are modifiable by early effective intervention. • However, compared to the normal population, patients with lupus

have a fivefold increased mortality. • This mainly results from premature cardiovascular disease to which

chronic steroid therapy makes a major contribution.

Drugs induce lupus• Definite -Procainamide , hydralazine , minocycline , diltiazem , penicillamine , isoniazid , quinidine

, anti-TNF(with infliximab and etanercept ), interferon-a, methyldopa , chlorpromazine , and practolol .

• Probable — Anticonvulsants ( phenytoin , ethosuximide , carbamazepine ), antithyroid drugs, antimicrobial agents (sulfonamides, rifampin , nitrofurantoin ), beta blockers, lithium , captopril , interferon gamma, hydrochlorothiazide , glyburide , sulfasalazine , terbinafine , amiodarone , ticlopidine.

• The presence of drug-induced lupus should be suspected when a patient taking one or more of the above drugs for at least 1 mnth, and usually much longer, presents with some combination of arthralgia, myalgia, malaise, fever, rash, and/or serositis.

• The "gold standard" is spontaneous resolution of the disease within 1-7mnths after the offending drug has been discontinued.

• Treatment is focused on stopping the medication. NSAID and antimalarials can be temporarily used if constitutional and musculoskeletal symptoms do not clear rapidly.

Spontanous LUPUS Drug induced LUPUS

Usual age 20-40 50

F:M 9:1 1:1

Onset Gradual Abrupt

Constitutional symptoms ++ +

Arthalgia/ serositis/ hepatomegaly ++ ++

Rash ++ +

Renal ++ +CNS ++ -Hematologic Common UnusualImmunologic abnormalitiesANALE CELLSANTI RNPANTI HISTONEANTI SMANTI DSDNACOMPLEMENTSIMMUNE COMPLEX

+++++++++++ReducedElevated

+++++++--NormalNormal

End of slidesReferences:• Davidson

• Harrison’ s Internal Medicine 18th ed

• Uptodate

• Medscape