AUTOIMMUNE DISEASES

SYSTEMIC LUPUS ERYTHEMATOSUS

Definition: Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs, tissues, and cells
undergo damage mediated by tissue-binding autoantibodies and immune complexes.
Epidemiology: Ninety percent of patients are women of child-bearing years. re!alence of SLE is "# to #$
per "$$,$$$.
Etiology: SLE is caused by interactions between susceptibility genes and en!ironmental factors, resulting in
abnormal immune responses. %emale gender is permissi!e for SLE& females of many mammalian species ma'e
higher antibody responses than males. (omen exposed to estrogen-containing oral contracepti!es or hormone
replacement ha!e an increased ris'of de!eloping SLE (approximately twofold). Se!eral en!ironmental stimuli may
influence SLE. Exposure to ultra!iolet light causes SLE flares in approximately )$* of patients, possibly by
increasing apoptosis in 'eratinocytes and other cells or by altering +N, and intracellular proteins to ma'e them
antigenic. -t is li'ely that !arious infections that stimulate immune responses.
Pt!ogene"i": .he immune responses include hyperreacti!ity and hypersensiti!ity of . and / lymphocytes
and ineffecti!e regulation of antigen a!ailability and of ongoing antibody responses. .he end result of these
abnormalities is sustained production of pathogenic autoantibodies and formation of immune complexes that bind
target tissues, resulting in (") se0uestration and destruction of -g-coated circulating cells& (1) fixation and clea!ing of
complement proteins& and (2) release of chemotaxins, !asoacti!e peptides, and destructi!e en3ymes into tissues.
4any autoantibodies in persons with SLE are directed against +N,5protein or 6N,5protein complexes such as
nucleosomes, some nucleolar 6N,, and spliceosomal 6N,. .hus, in SLE, antigens are a!ailable& they are presented
in locations recogni3ed by the immune system& and the antigens, autoantibodies, and immune complexes persist for
prolonged periods of time, allowing tissue damage to accumulate to the point of clinical illness.
Pt!ology: -n SLE, biopsies of affected s'in show deposition of -g at the dermal-epidermal 7unction (+E8),
in7ury to basal 'eratinocytes, and inflammation dominated by . lymphocytes in the +E8 and around blood !essels
and dermal appendages. -n renal biopsies, finding range from no histologic changes, proliferati!e changes in
mesangium and in glomeruli, predominantly membranous changes to scarred glomeruli. 9istologic abnormalities in
blood !essels are not specific for SLE: leu'ocytoclastic !asculitis is most common. Lymph node biopsies show
nonspecific diffuse chronic inflammation.
Cl""ifi#tion:
Clini#l Mnife"ttion":
Systemic Manifestations ,t its onset, SLE may in!ol!e one or se!eral organ systems& o!er time, additional
manifestations of disease may occur Se!erity of SLE !aries from mild and intermittent to se!ere and fulminant.
Systemic symptoms, particularly fatigue and myalgias. arthralgias, are present most of the time. Se!ere systemic
illness re0uiring glucocorticoid therapy can occur with fe!er, prostration, weight loss, and anemia in addition to any
other organ-targeted manifestations.
Musculoskeletal Manifestations 4ost people with SLE ha!e intermittent polyarthritis, !arying from mild to
disabling, characteri3ed by soft tissue swelling and tenderness in 7oints, most commonly in hands, wrists, and 'nees.
4yositis with clinical muscle wea'ness, ele!ated creatine 'inase le!els, and biopsy e!idence of muscle necrosis and
inflammation can occur, although most patients ha!e myalgias without myositis.
Cutaneous Manifestations Lupus dermatitis can be classified as discoid lupus erythematosus (+LE), systemic
rash, subacute cutaneous lupus erythematosus (S;LE), or <other.= +iscoid lesions are roughly circular with slightly
raised, scaly hyperpigmented erythematous rims and depigmented, atrophic centers in which all dermal appendages
are permanently destroyed. Lesions can be disfiguring, partic ularly on the face and scalp. .he most common SLE
rash is a photosensiti!e 4any other rashes are seen less fre0uently in SLE, including recurring urticaria, lichen
planus>li'e dermatitis, bullae, and panniculitis (<lupus profundus=). Small, painful ulcerations on the oral or nasal
mucosa are common in SLE.
Renal Manifestations Nephritis is usually the most serious manifestation of SLE, particularly since nephritis
and infection are the leading causes of mortality in the first decade of disease. Since nephritis is asymptomatic in
most lupus patients, urinalysis should be ordered in any person suspected of ha!ing SLE. atients with dangerous
proliferati!e forms of glomerular damage usually ha!e microscopic hematuria and proteinuria (?#$$ mg per 1@ h)&
approximately one-half de!elop nephrotic syndrome, and most de!elop hypertension.
Nervous System Manifestations .here are many central ner!ous system (;NS) and peripheral ner!ous system
manifestations of SLE& in some patients these are the ma7or cause of morbidity and mortality. .he most common
manifestation of diffuse ;NS lupus are cogniti!e dysfunction, headaches, sei3ures, psychosis, myelopathy.
Vascular Occlusions .he pre!alence of transient ischemic attac's, stro'es, and myocardial infarctions is
increased in patients with SLE. .wo processes can occur at onceA!asculitis plus bland !ascular occlusionsAin
which case it is appropriate to treat with anticoagulation plus immunosuppression.
Pulmonary Manifestations .he most common pulmonary manifestation of SLE is pleuritis with or without
pleural effusion. ulmonary infiltrates also occur as a manifestation of acti!e SLE and are difficult to distinguish
from infection on imaging studies. Life-threatening pulmonary manifestations include interstitial inflammation,
leading to fibrosis, and intraal!eolar hemorrhage.
Cardiac Manifestations ericarditis is the most fre0uent cardiac manifestation. 4ore serious cardiac
manifestations are myocarditis and fibrinous endocarditis of Libman-Sachs.
Hematologic Manifestations .he most fre0uent hematologic manifestation of SLE is anemia, usually
normochromic normocytic, reflecting chronic illness. 9emolysis can be rapid in onset and se!ere. Leu'openia is also
common and almost always consists of lymphopenia, not granulocytopenia. .hrombocytopenia may be a recurring
problem.
Gastrointestinal Manifestations Nausea, sometimes with !omiting, and diarrhea can be manifestations of an
SLE flare, as can diffuse abdominal pain caused by autoimmune peritonitis. -ncreases in serum ,S. and ,L. are
common when SLE is acti!e. Basculitis in!ol!ing the intestine may be life-threatening& perforations, ischemia,
bleeding, and sepsis are fre0uent complications.
Ocular Manifestations Sicca syndrome and nonspecific con7uncti!itis are common in SLE and rarely threaten
!ision. -n contrast, retinal !asculitis and optic neuritis are serious manifestations: blindness can de!elop o!er days to
wee's. ;omplications of glucocorticoid therapy include cataracts (common) and glaucoma.
$o%&'p:
Tests for Autoantiodies +iagnostically, the most important autoantibodies to detect are ,N, since the test is
positi!e in ?C#* of patients, usually at the onset of symptoms. 9igh-titer -gD antibodies to double-stranded +N,
(ds+N,) (but not to single-stranded +N,) are specific for SLE. ,ntibodies to Sm are also specific for SLE and
assist in diagnosis& anti-Sm antibodies do not usually correlate with disease acti!ity or clinical manifestations. 9igh
titers of -gD anticardiolipin (?#$ -E) indicate high ris'for a clinical episode of clotting.
Standard Tests for !iagnosis Screening tests for complete blood count, platelet count, and urinalysis may
detect abnormalities that contribute to the diagnosis and influence management decisions.
Digno"i": .he diagnosis of SLE is based on following criteria.
". 4alar rash. %ixed erythema, flat or raised, o!er the malar eminences.
1. +iscoid rash. Erythematous circular raised patches with adherent 'eratotic scaling and follicular plugging&
atrophic scarring may occur.
2. hotosensiti!ity. Exposure to ultra!iolet light causes rash.
@. Fral ulcers -ncludes oral and nasopharyngeal ulcers, obser!ed by physician.
#. ,rthritis Nonerosi!e arthritis of two or more peripheral 7oints, with tenderness, swelling, or effusion.
G. Serositis leuritis or pericarditis documented by E;D or rub or e!idence of effusion.
). 6enal disorder. roteinuria ?$.# g5d, or cellular casts.
H. Neurologic disorder. Sei3ures or psychosis without other causes.
C. 9ematologic disorder. 9emolytic anemia or leu'openia (I@$$$5 JL) or lymphopenia (I"#$$5JL) or
thrombocytopenia (I"$$,$$$5 JL) in the absence of offending drugs.
"$. -mmunologic disorder. ,nti-ds+N,, anti-Sm, and5or antiphospholipid.
"". ,ntinuclear antibodies. ,n abnormal titer of ,N, by immunofluorescence or an e0ui!alent assay at any
point in time in the absence of drugs 'nown to induce ,N,s.
,ny combination of @ or more of "" criteria, well-documented at any time during a patientKs history, ma'es it
li'ely that the patient has SLE (specificity and sensiti!ity are LC#* and )#*, respecti!ely).
Diffe%entil": ,ntiphospholipid Syndrome, %ibromyalgia, 9epatitis ;, -nfectious 4ononucleosis, -nfecti!e
Endocarditis, Lyme +isease, /-;ell Lymphoma, 4ixed ;onnecti!e-.issue +isease, olyarteritis Nodosa,
reeclampsia (.oxemia of regnancy), 6heumatic %e!er, 6heumatoid ,rthritis, Scleroderma, Serum Sic'ness,
.hrombotic .hrombocytopenic urpura, Endifferentiated ;onnecti!e-.issue +isease, +rug-induced lupus
erythematosus, Basculitis, Leu'emia, Neoplasia, 9-B, 4ultiple sclerosis, ar!o!irus or other !iral infections.
T%etment: .here is no cure for SLE, and complete sustained remissions are rare. .herefore, the physician
should plan to control acute, se!ere flares then de!elop maintenance strategies that suppress symptoms to an
acceptable le!el and pre!ent organ damage.
Conservative T"era#ies for Management of Non$%ife$T"reatening !isease ,mong patients with fatigue,
pain, and autoantibodies of SLE, but without ma7or organ in!ol!ement, management can be directed to suppression
of symptoms. ,nalgesics and antimalarials are mainstays. NS,-+s are useful analgesics5anti-inflammatories,
particularly for arthritis5arthralgias& howe!er, SLE patients compared to the general population are at increased
ris'for NS,-+-induced aseptic meningitis, ele!ated serum transaminases, hypertension, and renal dysfunction.
,ntimalarials (hydroxychloro0uine, chloro0uine, and 0uinacrine) often reduce dermatitis, arthritis, and fatigue& a
randomi3ed placebo-controlled prospecti!e trial has shown that hydroxychloro0uine reduces the number of disease
flares. /ecause of potential retinal toxicity, patients recei!ing antimalarials should undergo opthalmologic
examinations at least annually. , recent placebo-controlled prospecti!e trial suggests that administration of
dehydroepiandrosterone may reduce disease acti!ity. -f 0uality of life is inade0uate in spite of these conser!ati!e
measures, treatment with low doses of systemic glucocorticoids may be necessary.
%ife$T"reatening S%&' Proliferative (orms of %u#us Ne#"ritis .he mainstay of treatment for any
inflammatory life-threatening or organ-threatening manifestations of SLE is systemic glucocorticoids ($.# to 1 mg5'g
per day orally or "$$$ mg of methylprednisolone sodium succinate intra!enously daily for 2 days followed by $.#>"
mg5'g of daily prednisone or e0ui!alent).
;ytotoxic drugs are another important class of drugs used to treat serious SLE. ,lmost all prospecti!e
controlled trials in SLE in!ol!ing cytotoxic agents ha!e been conducted in patients with lupus nephritis. .he
al'ylating agent cyclophosphamide has become the standard drug used for controlling life-threatening acti!e lupus
nephritis. ,ll successful studies with cyclophosphamide ha!e also used concomitant glucocorticoid therapy&
cyclophosphamide responses begin 2 to "G wee's after treatment is initiated, whereas glucocorticoid responses may
begin within 1@ h. ,3athioprine (a purine antagonist) could be added to glucocorticoids and probably reduces the
number of SLE flares and the maintenance glucocorticoid re0uirement& howe!er, this approach re0uires se!eral
months to be effecti!e, and cyclophosphamide is effecti!e in a higher proportion of patients. 4ycophenolate mofetil
(a relati!ely lymphocyte-specific inhibitor of inosine monophosphate dehydrogenase) is an effecti!e cytotoxic agent
in some patients with se!ere SLE. ;hlorambucil is an al'ylating agent that can be substituted for cyclophosphamide.
4ethotrexate (a folinic acid antagonist) may ha!e a role in the treatment of arthritis and dermatitis but probably not
in life-threatening disease. .he role of leflunomide, a relati!ely lymphocytespecific pyrimidine antagonist, is being
studied in patients with SLE. ;yclosporine, which inhibits production of -L-1 and inhibits . lymphocyte functions,
has not been studied in prospecti!e controlled trials in SLE but is nonetheless used by some clinicians.
%u#us and APS atients with SLE who ha!e !enous or arterial clotting, and5or repeated fetal losses, and at
least two positi!e tests for aL ha!e ,S and should be managed with long-term anticoagulation. , target -N6 of 2.$
is recommended, based on reduction of new clotting e!ents in patients treated to this target -N6 compared to patients
treated to lower -N6 le!els, in retrospecti!e analyses of cohorts with primary or secondary ,S.
P%ogno"i": Sur!i!al in patients with SLE is C$ to C#* at 1 years, H1 to C$* at # years, )" to H$* at "$ years,
and G2 to )#* at 1$ years. oor prognosis (approximately #$* mortality in "$ years) is associated with (at the time
of diagnosis) high serum creatinine le!els MN"1@ Nmol5L (N".@ mg5dL)O, hypertension, nephrotic syndrome (1@-h
urine protein excretion N1.G g), anemia Mhemoglobin N"1@ g5L (N"1.@ g5dL)O, hypoalbuminemia,
hypocomplementemia, and aL. ,s many as 1#* of patients may experience remissions, sometimes for a few years,
but these are rarely permanent. .he leading causes of death in the first decade of disease are systemic disease acti!ity,
renal failure, and infections& subse0uently, thromboembolic e!ents become increasingly fre0uent causes of mortality.