2014 - SLE Lecture

Systemic Lupus Erythematosus (SLE)

4th year, General Medicine, 2014

DIFFUSE CONNECTIVE TISSUE DISEASES

1. SYSTEMIC LUPUS ERYTHEMATOSUS : SLE

2. SCLERODERMA (“ scleroderma : Scl”)

3. POLIMYOSITIS (PM)4. 4. DERMATOMYOSITIS (DM)

5. RHEUMATOID ARTHRITIS (RA)

6. SJÖGREN SYNDROME :1. 6.1 primary2. 6.2. secondary : usually associated with each of the five connective

tissue diseases/ collagen diseases

DIFFUSE CONNECTIVE TISSUE DISEASES

• “OVERLAP SYNDROME” : – collagen disease with an intricate

simptomatology (RA, SS, SLE)– present in 25% cases of the patients

SLE DEFINITION

• Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs and cells undergo damage mediated by tissue-binding autoantibodies and immune complexes.

EPIDEMIOLOGY

• SLE primarily is a disease of young women (90 % of patients are women of child-bearing years);

– SLE is usually a postpubertal disease, with onset of clinical symptoms usually in the 20s to 30s

– female : male ratio is 9 : 1

• but, people of both sexes, all ages, and all ethnic groups are susceptible;

EPIDEMIOLOGY

• The prevalence varies with race, ethnicity, and socioeconomic status, but in a general outpatient population, SLE affects ~ 1 in 2000 individuals;

• Prevalence of SLE in the United States is 15–50 cases per 100,000;

• The highest prevalence among ethnic groups studied is in African Americans.

PATHOGENESIS AND ETIOLOGY

Interactions between: susceptibility genes + environmental factors

result in abnormal immune responses

that generate pathogenic autoantibodies and immune complexes

that deposit in tissue, activate complement, cause inflammation, and over time lead to irreversible organ

damage.

Despite the influence of heredity, most cases of SLE appear sporadic

PATHOGENESIS AND ETIOLOGY: THE SUSCEPTIBILITY

• Like other autoimmune diseases, SLE can display familial aggregation, with a higher frequency among first-degree relatives of patients :

– The disease occurs concordantly in approximately 25% to 50% of monozygotic twins and 5% of dizygotic twins

– Moreover, in extended families, SLE may occur with other autoimmune conditions, such as hemolytic anemia, thyroiditis, and idiopathic thrombocytopenia purpura.

• An association of human leukocyte antigen (HLA)-DR2 and HLA-DR3 (and various subspecificities) with SLE has been commonly observed, with these alleles producing a relative risk of disease that ranges approximately from 2 to 5

• SLE is also associated with inherited deficiency of Clq, Clr/s, and C2 :– A decrease in complement activity could promote

disease susceptibility by impairing the clearance of foreign antigen or apoptotic cells;

PATHOGENESIS AND ETIOLOGY: THE SUSCEPTIBILITY

PATHOGENESIS AND ETIOLOGY: THE ENVIRONMENTAL FACTORS

• Infectious agents : could induce specific responses by molecular mimicry and perturb overall immunoregulation;

• Stress : can provoke neuroendocrine changes affecting immune cell function;

• Diet : can affect production of inflammatory mediators;

• Toxins (including drugs): could modify cellular responsiveness and the immunogenicity of self-antigens;

• Physical agents (e.g. sunlight) : can cause inflammation and tissue damage.

ABNORMAL IMMUNE RESPONSES - IMMUNE CELL DISTURBANCES -

• These immune cell disturbances appear to promote B-cell hyperactivity, leading to hyperglobulinemia, increased numbers of antibody-producing cells, and heightened responses to many antigens, both self and foreign.– Autoantibody production in SLE occurs in the setting of

generalized immune cell abnormalities that involve the B cell, T cell, and monocyte lineages.

• Another consequence of B-cell and T-cell disturbance in SLE may be abnormal tolerance. In healthy individuals, anti-DNA precursors are tolerated by anergy or deletion; however, people with SLE or animals with SLE models may retain such precursors, which can be stimulated to generate high affinity autoantibody responses (15).

ANTINUCLEAR ANTIBODIES (ANA)

• Autoantibody production is the central immunologic disturbance in SLE.

• ANA are directed to a host of self-molecules found in the nucleus, cytoplasm, or surface of cells. In addition, SLE sera contain antibodies to such soluble molecules as IgG and coagulation factors.

• SLE is classified as a disease of generalized autoimmunity because of the wide range of its antigenic targets.

PATHOGENESIS AND ETIOLOGY

AUTOANTIBODIES IN SLE

1. Antinuclear antibodies : best screening test; repeated negative tests make SLE unlikely

- Prevalence : 98%- Ag. recognized : multiple nuclear

2. Anti-dsDNA : high titers are SLE-specific and in some patients correlate with disease activity, nephritis, vasculitis

- Prevalence : 70% - Ag. Recognized : DNA (double-stranded)


1. Anti-Sm : specific for SLE, no definite clinical correlations

- Prevalence : 25%- Ag. recognized :Protein complexed to 6 species of nuclear U1 RNA

2. Antiphospholipid : predisposes to clotting, fetal loss, thrombocytopenia

- Prevalence : 50% - Ag. Recognized : Phospholipids, 2 glycoprotein 1

cofactor, prothrombin


1. Antierythrocyte 1. Prevalence : 60%2. Ag. recognized : Erythrocyte membrane 3. Measured as direct Coombs' test

2. Antiplatelet 1. Prevalence : 30% 2. Ag. Recognized : Surface and altered cytoplasmic antigens in platelets 3. Associated with thrombocytopenia but sensitivity and specificity are not good; this is not a useful clinical test

3. Antineuronal 1. Prevalence : 60% 2. Ag. Recognized : Neuronal and lymphocyte surface antigens3. In some series a positive test in CSF correlates with active CNS lupus


1. Anti-Ro (SS-A) : not specific for SLE1. Prevalence : 30%2. Ag. recognized : Protein complexed to hY RNA, primarily 60 kDa and 52 kDa; 3. associated with sicca syndrome, subacute cutaneous lupus, and neonatal lupus

with congenital heart block; associated with decreased risk for nephritis

2. Anti-La (SS-B): not specific for SLE 1. Prevalence : 10% 2. Ag. Recognized :47-kDa protein complexed to hY RNA 3. Usually associated with anti-Ro; associated with decreased risk for nephritis

3. Antihistone

1. Prevalence : 70% 2. Ag. Recognized : Histones associated with DNA (in nucleosome, chromatin) 3. More frequent in drug-induced lupus than in SLE

DIAGNOSTIC CRITERIA FOR SLE

1. Malar rash; 2. Discoid rash; 3. Photosensitivity : exposure to

ultraviolet light causes rash;4. Oral ulcers : includes oral and

nasopharyngeal ulcers, observed by physician

5. Arthritis : nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion


6. Serositis : pleuritis or pericarditis documented by ECG or rub or evidence of effusion

7. Renal disorder : proteinuria >0.5 g/d or 3+, or cellular casts

8. Neurologic disorder : seizures or psychosis without other causes


9. Hematologic disorder :– Hemolytic anemia or – leukopenia (<4000/ L) or – lymphopenia (<1500/ L) or – thrombocytopenia (<100,000/ L) in the absence of

offending drugs

10. Immunologic disorder :– Anti-dsDNA, anti-Sm, and/or anti-phospholipid

11. Antinuclear antibodies : an abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time in the absence of drugs known to induce ANAs


• If 4 of these criteria, well documented, are present at any time in a patient's history, the diagnosis is likely to be SLE. Specificity is 95%; sensitivity is 75%.


• Malar rash : fixed erythema, flat or raised, over the malar eminences;

• It is the most classic of all the rashes in SLE and it is categorized among the acute rashes.

• It occurs in 30% to 60% of all patients.

SLE: PHOTOSENSITIVITY, FACE AND NECK


• The most common form of chronic disease is discoid lupus (DLE; 15%–30) which can occur as part of the systemic disease or exist in isolation in the absence of any autoantibodies (2%–10% will develop SLE)

• Discoid rash : erythematous circular raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur


Discoid rash : erythematous circular raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur


Oral ulcer Oral or nasopharyngeal ulceration, usually painless, observed by a physician


• Nonerosive arthritis involving two or more peripheral joints,characterized by tenderness, swelling or effusion

SLE: JACCOUD’S ARTHROPATHY (CLINICAL AND RADIOGRAPH)

• At its onset, SLE may involve one or several organ systems; over time, additional manifestations may occur

• Most of the autoantibodies characteristic of each person are present at the time clinical manifestations appear

• Severity of SLE varies from mild and intermittent to severe and fulminant.

• Most patients experience exacerbations interspersed with periods of relative quiescence;

• Permanent complete remissions (absence of symptoms with no treatment) are rare.

SYSTEMIC MANIFESTATIONS

• Systemic symptoms :

– particularly fatigue and myalgias/arthralgias, are present most of the time.

– severe systemic illness requiring glucocorticoid

therapy can occur with fever, prostration, weight loss, and anemia with or without other organ-targeted manifestations

Musculoskeletal Manifestations • Most people with SLE have :

– intermittent polyarthritis, varying from mild to disabling, characterized by soft tissue swelling and tenderness in joints, most commonly in hands, wrists, and knees.

– joint deformities (hands and feet) develop in only 10%

• Erosions on joint x-rays are rare; their presence suggests a non-lupus inflammatory arthropathy such as rheumatoid arthritis

• If pain persists in a single joint, such as knee, shoulder, or hip, a diagnosis of ischemic necrosis of bone should be considered, particularly if there are no other manifestations of active SLE. The prevalence of ischemic necrosis of bone is increased in SLE, especially in patients treated with systemic glucocorticoids

• Myositis with clinical muscle weakness, elevated creatine kinase levels, positive MRI scan, and muscle necrosis and inflammation on biopsy can occur, although most patients have myalgias without frank myositis. Glucocorticoid therapies (commonly) and antimalarial therapies (rarely) can also cause muscle weakness; these adverse effects must be distinguished from active disease

Musculoskeletal Manifestations

• Painful joints are the most common presenting symptom of SLE, with frequencies reported between 76% to 100%

• In some cases the pain is more characteristic of arthralgia because it is unaccompanied by the traditional signs of inflammation

• In others the classical signs of a true arthritis, such as swelling, erythema, heat, and decreased range of motion, are present.


• Although arthritis can affect any joint, it is most often symmetrical with involvement of the small joints of the hands (proximal interphalangeal and metacarpal phalangeal), wrists and knees, but sparing the spine

• The arthritis can be evanescent, resolving within 24 hours, or more persistent.


• In contrast to RA, the arthritis in SLE is nonerosive and generally nondeforming

• In those patients that do appear to have deforming features, such as ulnar deviation, hyperflexion, and hyperextension, the deformities are generally reducible

• These hypermobile digits with reducible deformities are secondary to involvement of paraarticular tissues, such as the joint capsule, ligaments, and tendons, and are referred to as Jaccoud-like arthropathy.

Jaccoud-like arthropathy in SLE


• Rheumatic complaints localized to the hips should raise serious consideration of osteonecrosis, the frequency of which has been reported to be 5% to 10%.

• Although the femoral head is the most common site of involvement, other sites include the femoral condyles, talus, humeral head, and, occasionally, the metatarsal heads, radial head, carpal bones, and metacarpal bones.

• Bilaterality is frequent but not necessarily simultaneous.

• Most cases are associated with the use of corticosteroids, but causality has also been attributed to Raynaud’s, small vessel vasculitis, fat emboli, or the presence of antiphospholipid antibodies.

• Typically, patients with osteonecrosis complain of persistent painful motion localized to a single joint, and symptoms are relieved by rest


• Generalized myalgia and muscle weakness, frequently involving the deltoids and quadriceps, can be accompanying features of disease fl ares.

• Overt myositis with elevations of CPK occurs in <15% of patients.

• Electromyogram (EMG) and muscle biopsy findings range from normal to those seen in dermato/polymyositis.

• Exceptionally high levels of creatine kinase (CPK) are rare. Patients with SLE can develop myopathy as a consequence of glucocorticoids or antimalarials.

Mucocutaneous Manifestations • Lupus dermatitis can be classified as :

– discoid lupus erythematosus (DLE),– systemic rash, – subacute cutaneous lupus erythematosus (SCLE), or "other.“

• Only 5% of people with DLE have SLE (although half have positive ANA);

• The most common SLE rash is a photosensitive : worsening of this rash often accompanies flare of systemic disease.

• SCLE : patients with these manifestations are exquisitely photosensitive; most have antibodies to Ro (SS-A).

• Other SLE rashes include recurring urticaria, lichen planus–like dermatitis, bullae, and panniculitis ("lupus profundus").

• Small, painful ulcerations on the oral or nasal mucosa are common in SLE; the lesions resemble aphthous ulcers.

Mucocutaneous Manifestations

• The cutaneous system is one of the most commonly affected, approaching 80% to 90%

• SLE-specific skin lesions are classified into three types :– chronic, – subacute– acute

Malar rash

Discoid lupus erythematosus (DLE),

Subacute cutaneous lupus erythematosus (SCLE)

• Subacute cutaneous lupus erythematosus (SCLE) lesions are seen in 7% to 27% of patients

Subacute cutaneous lupus erythematosus

Alopecia

• Alopecia associated with SLE may be diffuse or patchy, reversible or permanently scarring as a result of discoid lesions in the scalp.

Alopecia

Livedo reticularis

Vasculitis

• Vasculitis is another component of skin disease in SLE. It may be manifest as :– urticaria, palpable

purpura,– nailfold or digital

ulcerations,– erythematous papules

of the pulps of the fingers and palms, or splinter hemorrhages

Vasculitis

Leziuni tegumentare vasculitice : dermatita interarticulara a mainilor

Vasculitis: fingers

Vasculitis

Raynaud’s phenomenon

Subacute cutaneous lupus erythematosus (SCLE)

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 having SLE

• Lupus nephritis tends to be an ongoing disease, with flares requiring re-treatment over many years.

• For most people with lupus nephritis, accelerated atherosclerosis becomes important after several years of disease; attention must be given to control of blood pressure, hyperlipidemia, and hyperglycemia.

Renal Manifestations

Renal Manifestations • Renal biopsy is useful in planning current and near-

future therapies.

• Patients with dangerous proliferative forms of glomerular damage (ISN III and IV) usually have :– microscopic hematuria and proteinuria (>500 mg per 24 h– approximately one-half develop nephrotic syndrome, – and most develop hypertension.

• If diffuse proliferative glomerulonephritis (DPGN) is untreated, virtually all patients develop ESRD within 2 years of diagnosis. Therefore, aggressive immunosuppression is indicated (usually systemic glucocorticoids plus a cytotoxic drug), unless damage is irreversible

Nervous System Manifestations

• Approximately two thirds of patients with SLE have neuropsychiatric manifestations.

• In some patients these are the major cause of morbidity and mortality

• Neuropsychiatric systemic lupus includes :– neurologic syndromes of the central, peripheral, and autonomic nervous

systems,– psychiatric disorders

• The pathophysiology of this broad clinical category is not well understood; proposed mechanisms include :

– vascular occlusion due to• vasculopathy,• leukoaggregation or • thrombosis,

– and antibody-mediated neuronal cell injury or dysfunction


The most common manifestation of diffuse CNS lupus is :

– Cognitive dysfunction, including difficulties with memory and reasoning.

– Headaches are also common. When excruciating, they often indicate SLE flare; when milder, they are difficult to distinguish from migraine or tension headaches.

– Seizures of any type may be caused by lupus; treatment often requires both antiseizure and immunosuppressive therapies.

– Psychosis can be the dominant manifestation of SLE; – Acute confusional state : the syndrome covers a wide

spectrum ranging from mild alterations of consciousness to coma.

– Myelopathy is not rare and is often disabling; rapid immunosuppressive therapy starting with glucocorticoids is standard of care.


• Examination of the cerebrospinal fl uid is useful to rule out infection.

• Computerized tomography is sufficient for the initial diagnosis of most mass lesions and intracranial hemorrhages.

• The findings of magnetic resonance imaging (MRI) reflect the histopathologic findings of vascular injury and may involve the white or gray matter – Abnormalities on MRI are more likely with focal findings. – Unfortunately, the correlation between MRI fi ndings and

clinical presentation is low.

CARDIOVASCULAR INVOLVEMENT

• A variety of cardiac manifestations can be seen in SLE :

– Pericarditis is the most common (6% to 45%) : pericardial effusions may be asymptomatic and are usually mild to moderate; tamponade is rare, but can occur.

– Myocardial involvement is rare (<5 -10% of patients) and typically occurs in the presence of generalized SLE activity

– Endocarditis : Libman–Sacks endocarditis– Accelerated atherosclerosis is an important cause of morbidity

and mortality in SLE• The proportionate mortality from myocardial infarction is

approximately 10 times greater in patients with SLE than in the general age- and sex-matched population.

CARDIOVASCULAR INVOLVEMENT

• Pericarditis : – there is a substernal or pericardial pain, a pericardial rub– the electrocardiogram may show the typical T-wave abnormalities,

echocardiography is the best diagnostic test– Importantly, when a young woman presents with shortness of breath

and pleuritic chest pain, the differential diagnosis must include SLE, and the patient should be tested for ANA.

• Primary myocardial involvement (myocarditis): – fever, dyspnea, palpitations, heart murmurs, sinus tachycardia, ventricular

arrhythmias, conduction abnormalities, or congestive heart failure.

• Endocarditis– Libman–Sacks, is the classic cardiac lesion of SLE– atypical verrucous endocarditis is comprised of verrucous vegetations ranging

from 1 to 4 mm in diameter, initially reported to be present on the tricuspid and mitral valves

– prophylactic antibiotics for surgical and dental procedures have been recommended for all SLE patients.

Pleura and Lungs• Pleura and lungs are commonly affected in SLE, but are generally not as

life threatening as the renal and central nervous system complications.

• Pulmonary involvement includes :– pneumonitis, – pulmonary hemorrhage,– pulmonary embolism,– pulmonary hypertension

• Pleurisy is a more common feature of serositis than pericarditis : over 30% of patients have some form of pleural disease in their lifetime

– Pleural effusions are most often small and bilateral– The pain of pleuritis can be quite severe and must be distinguished from

pulmonary embolus or infection.– The fluid is usually clear, exudative with increased protein, normal glucose, white

blood cell count <10,000, a predominance of neutrophils or lymphocytes, and decreased levels of complement.

Antiphospholipid AntibodySyndrome

• Antiphospholipid syndrome (APS) is an autoimmune disease associated with recurrent arterial or venous thromboses, pregnancy losses, livedo reticularis, and mild thrombocytopenia.

• Patients who have antiphospholipid antibodies and one of the above clinical features in the absence of any other manifestations of SLE are classified as having primary antiphospholipid syndrome (APS) – Anticardiolipin antibody – Lupus anticoagulant

• Alternatively a patient can have these antibodies in the context of SLE (secondary APS).

Drug-Related Lupus• The term drug-related lupus (DRL) refers to the development of a

lupuslike syndrome which follows exposure to :– chlorpromazine, hydralazine, isoniazid, methyldopa, minocycline,

procainamide, or quinidine, anti – TNF

• There are no specified ACR criteria for DRL, but in general these patients present with fewer than four SLE criteria.

• Drug-related lupus patients frequently present with constitutional symptoms such as malaise, low grade fever, and myalgia, which may occur acutely or insidiously; articular complaints are present in over 80%, with arthralgia being more common than arthritis

• Typically the ANA is a diffuse-homogenous pattern, which represents binding of autoantibodies to chromatin that consists ofDNA and histones. Anti-dsDNA and anti-Sm are not characteristic of DRL.

Neonatal Lupus• This illness of the fetus and neonate is considered a model

of passively acquired autoimmunity, in which immune abnormalities in the mother lead to the production of anti-SSA/Ro-SSB/La antibodies that cross the placenta and presumably injure fetal tissue

• The incidence of neonatal lupus in an offspring of a mother with anti-SSA/Ro antibodies is estimated at 1% to 2%.

• The most serious manifestation is damage to the cardiac conducting system resulting in congenital heart block (CHB), which is most often third degree. – CHB is generally identified between 16 and 24 weeks of

gestation. – The mortality rate is ∼20% and– The majority of children require pacing.

LABORATORY FEATURES• Hematologic Abnormalities

• ANEMIA :– Autoimmune hemolytic anemia is present in <10% of patients.– A Coombs test can be positive (both direct and indirect) without active

hemolysis.– A nonspecific anemia reflecting chronic disease is present in up to 80% of

patients

• LEUKOPENIA : – Leukopenia is seen in over 50% of patients. – Absolute lymphopenia (<1500/mm3)

• THROMBOCYTOPENIA :– can be modest (platelet counts of 50,000–100,000/mm3), chronic and totally

asymptomatic,– or profound (<20,000/mm3) and acute, with gum bleeding and petechiae. – Moreover thrombocytopenia can be the initial presentation of SLE,

antedating the development of other symptoms or signs by years. Any young woman presenting with “idiopathic” thrombocytopenia should be evaluated for SLE.

LABORATORY FEATURES

• The erythrocyte sedimentation rate is frequently elevated in SLE and is generally not considered a reliable marker of clinical activity.

• A rise in the C-reactive protein may be an indicator of infection, but this has not proven to be absolute.

LABORATORY FEATURES

• SEROLOGIC PARAMETERS:

– Complement proteins,– Antibodies– Immune complexes

Treatment

● Patient education – Crucial to optimizing clinical outcomes, as with any chronic illness.

● Identify concomitant conditions – Treat conditions that could contribute to fatigue, particularly hypothyroidism, anemia, fibromyalgia, and depression.

● Photoprotection – Patients who are photosensitive should be instructed to avoid excessive exposure to sunlight and routinely wear sunscreen and photoprotective clothing.

● Review prescription drugs – Some can exacerbate photosensitivereactions and other manifestations of systemic disease..

Treatment

● Infections – Common in lupus; patients should be advised to seekmedical attention urgently for unexplained fevers.

● Pregnancies – Considered high risk, because of potential disease flares in the mother and risk to the fetus. Anti-Ro/SSA and antiphospholipid antibodies are of particular concern.

● Cardiovascular disease – People with SLE are at increased risk for coronary artery disease. Attention to risk factors (e.g. hyperlipidemia, hypertension) and to primary and secondary prevention measures is important.

● Osteoporosis – Glucocorticoids and periods of inactivity because of active disease heighten the risk of poor bone health.

Treatment

• NSAIDs• Glucocorticoids• Antimalarials• MTX• Cyclophosphamide • Azathioprine • Mycophenolate mofetil

Treatment

• NSAIDs – – Used widely for the treatment of

musculoskeletal complaints, pleuritis, pericarditis, and headache.

– Adverse effects of NSAIDs – Effects on the kidneys, liver, and central nervous system that may be confused with worsening lupus activity.

Treatment

• Glucocorticoids –

– Effective in the management of many different manifestations of SLE.

– Topical or intralesional preparations – Often used for cutaneous lesions.

– Intra-articular glucocorticoids – Used occasionally for arthritis.– Oral or parenteral therapy – Used for the control of systemic

disease.• Low dose – Oral administration, ranging from 5 mg to 30 mg

prednisone daily, in single or divided doses, is effective in treating constitutional symptoms, cutaneous disease, arthritis, and serositis.

• Higher dose – More serious organ involvement, particularly nephritis, cerebritis, hematologic abnormalities, or systemic vasculitis, generally requires high-dose prednisone, 1–2 mg/kg/day.

Treatment

• Antimalarials – – Some of the most commonly described

medications for SLE.– Include hydroxychloroquine, chloroquine, and

quinacrine.– Uses – Frequently used in the management

of constitutional symptoms, cutaneous and musculoskeletal manifestations, and in some cases, serositis.

Treatment• Cyclophosphamide – The mainstay of treatment for

severe organ - system disease, particularly lupus nephritis.

• Methotrexate – Continues to be used most commonly as a steroidsparing agent for milder manifestations of disease. Particularly helpful in the arthritis of SLE

• Azathioprine – Used as an alternative to cyclophosphamide for treatment of nephritis or as a steroid-sparing agent for nonrenal manifestations

• Mycophenolate mofetil – Now preferred to both cyclophosphamide and azathioprine for the management of moderate renal disease. Also used empirically for other SLE manifestations.

Treatment

• Methotrexate :

– numerous case series and few retrospective studies have demonstrated success in the treatment of active cutaneous and/or articular involvements, allowing corticosteroid taper

– the methotrexate is given in the range of 7.5 to 15 mg/week

– Methotrexate should therefore be discontinued 6 months prior to pregnancy, regardless of the patient’s gender.

Treatment

• Cyclophosphamide :• It is reserved for the treatment of

severe SLE, including lupus nephritis, central nervous system disease, pulmonary hemorrhage, and systemic vasculitis

Vascular Occlusions • The prevalence of transient ischemic attacks, strokes, and

myocardial infarctions is increased in patients with SLE. These vascular events are increased in, but not exclusive to, SLE patients with antibodies to phospholipids (aPL). It is likely that antiphospholipid antibodies are associated with hypercoagulability and acute thrombotic events, whereas chronic disease is associated with accelerated atherosclerosis. Ischemia in the brain can be caused by focal occlusion (either noninflammatory or associated with vasculitis) or by embolization from carotid artery plaque or from fibrinous vegetations of Libman-Sacks endocarditis. Appropriate tests for aPL (see below) and for sources of emboli should be ordered in such patients to estimate the need for, intensity of, and duration of anti-inflammatory and/or anticoagulant therapies.

Vascular Occlusions • . In SLE, myocardial infarctions are primarily manifestations of

accelerated atherosclerosis. The increased risk for vascular events is seven- to tenfold overall, and higher in women <45 years old with SLE. Characteristics associated with increased risk for atherosclerosis include older age, hypertension, dyslipidemia, dysfunctional proinflammatory high-density lipoproteins, repeated high scores for disease activity, high cumulative or daily doses of glucocorticoids, and high levels of homocysteine. When it is most likely that an event results from clotting, long-term anticoagulation is the therapy of choice. Two processes can occur at once—vasculitis plus bland vascular occlusions—in which case it is appropriate to treat with anticoagulation plus immunosuppression. The role of statin therapies in SLE is being investigated.

ILLUSTRATIVE CLINICAL CASE

• JG, 24 year old, white female;

• She presents with a 3 month history of fatigue and pain in her wrists, fingers and left knee;

• She has also noted an increased sensitivity to sunburn and this past winter she experienced pain in her fingers on exposure to cold, stating that her fingers turned colors when they were cold.

PLEURA AND LUNGS

• The most common pleuropulmonary manifestation of SLE is pleuritis.

• Pleuritic pain is present in 45% to 60% of patients and may occur with or without a pleural effusion. Clinically apparent pleural effusions have been reported in 50% of patients with SLE and may be found in 93% of cases at autopsy.

• Effusions are usually bilateral, but may be unilateral, equally distributed between the left and the right hemithoraces.

• Pleural effusions in SLE are invariably exudative, but with higher glucose and lower lactate dehydrogenase levels than those found in rheumatoid arthritis


• Past Medical History: • Asthma, currently controlled with theophylline • Spontaneous abortion x2 • Febrile seizures as a child, treated with phenobarbital x3 years • Social History: • Smokes 1 pack/day, no Etoh, 3-4 cups of coffee/day • Physical Exam: • WNWD female in NAD • Weight 135lbs • BP 120/75 • Malar rash, swelling of wrists and MCPs bilaterally and Left knee


• Medications: • Theophylline 300mg tid • LoOvral (started 4 months ago) • Multivitamin qd • Acetaminophen prn for pain • Laboratories: • Hct/Hgb 35/10.2 MCV 92 • ANA +1:1280 speckled pattern • + ds DNA, + anticardiolipin antibody • PTT 50, PT 11.2 (Control 11.6) • UA 1+ protein, negative for glucose/blood/casts


1. What signs and symptoms does she have that are consistent with SLE?

2. Could her illness be drug-induced?

3. Formulate a treatment plan for this patient, including drugs, doses and monitoring parameters.

4. What parameters should be monitored in this patient?


• -fatigue-Raynaud's

• -arthralgias

• -+ANA in speckled pattern*/dsDNA Ab*-malar rash

• -photosensitivity

• -h/o spontaneous abortion (seen with "lupus anticoagulant")


• Unlikely to be drug-induced lupus because: • Phenobarbital: given too long ago • Theophylline: not associated with SLE or DIL • Lo-Ovral: oral contraceptives are implicated in

unmasking idiopathic lupus but are not thought to cause drug-induced lupus. Other factors against this being DIL are the presence of a speckled ANA pattern (with DIL generally see a homogenous pattern) and the + ds DNA antibody (in DIL see ssDNA).


• General: • Birth control pills should be discontinued and some alternate form of

contraception initiated since the onset of SLE may have been triggered/exacerbated by the BCP.

• Arthralgias: • can be treated with NSAIDs, e.g. naproxen 375mg tid. Avoid ibuprofen as

first choice NSAID because of association with aseptic meningitis in patients with SLE. If symptoms do not respond to an adequate trial of NSAIDs, would consider starting hydroxychloroquine 200mg bid. Systemic steroids are not indicated for treatment of lupus arthritis alone and patient has no other indications for systemic steroids at this time.

• Raynaud's: • try non-drug measures first: stop smoking, wear gloves/mittens, avoid

cold/precipitating factors. If necessary, nifedipine 10mg bid to tid (or 30mgXL qd) is drug of choice. If symptoms are not constant/severe, patient may taken nifedipine prn. If patient unable to tolerate nifedipine, can try diltiazem or isradipine.


• Malar rash: • if bothersome to patient can be treated with low potency topical steroid, i.e.

1-2.5% hydrocortisone cream; otherwise need not treat. • Lupus anticoagulant: • patient does not have history of thrombosis. Presence of this antibody

increases risk of stroke or thromboembolism. Patients with strong evidence (e.g. history of CVA/DVT/PE) can be treated prophylactically with coumadin. In patients like JG less risky measures are sometimes used, e.g. low-dose aspirin. Corticosteroids will also decrease risk for these patients by decreasing antibody formation, but long term toxicity usually precludes their use. The lupus anticoagulant may also be associated with recurrent spontaneous abortions. If JG wishes to get pregnant, this should be addressed prior to conception, due to her past history 2 miscarriages.

• Photosensitivity: • use sunblock with SPF > 15 that blocks both UVA and UVB light • Proteinuria: • minimal, doesn't require treatment at this time, however, should be

monitored carefully


• Rash • Arthralgias • Proteinuria monitors of disease activity • Fingers for digital ulcers • Anemia • Renal function (BUN/Cr) if on NSAIDs • Eye exams every 6 months if on antimalarials

monitors of drug toxicity • Blood pressure if on drug therapy for Raynaud's

2014 - SLE Lecture

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