LUPUS AND RELATED DISORDERS

I. Epidemiology

  1. Prevalence 2.9-400/100,000 depending on population
  2. Female:male 7-9:1
  3. Typical age at onset 20-50yo
  4. More commmon in people of African or Asian descent
  5. Familial predisposition
  6. Associated with HLA types DR2, DR3 (associated with deficiencies of early complement components which are involved in clearing circulating immune complexes)

II. Diagnosis

  1. American College of Rheumatology criteria. Established 1982. Four or more, together or in sequence, makes diagnosis for clinical studies; clinical diagnosis can be somewhat looser--some patient who go on to meet criteria do not do so early on in the course of the illness.
  1. Malar rash: fixed erythema, flat or raised, over malar eminences, tending to spare the nasolabial folds
  2. Discoid rash: erythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions
  3. Photosensitivity: Skin rash as a reaction to sunlight, by pt hx or clinicial observation
  4. Oral or nasopharyngeal ulcers: Usually painless, observed by clinician
  5. Arthritis: nonerosive arthritis involving 2 or more peripheral joints, with tenderness, swelling, or effusion
  6. Serositis: either of
  1. Pleuritis-pleuritic pain, rub heard by clinician, or evidence of pleural effusion
  2. Pericarditis-evidence on EKG, rub heard by clinician, or evidence of pericardial effusion
  1. Renal involvement: either of
  1. Persistent proteinuria > 500mg/d or >3+
  2. Cellular casts, any type
  1. Neurologic disorders: either of
  1. Seizures-not caused by drugs or known metabolic derangement
  2. Psychosis-not caused by drugs or known metabolic derangement
  1. Hematologic disorder: any of
  1. Hemolytic anemia with reticulocytosis
  2. Leukopenia < 4,000 on 2 or more occasions
  3. Lymphopenia < 1,500 on 2 or more occasions
  4. Thrombocytopenia < 100,000 not caused by drugs
  1. Immunologic disorder: any of
  1. Positive LE cell preparation
  2. Anti-DNA antibodies in abnormal titer
  3. Anti-Sm antibodies
  4. False-positive serologic test for syphilis known to be positive for at least 6 mos
  1. Antinuclear antibody: in abnormal titer, in absence of drugs known to cause "drug-induced lupus"
  1. Serologic studies
  1. ANA: current tests using human cell lines will result in positive ANA in > 99% of SLE pts. However, highly nonspecific; also, titer does not corelate with disease activity
  1. Anti-DNA: used in monitoring disease activity; titer of anti-ds-DNA correlates with risk of nephritis
  2. Anti-Sm: highyl specific for lupus
  3. Anti-Ro (anti SSA)
  4. Anti-La (anti SSB)
  5. Anti-histone (seen in systemic and drug-induced lupus)
  1. Antiphospholipid antibodies (anticardiolipin Ab, lupus anticoagulant)
  2. Complement studies (CH50, C3, C4): used in monitoring disease activity
  3. Immune complex assays (C1q binding, Raji cell assay)
  4. Other: anti-neuronal, anti-ribosomal P, rheumatoid factor, false pos. RPR

III. Clinical Features-n.b. many lupus pts at increased risk for infection b/c of chronic steroids, so keep infection on differential for diff. organ system derangements!

  1. Sx on initial presentation:
  1. Arthritis or arthralgias 56%
  2. Skin involvement 20%
  3. Nephritis 5%
  4. Fever 5%
  5. Neurologic manifestations--Uncommon on inital presentation in adults but not in children (chorea, quadriplegia, dizziness, etc.--J. Peds. 135:500, 1999--JW)
  1. Dermatologic manifestations-70% of SLE pts
  1. Skin in involved and uninvolved areas shows positibe "LE band test" which is IgG and complement at dermal-epidermal junction
  2. Malar rash: see above; photosensitive; non-scarring but may develop telangiectasias with time. Also seen a similar erythematous rash in "V" region of neck and with erythema of periungual regions
  3. Discoid rash: see above; seen in 30% of pts with SLE, also in discoid lupus which is limited to the skin. Does scar; can get hyperpigmentation during "active phase" then hypopigmentation during "atrophied phase."
  4. Vasculitis skin lesions-multiple forms; may show as nonblanching erythematous lesions on fingers and palms.
  5. Livedo: Lacy bluish-red venular pattern, often associated with antiphospholipid antibodies. Particularly associated with cerebrovascular thrombosis or other CNS manifestations
  6. Subacute cutaneous lupus lesions: annular, nonscarring; may be seen in the subacute cutaneous form of LE
  7. Alopecia: 40% of SLE pts; reversible with treatment unless associated with discoid lesions. Us. see broken or short hairs along frontal hairline.
  8. Oral ulcers: see above; 15% of pts will get them; often on hard palate. Can become painful if superinfected, but pt usually unaware.
  9. Urticaria: may occur
  10. Purpura: seen with thrombocytopenia
  1. Musculoskeletal manifestations
  1. Synovitis-90% of SLE pts
  1. Symmetrical, with morning stiffness. Easily confused with early RA
  2. Hands most involved with fusiform swelling of PIP's; also MCP's, then wrists and knees
  3. Get ligamentous laxity, so ulnar deviation is seen; sometimes also swan-neck deformities
  4. Get little bone destruction
  1. Avascular necrosis
  1. Most common cause of musculoskeletal disability in SLE
  2. Most common in femoral head, often bilateral
  3. Also seen with humeral head, femoral condyles
  4. Steroid Rx compounds risk
  1. Myopathy: inflammatory or secondary to meds (steroids or antimalarials)
  1. Renal manifestations: lupus nephritis (almost all have histologic changes; 50% of pts will have clinically significant involvement)
  1. Renal failure is the main cause of death from SLE
  2. Immune complex deposits in glomerular basement membrane
  3. Often see proteinuria or cellular casts in urine sediment
  4. WHO classification: six pathologic groups:
  1. Normal glomeruli
  2. Pure mesangial nephritis
  3. Focal segmental glomerulonephritis
  4. Diffuse proliferative glomerulonephritis
  5. Membranous glomerulonephritis
  6. Advanced sclerosing glomerulonephritis (irreversible)
  1. Cardiovascular manifestations
  1. Pericarditis: most common cardiac complication. Tamponade is rare
  2. Myocarditis: can cause CHF, arrhythmias
  3. Liebman Saks endocarditis: non-infectious; little clinical significance though may cause some AR and MR. Vegetations left on valves, however, may predispose to bacterial endocarditis
  4. Coronary artery disease: major cause of morbidity/mortality in SLE pts; accelerated coronary atherosclerosis c/w non-SLE pts; MI's do occur in young SLE pts
  5. Raynaud's: 20% of pts will get it
  1. Hematologic manifestations
  1. Anemia: Coomb's positive hemolytic anemia; also, "anemia of chronic disease"
  2. Leukopenia: usually due to lymphopenia; not associated with increased risk of infection on its own
  3. Lymphopenia: due to SLE or to steroid use
  4. Thrombocytopenia: us. mild; if severe, us. responds to steroids or splenectomy
  5. Hypercoagulability: us. associated with APlAb's
  1. Nervous system involvement; 15% will get, though possibly many more (about 80%) will have subtle cognitice impairment
  1. Keep in mind infection as a cause of CNS sx, esp. in pts on chronic steroids
  1. Pathophysiology of CNS manifestations of SLE
    1. True vasculitis caused by immune-complex deposition occurs but is absent in most pts with "lupus cerebritis"
    2. Many pts with SLE have an autoantibody that binds to the NMDA neurotransmitter receptor in the CNS (Nature Medicine 7:1189, 2001--JW)
  1. Focal involvement-often due to vasculitis or thrombosis
  1. Sz
  2. CVA
  3. Migraines
  1. Diffuse involvement-may be associated with antineuronal Ab's and anti-ribosomal P
  1. Psychosis
  2. Cognitive impairment
  1. Peripheral involvement-15% of pts will get mononeuritis multiplex with stocking-glove paresthesias
  1. Pulmonary involvement
  1. Pleuritis: most common pulmonary manifestation
  2. Acute pneumonitis and parenchymal hemorrhage: difficult to distinguish from infection; usually no hemoptysis
  3. Shrinking lung syndrome: myopathy of diaphragm leading to poor lung expansion; get dyspnea when recumbent
  4. Interstitial lung involvement: uncommon
  1. Reproductive
  1. Elevated risk of miscarriage and stillbirth (30-50%); poss. due to APlAb sd.
  2. Neonatal lupus syndrome
    1. Most common in infants of mothers positive for anti-Ro/SS-A
    2. Consists of auto-immune effects in baby related to passive transfer of maternal autoantibodies
    3. Most common clinical features include cutaneous manifestations and congenital heart block
    4. Cutaneous manifestations are usually transient
    5. Cardiac manifestations are often irreversible and can cause early cardiac death
    6. In a case series of 58 mothers of a child with neonatal lupus syndrome and at least one subsequent pregnancy, 49% of the subsequent pregnancies had some neonatal lupus manifestation (18% with cardiac features, 30% with cutaneous features, and 1% with hematologic/hepatic features). (Arth. Rheum. 62:1153-JW)
  3. Pregnancy may or may not induce flares; no clear evidence
  1. Other systems:
  1. GI: rare involvement from SLE; Rx, however, can cause problems; rarely, SLE causes serositis and ascites and vasculopathy of GI tract; 15% will have abnormal liver functions but unclear if disease or drugs
  2. Spleen: SLE pts often functionally asplenic!

IV. Initial workup

  1. CBC to look for leukopenia, thrombocytopenia, and anemia
  2. Urinalysis to look for proteinuria and casts
  3. CXR to look for pleural effusion and pulmonary infiltrates
  4. Serum creatinine (or CrCl) to assess renal function

V. Treatment

  1. Antimalarials
  1. Useful in mild disease and for control of skin manifestations
  2. Hydroxychloroquine (Plaquenil) 200-400 mg/d--can cause rash, GI disturbance, and retinal toxicity (ophthalmologic monitoring often advised)
  1. Corticosteroids
  1. A mainstay of tx
  2. Dose according to disease activity; often as low as 5-20 mg/d prednisone
  3. Higher doses with disease flare (40-100mg/d prednisone)
  4. Pulse rx with accelerated end-organ damage (1g methylprednisolone IVQD x 3d)
  5. See section on steroids (link above) for more info, including on prevention of steroid-associated osteoporosis
  1. Cytotoxic agents
  1. Used mostly in steroid-resistant cases or nephritis of proliferative/inflammatory histology or with CNS involvement
  2. Usually given in addition to high dose steroids
  3. Usually cyclophosphamide IV Q mo.
  4. Azathioprine also used
  1. Biologics
    1. Belimumab (Benlysta)
      1. Human IgG-1 gamma monoclonal Ab against human B lymphocyte stimulator protein (BLyS)
      2. Blocks binding of soluble BLyS to B cells, thus inhibiting B cell survival (including the autoreactive B cells involved in the pathophysiology of SLE), and reduces differentiation of B cells into plasma cells
      3. Associated with improved disease severity scores when used as adjunct to standard SLE therapy e.g. corticosteroids, antimalarials, and immunosuppressives, in placebo-controlled trials.
      4. However, package insert refers to higher mortality in clinical trials with belimumab c/w placebo (!)
      5. Also may cause immunosuppression
  2. Plasmapheresis has been used
  3. NSAIDS for symptomatic control of arthralgias
  4. Topical steroids may help with malar & discoid rash
  5. Ca-channel blockers may help with Raynaud's syndrome
  6. Sun avoidance and sunblocks if photosensitive
  7. Psychotherapy, vocational counseling, etc. as indicated

VI. Drug-induced lupus

  1. Drugs known to cause it:
  1. Hydralazine
  2. Procainamide
  3. Isoniazid
  4. Anticonvulsants
  5. Quinine
  6. Alphamethyldopa
  7. Antithyroid drugs
  8. Beta-blockers.
  1. Will be ANA-positive and us. have anti-histone Ab's
  2. Clinical presentation
  1. Serositis, arthralgias, constitutional sx common
  2. Rarely see CNS or renal involvement
  1. Improves over months with withdrawal of drug; ANA may remain positive for years

VII. Discoid lupus-limited to skin manifestations

VIII. Subacute cutaneous lupus-extensive non-scarring skin lesions. Often have anti-Ro Ab's, leukopenia, arthritis and fatigue; no renal or CNS involvement

(Source: talk by Joyce Gauthier, 1994; notes from Phil Mease, and other sources as cited)