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Rheum Round Skin Disease in SLE Dr. Emily Ching April 18

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					Rheumatology Round
Skin Disease in Lupus
Dr. Emily Ching, PGY-1
April 18, 2006

Outline
    

Case Classification Pathogenesis Diagnosis Treatment

Case


Mrs. L 49 F with SLE admitted with multiple open ulcerations and severe distal extremity pain. Long standing SLE x12-13 yrs – mostly discoid lupus, positive serology (ANA, antidsDNA) on Plaquenil & Predisone Skin biospy showed chronic inflammation of epidermis & dermis  suggestive of discoid lupus flare





Skin Disease in Lupus
  

Acute Cutaneous LE (ACLE) Subacute Cutaneous LE (SCLE) Chronic Cutaneous LE (CCLE)


 
 

Discoid LE Hypertrophic LE Lupus Profundus Mucosal LE Palmar-plantar LE



Skin lesions in LE and other diseases

 

Vasculitis Alopecia Others



Photosensitivity

Acute Cutaneous Lupus Erythematosus
(ACLE)
Most typical – flattened areas of red skin on the face that resemble a persistent sunburn. Typically do not produce scarring Often seen in people who have active, sometimes severe, SLE



 

Malar Rash

Subacute Cutaneous Lupus Erythematosus (SCLE)
Non-itchy Do

dry rash

not scar

– sun exposed areas Types:
Photosensitive



Annular/polycyclic




Annular or polycyclic (ring-shaped) - 42% Papulosquamous (scaly bumps) Vasculitis (purple spots) Nodular (lumps)
Papulosquamous

Chronic Cutaneous Lupus Erythematosus (CCLE)
Discoid


lupus (DLE)

most common form of CCLE Painless & non-itchy Scarring & discoloration Coin shaped predominantly affects the face and scalp (80%), but can be seen at other parts of body.
When DLE lesions occur in the scalp, permanent hair loss (alopecia) can result.  Risk of developing SCC
Scarring alopecia

  

Widespread discoid LE





Chronic Cutaneous Lupus Erythematosus (CCLE)
Hypertrophic

or

verrucous LE


results in thickened and warty skin resembling warts or skin cancer
Hypertrophic plaques

Lupus Profundus  aka “lupus panniculitis”


Lupus profundus

affects the fat underlying skin
face mostly affected. chronic inflammation of fat cells results in results in firm deep nodules and dented scars
Lip ulceration Palmar-plantar LE

 

Mucosal DLE Palmar-plantar DLE

Skin lesions in LE and other diseases
Vasculitis


Cutaneous vasculitis – damage of small vessels





Typically palpable purpura – lower extremities Rarely larger knots (nodules) and ulcers can develop.

Vasculitis
Alopecia areata

Alopecia





Non-scarring hair loss Telogen effluvium – severely ill SLE pt may develop a temporary pattern of hair loss which is replaced by new hair growth “lupus hair” – severe flare of SLE can result in fragile hair that breaks easily

Skin lesions in LE and other diseases
Raynaud’s with digital infarcts

 Others
  

Raynaud's phenomenon Telangectasia calcinosis (calcium deposits in the skin)
rheumatoid nodules

 

livedo reticularis

Telangectasia at nailfolds

Photosensitivity


~ 40-70% of LE pts noted their cutaneous and/or systemic disease is aggravated by sun exposure.
SCLE lesions are more likely to be worsened by sunlight exposure than DLE lesions.

 

Ultraviolet B (UV-B) rays in sunlight are particularly bad for LE patients. Longer wavelength ultraviolet A (UV-A) rays can also aggravate cutaneous LE, especially SCLE.



Pathogenesis
 Genetic

association

 Environment
 Cellular

Immune Mechanisms Immune Mechanisms

 Humoral

Pathogenesis: Genetic
 Mainly
 


FcRIIA – 1q23 IL-10 & Ro-60 – 1q31 MHC class III – 6p21.3

on long arm of chromosome 1

 HLA
 

ACLE – HLA-DR2, HLA-DR3 SCLE – HLA-DR3, HLA-DRw52, HLA-DQ1, HLA-DQ2

subtypes

 Complement



SCLE – C2 & C4 DLE & LE panniculitis – C1q, C3 & C5

deficiency (MHC-class III)

Pathogenesis: Genetic
 TNF
 

and TNF (MHC-class III)



SCLE & SLE – higher 308A form of TNF UVB activates 308A form of TNF promoter regions   TNF levels A role for TNF in the UV-induced flares seen in photosensitive forms of SLE

 Heat


Shock Protein (MHC-class III)

Increase expression in Hsp70
  binding of anti-Ro Ab to keratinocytes  exacerbate CLE

Pathogenesis: Environment


UV light exposure


70% SLE, 63-100% SCLE, 64% DLE pts have a pathologic photoprovocation reaction when exposed to UVA and UVB lights. Irradiation of keratinocytes with UVB  TNF
 induces apoptosis of keratinocytes  translocation of nuclear Ag (Ro, La, RNP, Sm) to cell membrane   production of auto-Ab (anti-Ro, anti-La, anti-snRNP, & antiSm)





Time dependent – Anti-Ro, Anti-La, U1RNP appeared 20-24 hrs post keratinocytes UVB irradiation.

Pathogenesis: Cellular Immunity
T


lymphocytes
DLE lesions are characterized by a dense junctional and perivascular T cellular infiltrate. Immunofluorescence double staining for CD8 (green) and CCR4 (red) revealed the presence of CCR4-expressing CD8+ T cells in the upper dermis



Wenzel et al. J Invest Dermatol 124:1241-48, 2005

T-cell cytokine network in CLE

The presence of IL-5 mRNA in CLE suggests that Th2 combine with local IFN production to augment disease by increasing ICAM adhesion expression.
Stein et al. J Am Acad Dermatol 1997; 37: 191-6

Pathogenesis: Humoral Immunity
 Ro/SSA


– 2 components

60 kd RNA-binding protein -> transcription regulation



52 kd peptide -> T-cell regulator 48 kd peptide  transcription termination factor of RNA polymerase III

 La/SSB


Pathogenesis: Humoral Immunity
 UVB-induced


apoptosis of keratinocytes

Calreticulin, Ca2+-binding autoantigens appear on surface blebs of epidermal keratinocytes Calreticulin binds to 52-kd Ro & hYRNA, RNA backbone of Ro ribonuclear particles Calreticulin bridging facilitates the binding of 60 kd Ra protein with hYRNA Formation of Ro autoantigens Epitope spreading results in antibody response









Diagnosis: ACLE
 

100% pts developing SLE Distribution
 

Localized – malar rash Generalized – photosensitive lupus dermatitis



Serology
 

95% ANA positive Often anti-dsDNA & anti-Sm positive



Histology


granular immune deposition (C1q) at the dermalepidermal junction & around superficial dermal vasculature.

Diagnosis: SCLE


Characteristics

  

67-60% pts have extracutaneous signs of SLE more photosensitive subset of CLE usually presents at 3rd or 4th decade of life F:M = 3-4:1



Serology
 



70-80% ANA positive 50-71% anti-Ro/SSA positive only ~5% anti-dsDNA positive



Histology


Interface lichenoid dermatitis with suprabasilar excytosis of lymphocytes showing necrotic spinous layer of keratinocytes



“dust-like particles” of IgG deposition on DIF at dermal-epidermal junction is specific in SCLE

Diagnosis: CCLE


Characteristics

 

5-10% pts develop SLE Generalized skin  severe systemic involvement 15% pts has Raynaud’s phenomenon



Serology


Lower tendency to be positive for ANA, dsDNA, Sm, U1RNP, and Ro/SSA but positive serology correlates worse prognosis



Histology
 

Most common immune deposits are C3 & IgM at dermalepidermal junction. C1q deposits are found in 88% of DLE who have concurrent SLE

Treatment
 Goal
 

of treatment in CLE

Prevent scarring Improve patient appearance

 General/Conservative
 

 


Smoking cessation Drug avoidance – if drug induced. Sun-protection clothing Sunscreen protection – both UVA & UVB (SPF 30+) Cosmetic Camouflage – disguise unsightly plaques

Treatment - Topical
 Steroids
 





Face – low-potency (hydrocortisone, aclomethasone) Trunk & arms – mid-potency (betamethasone valerate) Soles & palms – high-potency (halobetasol, betamethasone disproporationate) SE – prolonged use  impair collagen synthesis  skin atrophy & telangectasia

– localized CCLE

Treatment - Topical
 Macrolides (Tacrolimus or Pimecrolimus)


Immunomodulator
 inhibits calcineruin activity  inhibits T lymphocytes  inhibits IL-2, IL-3, IL-4, TNF, GM-CSF

 

Anti-inflammatory action SE – burning sensation, itchy, erythema

Topical tacrolimus therapy of resistant cutaneous lesion in LE


Case report n=12 (6-DLE, 4-SCLE, 2-SLE)  All pts had extensive skin lesion refractory to previous treatment  0.1% tacrolimus x >6wk  11 pts complete tx, 6 pts clearly improved, 1 pt partial response, 4 pts unchanged. Lampropoulos et al. Rheumatology 2004;43:1383-85

Pimcrolimus 1% cream for cutaneous LE

P<0.001

Clinical score based on erythema, infiltration & squamation (0-normal, 1-slight, 2-mod, 3-severe)

Kreuter et al. J Am Acad Dermatol 2004;51:407-10

Treatment - Laser
 Treat

superficial localized lesions

 Argon

laser – effective in treating vascular lesions (telangectasia) ~70% clearance rate laser – treat scarring 2o to CCLE – temporary hyperpigmentation, 2530% usually resolves in 2-3 months

 CO2

 SE

Treatment - Oral
 Antimalarial


Interferes digestive vacuole function by increasing the pH and interfering with lysosomal degradation
 impairs Ag presentation



inhibits locomotion of neutrophils and chemotaxis of eosinophils impairs complement-dependent antigenantibody reactions



Treatment: antimalarials
 Plaquenil


 

1st line treatment 400mg/d or <6.5mg/kg/d onset of response ~ 6-8 wks

 Quinacrine
 

adjunct if refractory to plaquenil 100mg/d

 Chloroquin



substitute for Plaquenil if refractory <3.5mg/kg/d to reduce eye toxicity

Treatment: Thalidimide
 Reduce  Start

TNF activity and inhibits angiogenesis. at 100mg/d  25-50mg/d for maintenance after remission
response in pts refractory to antimalarial therapy


 Excellent

 SE


peripheral neuropathy potent teratogen in pregnancy

Long-term Thalidomide Use In Refractory Cutaneous Lesion Of Lupus Erythematosus: Case Study (65 Pt)

Clinical Efficacy
• 60 (92.3%) complete response • 3 (4.6%) partial response • remission occurred 2 -12 wks • 28 pts developed neuropathy

Coelho et al. Lupus (2005)14, 434-39

Long-term Thalidomide Use In Refractory Cutaneous Lesion Of Lupus Erythematosus: Case study (65 pt)

Coelho et al. Lupus (2005)14, 434-39

Treatment: Retinoids
Effective

in treating hypertrophic DLE & acral CLE (~50% response rate)

SE  potent teratogen during pregnancy  drug induced hepatitis  Hypertriglyceridemia  DISHS (diffuse idiopathic skeletal hyperostosis syndrome)  Pseudotumor cerebri  Visual disturbance Need

HCG, CBC, lipid profiles, and liver enzymes every month during treatment

Treatment: Dapson
 Effective

in pts with vasculitis LE lesions, nonscarring CLE, bullous LE, and oral ulcerations with Plaquenil – effective in treating DLE


 Combine

 SE
Hemolysis (>10%, dose-dependent) -- in pts with or without G6PD deficiency

Treatment: other oral agents
 Azathioprine


25-50 mg/d 10-20 mg/wk

 Methotrexate


 Cyclophosphamide  Cellcept
 IVIG


1 g/kg/d for 2 consecutive days


				
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