Organ System and ABVP Core
Examination Review Module C : Autoimmune Skin
Disorders
Overview
Autoimmune skin disease is a group of
confusingly similar diseases. In this section, I will present the most
common autoimmune skin diseases and attempt to place them in clinical
perspective. All of the autoimmune skin diseases are treated similarly and
this will be discussed in the last part of this section.
Pemphigus Foliaceus and Discoid Lupus Erythematosus are the
most common autoimmune diseases. You will see them.
- Autoimmunity - a condition characterized by a
specific humoral or cell-mediated immune response against the body's own
tissue.
Normal immune tolerance
Lymphocyte clones that
are capable of recognizing self antigens (skin proteins, DNA, etc) are
selectively killed through a series of cell surface receptor
interactions. The clonal deletion of these autoreactive lymphocytes is
essential to prevent self destruction.
The protein targets in autoimmune skin disease are usually hidden or
masked by the normal tissue and cell architecture. When hidden, these
potential self antigens are not allowed to interact with the immune
system and thus can not become involved in a immune response.
Disease occurs when the process fails.
- Loss of self tolerance
- exposure of previously hidden antigens through tissue damage
such as inflammation, infection, trauma, and neoplasia
- change in T cell activity
- loss of T cell suppression
- self reactive lymphocytes escape into the circulation
- activation of auto-reactive response
- Antigen mimicry can trigger an immune response to autoantigens.
The foreign antigen is similar to a self antigen. When the immune
system reacts to the foreign antigen it also attacks the self antigen
with similar characteristics.
- infectious agents - viral, bacterial, fungal
- environmental agents - insect vectors
- parasitic exposure
- vectors for infectious agents
- increases antigenic exposure
- Genetic influences can also play a role in autoimmunity.
- Familial links have been recognized in several diseases.
- HLA associations may be the link in these diseases and families.
See Article:
Brunner C. Autoimmunity. In Kirk's Current
Veterinary Therapy XII. W.B. Saunders. 1995, P 554-560.
- Clinical Presentation
- Autoimmune skin diseases can show great variation in cutaneous
lesions; however, certain lesion patterns are consistently observed.
Crusts, erosions, and ulcers
- Pustules, vesicles, bulla, papules
- Face
- Foot pads
- Mucus membranes - oral, ocular, genital
Autoimmune Skin Disease: Comparison of Important
Characteristics
- Relative Occurrence
- Pemphigus foliaceous
- DLE
- SLE
- Pemphigus vulgaris
- Bullous pemphigoid
- Pemphigus erythematosus
- Pemphigus vegetans
- Self-Antigen (target of the immune
respnse)
Pemphigus foliaceous = Desmoglein I
Pemphigus
vulgaris = Desmoglein III
Bullous pemphigoid = B.P. Antigen (DP
I)
Paraneoplastic pemphigus = Desmoplakin I = II
- Acantholytic Cells (present on cutaneous
cytology)
Pemphigus complex
- ANA +
SLE
Pemphigus erythematosus
- Systemic Signs
SLE = primary signs
- UV Aggravated lesions
SLE
DLE
Pemphigus
erythematosus
- Facial Lesions (Only or
Predominantly)
Pemphigus erythematosus
DLE
- Oral Lesions
Pemphigus vulgaris
Bullous
pemphigoid
SLE
- Diagnosis
Once suspected, diagnosing autoimmune
skin diseases is somewhat cookbook.
- Cutaneous biopsies are essential and are the
ONLY method to diagnose these diseases
- Histopathology is essential and is diagnostic
most of the time
- Immunofluorescence can be helpful to further classify the
disease if histopathology was not definitive.
- Direct - immunologic agents are applied to the patient's skin
biopsy. Two techniques are commonly used; immunofluorescence and
immunoperoxidase. Each gives similar information; however,
immunoperoxidase stains can be performed on formalin fixed tissue
making the sample collection much easier.
- Indirect - the patient's serum is tested for auto-antibodies.
This technique is used in human medicine and research but not
commonly performed in veterinary practice.
Biopsy technique - histopathology
- Biopsy
- Primary lesions - intact vesicles, bulla, pustules (when
possible)
- lesion margins, crusts, and early papules
- obtain several samples (3-5)
- USE A DERMATOHISTOPATHOLOGIST or someone
highly interested in skin. The skill of the pathologist determines
the quality of the information you receive. To help the process,
you should include a discription of the clinical signs and a list
of rule-outs based on your clinical judgement. A good pathologist
will evaluate the samples and report a diagnosis and discuss your
rule-outs (i.e. No evidence of infection was identified. Based on
the samples and clinical features you provided, Pemphigus is the
most likely differential…).
- Do not surgically prep the biopsy sites as this will destroy the
lesion. Use alcohol to dab the lesion (don't wipe or scrub).
- Do not pinch, squeeze, or even grab the skin biopsy sample, this
will damage the tissue and change the histopathologic features (we
can tell when you did it). Use the forceps to grab the subcutaneous
fat when manipulating the sample.
- Formalin fixation - quickly get the sample into the Formalin
- Histopath results
- depending on the pathologist and biopsy samples the diagnosis
may not be apparent
- read the histopathology description for clues
- acantholysis = pemphigus
- acanthosis = thickened skin not pemphigus
- Provide the pathologist with a clinical description and list
of differential diseases. If the biopsy report is not diagnostic,
consider calling the pathologist to discuss your rule-out list.
- This process is not fail proof. If a diagnosis was not made,
consider repeating the biopsy procedure, consulting a specialist,
or refer the case.
- DO NOT treat without a diagnosis - the animal may be treated
for life
Biopsy technique - immunofluorescence and
immunoperoxidase
- Biopsy intact vesicles & pustules & perilesional skin
- No prep
- Avoid old and chronic lesions
- Media
-
Immunofluorescence
Michel's
fixative (fresh)
-
Immunoperoxidase
- formalin
fixed tissue
False negative results on histopathology and/or
immunofluorescence are often seen due to:
- Absence of recent lesions
- Improper selection and handling of biopsies
- Loss of antigenicity of immunoglobulin deposits
- Prior steroid therapy
- Complete Blood Count, Serum Chemistries,
Urinalysis
- Usually normal in most autoimmune skin diseases
- May show inflammatory changes associated with the primary
disease or secondary infection.
- Identify possible problems before beginning
immunosuppressive therapies (liver disease that could be complicated
by treatment)
- Serve as baseline values for monitoring side effects of
chemotherapy therapy
- Systemic Lupus Erythematosus
- SLE has multiorgan involvement and will often demonstrate
abnormal blood work.
- renal disease - BUN/creatinine
- bone marrow abnormalities - any cell line can be suppressed
- glomerular nephropathy and proteinuria
- Anti-Nuclear Antibody assay
- Positive in SLE and Pemphigus Erythematosus
- 10% of SLE cases can have negative ANA results
- Many false positives
- Pemphigus
- Pathogenesis
Autoantibodies (usually IgG) are directed against
components of the epidermal cell membrane (desmoglein - part of the
desmosome). The binding of the antibodies initiates cellular events
that eventually degrades the desmosomal components and results in
acantholysis (release of the cellular attachments allowing the cell
to float, roundup, and subsequent cleft formation).
Acantholytic
cells (big, purple, fried egg cells) are immature, detached,
keratinocytes that are the hallmark of Pemphigus
diseases. See Articles:
Stanley J. Cell Adhesion
Molecules as Targets of Autoantibodies in Pemphigus and Pemphigoid,
Bullous Diseases Due to Defective Epidermal Adhesion. Advances in
Immunology. Vol 53;291-325,1992/3.
Espana A, Diaz L, Mascaro JM, et
al. Mechanisms of Acantholysis in Pemphigus. Clinical Immunology and
Immunopathology. Vol 85;83-89,1997.
- Forms of Pemphigus Complex
- Superficial-subcorneal intraepidermal pustules
- Pemphigus foliaceus -
- Pemphigus erythematosus
- Deep-suprabasilar intra-epidermal bullae/pustule
- Pemphigus vulgaris
- Pemphigus Foliaceus
- Dogs and cats - PF is the most common autoimmune skin
disease in both
- Lesions (superficial)
1o lesions = papules and
rare pustules
2o lesions = (common) - erythema,
crusts, scales, alopecia, erosions
+
pain/pruritus - variable (not usually as itchy as
allergy)
systemic signs uncommon
secondary pyoderma may be
present
pet usually feels good
- Distribution may involve:
Nasal planum - +/-
mucocutaneous junctions
Ear pinnae - not an
otitis externa but rather on the pinnae
Footpads
(hyperkeratotic) - may be only sign
Total body - general
distribution
*oral mucosal involvement is usually not
seen
- Differential diagnoses - superficial crusting disorders
- Bacterial folliculitis
- Dermatophytosis
- Demodicosis
- Other immune mediated disease
- pemphigus complex
- SLE,
DLE
-- Dermatomyositis
- zinc-responsive dermatitis
- cutaneous lymphosarcoma
- Diagnosis
- Clinical signs
- papules and crusts
- nose, ear pinnae, foot pads
- Cytology - acantholytic cells, neutrophils,
may have few bacteria
- Histopathology - subcorneal vesicles or pustules containing
acantholytic cells, neutrophils +
eosinophils
- depending on the pathologist and biopsy samples
the diagnosis may not be apparent
- read the histopathology
description for clues
- acantholysis (not acanthosis)
- Immunofluorescence - intercellular deposition of
immunoglobulins within the epidermis.
- CBC, Serum chemistries, UA
- usually normal
- maybe
inflammatory
- ANA - negative
- Pemphigus Vulgaris
- rare in dogs and cats
- Most severe form of pemphigus
Lesions -
deeper than Pemphigus foliaceus
1o lesions are rare - vesicles,
bulla
2o lesions are common - erosions,
ulcers, crusts
+ pain - deep lesions are
painful
secondary systemic signs are common due to the deep
lesions and secondary infections(pyrexia, anorexia,
depression)
sick animal on
presentation
- Distribution may involve:
nasal planum, ear pinnae,
foot pads
oral cavity (80% of
cases)
mucocutaneous junctions
nail
beds
axillary and inguinal region
generalized
over trunk
- Differentials for ulcerative skin disease
- Bullous pemphigoid - looks identical to Pem. vulgaris
- SLE - oral lesions
- Drug eruption - oral lesions
- Cutaneous lymphosarcoma
- Deep pyoderma
- Deep mycoses
- Diagnosis
- Clinical signs
- erosions/ulcers
-
nose, ear pinnae, foot pads
- oral
lesions
- axillary and inguinal
- Cytology - acantholytic cells, neutrophils,
few bacteria
- Histopathology - suprabasilar vesicles or pustules containing
acantholytic cells, neutrophils + eosinophils
- depending on the pathologist and biopsy samples
the diagnosis may not be apparent
- read the histopathology
description for clues
- Immunofluorescence - intercellular deposition of
Immunoglobulins within the epidermis.
- CBC, Serum chemistries, UA, ANA
-
usually inflammatory
- changes
associated with secondary infection
-
ANA - negative
- Pemphigus Erythematosus
- Rare in dogs and cats
- Benign form of Pemphigus foliaceus
- Some similarities to Systemic Lupus Erythematosus
- ANA positive
- Immunofluorescence similar to both
Pemphigus and Lupus with intraepidermal staining seen in
Pemphigus and staining along the basement membrane as seen in
Lupus.
- UV aggravated similar to Lupus
- Lesions - similar to Pemphigus foliaceus
1o
lesions are rare - papules and rare
pustules
2o lesions are common - erythema,
oozing, crusts, scales, alopecia, erosions
- Distribution
Face and ears - only (no lesions on body
or feet)**
Oral cavity is not involved
- Differentials - facial dermatitis
- Pyoderma
- Dermatophytosis
- Demodicosis
- Dermatomyositis
- Seborrheic dermatitis
- Cutaneous lymphosarcoma
- Zinc-responsive dermatitis
- Other immune mediated disease
- pemphigus complex
- SLE, DLE
- Dermatomyositis
- Diagnosis
- Clinical signs
- face only
- Exclusion of other dermatoses
- Pemphigus foliaceus
- Histopathology - subcorneal vesicles or
pustules containing acantholytic epidermal cells, neutrophils +
eosinophils (+/-basement membrane changes similar to Lupus)
- Immunofluorescence - intercellular + basement
membrane zone deposition of immnoglobulin
- ANA may be positive
- Bullous Pemphigoid
- Pathogenesis
Autoantibodies (usually IgG) are directed against a
component of the hemidesmosome (Bullous pemphigoid antigen).
Activation of complement with subsequent neutrophil, eosinophil, and
mast cell infiltration causes loss of dermo-epidermal cohesion
followed by epidermal separation and vesicle formation. The cellular
infiltrates are essential for the pathogenesis of the lesions
(unlike Pemphigus diseases). See Articles (same as for
Pemphigus):
Stanley J. Cell Adhesion Molecules as Targets of
Autoantibodies in Pemphigus and Pemphigoid, Bullous Diseases Due to
Defective Epidermal Adhesion. Advances in Immunology. Vol
53;291-325,1992/3.
Espana A, Diaz L, Mascaro JM, et al. Mechanisms of Acantholysis in
Pemphigus. Clinical Immunology and Immunopathology. Vol
85;83-89,1997.
- Dogs (very rare in cats)
- Lesions - deep (clinically identical to Pemphigus
vulgaris )
1o lesions are rare - vesicles and
bulla
2o lesions are common - ulcers,
crusts
+ systemic signs due to severity of lesions and secondary
infection
pet is usually sick
- Distribution may involve
nasal planum, ear pinnae, foot
pads
oral cavity (80% of cases) similar to
Pemphigus vulgaris
mucocutaneous junctions
nail beds
axillary
and inguinal region
generalized over trunk
footpads (ulcers)
- Diagnosis
- Clinical signs
- Exclusion of other dermatoses
- Pemphigus vulgaris, SLE, drug
reaction
- Cytology
- purulent inflammation +/- bacteria
- no
acantholytic cells (only in pemphigus)
- CBC/Serum Chemistry/UA/ ANA
- Histopathology - large
subepidermal cleft and vesicle formation. The
entire epidermis will lift off of the basement membrane.
- Immunofluorescence - linear deposition of immunoglobulin along
the basement membrane zone
- Systemic Lupus Erythematosus
- A generalized connective tissue disorder that usually involves
many organ systems and is characterized by the presence of antinuclear
antibodies. Nuclear antigens become recognizable by the immune system
which causes an immune response and subsequent tissue damage. Since
these nuclear antigens are not limited to the skin, all tissues and
organ systems are possible targets of the autoimmune reaction (joints,
skin, bone marrow, kidney, etc.).
See Article:
Rothfeild NF. Cutaneous Manifestations of
Multisystem Diseases:Systemic Lupus Erythematosus. In Fitzpatrick TB,
Eisen AZ, Wolff K, et al., Dermatology in General Medicine, 4th ed..
McGraw-Hill, Inc. Volume II;2143-2148,1993.
- Uncommon multisystem disease effecting dogs and cats.
- Similar to Pemphigus erythematosus
- UV sensitivity aggravates skin lesions
- Immunofluorescence staining along basement membrane
- ANA positive
- Similar to Discoid Lupus Erythematosus
- Cutaneous manifestations - lesions are extremely variable. Animals
can develop any kind of skin lesion from chronic, mild skin lesions or
develop severe, deep and potentially life threatening disease.
oral lesions - common (similar to Pem. Vulgaris and Bullous
pemphigoid)
- seborrheic skin disease
- vesicular/bullous skin
disorders
- footpad ulcers and hyperkeratosis
- nail growth
disorders - onychodystrophy
- refractory secondary pyoderma
-
gingivitis/ulcerative stomatitis
- Diagnosis
- Polysystemic signs
- Polyarthritis - most common clinical sign
- cutaneous lesions - second most common clinical sign
- 80% of SLE patients will eventually have skin lesions
- renal disease, glomerulonephritis
- RBC, WBC, platelet abnormalities
- Bone marrow
- Pet is usually sick
- CBC/Serum chemistries/UA
- renal failure
- proteinuria
- pancytopenia (or any single cell line)
- Immunologic tests: LE cell test, ANA test usually
positive
- Histopathology - variable changes can be seen. The most
consistent findings include hydropic degeneration of basal cells,
interface (lichenoid) dermatitis, subepidermal vacules (bubbles),
and pigmentary incontinence (the pigment leaks from the epidermis
into the underlying dermis). Unfortunately, the biopsies may be
nondiagnostic.
- Immunofluorescence - deposition of
immunoglobulin or complement at the basement membrane zone
- Discoid Lupus Erythematosus
- Second most common autoimmune disease
- Similar to Systemic Lupus Erythematosus
- Unlike SLE
- no systemic signs; only skin (usually only on face like P.E.)
- ANA usually negative
- lesions - most often limited to the
nose
erosions, ulcers, erythema,
alopecia, scaling, + scarring, nasal
depigmentation
distribution - usually confined to
face especially the
nose
-
can develop lesions on the scrotum and body
pet feels
good
- differentials for facial dermatitis
- Other immune mediated disease
- pemphigus complex
-
SLE
- Dermatomyositis
- Cutaneous lymphosarcoma
- Zinc-responsive dermatitis
- Diagnosis
- clinical signs - nose (erosions,
depigmentation)
- exclusion of other dermatoses
- CBC/Serum chemistries/UA/ANA
- Histopathology - variable changes can be seen. The most
consistent findings include hydropic degeneration of basal cells,
interface (lichenoid) dermatitis, subepidermal vacules (bubbles),
and pigmentary incontinence (the pigment leaks from the epidermis
into the underlying dermis). Unfortunately, the biopsies may be
non-diagnostic.
- Immunofluorescence - deposition of
immunoglobulin or complement at the basement membrane zone
- ANA is usually negative
Treatment of Autoimmune Skin Disorders
See
Articles:
Rosenkrantz WS. Pemphigus Foliaceus. In Griffen
CE, Kwochka KW, MacDonald JM. Current Veterinary Dermatology. Mosby.
Chpt 13,141-148.1993.
White SD, Rosychuk RAW, Reinke SI, et al. Use of Tetracycline and
Niacinamide for Treatment of Autoimmune Skin Disease in 31 Dogs. Journal
of the American Veterinary Medical Association. Vol
200:10;1497-1500,1992.
RosenKrantz WS. Common Questions on Autoimmune Skin Disease.
Proceedings from The North American Veterinary Conference.
152-153,1996.
Prognosis - variable
- Treatment must be individualized for each patient
- Some patients do not respond well to any treatment
- Life long therapy - relapses common
- Treatment may be worse than the disease
- Symptomatic Therapy
- Crust removal - shampoo therapy (antibacterial
agents)
- hydrotherapy
- avoidance of sunlight - SLE, DLE, PE
- Vitamin E and Essential Fatty Acids
- Anti-inflammatory actions
- Alter arachidonic acid cascade
- Antioxidant activity
- long lag phase (1-2 mos)
- concurrent steroids may be used
- Vit. E - 400 IU orally bid
- no reported side effects
- Antibiotics for secondary bacterial infections
(treat as with pyoderma/folliculitis)
- High Dose Steroids
- 1.0-1.5 mg/lb prednisone orally, daily until
lesions are resolving (60-90% healed), usually 2-4 weeks
If not
responding after 2-4 weeks, additional treatments (azathioprine,
chlorambucil) should be added. High doses of daily prednisone should
not be continued for longer than 1 month before tapering begins.
- alternate day steroids - lowest possible dose
for maintenance changing the dosage from daily administration to
every-other-day dosing, may precipitate a relapse; therefore, the
steroid dosage should be slowly tapered to the every-other-day dose
over several weeks.
Example schedule (20 lb dog)
- Prednisone 20 mg orally every morning - 21 days
The lesions
are resolving so its time to taper.
- Prednisone 20mg orally - Mon, Wed, Fri, Sun
Prednisone 15
mg orally - Tue, Thur, Sat
Continue for 14 days then reduce
dose again.
- Lesions are still improving - no new ones.
Prednisone 20mg
orally - Mon, Wed, Fri, Sun
Prednisone 10 mg orally - Tue,
Thur, Sat
Continue for 14 days then reduce dose again
- Lesions are still improving - no new ones.
Prednisone 20mg
orally - Mon, Wed, Fri, Sun
Prednisone 5 mg orally - Tue, Thur,
Sat
Continue for 14 days then reduce dose again.
- Lesions are still improving - no new ones.
Prednisone 20mg
orally - Mon, Wed, Fri, Sun
Continue for 14 days then reduce
dose again.
- Lesions are still improving - no new ones.
Prednisone 15mg
orally - Mon, Wed, Fri, Sun
Continue to taper until the minimum
dose is identified that will control the clinical signs.
NOTE: Autoimmune diseases wax and wane
and will flare-up occasionally. Often, the medication dosages can be
maintained allowing disease to diminish on its own; however,
sometimes, the dosages must be increased to suppress the signs
(predicting is the tricky part). Pyoderma can mimic a flare-up and
must be ruled out.
- Alternative glucocorticoids: triamcinolone,
dexamethasone
Disadvantages - side effects of steroids often
intolerable to owner
- Chemotherapy Drugs - cytotoxic
agents
Used to lower necessary dose of steroids.
- Azathioprine
(Imuran)
try
to minimize the
dose
disadvantages
-myelosuppressive (monitor
CBCs)
-
Do not use in cats (extremely hepatotoxic and myelosuppressive)
- Chlorambucil
(Leukeran)
0.05
- 0.1
mg/lb/day
works
well in cats
- may take 1-2 months to work
- rare side effects
- myelosuppressive (monitor CBCs)
- GI (vomiting, diarrhea)
- Tetracycline and Niacinamide
- inhibits protease activity
- inhibits inflammatory cascades (WBC, arachidonic acid)
- variable response
- < 10 kg dog - 250 mg of each tid
- > 10 kg dog - 500 mg of each tid
- lag phase of 1-2 months
- GI side effects - anorexia, vomiting, diarrhea
- Chrysotherapy
Gold Salt Therapy
(Aurothioglucose, Solganol)
- for Pemphigus complex and Bullous pemphigoid
- mechanism of action unclear
- may suppress antibody
formation, inhibit lysosomal enzymes, decrease macrophage and
neutrophil function, be anti-complementary
- Dosage Regimen
1 mg/kg IM weekly until response (6-12
weeks)
then 1 mg/kg IM every 2 weeks for 1-2 mos.
then 1 mg/kg
IM every month
- Disadvantages
- long lag phase
concurrent steroids may be used
if no
response in 4 mos, dose to 1.5 mg/kg/week
- reported side effects in dogs and
cats
anemia
thrombocytopenia (fatal)
drug eruption/TEN
(fatal)
therefore monitor CBCs, platelet counts,
avoid
cytotoxics - may potentiate side effects
- Cyclosporine
Successful therapy is dependent on
careful monitoring of the skin disease and toxic side effects from the
medication. Patients require constant medical attention with frequent dose
adjustments.
Good luck
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