2.3 Immune-Mediated Diseases in Practice Flashcards
What is the “spectrum” of immune-mediated diseases (IMDs)?
IMDs can range widely from organ-specific (e.g., myasthenia gravis) to non-organ specific (systemic lupus erythematosus)
- there may be primary idiopathic diseases and diseases secondary to an underlying trigger
What is the general pathogenesis of IMDs?
etiology of many autoimmune diseases is UNCLEAR, and likely multi-factorial (genetic, infectious, and less likely: hormonal)
(1) loss of tolerance: the immune system overreacts to normal tissues or harmless exogenous proteins
- exposure to pathogenic antigen is usually seen in association with an inflammatory response (PAMPs, and thus cytokines)
- exposure to dietary antigen is usually seen in an anti-inflammatory environment (no PAMPs, no cytokines)
- with loss of tolerace, T cells proliferate in an inflammatory environment, making them reactive to harmless subtances or self
(2) trigger factors:
- release of sequestered antigens (eye, sperm), which the immune system does not normally contact
- molecular mimicry: similarities between foreign and self molecules
- polyclonal T and B cell activation
- abnormal immunoregulation
(3) infection:
- thought to influence autoimmune diseases at several levels: expose sequestered antigens (e.g., testicular infection)
- incite inflammation: “bystander activation”
- bacterial superantigens: polyclonal activation of T/B cells
- molecular mimicry
Is there a link between vaccination and IMDs?
IMHA and IMPA have been linked to vaccination
- if an animal has been vaccinated within 4 weeks of IMD development, this should be investigated before continuing the vaccination regimen
- it could simply be a coincidence, so do not jump to conclusions
What is the signalment of patients with IMDs?
idiopathic / primary / non-associative IMDs are often seen in
- juvenile to middle-aged patients, though dogs and cats of any age may be affected
What is the most important diagnostic we do to investigate IMDs?
history and physical exam!
- IMDs are generally characterized by remission and exacerbation: “waxing and waning”
various presentations, including: lameness, pyrexia, mucocutaneous lesions, lethargy, dyspnea, weight loss, PU/PD, seizures, effusive, painful joints, skin lesions, pallor +/- petechiae, and more!
What is the minimum database
begin with a thorough history and physical exam and then move on to:
(1) blood tests, especially in cases of pallor
- CBC/coagulation profile
- blood smears
- biochemistry
(2) next, perform a urinalysis
(3) other tests to eliminate specific IMDs: radiography and arthrocentesis
What could you expect to see on CBC / coagulation profile in IMD cases?
(1) anemia
- regenerative: IMHA
- non-regenrative: infection, uremia, hepatic disease, chrinic bleeding, attack of precursors, etc.
(2) thrombocytopenia
- immune mediated thrombocytopenia (IMTP): expect < 10,000-20,000
(3) leucopenia
- anti-leucocyte antibodies: SLE, imune-mediated neutropenia
- cannot diagnose commercially: by exclusion only
(4) coagulation abnormalities
- increased APTT, PT
What could you expect on a blood smear in IMD cases?
identify whether there is regenerative / non-regenrative anemia
- look for the presence of sphereocytes and ghost cells to indicate anemia due to hemolysis (IMHA)
What could you expect on biochemistry in IMD cases?
MANY posibilities:
- azotemia, increased inorganic phosphate: glomerular lesions
- hypoalbuminemia, hypercholesterolemia: PLN
- hyperbilirubinemia: prehepatic disease / hemolysis
- hyperglobinemia: inflammatory disease, polyclonal B cell activation
- increased CK and lactate dehydrogenase activity: polymyostitis and or myocarditis
note, one would not see all of these in the same patient
What could one see on urinalysis in IMD cases?
proteinuria: PLN
- rule out UTI
- rule out occult (hidden) infections: many arthropod-borne (e.g., anaplasma, rickettsia): vector-borne diseases are one cause of inflammatory glomerular nephritis
- 34% of proteinuric dogs were seropositive for a vector-borne disease
- make sure to always read ion context of hydration status. E.g., 1+ protein with very concentrated urine, likely not a problem. 1+ protein with very dilute urine, like a problem
hematuria, pyuria, erythrocyte casts: membranoproliferative GN (IMD)
- rule out UTI and occult infections
What specific immunological tests can indicate IMD?
(1) in-saline agglutination
- IMHA
(2) coomb’s tests
- follow-up for negative in-saline agglutination
(3) AChR autoantibodies
- tests for acquired myasthenia gravis
- most-common neuromuscular IMD
(4) antinuclear antibodies (ANA)
- hallmark of SLE
- indirect immunofluorescence / immunoperoxidase test
(5) biopsies
- lesions may not be specific to a disease, but often signal immune-mediated destruction
What are the common principles for IMD treatment?
treatment relies on halting ongoing damage while satisfying nutritional and nursing requirements
- non-specific immunosuppressants (corticosteroids) are the mainstay of therapy
- various adjunctive therapies (diet, surgery, GI protection, etc) are also often used
- nursing case is vital for QOL ansd treatment success (as treatment is long term)
List some of the immunomodulatory therapies
- corticosteroids
- alkylating agents
- antimetabolites (NEVER in cats)
- vinca alkaloids
- calcinerurin inhibitors
- ciclosporine
- human IVIG (polyspecific IgG derived from healthy donor plasma)
many of these are also anti-cancer drugs used in small animals
How do corticosteroids affect the cell?
- corticosteroids associate with albumin and transcortin in the blood
- they dissociate and passively diffuse into cells where they bind to a cytoplsamic receptor
- this unmasks a DNA binding domain which reveals corticosteroid-responsive sites
they can UPREGULATE regulatory proteins or DOWNREGULATE inflammatory molecules (eosinophols, T cell, mast cell, macrophage, DCs)
What are the main considerations when using corticosteroids as treatment for IMD?
dosing and adverse effects
dosing:
- VERY LOW dose: physiological
- LOW dose: anti-inflammatory (AA cascade inhibition, pro-inflammatory cytokine inhibition)
- HIGHER doses: immunosuppressive (likely due to immune cell downregulation - T cell, macrophage, APCs, etc.)
potential adverse effects:
- CNS: lethargy, aggressive, anxious
- musculoskeletal: atrophy, weakness, exercise intollerance
- GIT: ulceration
- mineralocorticoid action: fluid and electrolyte imbalanace
- metabolic: look cushinoid, can induce DM in cats
- also: opportunistic infections due to immunosuppression (stay away from public areas with your animal!)
What are the guidelines for immunomodulatory therapy?
(1) start with prednisone or prednisolone
- 2-4 mg/kg/day
- cats less senstitive - higher doses: but NOTE, cats never develop PU/PD with glucocorticoid use, so if PU/PD seen, indicates DM development!
- large dogs senstitive: lower dose or use mg/m^2
- give with doxyxycline of high risk of occult infection (vector-borne)
- consider adjunctive agent for IMHA or other aggressive IMD: azathioprine in dogs, chlorambucil in cats
should see improvement in 7 days, if not, give adunctive agent and review diagnosis
(2) MONITOR
- CBC / UA every 7-14 days
(3) TAPER
- taper corticosteroid over 3-4 months following remission
- 20-25% decrease evert 2-4 weeks as long as remission is maintained
- do NOT alter adjunctve treament at the same time, unless essential
- if signs recur, return to previous dose, and taper more slowly
NEVER use three immunosuprpessive drugs at the same time; if no response after second drug: wrong dose? wring diagnosis? not absorbing?
(4) STOP
- may end corticosteroid use if remission persists
- be cautious tapering adjuctive therapy (2 months +)
- all treatment may be stopped if long-term remission persists
- nursing care still vital!
