Immune Mediated Disease Flashcards
Pathogenesis and Pathophys of erosive and non-erosive IMPA in dogs
Non-erosive - type 3 hypersensitivity -> complement activation, increased inflammatory mediators in synovium
Erosive - anti-collagen II Ab and type 4 hypersensitivity reaction on synovium (CMI). Th17 recruitment to synovium and development of pannus (fibrovascular tissue that p[roduces proteases)
May also have Ab targeted at other components of synovium
Investigation for IMPA and justifcations/reasoning
CBC, Biochem
UA, UPCR, C+S (type 2 triggered by UTI)
Chest rads (type II triggered by respirato5ry infections)
+/- abdo u/s (type 4 triggered by neoplasia)
Joint fluid - >10% neuts, >5000 cell count
CRP - can be used for monitoring and differentiating IMPA from OA in dogs
Cervical spine imaging and CSF if concurrent neck pain - IMPA/SRMA combined dz
Check for sulfonamides (Dobermans especially)
Infectious dz testing (Rickettsial, Borrelia, Bartonella, Mycoplasma, Endocarditis)
ANA - if another immune mediated disease process present, to investigate for SLE whcih carries poorer prognosis.
Recent Publications on canine IMPA
JSAP 2018 39 dog retrospective evaluation for correlation of IMPA with vaccination. No significant correlation but study may not have been large enough (OR 1.44 but wide 95% confidence interval)
JAAHA 2019 - 5 case description of IMPA with devedlopment of ligament laxity, theorised due to destruction of periarticular soft tissues.
Multiple disease relapses, poorly controlled by available immunosuppressives
JSAP 2022 - 73 case type I IMPA descriptive study.
95% ORR, 53% relapse, 63% complete cure. Half of dogs treated with pred alone needed 2nd immunosuppressive
19% death related to IMPA disease
Evidence for Tx of canine non-erosive IMPA
Pred as first line Tx standard, but small studies have shown similar efficacy of cyclosporine, mycophenolate and leflunomide as sole treatments. Different side effect profiles and choice may be dictated by individual patient.
Half of dogs needed 2nd line treatment in recent JSAP study
As this is a type 3 hypersensitivity disease treatments that target CMI adn complement seem more likely to be efficacious
Investigation/tests for erosive polyarthritis in dogs
Same as for IMPA but also:
Joint rads - takes a few months to see destruction but then see symmetrical subchondral bone lysis and alterations to joint space.
RF - rate of positivity reported is 30-70% depending on study.
ANA - recommended to screen for SLE
Synovial Bx - confirm diagnosis and r/o cancer.
Pathogenesis of Feline nonerosive polyarthritis
MOST are infectious aetiology with direct infection of the synovium and secondary inflammation (though there is likely some type 3 hypersensitivity reaction in some diseases)
Known infectious causes include: Mycoplasma (felis, galeae); GIP, L-form bacteria (from cat bites, cause concurrrent cellulitis); Calicivirus (natural or vaccine); Streptococcal, Rickettsial.
For M. galeae disease may only be seen in immunocompromised cats that are infected.
For FCV vaccine induced disease it may be due to gain of virulence in vaccine or recent incubation of natural infection.
Recommended investigation for feline non-erosive polyarthritis
CBC, Bio, UA, C+S, test for haematological infections and rickettsial dz depending on geographical location
Joint fluid should always be cultured and mycoplasma PCR performed. Sample >/=5 joints
Consider synovial bx for histo and culture (consider additional infectious dz testing on this though it has not been previously reported)
Oropharyngeal swab for FCV - may not be causative if positive and not always positive if the cause.
Causes of feline erosive polyarthritis
Mycoplasma can cause erosive disease in some cats, as can some of the other infectious causes.
Also 2 distinct disease processes:
Feline periosteal proliferative polyarthritis - seen in young cats, progressive periosteal proliferation eventually causing ankylosis of the joints
May be improved with pred/2nd line drugs. Quite rare
Feline rheumatoid-like polyarthritis. Middle aged cats, Siamese may be overrepresented
Radiographs show severe subchondral central bone erosions. RF reported to be increased but cannot be measured commercially. Small treatment study reported response to combined methotrexate and leflunomide Tx.
Treatment and recent publications for feline non-erosive polyarthritis
Start with doxycycline to cover rickettsial, L-form and Mycoplasma infections even if tests negative. Due to poor test specificity.
Should see quick response if infectious aetiology.
INI then consider immunosuppression (or trial fluoroquinolone treatment instead)
JFMS 2020 study reported 70% RR to immunosuppression in idiopathic disease, earlier studies reported only 50% response. but 8/11 cats needed 2nd line treatment (other cats had concurrent disease distant to the joint causing reactive polyarthritis).
Pathogenesis and Pathophysiology of SLE
A combination of genetic mutations, environmental triggers and defects in B cell apoptosis result in T cell abnormalities including: reduced TCR signalling, decreased IL2 and T reg activation and increased IL 17 and IL6. The net result of which is increased B cell activity and autoreactive T cells.
There are multiple susceptibility and protective genes that have been identified including those involved with complement, APC; T cell signalling and B cell apoptosis
Once there is B cell hyperactivity there is generation of a large number of autoantibodies which result sin uncontrolled cytokine production and complement activation progressing to deficiency.
Antinuclear Ab (may be DnA or histones, combined with organ or tissue specific Ab. Causes IM damage via opszonisation or CD8 T cell apoptosis
B cell antibodies may cause type III immune reactions (polyarthritis, MPGN, vasculitis) or may be organ/tissue specific causing type II mediated disease (IMHA, IMT, dermatopathy, thyroiditis, myositis)
A single predisposing factor is not identified (though drugs and infections can cause SLE like syndromes). Though often affected patients are worsened by exposure to UV, as the damaged skin cells cannot undergo apoptosis and normal clearance (by macrophages or complement) so they become a source of antigenic stimulation for the disease.
Diagnostic criteria for SLE
Positive ANA and 2 syndromes
Negative ANA and 3 syndromes
Syndromes include:
Polyarthritis
Oral ulcerations
Skin lesions consistent with immune mediated dermatopathy
Anaemia or thrombocytopaenia due to destruction
MPGN
Polymyositis
Neurological signs (seizures, CN deficits)
Serositis (effusion with no septic cause)
Breeds overrepresented with SLE
GSD, Setters, Poodles, Collies
Diagnosis for immun mediated neutropenia
Diagnosis of exclusion of other causes of neutropenia and demonstration of lack of improvement with time, then improves with steroids.
Think about infection, BM dz; inherited deficiency, low B12
DDx to exclude: rickettsial disease, BM injury (reversible); sequestration/septic focus, Grey collie cyclic haematopoiesis; border collie trapped neutrophil syndrome, B12 deficiency
Perform full baseline bloods, UA and rickettsial disease testing. imaging to look for infectious focus.
BM< will show myeloid hyperplasia, orderly maturation, incrreased M:E, peripheral cytopaenia and no bands.
Pathogenesis and causes of immune mediated vasculidities
Pathogenesis poorly understood but likely a combination of type II and III immune mediated reactions
May be direct IM damage of vascular cells vs immune complex deposition in capillaries.
Possible causes are many but main exclusions are looking for systemic disease as this is a reaction not a primary disease process (though in some cases a trigger is not found).
DDx: ionfection, sepsis, DIC, rickettsial diseases, cold agglutinin (fibrinogen or globulin mediated); drug/food reaction; SLE
Treatment options for cutaneous vasculidities
First of all treat/remove the trigger - in many cases this may result in resolution without any direct treatment of cutaneous lesions.
If there is no trigger or ddz is progressing rapidly anti-inflammatory to immunosuppressive doses of pred can be used (NB these may delay healing of any erosions).
Additional treatments include pentoxifylline, cyclosporine, tetracyclines or niacinamide
Recent publications about sterile lymphadenitis
Both JSAP 2019
1 - English Springer Spaniels only (64 case descriptive study) - many had other cutaneous lesions and systemic signs of illness. Treatment response reported for 38 cases, 34 were pred alone and had good to excellent response. 8 required a seocond immunosuppressive medication
5 died/euth due to poor response
2 - Series of 49 cases of steroid responsive lymphadenitis, 16 were ESSp which were an overrepresented breed. 97% responded to treatment with pred, 18 relapsed (13 were ESSp.
4 dogs had other immune mediated disease at same time.
ESSp breed is overrepresented but not only breed affected, all dogs had some degree of lymph neutrophilic/macrophagic inflammation in nodes with or without necrosis.
What is the mechanism of ITP
IgG autoantibodies binding to the GIIbIIIa receptor (fibrinogen) on platelets -> unable to aggregate with fibrin. Also affects megakaryocytes
The Ab designate the platelet for removal by macrophages (RES) in the liver and/or may enhance desialyation in the liver (causing early platelet dysfunction)
JVIM 2020 study of anti-platelet Ab detection and dynamics found??
Used flow cytometry:
20% of secondary/non-ITP dogs had APA
All primary ITP dogs were positive.
Contrasts previous studies where some dogs with primary ITP were negative. So use as a rule out test may be useful.
Also reported that persistence of APA was not associated with response to treatment but that recurrence of APA after resolution was correlated with relapse. So Flow Cytom may be useful monitoring tool
HOWEVER relapse only occurred in 2 of 22 monitored dogs.
Unclear how long it takes for dogs to become negative for APA
What did the JSAP ITP long term outcome study find
45 dogs monitored for >12months
90% survived to discharge; 31% relapse.
50% relapsed more than once
Relapsing group had longer time to platelet recovery.
As majority came off medication and did not relapse there is not indication for long term therapy - though those that do relapse have a high chance of doing so again
1 year mortality caused by ITP was 11.9% so not much more than hospitalisation
How does the DOGiBAT score work
Validation study in JVIM 2018 - scoring of 9 anatomic sites as 0-2 for presence of bleeding.
Thus total score out of 18
Higher scores were correlated with need for transfusion and hospital stay duration
Further study to determine use in monitoring
What is the evidence for current ITP treatment recommendations
- majority respond to pred without any adjunctive treatment.
- Small studies have demonstrated efficacy of MM as a single agent in ITP but it is slower onset
- no comparative prospective studies to determine superiority of one treatment over another.
A study of plt number and function after Vinc showed more rapid increase compared to pred alone and platelet function measured by P-selectin expression was not affected
Though another study reported development of neutropaenia after Vinc correlated with longer hosp stay - though was sstrongly correlated with concurrent cyclosporine administration
Minimal use for platelet transfusion because of their short half life and thus only short effect on haemostasis but could be used in life threatening scenario. RBC transfusion or whole blood best if haemorrhage induced anaemia/hypovolaemia
- recent study of lyophilised platelets compared to cryopreserved platelets found them to be non- inferior using DOGiBAT bleeding score (and is logistically superior for storage)
Small study of TPE in 4 ITP dogs unresponsive to conventional Tx - there was improved plt count in treated dogs though 1 was euthanised because of persistent bleeding after 3 treatments.
DDx for thrombocytopenia
ITP - if severe
Secondary:
Infectious: Babesia, Ehrlichia, Anaplasma, Leishmania, FeLV
Neoplasia - lymphoma, HSA, Histiocytic sarcoma - others have lower levels of evidence.
Causes of inflammation - low LoE
Drugs - sulfonamides and cephalosporins
Causes of IMHA and classes
Epitope unmasking - damage to tissue or cells resulting in exposure of previously cryptic antigen.
Molecular mimicry - drug or infectious epitope similar to self
Haptenization - reaction of an antigen with a carrier protein generating a new epitope and immune response
Superantigens - a class of immunostimulatory molecules produced by bacteria and viruses. Have potent immune effects due to their ability to bind to the MHC outside the antigen-binding cleft and to stimulate T cells in a T-cell receptor (TCR)-specific manner.
Class I = IgG and IgM agglutinate RBCs and opsonise
Class II = IgM activates complement -> intra/extravascular haemolysis
Class III - IgG mediated opsonisation but NOT complement or agglutination.
Class IV - IgM binding at low temps, causing tissue necrosis +/- anaemia
Class V - IgM binding at <4C
What does carboxyhaemoglobin measure/what are its uses/recent publications
Carboxyhemoglobin (COHb) is a stable complex of carbon monoxide (CO) and haemoglobin and serves as a useful biomarker of blood CO concentration. Endogenous CO production also occurs under physiological and pathological conditions because of metabolism of heme-containing proteins, most notably of Hgb
Metabolism of Hgb and increased inflammatory cytokines in IMHA should both cause increase in CO-Hgb
JVIM 2022 study found significant difference between dogs with haemolytic and non-haemolytic anaemia
Be4st Sens/Spec combo was 96 and 96% can get 100% of either without misclassification with slight adjustment to reference. ALL WERE TRANSFUSION NAIVE!!
Not assessed in PIMA or with other inflammatory diseases
Differential diagnoses for elevated COHb other than hemolysis and CO intoxication are myriad, and include internal bleeding, exposure to drugs, sepsis,hepatic and respiratory diseases, and various additional inflammatory diseases
