Immunosuppression Flashcards
When to start 2nd immunosuppressive in IMHA - ACVIM consensus
severe life threatening disease at presentation (increased T bili or Urea at presentation are negative Px indicators)
PCV decreasing by >5% within 24h in the first 7 days (on GC)
dependent on blood transfusions
high risk of GC side effects
LoE for these recommendations is weak and based on clinical experience. 2 drugs from outset is recommended in severe cases due to possibility that some dogs will have insufficient response to single agent
Evidence for hIVIg in treatment of IMHA
As a salvage measure in dogs not responsive to 2 treatments.
While an attractive Tx option due to rapid onset of action, several studies have shown no benefit in comparison to current immunosuppressive regimens (various designs and risk of bias but all same conclusion). Efficacy and safety in dogs has not been established beyond 3 days of treatment
When should tapering of immunosuppressive drugs be started for IMHA
When PCV has been >30% and stable for 2 weeks and with improvement of other measures of disease activity.
Can start with GC or the 2nd line treatment depending on case specifics and AEs occurring.
Typical treatment duration of 4-8 months for all immunosuppressives. Tapering every 3 weeks by 25% pred dose reduction - greater reduction or shorter intervals if good response or on 2nd line
Monitoring recommendations for immunosuppressive drugs
Aza - CBC and Bio fortnightly fdor 2 months then every 2 months on Tx
Cyclo - biochem every 2-3 months, clinical signs of GI disease or gingival hyperplasia
Monitoring with serum levels is not beneficial, but activity of the drug is with IL2 suppression assays is best
Myco - GI upset, CBC fortnightly for month then every 2 months
If myelosuppression occurs the causative drugs should be discontinued
ACVIM recommended approach to IMHA relapse
True prevalence of IMHA relapse is not reported but based on previous publications is 10-15%.
Guidelines based on clinical reasoning.
Confirm using IMHA criteria
Be aware some test results may be affected by use of immunosuppressive drugs
Reassess for any potential new trigger/emergence of undiagnosed old trigger especially emerging infection if patient is still on immunosuppression
evaluate compliance, dose, TDM, whether drug being given with food/GI absorption
increase back to previously effective dose if mild, if fulminant disease then back to immunosuppressive doses.
Consider addition of 2nd line or use of hIVIg if not responding to dose increase of pred
Once in remission again taper more slowly (doubling time)
If recurrent relapses then life-long immunosuppression may be required (weak LoE, ensure vector borne disease is ruled out).
Splenectomy may be considered if infectious causes are excluded (retrospective case series report possible benefit, more recent JVIM retrospective series reported no benefit in IMHA)
Reported IMHA outcome and prognostic factors
2y survival of 65-75%
Relapse in up to 12% maybe more, even several years later
Mortality - most deaths within first 2 weeks of disease or relapse, commonly attributed to thromboembolism, liver or renal failure.
DIC is common in those that succumb to IMHA
Mortality rate may be higher in dogs
AVJ 2019 long term outcome in 61 dogs - 23% relapse; 5 dogs euthansed as a result
Relpase can occur many years after treatment discontinuation
>50% had medications discontinued
Poor Px indicators: elevated BUN, Tbili, prolonged APTT, Tbili levels, concurrent thrombocytopaenia or hypoalbuminemia. Acute phase proteins do not seem prognostic
CHAOS score may be prognostic (higher score = lower survival)
Treatment recommendations for FCGS non-immunomodulatory
Dental extractions - 67% some or complete response –> reduction in chronic antigenic stimulation and thus reduced B and T cell proliferation
Medical management is an adjunct not a sole therapy
- Analgesia: tailored to patient and owner capabilities. NSAIDs, TM buprenorphine, adjunctive gabapentin and amantadine also reported
- Bovine lactoferrin oral spray: reported to reduce inflammation, it inhibits bacterial growth
- antibiotic RR 37% and only transient. Recommended only in the acute setting (5 days of amoxicillin or clinda). Scientific data are limited on utility of this
FCGS Tx options for refractoryt cases
Refractory = no response 2-3 mo after extractions
Immunosuppression (steroids have low success w/o surgical intervention <10%, thus give if ongoing inflammation despite FME, analgesia).
Randomised trial of ciclosporin reported improvement in Tx group in 78%, 45% cured long term.
In a study of 8 cats 50% improved with ciclosporin prior to dental extractions.
Avoid in viral infected cats.
Immunomodulation
- rIFNw has been reported to improve stomatitis in refractory cases especially those with concurrent FIV or with positive isolation of FCV virus on RT PCR.
- Mesenchymal stem cells: small studies have demonstrated substantial improvement in cats with FCGS in 57-71% of casses, higher success reported with autologous adipose derived MSC compared to the allogenic MSC. The proangiogenic and antifibrotic activities of MSC may facilitate faster healing if given earlier in treatment (which has not been explored)
What are the characteristics of mesenchymal stem cells
Multipotent, undifferentiated cells that can become chondrocytes, adipocytes or osteocytes. They can be harvested from umbilical tissue, bone marrow, adipose (used most commonly) and placenta.
They have the ability to undergo clonal expansion and potentially unlimited replicative potential.
It remains to be determined whether particular clones are linked to specific functions of MSCs. Some clones may
have a stronger immunomodulatory capacity or specific lineage differentiation qualities than others
How do MSCs modulate the immune system in cats
Stimulation of MSC with IFNy (upregulated in FCGS) and TNFa results in secretion of anti-inflammatory factors.
They also have direct interactions with T cells
In FCGS MSC resulted in a reduced quantity of circulating CD8+ cells. They also altered the phenotypic and functional characteristics of cytotoxic T cells, increasing IL2 expression (favouring Th2 and Treg proliferation over Th1)
Through cytokine expression they reduce neutrophil apoptosis, enhance macrophage differentiation to M2 (recovery), reduce B and T cell proliferation, reduce NK cell proliferation and cytotoxicity, reduce APC activity
Adverse effects associated with MSCs
Acute - transfusion like reaction increased RR and lethargy
vomiting and diarrhoea in rare cases
Chronic - potential tumorigenesis given proliferative potential of the MSC
Data limited at this stage, 9y follow up in 38 patients reported no evidence of tumours.
Possible effects of MSCs
Assist tissue regeneration and repair:
- enhance angiogenesis
- inhibit fibrosis
- promote cell to cell contact
- reduce inflammation
- immune modulation
In organ damage thought that they inhibit fibrosis and recruit local stem cells stimulating the proliferation and survival
