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==Classification==
==Classification==
The side effects that occur as a result of checkpoint inhibitors are known as Immune related Adverse Effects (IrAEs). these can be classified as follows.Based on the severity of adverse effect


== Pathophysiology==
'''Grade 1 irAEs''' – For most patients with grade 1 irAEs (asymptomatic or mild symptoms), immunotherapy may be continued, and patients may be closely monitored for worsening irAEs and/or managed symptomatically.


=== Genetics ===
'''Grade 2 irAEs''' – For most patients with grade 2 (moderate) immune-mediated toxicities (excluding endocrinopathies), treatment with immunotherapy should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Glucocorticoids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within one week.


=== Associated Conditions===
'''Grade 2 endocrinopathies''' – An exception is for patients who experience immune-mediated endocrinopathies but do not require immunosuppressive therapy. In such patients, depending upon the severity of symptoms, immunotherapy may be withheld until hormone replacement is initiated. Immunotherapy may subsequently be resumed once acute symptoms have resolved and (in the event of adrenal insufficiency or hypophysitis) patients are receiving adequate adrenal glucocorticoid replacement. (See 'Endocrinopathies' below and 'Retreatment after prior toxicity' below.)


===Gross Pathology===
'''Grade 3 or 4 irAEs''' – For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with immunotherapy is usually permanently discontinued. High doses of glucocorticoids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, glucocorticoids can be gradually tapered, typically over at least four weeks (table 2).


===Microscopic Pathology===
'''Refractory toxicity''' – In the authors' experience, patients who will benefit from glucocorticoids generally do so within days to a week. If symptoms do not clearly improve or worsen on steroids, our approach is to administer an additional immunosuppressive agent. Examples of available agents include infliximab, vedolizumab, and mycophenolate mofetil, among other options.<ref name="pmid34724392">{{cite journal|author=Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M|display-authors=etal|title=Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.|journal=J Clin Oncol|year=2021|volume=39|issue=36|pages=4073-4126|pmid=34724392|doi=10.1200/JCO.21.01440|pmc=|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=34724392}}</ref>


==Causes==
== Pathophysiology==
===Life Threatening Causes===
Triple M Syndrome emerges in correlation with the utilization of immune checkpoint inhibitors that specifically target CTLA-4, PD-1, and PD-L1 receptors situated on T-cells and antigen presenting cells. These receptors fulfill a pivotal role in the modulation of T-cell activity. Through the inhibition of these receptors, a continuous activation of T-cells is incited, facilitating the eradication of neoplastic cells. It is imperative to note that the augmentation of the immune response, though beneficial for combatting malignancies, can also give rise to immune-related adverse effects.
Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.


===Common Causes===
One prominent manifestation of these immune-related effects is the enigmatic Triple M Syndrome.The precise underlying mechanisms responsible for the onset of Triple M Syndrome remain unclear. Current hypotheses suggests on potential factors such as molecular mimicry and the autoimmune functions of the PD-1 pathway.<ref name="pmid31960755">{{cite journal|author=Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A|title=Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment.|journal=J Am Heart Assoc|year=2020|volume=9|issue=2|pages=e013757|pmid=31960755|doi=10.1161/JAHA.119.013757|pmc=7033840|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31960755}}</ref><ref name="pmid22491251">{{cite journal|author=Tarrio ML, Grabie N, Bu DX, Sharpe AH, Lichtman AH|title=PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis.|journal=J Immunol|year=2012|volume=188|issue=10|pages=4876-84|pmid=22491251|doi=10.4049/jimmunol.1200389|pmc=3345066|url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22491251}}</ref>


===Causes by Organ System===
==Causes==
 
Checkpoint inhibitors like Ipilimumab, nivolumab etc are suspected to be the potential cause of Triple M Syndrome.
{|style="width:80%; height:100px" border="1"
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Chemical / poisoning'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Dermatologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Drug Side Effect'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Ear Nose Throat'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Endocrine'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Environmental'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Gastroenterologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Genetic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Hematologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Iatrogenic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Infectious Disease'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Musculoskeletal / Ortho'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Neurologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Nutritional / Metabolic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Obstetric/Gynecologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Oncologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Opthalmologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Overdose / Toxicity'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Psychiatric'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Pulmonary'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Renal / Electrolyte'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Rheum / Immune / Allergy'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Sexual'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Trauma'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Urologic'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Dental'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Miscellaneous'''
|bgcolor="Beige"| No underlying causes
|-
|}
 
===Causes in Alphabetical Order===
 
*A...
*Z...
 
Make sure that each diagnosis is linked to a page.
 
==Differentiating type page name here from other Diseases==
 
== Epidemiology and Demographics ==
===Age===
===Gender===
===Race===
===Developed Countries===
===Developing Countries===
 
== Risk Factors ==
 
== Screening ==
 
== Natural History, Complications and Prognosis==
 
== Diagnosis ==
===Diagnostic Criteria===
If available, the diagnostic criteria are provided here.
 
===History===
A directed history should be obtained to ascertain
 
=== Symptoms ===
"Type symptom here" is pathognomonic of the "type disease name here".
 
"Type non specific symptoms" may be present.
 
===Past Medical History===
 
===Family History===
 
===Social History===
====Occupational====
====Alcohol====
The frequency and amount of alcohol consumption should be characterized.
====Drug Use====
====Smoking====
 
===Allergies===
 
=== Physical Examination ===
 
==== Appearance of the Patient ====
 
====Vital Signs====
 
====Skin====
 
====Head====
 
==== Eyes ====
 
==== Ear ====
 
====Nose====
 
====Mouth====
 
====Throat ====
 
==== Heart ====
 
==== Lungs ====
 
==== Abdomen ====
 
==== Extremities ====
 
==== Neurologic ====
 
====Genitals====
 
==== Other ====
 
=== Laboratory Findings ===
 
==== Electrolyte and Biomarker Studies ====
 
==== Electrocardiogram ====
 
==== Chest X Ray ====
 
====CT ====
 
==== MRI ====
 
==== Echocardiography or Ultrasound ====
 
==== Other Imaging Findings ====
 
=== Other Diagnostic Studies ===
 
== Treatment ==
=== Pharmacotherapy ===
 
==== Acute Pharmacotherapies ====
 
==== Chronic Pharmacotherapies ====
 
=== Surgery and Device Based Therapy ===
 
==== Indications for Surgery ====
 
==== Pre-Operative Assessment ====
 
==== Post-Operative Management ====
 
==== Transplantation ====
 
=== Primary Prevention ===
 
=== Secondary Prevention ===
 
=== Cost-Effectiveness of Therapy ===
 
=== Future or Investigational Therapies ===


==References==
==References==

Latest revision as of 20:12, 16 January 2024

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Muhammad Waleed, M.B.B.S.[2]

Synonyms and keywords: myocarditis with myositis and/or myasthenia gravis overlap syndrome (IM3OS)

Overview

Myocarditis-myositis-myasthenia gravis (Triple-M) overlap syndrome occurs as a rare complication in patients receiving immune checkpoint inhibitors (ICI).

Historical Perspective

Immune checkpoint inhibitors represent a form of immunotherapy that gained FDA approval in 2011. These medications are accompanied by various side effects. Among these, Triple M emerges as a rare yet lethal side effect linked to checkpoint inhibitors. The initial documented instance of Triple M occurred in 2016.[1]

Classification

The side effects that occur as a result of checkpoint inhibitors are known as Immune related Adverse Effects (IrAEs). these can be classified as follows.Based on the severity of adverse effect

Grade 1 irAEs – For most patients with grade 1 irAEs (asymptomatic or mild symptoms), immunotherapy may be continued, and patients may be closely monitored for worsening irAEs and/or managed symptomatically.

Grade 2 irAEs – For most patients with grade 2 (moderate) immune-mediated toxicities (excluding endocrinopathies), treatment with immunotherapy should be withheld and should not be resumed until symptoms or toxicity is grade 1 or less. Glucocorticoids (prednisone 0.5 mg/kg/day or equivalent) should be started if symptoms do not resolve within one week.

Grade 2 endocrinopathies – An exception is for patients who experience immune-mediated endocrinopathies but do not require immunosuppressive therapy. In such patients, depending upon the severity of symptoms, immunotherapy may be withheld until hormone replacement is initiated. Immunotherapy may subsequently be resumed once acute symptoms have resolved and (in the event of adrenal insufficiency or hypophysitis) patients are receiving adequate adrenal glucocorticoid replacement. (See 'Endocrinopathies' below and 'Retreatment after prior toxicity' below.)

Grade 3 or 4 irAEs – For patients experiencing grade 3 or 4 (severe or life-threatening) immune-mediated toxicities, treatment with immunotherapy is usually permanently discontinued. High doses of glucocorticoids (prednisone 1 to 2 mg/kg/day or equivalent) should be given. When symptoms subside to grade 1 or less, glucocorticoids can be gradually tapered, typically over at least four weeks (table 2).

Refractory toxicity – In the authors' experience, patients who will benefit from glucocorticoids generally do so within days to a week. If symptoms do not clearly improve or worsen on steroids, our approach is to administer an additional immunosuppressive agent. Examples of available agents include infliximab, vedolizumab, and mycophenolate mofetil, among other options.[2]

Pathophysiology

Triple M Syndrome emerges in correlation with the utilization of immune checkpoint inhibitors that specifically target CTLA-4, PD-1, and PD-L1 receptors situated on T-cells and antigen presenting cells. These receptors fulfill a pivotal role in the modulation of T-cell activity. Through the inhibition of these receptors, a continuous activation of T-cells is incited, facilitating the eradication of neoplastic cells. It is imperative to note that the augmentation of the immune response, though beneficial for combatting malignancies, can also give rise to immune-related adverse effects.

One prominent manifestation of these immune-related effects is the enigmatic Triple M Syndrome.The precise underlying mechanisms responsible for the onset of Triple M Syndrome remain unclear. Current hypotheses suggests on potential factors such as molecular mimicry and the autoimmune functions of the PD-1 pathway.[3][4]

Causes

Checkpoint inhibitors like Ipilimumab, nivolumab etc are suspected to be the potential cause of Triple M Syndrome.

References

  1. Pathak R, Katel A, Massarelli E, Villaflor VM, Sun V, Salgia R (2021). "Immune Checkpoint Inhibitor-Induced Myocarditis with Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases". Oncologist. 26 (12): 1052–1061. doi:10.1002/onco.13931. PMC 8649039 Check |pmc= value (help). PMID 34378270 Check |pmid= value (help).
  2. Schneider BJ, Naidoo J, Santomasso BD, Lacchetti C, Adkins S, Anadkat M; et al. (2021). "Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update". J Clin Oncol. 39 (36): 4073–4126. doi:10.1200/JCO.21.01440. PMID 34724392 Check |pmid= value (help).
  3. Palaskas N, Lopez-Mattei J, Durand JB, Iliescu C, Deswal A (2020). "Immune Checkpoint Inhibitor Myocarditis: Pathophysiological Characteristics, Diagnosis, and Treatment". J Am Heart Assoc. 9 (2): e013757. doi:10.1161/JAHA.119.013757. PMC 7033840 Check |pmc= value (help). PMID 31960755.
  4. Tarrio ML, Grabie N, Bu DX, Sharpe AH, Lichtman AH (2012). "PD-1 protects against inflammation and myocyte damage in T cell-mediated myocarditis". J Immunol. 188 (10): 4876–84. doi:10.4049/jimmunol.1200389. PMC 3345066. PMID 22491251.