Triple M Syndrome

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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.

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.

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.

Causes

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