Myasthenia Gravis: Understanding Fatigable Weakness and Modern Immunotherapy

Myasthenia gravis isn't just muscle weakness. It’s weakness that gets worse when you use your muscles-and gets better when you rest. Imagine lifting your eyelids, only to have them droop halfway through the day. Or struggling to chew your food, then suddenly being able to swallow again after a nap. That’s the hallmark of myasthenia gravis (MG): fatigable weakness. It doesn’t stay constant. It comes and goes, flares up with activity, and fades with rest. This isn’t laziness or aging. It’s your immune system mistakenly attacking the connection between your nerves and muscles.

What Causes the Weakness?

Your muscles don’t move on their own. They need a signal from your nerves. That signal is sent using a chemical called acetylcholine. At the junction where nerve meets muscle, acetylcholine binds to receptors-like a key turning in a lock-to make the muscle contract. In myasthenia gravis, your body makes antibodies that block or destroy those receptors. Without enough working receptors, the signal gets lost. The muscle doesn’t respond. That’s the weakness.

Eighty to ninety percent of people with generalized MG have antibodies against the acetylcholine receptor (AChR). A smaller group-5 to 8%-have antibodies against something called MuSK. The rest are seronegative, meaning no known antibodies are found, but the disease still behaves the same. This isn’t random. These antibodies are the direct cause. They’re not just a marker-they’re the enemy.

It often starts in the eyes. About 85% of people first notice drooping eyelids (ptosis) or double vision (diplopia). For some, it stays there. But for half to 80% of those with only eye symptoms, it spreads to other muscles within two years. That’s called generalized MG. Then you might have trouble speaking clearly, swallowing, lifting your arms, or climbing stairs. The weakness is most noticeable after activity and improves after rest. That’s why it’s called fatigable.

Who Gets It and Why?

Myasthenia gravis can strike at any age, but it has two clear peaks. People under 50-especially women-are more likely to develop early-onset MG. In these cases, the thymus gland (a small organ in the chest that helps train immune cells) is often enlarged and overactive. The thymus is thought to be where the bad antibodies are first made.

People over 50, especially men, tend to develop late-onset MG. Here, the thymus is often shrunken, but about 10 to 15% have a thymoma-a benign tumor. That tumor can trigger the same autoimmune response. The reason why the immune system turns on itself isn’t fully known. Genetics may play a role, but environmental triggers like infections or stress are likely involved too.

How Is It Diagnosed?

Doctors don’t just guess. They use tests that show the nerve-muscle connection is broken. The most common is the edrophonium test-a quick injection that temporarily boosts acetylcholine. If your eyelids lift or your speech clears within seconds, it’s a strong sign of MG.

Blood tests look for AChR or MuSK antibodies. These confirm the diagnosis in most cases. But even if antibodies are negative, the disease can still be there. That’s when doctors use nerve conduction studies, especially repetitive nerve stimulation. In MG, the muscle response gets weaker with repeated stimulation-something that doesn’t happen in healthy nerves.

They also use the Quantitative Myasthenia Gravis Score (QMGS). It’s a checklist of 15 tasks: lifting arms, walking up stairs, speaking, swallowing. Each gets a score. A total over 11 means moderate to severe disease. That tells doctors when it’s time to move beyond symptom relief and start immunotherapy.

First-Line Treatment: Symptomatic Relief

Before attacking the immune system, doctors often start with pyridostigmine. This drug slows down the breakdown of acetylcholine, so more of it hangs around to bind to the remaining receptors. It’s not a cure. It’s a bridge. People take 60 to 240 mg a day, split into doses. It helps with eyelid drooping, speech, and swallowing-but it doesn’t stop the immune attack. It just buys time.

Side effects? Nausea, cramps, increased saliva. But it’s usually well-tolerated. Many people live for years on pyridostigmine alone, especially if their disease is mild or stays in the eyes.

Immunotherapy: Turning Off the Attack

Once the disease spreads beyond the eyes, or symptoms get worse, it’s time for immunotherapy. This isn’t about fixing the muscle. It’s about stopping your immune system from destroying it.

Corticosteroids like prednisone are the most common first-line immunosuppressant. They’re powerful. About 70 to 80% of patients see major improvement or even complete remission. But they come with a cost. Weight gain, mood swings, bone thinning, high blood sugar. Many people gain 10 to 20 pounds within months. Long-term use isn’t sustainable.

That’s why doctors add steroid-sparing agents as soon as possible. Azathioprine and mycophenolate mofetil are the two main ones. Azathioprine takes 6 to 18 months to work fully, but once it does, about 60 to 70% of patients can reduce or stop steroids. Mycophenolate works faster-often within 3 to 6 months-and has fewer liver side effects. About half to 60% respond well.

But here’s the catch: not all types of MG respond the same.

Subtype Matters: AChR vs. MuSK

MG isn’t one disease. It’s two or three different ones, depending on the antibody. That changes treatment.

AChR-positive MG responds well to standard immunosuppressants. But MuSK-positive MG? It’s different. These patients often have severe bulbar weakness-trouble speaking and swallowing-and don’t respond as well to pyridostigmine or azathioprine. For them, rituximab is a game-changer. It targets B-cells-the immune cells that make the bad antibodies. Studies show 71 to 89% of MuSK-positive patients reach minimal symptom status with rituximab, compared to just 40 to 50% of AChR-positive patients.

That’s why testing for antibody type isn’t optional. It’s essential. Giving the wrong drug can waste months and let symptoms worsen.

Fast-Acting Options for Crises

What if someone can’t swallow, can’t breathe, or is about to be rushed to the ICU? That’s a myasthenic crisis. You need fast action.

Two treatments work quickly: intravenous immunoglobulin (IVIG) and plasma exchange (PLEX). Both clear out the bad antibodies-but differently.

IVIG gives you healthy antibodies from donors. These flood your system and confuse your immune system into stopping the attack. It takes 5 to 7 days to work, and the effect lasts 3 to 6 weeks. It’s easier to give-just an IV drip-but it’s expensive and can cause headaches or fever.

PLEX literally pulls your blood out, removes the plasma (where the bad antibodies live), and returns your blood cells with fresh plasma. It works faster-2 to 3 days-and is often preferred in life-threatening cases like respiratory failure. But it needs a central line, carries infection risks, and isn’t available everywhere.

Both are equally effective in trials. The choice comes down to speed, availability, and patient condition.

Thymectomy: Removing the Source

If you’re under 65, have AChR-positive MG, and have a thymus that’s enlarged or abnormal, surgery to remove it-thymectomy-is recommended. The MGTX trial showed that patients who had thymectomy plus steroids reached remission faster than those on steroids alone. After five years, 35 to 45% of early-onset patients were in complete remission without any drugs.

It’s not a magic fix. But for the right person, it’s the best shot at long-term freedom from meds.

New Frontiers: Targeted Immunotherapies

The last five years have changed everything. New drugs don’t just suppress the whole immune system. They target specific parts of the problem.

Efgartigimod blocks the FcRn receptor-the body’s recycling system for antibodies. Normally, your body saves IgG antibodies (including the bad ones) and reuses them. Efgartigimod tells the body to destroy them instead. In the ADAPT trial, 68% of patients reached minimal manifestation status within weeks. It’s given weekly by IV, and the FDA approved it in 2021.

Then came ravulizumab, a complement inhibitor approved in 2023. It stops a specific part of the immune system from attacking the muscle membrane. It’s given every 8 weeks by IV.

These drugs are faster, more precise, and have fewer side effects than steroids or azathioprine. But they’re expensive. And long-term data beyond two years is still limited.

The Dark Side: Immune Checkpoint Inhibitors

There’s a dangerous twist. Cancer drugs called immune checkpoint inhibitors (ICIs) are designed to wake up the immune system to fight tumors. But in about 60% of cases, they accidentally trigger or worsen MG. These cases are often severe-60% involve heart inflammation (myocarditis), and 83% need ICU care. Doctors now warn: if someone on these drugs suddenly gets weakness, think MG. It’s a medical emergency.

Living With MG: Long-Term Realities

Most people with MG need long-term treatment. About 85 to 90% stay on some form of immunosuppression. But that doesn’t mean a life of constant struggle. With the right treatment, most reach “minimal manifestation status”-meaning symptoms are so mild they barely notice them.

Thymectomy, early treatment, and choosing the right immunotherapy can lead to remission. Younger patients have the best shot. About 10 to 20% go into spontaneous remission without any treatment-but that’s rare and unpredictable.

The biggest challenge? Tapering drugs too soon. If you stop immunosuppressants before you’ve been symptom-free for at least two years, you have a 40 to 50% chance of relapse. Patience is key.

Side effects are real. Weight gain from steroids. Liver damage from azathioprine. Infections are 2 to 3 times more common when you’re on multiple immunosuppressants. Vaccines are critical. Avoid live vaccines. Stay up to date on flu, pneumonia, and shingles shots.

What’s Next?

The future is targeted. New drugs are in trials: rozanolixizumab (subcutaneous, weekly), inebilizumab (B-cell targeting), and more FcRn blockers. The goal? Not just control-but cure. Researchers want to eliminate the bad antibodies without shutting down the whole immune system.

Right now, the best outcomes come from matching the treatment to the subtype, acting early, and avoiding unnecessary steroids. Myasthenia gravis isn’t a death sentence. It’s a chronic condition that can be managed-with the right science, the right drugs, and the right plan.