Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatigue. It occurs when the immune system mistakenly attacks the body’s own tissues, in this case the connection between nerves and muscles. This prevents proper communication between the nervous system and muscles, leading to impairments in muscle contraction and weakness. MG is associated with several other autoimmune conditions, meaning there is an increased prevalence of these diseases among MG patients compared to the general population.
Thyroid diseases
The most common autoimmune diseases associated with MG are thyroid disorders like Graves’ disease and Hashimoto’s thyroiditis. Studies estimate that up to 15% of people with MG also have a thyroid condition, while only around 5% of the general population has a thyroid disorder. The thyroid gland produces hormones that regulate metabolism. In autoimmune thyroid disease, the immune system attacks the thyroid, causing either overproduction of thyroid hormones (Graves’ disease) or underproduction (Hashimoto’s). This leads to symptoms like weight changes, fatigue, and sensitivity to temperature.
There are several reasons for the link between MG and thyroid autoimmunity. First, they are both caused by similar autoantibodies targetingacetylcholine receptors. Acetylcholine is a neurotransmitter that stimulates muscle contractions. When autoantibodies disrupt this signaling, muscle weakness occurs. Second, MG and thyroid disease have shared genetic risk factors related to immune system regulation. Finally, dysfunction of the thymus gland contributes to both conditions. The thymus plays a key role in development of the immune system. Abnormalities in the thymus can lead it to mistakenly target the body’s own tissues.
Treatment implications
Due to the close relationship between thyroid disorders and MG, all MG patients should be screened for thyroid autoantibodies and hormone levels at diagnosis. If a thyroid condition is identified, it should be treated to prevent it from exacerbating MG symptoms. Thyroid hormones help regulate metabolism of acetylcholine and muscles, so thyroid dysfunction could aggravate muscle weakness. Optimizing thyroid status helps ensure MG treatment is as effective as possible.
Rheumatoid arthritis
Another relatively common comorbidity of MG is rheumatoid arthritis (RA), affecting around 6-8% of MG patients. RA is an autoimmune disorder characterized by joint inflammation, pain and stiffness, particularly in the smaller joints of the hands and feet. In RA, the immune system mistakenly attacks the lining of joints, causing painful swelling. RA shares some similarities with MG, including female predominance, thymic abnormalities, and genetics related to immune function.
The specific mechanisms linking the two conditions are not fully understood. One possibility is molecular mimicry, where an immune response originally targeting one antigen ends up also reacting to a similar antigen in a different tissue. The initial immune response could be provoked by a virus or other infection. For example, antibodies formed against a virus may also bind to acetylcholine receptors or joint tissues, instigating MG or RA. Another link may be generalized activation of the inflammatory immune response, which then non-specifically attacks multiple sites like muscle connections and joints.
Management considerations
The presence of RA along with MG can make symptom management more complicated. Certain RA medications like anti-inflammatories and steroids may worsen MG. On the other hand, some MG treatments like corticosteroids, immunosuppressants, and IVIG may help control RA inflammation. Doctors must find the right balance of medications to adequately control both diseases. Lifestyle approaches like low-impact exercise and stress reduction can also help minimize symptoms of both MG and RA.
Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) co-occurs with MG in approximately 1-2% of patients. SLE is an autoimmune disorder that can affect almost any organ system of the body. It causes widespread inflammation and can result in joint pain, rashes, kidney dysfunction, and fatigue. In SLE, the immune system overproduces autoantibodies that bind to the body’s own tissues. This provokes widespread inflammatory damage to organs, blood vessels, and joints.
MG and SLE share multiple similarities and risk factors. Women disproportionately develop both diseases due to hormonal influences on autoimmunity. Abnormalities in B cells, T cells, and cytokine activity contribute to the immune system dysfunction seen in MG and SLE. Impaired clearance of apoptotic cells and debris may also provoke autoantibody formation in both disorders. Finally, associations with certain genetic markers related to immune function have been identified.
Impacts on prognosis and treatment
When MG and SLE occur together, patients may experience more severe or refractory disease. The combination of muscle weakness from MG and extreme fatigue from SLE can substantially reduce quality of life. SLE also carries higher risks of life-threatening kidney, heart, and lung complications. On the treatment side, antimalarial drugs effectively used for SLE like hydroxychloroquine can worsen MG symptoms. Corticosteroids and other immunosuppressants may help both diseases but have significant side effects with prolonged use. Careful monitoring and management are required when MG and SLE co-occur.
Inflammatory bowel disease
Inflammatory bowel diseases (IBD) like Crohn’s disease and ulcerative colitis have an association with several autoimmune disorders, including MG. Approximately 1-2% of MG patients also have IBD. These conditions cause chronic inflammation in the digestive tract, leading to symptoms like diarrhea, abdominal pain, and weight loss. In IBD, the immune system inappropriately attacks the intestinal lining, damaging its ability to properly absorb nutrients and act as a barrier. This provokes additional inflammation as bacteria and undigested food leak through the damaged intestinal wall.
It is not entirely clear why MG is linked to IBD, but some possible explanations have been proposed. One is the theory of molecular mimicry described earlier, where antibodies originally targeting an infection also bind to acetylcholine receptors. Infection with intestinal bacteria may be the initial trigger provoking cross-reactive antibodies in this scenario. More general immune system dysregulation characterized by excessive inflammatory responses may also contribute to the co-occurrence of MG and IBD.
Effects on management
When MG and IBD occur together, gastrointestinal symptoms can be mistakenly attributed to IBD flares alone. However, they may also represent impaired intestinal muscle contraction and motility from MG. This highlights the importance of considering how both conditions could contribute to a patient’s symptoms. From a treatment perspective, IBD therapies like TNF-alpha inhibitors and leukocyte inhibitors can potentially worsen MG. On the other hand, some MG treatments like corticosteroids also help control IBD inflammation. Balancing therapies for both diseases is essential.
Pernicious anemia
Pernicious anemia is another autoimmune condition associated with MG, affecting around 5-8% of patients. Pernicious anemia occurs when autoantibodies interfere with absorption of vitamin B12 from food. Vitamin B12 plays key roles in nerve function and red blood cell production. When B12 levels fall too low, pernicious anemia causes symptoms like fatigue, numbness, and pale skin from anemia. Autoantibodies block uptake of B12 by binding to stomach cells that normally absorb the vitamin.
The association between MG and pernicious anemia is thought to relate to atrophic gastritis, which underlies the impaired B12 absorption. Atrophic gastritis is inflammation and damage to the stomach lining, provoked by autoimmune attack on stomach cells. Atrophic gastritis is seen in around 50% of MG patients. The resulting dysfunction in stomach cells leads to inadequate production of intrinsic factor needed for B12 absorption, causing pernicious anemia. MG and pernicious anemia also share some genetic risk factors related to immune regulation.
Diagnostic and treatment considerations
The fatigue and neurological symptoms of pernicious anemia can mimic or worsen myasthenia gravis symptoms. Pernicious anemia may also exacerbate muscle weakness by impairing proper muscle function. Therefore, screening MG patients for B12 deficiency and pernicious anemia markers is recommended. Correction of low B12 levels through injections or high oral doses may improve some neuromuscular symptoms. However, B12 therapy alone does not correct the underlying autoimmune attack on stomach cells in pernicious anemia and atrophic gastritis.
Autoimmune hepatobiliary disease
A small proportion of MG patients, around 2-4%, also have autoimmune conditions affecting the liver and biliary system. These include autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. In these disorders, the immune system chronically damages the liver, bile ducts, or both. This causes gradual liver scarring, impairment of liver function, and symptoms like jaundice and itching. The mechanisms provoking these conditions are not fully understood but involve loss of immune tolerance to liver and bile duct cells.
The reasons for co-occurrence with MG are not clear either. One possibility is these diseases share some similar genetic risk factors related to immune regulation. One gene implicated in both MG and primary biliary cholangitis plays a role in clearing away debris from dead cells. Faulty debris clearance could expose the immune system to molecules it then attacks. More general immune system over-activity and loss of self-tolerance may also contribute to development of MG along with hepatobiliary autoimmunity.
Monitoring and management
When autoimmune liver or bile duct dysfunction occurs with MG, monitoring liver health is important, as some MG medications can be hepatotoxic. Medications may need adjustment if liver tests become abnormal. Steroids and other immunosuppressants used in MG may also help calm autoimmune liver inflammation. However, hepatotoxic drugs should be avoided. Overall, a multidisciplinary approach with both a neurologist and hepatologist helps optimize care for those with both MG and liver autoimmunity.
Celiac disease
Celiac disease is an autoimmune disorder estimated to occur in around 4-6% of people with MG. It is caused by an inflammatory reaction to gluten, a protein found in wheat, rye, and barley. In celiac disease, ingestion of gluten leads to immune system attack on the small intestine. This damages the lining of the small intestine and impairs its ability to absorb nutrients. Symptoms can include diarrhea, bloating, weight loss, and fatigue.
The association between MG and celiac disease may relate to a shared predisposition for autoimmune reactions targeting epithelial cells lining hollow organs like the intestine. Impaired intestinal barrier function and intestinal permeability allow gluten peptides to cross the gut lining, provoking the autoimmune response. Genetic factors, thyroid disease, and other autoimmune conditions can increase risk for both MG and celiac.
Evaluating celiac disease in MG
Since celiac disease causes malabsorption, vitamin and nutrient deficiencies can develop and worsen neurological symptoms like muscle weakness. Screening MG patients for celiac antibodies and inflammation can identify cases that may benefit from a gluten-free diet. A gluten-free diet not only improves intestinal damage in celiac disease but may also reduce systemic immune system activation. This helps control multiple autoimmune conditions.
Autoimmune skin disorders
Some autoimmune skin conditions occur more frequently in those with myasthenia gravis. The most common of these is vitiligo, affecting up to 4% of MG patients. Vitiligo involves patchy loss of skin pigment, causing white spots to appear on the skin. It occurs when the immune system attacks and destroys melanocytes, the pigment-producing cells. Other autoimmune skin diseases associated with MG include alopecia areata, psoriasis, and bullous pemphigoid, though these are relatively rare.
The co-occurrence of these skin conditions with MG may relate to shared autoimmune predispositions, such as a tendency for the immune system to target epithelial cells. Certain genetic variants related to immune function also increase susceptibility to both MG and autoimmune skin disorders. Skin represents a highly visible and accessible immune organ. When systemic immune dysregulation is present, it can manifest in the skin as well as internally.
Impact on prognosis and quality of life
For the most part, autoimmune skin disorders do not directly affect the course and treatment of MG. However, in severe cases, they can have emotional impacts and reduce quality of life. Management focuses on treating each condition, as most skin-directed therapies do not affect MG. Topical creams, light therapy, and immune-modulating medications can improve autoimmune skin lesions. Proper sun protection is important, as some MG medications increase sun sensitivity.
Other associated autoimmune conditions
In addition to the autoimmune diseases described above, myasthenia gravis shows associations with several other immune-mediated conditions. These include:
- Type 1 diabetes – About 2% of MG patients have this autoimmune disease characterized by destruction of insulin-producing pancreatic cells.
- Autoimmune hemolytic anemia – Autoantibody attack on red blood cells causes anemia in around 1% of those with MG.
- Sjögren’s syndrome – 1% of MG patients develop this autoimmune disorder affecting moisture-producing glands like salivary glands.
- Autoimmune myocarditis – Up to 1% have inflammation of the heart muscle due to autoimmune attack.
- Autoimmune neuropathy – A small proportion develops neurological impairment from autoimmune nerve damage.
Though less common, the occurrence of these other immune diseases in MG highlights the systemic nature of the underlying autoimmunity. Multiple aspects of the immune system are dysregulated, with widespread impacts on health.
Conclusion
Myasthenia gravis has associations with numerous autoimmune conditions, most commonly thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and pernicious anemia. These diseases share some common mechanisms like generalized immune system over-activity and loss of self-tolerance. However, the specific reasons for co-occurrence are not always fully understood.
The presence of comorbid autoimmune diseases in MG can affect disease severity, treatment options, and quality of life. Screening and monitoring for associated autoimmune conditions is an important component of comprehensive MG care. A multidisciplinary approach helps optimize management of MG and any related autoimmune disease. Continued research to elucidate the overlapping mechanisms among these immune disorders could reveal new therapeutic targets and approaches.
