From Uncertainty to Strategy: Guiding Vaccine Decisions in Rare Autoimmune Conditions

Rare diseases, although individually uncommon, collectively affect a significant proportion of the general population. More than 10,000 rare diseases have been identified, and although definitions vary across countries and regions, the global average is that a condition is considered rare when its prevalence is 1:2500.¹ Rare diseases affect more than 300 million people worldwide, and approximately 70% of them occur in the pediatric population.²

Vaccination can be critical for people living with rare diseases, especially since many have an increased risk of infection due to the disease or associated comorbidity. People with rare autoimmune disorders are one group, in particular, that must carefully consider vaccine schedules. In fact, for some rare autoimmune patients, immunosuppression-related infection may pose a higher mortality risk than the autoimmune condition itself.^3,4

However, there are challenges to providing vaccine guidance for rare autoimmune diseases, given the low prevalence of some of these conditions, limited knowledge of their natural history or course of illness, and limited understanding of the impacts of vaccines in these patients. Although knowing how to proceed for these rare autoimmune conditions can be difficult, understanding the disease and key factors, such as vaccine modality, mechanism of disease and immunological response, can guide vaccine decisions.

Understanding rare autoimmune disorders

An autoimmune disorder occurs when the body’s immune system misidentifies healthy tissues as foreign and attacks them. For many rare autoimmune disorders, the exact causes are unclear, but they are primarily thought to occur as a combination of genetic predisposition and exposure to environmental risk factors.³ Because these conditions are usually not solely inherited and can be acquired in maturity, patients commonly span adults, as well as children — a distinct contrast to other categories of rare disease, which are often genetic and have primarily paediatric patients.

There are many ways rare autoimmune disorders can manifest, leading to a wide range of expressions and effects on the body. Exploring some of these conditions helps paint a picture of the scope of this category of disease. Some illustrative examples include:

1. Systemic scleroderma is thought to develop due to excessive collagen production and disproportionate inflammation following a microvascular injury, leading to the replacement of healthy tissue with fibrous tissue and internal organ scarring that can affect the lungs, nerves, and muscle, the gastrointestinal tract, and other organs and systems.
2. Chronic inflammatory demyelinating polyneuropathy (CIDP) occurs when immune cells attack the myelin sheaths of motor nerves, disrupting the central nervous system’s ability to communicate with the peripheral nervous system and causing muscle weakness, paralysis, and impaired motor function.
3. Pemphigus is a condition in which the immune system produces antibodies against desmoglein proteins that bind skin cells to one another, resulting in blisters on the skin and mucous membranes.
4. Primary biliary cholangitis occurs when the body loses tolerance to a protein expressed in biliary epithelial cells, leading to bile duct injury and putting patients at risk of other liver conditions.

The importance of vaccines for rare autoimmune patients

The expression of rare autoimmune diseases can leave patients particularly vulnerable to infection in different ways. For many, the dysfunction of the immune system makes it more difficult to defend against pathogens. The physiological effects of autoimmune disease can also lead to increased risk: In pemphigus, for instance, the disruption of the skin and mucous membranes, which are the body’s first barrier against infection, makes it easier for pathogens to enter the body.⁵

Additionally, the primary treatment for autoimmune diseases is immunosuppression, which impairs the immune response. While this weakens the immune system’s attack on the body’s own tissues, it also reduces its ability to defend against infectious agents. Combined with any vulnerabilities caused by the disease itself, this means that autoimmune patients receiving treatment have a particularly heightened susceptibility to infection and a likelihood of more severe disease when infected.⁶ Clearly, preventing infectious disease as much as possible is critical to this population—and vaccines are an essential element of prophylaxis.

Considerations for selecting vaccines

Modality

How a vaccine is delivered is one of the more clear-cut deciding factors for rare autoimmune patients. Generally speaking, live vaccines, which contain an attenuated, but still active, form of the virus in question, are not recommended for this population, particularly for those taking immunosuppressants.^4,7 Although the live viruses used in vaccines are not typically a threat for those with healthy immune systems, those who are immunocompromised due to autoimmunity and immunosuppression may have difficulty defending against even a weakened pathogen.

However, there are some exceptions. For example, children with rheumatic autoimmune conditions may receive live attenuated measles and varicella booster vaccines.⁸ In this case, the danger posed by a lack of inoculation against the diseases in question is high, and studies have found these boosters to be safe.⁹

Other types of vaccines, such as inactivated, subunit, or mRNA vaccines, are considered safe for patients with rare autoimmune diseases taking immunosuppressive treatments. Because none of these modalities includes a whole, active virus, there is no risk of infection following vaccination.

Mechanism of disease

Another key consideration is how a given rare disease affects immune function. Depending on the mechanism of disease, a patient may be more vulnerable to certain types of infection, which can make some vaccines a high priority. An illustration of this is seen in complement deficiency, which involves the absence or suboptimal function of important proteins in the complement system of immune response. Complement deficiency can be a cause of autoimmune disease, and some forms of it put patients at higher risk of certain kinds of infection, including encapsulated bacteria, such as Streptococcus pneumoniae, or pathogens in the Neisseria family. This makes vaccination against diseases under these umbrellas, such as pneumonia and meningitis, particularly important.^10,11

System affected by disease

A final consideration is what biological systems a patient’s specific rare disease affects. As previously discussed, rare autoimmune disorders can be quite diverse in their systemic impact, ranging from dermatological to hepatic to nervous manifestations, among others.

Depending on which systems are affected by a condition, a patient may be at greater risk of certain types of infection. For example, fibrosis in systemic sclerosis affects numerous organs, including the lungs. Damage to lung tissue and vasculature can lead to pulmonary complications, such as interstitial lung disease and pulmonary arterial hypertension. Due to the potential and actual compromised respiratory function in patients with systemic sclerosis, vaccines for respiratory conditions, such as influenza, COVID-19, and pneumonia, are highly recommended for this patient population.^12,13

Accounting for immune response to vaccines

Once the appropriate vaccines have been identified, the next challenge is determining a vaccine schedule. Because immunosuppression interferes with typical immunological responses, in some cases, it may weaken the response to vaccines compared to healthy patients. This can reduce the vaccine’s effectiveness and necessitate a booster that might not otherwise be required.

Similarly, even if a patient’s initial response to vaccination is strong, the conferred immunity may wane faster. One study found that CIDP patients and the control group had a similar initial response to COVID-19 vaccination. However, compared to the control group, the CIDP patients had lower antibody levels and neutralization capacity for COVID-19 at 6, 18, and 24 months following vaccination.¹⁴

It is also worth noting that there is some evidence suggesting that the type of treatment may predict the strength of the vaccine response and the corresponding immunity.¹⁴ Immunosuppressive treatments are a broad category, spanning steroids, immunoglobulin, JAK inhibitors, B-cell depleting therapies (BCDTs), and others. Different treatments affect different elements of the immune pathway, which can, in turn, affect vaccine response.

In particular, BCDTs, methotrexate, and high-dose prednisolone have been shown to reduce the immune response to vaccines.¹⁵ Another study of COVID-19 vaccination in autoimmune patients found that biologics that deplete CD20-positive B cells, such as rituximab, resulted in a severely reduced antibody response compared to other medications, while others, such as JAK inhibitors, only moderately reduced the response.¹³ Some, including monoclonal antibodies against IL-1, IL-17, and TNF-alpha, were not associated with a negative effect on vaccination response at all.¹⁶

The unpredictability of immune response under these conditions can make it difficult to determine the exact vaccination needs of a specific patient. Antibody titers can therefore be a useful tool for quantifying the concentration of specific antibodies in a patient’s blood and for determining whether and when a booster or redosing is needed.

Taking it case-by-case

Deciding on the appropriate vaccine schedule for someone with a rare autoimmune disease is critical to preventing potentially serious outcomes of infection. Given the complexity of these conditions, vaccine decisions should be made on an individual basis, onbased to the disease in question, the patient's clinical presentation, and the patient’s specific treatment regimen. With time and care, this challenge is not insurmountable, particularly with a framework in place to guide decision-making and protect the health of these vulnerable populations.

References:

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6. Infections in systemic autoimmune diseases. In: Handbook of Systemic Autoimmune Diseases. Vol 16. Elsevier; 2020:143-166. doi:10.1016/B978-0-444-64217-2.00007-5
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9. Uziel Y, et al. Live attenuated MMR/V booster vaccines in children with rheumatic diseases on immunosuppressive therapy are safe: multicenter, retrospective data collection. Vaccine. 2020;38(9):2198-2201. doi:10.1016/j.vaccine.2020.01.037
10. Mollah F, Tam S. Complement deficiency. In: StatPearls [Internet]. StatPearls Publishing; 2023. Accessed January 28, 2026. https://www.ncbi.nlm.nih.gov/books/NBK557581/
11. Lewis LA, Ram S. Complement interactions with the pathogenic Neisseriae: clinical features, deficiency states, and evasion mechanisms. FEBS Lett. 2020;594(16):2670-2694. doi:10.1002/1873-3468.13760
12. Rosamilia F, et al. Flu and pneumococcal vaccine coverage in scleroderma patients still need to be prompted: a systematic review. Vaccines. 2021;9(11):1330. doi:10.3390/vaccines9111330
13. Lakin KS, et al. COVID-19 vaccinations and infections among individuals with systemic sclerosis: a Scleroderma Patient-Centered Intervention Network cohort study. Semin Arthritis Rheum. 2024;67:152453. doi:10.1016/j.semarthrit.2024.152453
14. Kodal LS, et al. Humoral immune response following COVID-19 vaccination in multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy. Vaccines. 2025;13(9):902. doi:10.3390/vaccines13090902
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16. Frommert LM, et al. Type of vaccine and immunosuppressive therapy but not diagnosis critically influence antibody response after COVID-19 vaccination in patients with rheumatic disease. RMD Open. 2022;8(2):e002650. doi:10.1136/rmdopen-2022-002650