Autoimmune vs. Autoinflammatory Disease: When the Immune System Misfires in Different Ways

During a weekly physician conference, I presented the case of an older gentleman who had suffered for years from unexplained fevers, hives, and elevated inflammatory markers. Despite multiple evaluations, no clear diagnosis had been made. He eventually developed renal amyloidosis, a serious condition in which inflammatory proteins build up in the kidneys, leading to kidney failure, and was referred to rheumatology. By that time, his disease had been quietly smoldering for years.

Although he had many classic signs and symptoms of an autoinflammatory disease,  none of his physicians had not recognized it.  Even at the conference where I was discussing the case with experienced academic clinicians, some physicians were unaware that this group of diseases even existed. When I mentioned “autoinflammatory disease,” several colleagues looked up with curiosity and tried to correct me, “you mean autoimmune?” they asked.

So what exactly is an autoinflammatory disease? And how does it differ from an autoimmune disease?

The Autoinflammatory System: When the Body’s Alarm Won’t Turn Off

Autoinflammatory diseases are a relatively newly recognized category of disorders that cause recurrent inflammation without infection or autoantibodies.

The problem lies in the innate immune system—our body’s first line of defense.

Cells like neutrophils, macrophages, and natural killer cells recognize common danger patterns (like bacterial cell walls) and rapidly respond by releasing inflammatory messengers called cytokines. These cytokines recruit more immune cells, raise the body temperature (fever), and trigger inflammation meant to destroy invaders.

In autoinflammatory diseases, however, this system misfires.

Due to genetic mutations in key signaling pathways, the body behaves as if an infection is present—even when it isn’t. The result: periodic flares of fever, rash, and joint pain, often mistaken for recurrent infections.

The best-known example of an autoinflammatory disease is Familial Mediterranean Fever (FMF), which causes brief attacks of fever and severe pain in the abdomen, chest, or joints—lasting 1–3 days—before completely resolving. In children, a syndrome called PFAPA (Periodic Fevers, Aphthous stomatitis, Pharyngitis, and cervical Adenitis) causes monthly episodes of fever, mouth sores, sore throat, and lymph nodes in the neck lasting 3-5 days.

The Autoimmune System: When Precision Backfires

If the innate immune system is the “first responder,” the adaptive immune system is the special operations unit.

It relies on B cells and T cells, each programmed to recognize one very specific target. This system takes longer to activate, but it learns and remembers—creating the foundation for immunity after infection or vaccination.

In autoimmune diseases, this precision goes awry.

B and T cells begin mistaking the body’s own tissues as foreign, mounting attacks that can cause chronic organ damage. In lupus, these immune cells may target the kidneys, heart, or lungs. In multiple sclerosis, they attack the brain and spinal cord. In rheumatoid arthritis, the joints become the target.

Interestingly, autoimmune diseases tend to affect women more often, while autoinflammatory diseases usually affect both sexes equally—reflecting differences in hormonal and genetic influences on each immune pathway.

Why These Differences Matter

Understanding whether inflammation stems from the innate or adaptive immune system isn’t just academic—it guides diagnosis and treatment.

• Autoimmune diseases are often treated with therapies that suppress B and T cells (e.g., rituximab, abatacept) or the cytokines they produce (TNF, IL-17).

• Autoinflammatory diseases respond better to drugs that block cytokines like IL-1 or IL-6 (e.g., anakinra, canakinumab, tocilizumab).

In my patient’s case, the pattern of fevers, hives, and amyloidosis pointed toward CAPS, a syndrome of recurrent fevers and hives, caused by mutations in the NLRP3 gene. Once recognized, these conditions can often be controlled remarkably well with modern biologic therapies.

A Rapidly Evolving Field

Autoinflammatory diseases were first described just over two decades ago—and new syndromes are being discovered every year.

Recent studies in journals like The New England Journal of Medicine highlight how the same inflammatory pathways implicated in rare disorders may also contribute to common conditions such as atherosclerosis, diabetes, and Alzheimer’s disease.

In other words, understanding these rare diseases may help us unravel the biology of inflammation itself—and, ultimately, improve health for millions.

Key Takeaway

The immune system has two powerful arms—innate and adaptive—and when either one misfires, disease results.

However, recognizing whether a disease is autoimmune or autoinflammatory can mean the difference between years of uncertainty and a targeted treatment that changes the trajectory of a patient’s life.

At Haus Health Rheumatology, we believe clarity begins when science meets empathy.

Our mission is to help patients and clinicians alike understand the why behind inflammation—because every patient deserves answers, and every diagnosis deserves precision.