Familial Mediterranean fever

Based on Wikipedia: Familial Mediterranean fever

The Fever That Chose Its People

Imagine a disease so particular about who it strikes that geneticists can trace its path through three thousand years of Mediterranean history. Familial Mediterranean fever—known to doctors simply as FMF—doesn't just run in families. It runs in civilizations.

This isn't a random genetic lottery. FMF overwhelmingly affects people whose ancestors lived around the Mediterranean Sea: Sephardic and Mizrahi Jews, Armenians, Turks, Arabs, Greeks, Kurds, Assyrians, Druze, and Italians. Even Ashkenazi Jews, who migrated to Eastern Europe centuries ago, carry the mutation—a molecular breadcrumb leading back to their Mediterranean origins.

The disease announced itself to modern medicine in 1945, when a New York allergist named Sheppard Siegal encountered something he'd never seen before. His patients—many of them from Middle Eastern Jewish families—would suddenly develop agonizing abdominal pain that mimicked appendicitis, only to recover completely within days. He called it "benign paroxysmal peritonitis," a name that sounds almost reassuring until you understand what peritonitis means: inflammation of the membrane lining your abdominal cavity. In most contexts, peritonitis is a medical emergency. In FMF, it's Tuesday.

What an Attack Feels Like

A typical FMF attack builds over two to four hours, like a storm rolling in. Then it stays for anywhere from six hours to five days before vanishing as mysteriously as it arrived. Most attacks bring fever. But fever is just the beginning.

The abdominal attacks are the signature of this disease, occurring in ninety-five percent of patients. The pain isn't localized—it spreads across the entire abdomen, mimicking the signs of acute appendicitis or a perforated bowel. For decades, surgeons would rush FMF patients into operating rooms, only to find nothing wrong. The inflammation was real. The emergency wasn't.

Joint attacks strike seventy-five percent of patients, typically targeting the large joints of the legs—knees, ankles, hips. Unlike rheumatoid arthritis, which often affects matching joints on both sides of the body, FMF usually attacks one joint at a time, as if the disease is taking turns.

Then there are the chest attacks. Forty percent of patients experience pleuritis—inflammation of the thin membrane surrounding the lungs. Every breath becomes a negotiation with pain. Lying flat feels impossible. Pericarditis, inflammation of the sac around the heart, can also occur, though mercifully it's rare.

Men with FMF sometimes experience attacks targeting the scrotum, inflammation of a membrane called the tunica vaginalis. These episodes can look exactly like testicular torsion—a genuine emergency requiring immediate surgery. More than a few FMF patients have undergone unnecessary operations because their doctors, reasonably, couldn't take the chance.

Ninety percent of people with FMF experience their first attack before age eighteen. For many, the attacks become a grim rhythm of their lives—unpredictable storms they learn to weather but never quite get used to.

The Pyrin Puzzle

The culprit behind FMF is a gene called MEFV, which sits on the short arm of chromosome 16. This gene provides instructions for building a protein called pyrin—named after the Greek word for fire, a nod to the fever it causes when it malfunctions.

To understand what goes wrong in FMF, you need to understand what pyrin is supposed to do. Your immune system has a critical job: detecting when bacteria or viruses have invaded your body and mounting an inflammatory response to destroy them. Pyrin is part of this detection system. It helps assemble molecular machines called inflammasomes—essentially alarm bells that trigger the release of inflammatory signals called cytokines.

In healthy people, pyrin sits quietly until it detects specific signs of bacterial invasion. Certain bacterial toxins tamper with a molecular switch inside your cells, and pyrin notices this tampering. It then springs into action, assembling an inflammasome and initiating inflammation to fight the infection.

But in FMF, pyrin is too sensitive. The mutations that cause the disease are "gain-of-function" mutations—they make pyrin more active, not less. It's like having a smoke detector that goes off whenever you make toast. The alarm is working, technically. It's just going off when there's no fire.

The molecular details are elegant and maddening. Normally, pyrin is held in check by chaperone proteins that cling to it through chemical handles called phosphorylated serine residues. Removing these phosphate groups is like releasing a safety catch—it's a necessary first step toward activating the inflammasome. But in healthy people, this alone isn't enough to trigger activation. There's a second safety mechanism.

In FMF patients, that second safety mechanism is broken. Simply removing the phosphate groups is enough to set off the alarm. The defect appears to be located in a region of the pyrin protein called the B30.2 domain, and it likely involves how pyrin interacts with the cell's internal skeleton—its network of structural filaments called microtubules.

The Colchicine Connection

Here's where FMF intersects with one of the oldest drugs in continuous medical use. Colchicine comes from the autumn crocus, and humans have been using it for millennia—ancient Egyptians described it in their medical texts. For most of history, it was known as a treatment for gout, the excruciating joint inflammation caused by uric acid crystals.

In the 1970s, physicians discovered something remarkable: colchicine could prevent FMF attacks. Patients who took one to two milligrams daily experienced dramatically fewer episodes. Their quality of life improved. And perhaps most importantly, colchicine prevented the most serious long-term complication of FMF: amyloidosis.

The connection between colchicine and pyrin makes molecular sense. Colchicine works by disrupting microtubules—the same cellular structures that appear to be involved in pyrin's malfunctioning regulation. By interfering with microtubules, colchicine may help restore the safety mechanism that FMF mutations have broken.

The Shadow of Amyloidosis

If FMF were just a matter of periodic suffering—attacks that come and go without lasting damage—it would be bad enough. But there's a darker complication lurking behind the fever and pain.

During every FMF attack, the body produces massive quantities of a protein called serum amyloid A. Even between attacks, production continues at a lower level. Over time, this protein can misfold and accumulate as deposits called amyloid in various organs. The kidneys are most vulnerable, but amyloid can also build up in the heart, spleen, thyroid, and digestive tract.

This is AA amyloidosis—the "AA" stands for amyloid A, the specific protein involved. As deposits accumulate in the kidneys, they gradually destroy tissue. Many FMF patients who go untreated eventually develop kidney failure. What's particularly insidious is that amyloidosis can progress silently, even in patients who don't seem to have typical attacks. Some people develop kidney failure without ever experiencing the dramatic fevers and abdominal pain that define classic FMF.

Colchicine slows this process dramatically. This is why lifelong treatment is so important—not just to prevent the acute misery of attacks, but to protect against the slow accumulation of amyloid that could destroy the kidneys decades later.

When Colchicine Isn't Enough

For most patients, daily colchicine transforms FMF from a relentless series of crises into a manageable condition. But about five to ten percent of patients don't respond adequately to colchicine alone. Their attacks continue. Their amyloid levels remain dangerously high.

For these patients, modern biotechnology offers an alternative. Remember that pyrin's ultimate effect is to trigger the release of inflammatory cytokines, particularly interleukin-1 beta? Drugs that block this cytokine can control FMF even when colchicine fails.

Anakinra is one such drug—a synthetic version of a natural protein that blocks the interleukin-1 receptor. Canakinumab is another option: a monoclonal antibody that specifically targets and neutralizes interleukin-1 beta before it can cause inflammation. These biologics represent a second line of defense for patients whose disease resists traditional treatment.

Diagnosis: Pattern Recognition Meets Genetics

Diagnosing FMF is an exercise in recognizing patterns. The Tel-Hashomer criteria, named after a hospital in Israel where much pioneering FMF research occurred, remain the gold standard. They're remarkably accurate—over ninety-five percent sensitivity and ninety-seven percent specificity.

A typical attack, according to these criteria, includes all of the following: it's recurrent (three or more episodes), febrile (rectal temperature of at least 38 degrees Celsius, or about 100.4 Fahrenheit), involves painful inflammation, and lasts between twelve and seventy-two hours. Attacks that don't quite fit this picture—lower fever, unusual duration, atypical location—are classified as "incomplete attacks," which can still support the diagnosis if they recur.

Genetic testing can confirm the diagnosis. Sequencing the key regions of the MEFV gene—exons 2, 3, 5, and 10—catches about ninety-seven percent of known disease-causing mutations. Having two mutations, either the same mutation inherited from both parents or two different mutations from each parent, meets the genetic threshold for diagnosis.

But genetics in FMF is surprisingly messy. Some patients with clear clinical disease have only one identifiable mutation. And many people who carry two mutations never develop symptoms at all. Something else—modifier genes, environmental factors, pure luck—determines whether genetic predisposition becomes clinical disease.

There's also a provocative test that seems almost too simple to work. Administering a single intravenous dose of metaraminol, a drug that raises blood pressure, can trigger a miniature FMF attack within forty-eight hours in susceptible patients. The test is highly specific but not perfectly sensitive—it catches many cases but misses some.

The Geography of a Gene

Why should a single disease cluster so specifically among Mediterranean populations? The answer almost certainly involves evolutionary pressure, though the details remain debated.

Genetic diseases that cause suffering and early death usually get weeded out of populations over time. Natural selection doesn't favor mutations that make it harder to survive and reproduce. Yet FMF mutations remain remarkably common in certain ethnic groups—so common that some researchers suspect carriers might have had some advantage.

One theory suggests that carrying one copy of an FMF mutation might provide some protection against other diseases, similar to how carrying one copy of the sickle cell mutation protects against malaria. The Mediterranean basin has historically been rife with infectious diseases. Perhaps a slightly overactive inflammatory response helped people survive epidemics of plague, cholera, or tuberculosis.

Another possibility is genetic drift. The populations most affected by FMF have historically been relatively small and sometimes isolated—conditions that allow random genetic fluctuations to have outsized effects. A mutation that happened to be present in founding populations could persist at high frequencies without conferring any particular advantage.

The truth is probably some combination of both factors, varying among different ethnic groups with different histories. What's certain is that FMF tells a story written in DNA—a story of ancient migrations, population bottlenecks, and the accidents of heredity playing out over millennia.

Living With Periodic Fire

For patients with FMF, the disease shapes life in ways both dramatic and subtle. There's the acute reality of attacks—the fever, the pain, the uncertainty about when the next episode will strike. There's the daily ritual of taking colchicine, the awareness that skipping doses courts disaster.

There are also the downstream complications to worry about. FMF patients have elevated risks of certain inflammatory conditions: Henoch-Schönlein purpura, a form of vasculitis that affects small blood vessels; polyarteritis nodosa, which targets medium-sized arteries; and Behçet's disease, an inflammatory disorder that causes mouth sores, genital ulcers, and eye inflammation. Prolonged arthritis and chronic muscle pain occur more often than in the general population.

Pregnancy raises special questions. Colchicine was once thought to be dangerous during pregnancy, and some physicians still advise stopping it. But accumulating evidence suggests that continuing colchicine may be safer than stopping—that the risks of uncontrolled FMF attacks may outweigh the theoretical risks of the drug. This remains an area of ongoing debate, requiring careful discussion between patients and their physicians.

Yet for most patients who receive proper treatment, FMF becomes a condition to manage rather than a life sentence. The transformation that colchicine provides—from unpredictable suffering to relative stability—represents one of medicine's genuine success stories. A drug derived from a flower that blooms in autumn, used since ancient times for an entirely different purpose, turned out to be the key to controlling a disease that had tormented Mediterranean families for generations.

The Historical Detectives

The story of FMF's discovery reads like a collaboration across continents and decades. Sheppard Siegal in New York. Hobart Reimann at the American University in Beirut, who expanded Siegal's observations into a fuller picture he called "periodic disease." Henry Mamou and Roger Cattan in France, who in 1952 connected the dots to kidney complications.

The disease has collected names like a traveler collects passport stamps: familial paroxysmal polyserositis, periodic peritonitis, recurrent polyserositis, benign paroxysmal peritonitis, periodic fever, Reimann syndrome, Siegal-Cattan-Mamou disease, Wolff periodic disease. Each name reflects a different observer, a different emphasis, a different piece of the puzzle.

Eventually, the geographic pattern became impossible to ignore. The disease followed the Mediterranean like a shadow—wherever people from that region migrated, FMF followed. The name we use today acknowledges this relationship directly: familial, because it runs in families; Mediterranean, because it emerged from that ancient crossroads of civilizations; fever, because that's what patients experience when the fire in their genes ignites.

Understanding FMF required advances in molecular biology that the early clinical observers couldn't have imagined. The identification of the MEFV gene in 1997, achieved simultaneously by two international research teams, opened a window into the fundamental biology of inflammation. Studying this rare genetic condition has taught researchers about how all human bodies regulate their immune responses—knowledge that extends far beyond the Mediterranean populations where FMF is most common.

The periodic fire that has burned through families for millennia continues to burn. But now we understand its fuel, and we have ways to control the flame.