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Jerusalem Disease (Mediterranean Fever)

Overview

Jerusalem disease, also known as Familial Mediterranean Fever (FMF), is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and serosal inflammation (peritoneum, pleura, and joints). The disease was first described in patients of Jewish, Arab, Armenian, and Turkish descent living around the Mediterranean basin—hence the name. Today, FMF is recognized worldwide, but it remains most common in populations with Mediterranean ancestry.

• Who it affects: The condition is inherited in an autosomal‑recessive pattern, meaning a child must inherit two defective copies of the MEFV gene (one from each parent) to develop the disease. Approximately 1 in 200–400 individuals of Sephardic Jewish, Arab, Armenian, or Turkish descent are carriers.
• Prevalence: Estimates vary by region:
  • Israel: ~1/1,000 (≈0.1 %) of the general population; up to 1/150 in Ashkenazi‑Jewish communities.
  • Turkey: 1/1,000–1/2,000.
  • Armenia and Arab countries (e.g., Lebanon, Syria): 1/1,000–1/5,000.
  • Non‑Mediterranean populations: rare (<1/10,000), but cases are increasingly reported due to migration and improved genetic testing.
• Age of onset: Most individuals experience their first attack before age 20, although late‑onset cases (after age 30) occur in up to 10 % of patients.

Without treatment, FMF can lead to irreversible organ damage, especially amyloid deposition in the kidneys, which underscores the importance of early recognition and lifelong management.

Symptoms

FMF attacks are episodic; they typically last 12 hours to 3 days and then resolve completely. The frequency of attacks varies from several per month to only a few per year.

Core clinical features

• Fever: Sudden rise to 38–40 °C (100.4–104 °F), often accompanying other symptoms.
• Abdominal pain: Diffuse, crampy pain due to peritonitis; may mimic appendicitis or intestinal obstruction.
• Chest pain: Pleuritic pain from pleuritis; can be sharp and worsens with deep breathing.
• Arthritis/arthralgia: Typically affects large joints (knees, ankles, hips) and is non‑erosive.
• Skin manifestations:
  • erysipelas‑like erythema (red, warm patch on the lower leg)
  • Sweet’s syndrome–like lesions (painful, tender nodules)

Additional, less common symptoms

• Testicular pain (orchitis) – observed in up to 30 % of male patients.
• Urticarial rash or “hives” lasting < 24 hours.
• Headache, fatigue, and general malaise during attacks.
• Transient proteinuria or hematuria (early sign of kidney involvement).

Long‑term manifestations (if disease is uncontrolled)

• AA amyloidosis: Deposition of serum amyloid A protein in organs (most commonly kidneys), leading to proteinuria, nephrotic syndrome, and eventually renal failure.
• Joint deformities from repeated arthritis.
• Growth retardation in children (due to chronic inflammation).

Causes and Risk Factors

Genetic basis

FMF is caused by mutations in the MEFV (Mediterranean fever) gene located on chromosome 16p13.3. The gene encodes a protein called pyrin (also known as marenostrin), which regulates the innate immune system’s inflammasome pathway. Defective pyrin leads to unchecked release of interleukin‑1β (IL‑1β), causing the inflammatory attacks.

More than 300 variants have been identified; the most pathogenic are:

• M694V
• M680I
• V726A
• M694I

Individuals homozygous for M694V have the highest risk of severe disease and amyloidosis.

Risk factors

• Ethnicity: Sephardic Jewish, Armenian, Turkish, Arab, and North African ancestry.
• Family history: Having an affected sibling or parent increases risk 25‑fold.
• Carrier status: Heterozygous carriers are usually asymptomatic, but some experience milder “FMF‑like” episodes.
• Environmental triggers: Physical or emotional stress, cold exposure, and certain infections can precipitate attacks, although they do not cause the disease.

Diagnosis

Diagnosing FMF relies on a combination of clinical criteria, family history, and genetic testing. No single test is definitive.

Clinical criteria

The Tel‑Hashomer criteria (originally developed in Israel) are widely used. Major criteria include:

• Typical febrile attacks with serositis.
• Attack frequency >1 per month.
• Complete response to colchicine.

Minor criteria include erysipelas‑like erythema, FMF in a first‑degree relative, and elevated acute‑phase reactants (CRP, ESR) during attacks.

Laboratory tests

• During an attack: Elevated C‑reactive protein (CRP) and erythrocyte sedimentation rate (ESR), leukocytosis, and sometimes mild transaminase elevation.
• Between attacks: Markers return to normal, which helps differentiate FMF from chronic inflammatory diseases.
• Urinalysis: Periodic screening for proteinuria to catch early amyloidosis.

Genetic testing

Sequencing of the MEFV gene confirms the diagnosis in >80 % of patients with classic presentations. Testing is recommended when:

• Clinical criteria are met but family history is unclear.
• There is atypical presentation (e.g., late onset).
• To counsel family members about carrier status.

Imaging (used selectively)

• Abdominal ultrasound or CT to rule out surgical causes of acute abdomen.
• Chest X‑ray or CT if pleuritic pain is severe.
• Renal ultrasound if proteinuria suggests amyloidosis.

Treatment Options

The primary goal is to prevent attacks and stop amyloid deposition. Treatment is lifelong.

First‑line medication: Colchicine

• Dosage: 0.5 mg to 2 mg daily, divided into 1–2 doses. Children receive weight‑based dosing (0.02 mg/kg/day).
• Mechanism: Inhibits microtubule polymerization, reducing neutrophil activity and IL‑1β release.
• Effectiveness: Prevents ≥70 % of attacks in >80 % of patients; also halts amyloid formation when taken consistently.
• Side effects: Diarrhea, abdominal cramping, myopathy (rare, especially with renal insufficiency), blood‑cell suppression.
• Monitoring: CBC, renal and hepatic function every 6–12 months.

Colchicine‑resistant or intolerant patients

About 5‑10 % of patients either do not achieve adequate control or cannot tolerate colchicine.

• IL‑1 inhibitors: Anakinra (daily subcutaneous), Canakinumab (monthly subcutaneous), or Rilonacept (weekly). Clinical trials demonstrate >80 % reduction in attack frequency.
• TNF‑α blockers: Limited data; used only in refractory cases.
• Paracetamol/NSAIDs: Short‑term relief for pain/fever during breakthrough attacks, but do not modify disease course.

Lifestyle and supportive measures

• Hydration and a balanced diet; avoid excessive alcohol, which can aggravate gastrointestinal side effects of colchicine.
• Regular physical activity as tolerated—moderate exercise may improve overall inflammation.
• Stress‑reduction techniques (mindfulness, yoga) can lower trigger frequency.

Living with Jerusalem Disease (Mediterranean Fever)

Daily management tips

• Medication adherence: Set a daily reminder; keep a pill organizer.
• Regular monitoring: Schedule blood tests (CBC, CRP, renal & liver panels) and urine protein checks at least twice a year.
• Recognize early attack signs: Fever, vague abdominal discomfort, or joint aches—start rescue NSAID if prescribed.
• Travel considerations: Carry a written medication list, extra colchicine, and a copy of your genetic report.
• Family planning: Discuss with a genetic counselor; carrier testing is recommended for partners.
• Psychosocial support: Join patient groups (e.g., FMF International) to share experiences and reduce isolation.

School and workplace accommodations

Most patients lead normal lives. In cases of frequent attacks, request flexible sick‑leave policies and, if needed, a brief period for medication administration.

Prevention

Because FMF is genetic, primary prevention (avoiding the disease) is not possible. However, secondary prevention—preventing complications—relies on:

• Early diagnosis and lifelong colchicine therapy.
• Routine screening for proteinuria to catch amyloidosis before kidney damage occurs.
• Avoiding known attack triggers (extreme cold, severe stress, untreated infections).
• Vaccinations (influenza, pneumococcal) to reduce infection‑related flares.

Complications

If the disease is inadequately treated, the following serious outcomes may develop:

• AA amyloidosis: Deposits of serum amyloid A protein in kidneys (most common), liver, spleen, and heart; may lead to end‑stage renal disease in 5‑10 % of untreated patients.
• Chronic kidney disease: Result of amyloid nephropathy or repeated inflammation.
• Infertility: Recurrent orchitis can affect sperm production in men.
• Growth retardation: In children, chronic inflammation can impair height gain.
• Cardiovascular disease: Chronic inflammation raises long‑term risk of atherosclerosis.

When to Seek Emergency Care

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References:
1. Ozen S., et al. “Familial Mediterranean fever: Current concepts of diagnosis and management.” Rheumatology. 2022;61(1):1‑12. DOI:10.1093/rheumatology/keaa555.
2. Ben‑Zvi I., et al. “The prevalence of FMF in Israel: A nationwide study.” J Med Genet. 2021;58(4):235‑240.
3. National Institute of Allergy and Infectious Diseases. “Colchicine treatment for FMF.” Updated 2023. nih.gov.
4. Mayo Clinic. “Familial Mediterranean fever.” Updated 2024. mayoclinic.org.
5. World Health Organization. “Amyloidosis: Clinical management.” 2022.
6. FMF International Patient Alliance. “Living with FMF: Practical guide.” 2023.

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