Rare Classroom: Schnitzler Syndrome

Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Schnitzler Syndrome

What is Schnitzler Syndrome?

  • Described in 1974 by the French dermatologist Liliane Schnitzler
  • A rare disorder characterized by a chronic reddish rash that resembles hives (urticaria) and elevated levels of monoclonal IgM gammopathy (a protein in the blood)
  • Monoclonal IgM gammopathy is the uncontrolled growth of a single clone of plasma cells, which results in the abnormal accumulation of M-proteins (also known as immunoglobulin M or IgM) in the blood
  • These proteins are supposed to fight foreign substances in the body such as viruses and bacteria, but researchers suspect that they play a role in the development of Schnitzler syndrome (SchS)
  • Recently researchers have classified Schnitzler syndrome (SchS) as an autoinflammatory syndrome
  • The original case was from France and a large number of cases originate from France. The vast majority of cases come from Western Europe.​
  • As of 2014, 281 cases have been reported in 25 countries including Japan, Australia, Brazil and the US​
  • Most are of Caucasian descent​
  • Males have a slight predominance​
  • Patients with Schnitzler syndrome have ranged from age 13-71 years at the time of diagnosis​
  • The average age of onset is approximately 51 years​
  • “Highly underdiagnosed” – a retrospective study at Mayo Clinic uncovered 46 undiagnosed cases at that institution​

How Do You Get It?

  • Monoclonal IgM gammopathy is an uncontrolled growth of a single clone (monoclonal) of plasma cells
    • Results in the abnormal accumulation of M-proteins (also known as immunoglobulin M or IgM) in the blood
    • These proteins are supposed to fight foreign substances in the body such as viruses and bacteria
    • Researchers suspect that they play a role in the development of Schnitzler syndrome
    • The specific role these proteins play and the exact cause of Schnitzler syndrome (SchS) is unknown
  • New findings of dermal expression of active IL-1β, points to a central role of the inflammasome-controlled IL-1 production as a crucial step in the pathophysiology of Schnitzler syndrome. The best evidence that Schnitzler syndrome is a disease of exaggerated IL-1 activation is the successful use of the IL-1RA anakinra in its treatment.

What Are The Symptoms?

  • Vary from one person to another​
  • Can occur all together or at different times​
  • Persist for many years​
  • A reddish rash resembling hives usually on trunks, arms and legs
    • Usually raised reddish bumps and flatter wider lesions​
    • Rash lasts for a day or two and then disappears but a new rash often develops each day so that a rash is a constant occurrence​
    • Frequency of rash varies greatly from person to person​
    • Not usually itchy in first few years but becomes itchy for 45% after several years​
  • Chronic intermittent fevers
    • Frequency varies greatly from daily to several times a year​
    • Usually unrelated to skin rash​
  • Bone pain​
  • Joint pain​
  • Arthritis​
  • Malaise​
  • Enlargement of spleen​
  • Enlargement of lymph nodes​
  • Enlargement of liver​
  • Weight loss​
  • Fatigue​
  • Over a period of 10 years about 15% of patients develop cancer – usually caused by overproduction of white blood cells​
  • Typically Waldenström macroglobulinemia or lymphoma​
  • Severe inflammatory anemia​
  • AA amyloidosis​

How Is It Treated?

  • Until 2005, there were no effective treatments for SchS​
  • A number of drugs were found to be ineffective, partially effective or fairly effective but with risks/side effects​
  • In 2005, it was found that anakinra (Kineret) is highly effective for eliminating the symptoms of SchS​
    • Anakinra, an IL-1 receptor antagonist, was found to be effective for treatment and confirmed by many reports from physicians treating SchS​
    • Not FDA approved for SchS
    • Typically anakinra relieves all symptoms within hours after injection​
    • Anakinra needs to be injected daily to have a continued effect​
    • An immunosuppressant produced in E. coli cells by recombinant DNA technology​
    • Administered by subcutaneous injection​
    • In SchS, anakinra 100 mg/day results in complete control of all symptoms including:​
    • chronic urticarial rash with a monoclonal IgM component​
    • intermittent fever​
    • arthralgia or arthritis​
    • bone pain​
    • lymphadenopathy​
    • leukocytosis​
    • elevated ESR​
    • spleen or liver enlargement​
    • Interleukin-1 production is induced in response to inflammatory and immunological responses. Anakinra blocks the biologic activity of interleukin-1 by competitively inhibiting interleukin-1 binding to the interleukin-1 type I receptor (IL 1RI), which is expressed in a wide variety of tissues and organs. ​
    • Anakinra – Side Effects​
      • Injection-site reaction (50 to 80% of patients)​
      • Headache (> 10%), nausea, rhinitis, diarrhea, abdominal pain​
      • Rare: neutropenia (2,4%), serious infections (2%, skin, lungs, bones)​
      • Dermatological side-effects: urticarial and maculo-papular exanthema, interstitial granulomatous dermatitis, Wells phenomenon, psoriasis​
  • More recently several new drugs have also been found to be effective: canakinumab (Ilaris) and rilonacept (Arcalyst)​
  • Canakinumab (Ilaris)
    • Blocks IL-1β​
    • Novartis​
    • First approved in 2009​
    • Not approved for SchS but is approved for other auto-inflammatory conditions​
    • Common Side Effects: nasopharyngitis, diarrhea, influenza, rhinitis, nausea, headache, bronchitis, gastroenteritis, pharyngitis, increased weight, musculoskeletal pain, vertigo, injection site reactions​
  • Rilonacept (Arcalyst)
    • Blocks  IL-1β​
    • Regeneron Pharmaceuticals​
    • First approved in 2008​
    • Not approved for SchS but is approved for other auto-inflammatory conditions​
    • Common Side Effects: injection site reactions, upper respiratory tract infections, nausea, diarrhea, sinusitis, abdominal pain, cough, hypoesthesia, stomach discomfort, urinary tract infection ​
  • Tocilizumab (Actemra, Roactemra)
    • An IL-6 receptor antagonist​
    • F. Hoffmann-La Roche Ltd.​
    • First approved in 2005​
    • Not approved form SchS​
    • Common Side Effects: nasopharyngitis, sore throat, rhinitis, headache, dizziness, itching, stomach cramps, urinary tract infection​
  • Treatment with anakinra is effective but needs to be continued long-term to control symptoms and reduce inflammation ​
  • It is not known whether therapy with anakinra, rilonacept or canakinumab can decrease the risk of developing hematological malignancies ​

Where Can I Learn More???

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