Schnitzler's Syndrome ,Cause,Diagnosis, Differential Diagnosesand Symptoms.
Author.
Hayk S. Arakelyan. Full Professor in Medicine,
Doctor of Medical Sciences, Ph.D , Grand Ph.D?.
Senior Expert of?Interactive?Clinical?Pharmacology?, Drug Safety,?????????????????????????????????????????????????????????????????????Treatment Tactics, General Medicine and Clinical Research.????????????????????????????????????????????????????????????????????????????????President of Rare and Incurable Diseases Association.
Yerevan-Armenia, Tokyo-Japan.
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“Natural forces within us are
the true healers of disease.”
“ Hippocrates”
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Introduction.
Schnitzler's syndrome is a?combination of chronic urticaria, fever of unknown origin, disabling bone pain, hyperostosis, increased?erythrocyte sedimentation rate, and macroglobulinemia. Since it was first described in 1974, only 26 cases have been published in the literature. Schnitzler syndrome?or?Schnitzler's syndrome?is a?rare disease?characterised by onset around middle age of?chronic?hives?(urticaria) and periodic?fever,?bone pain?and?joint pain?(sometimes with?joint inflammation),?weight loss,?malaise,?fatigue,?swollen lymph glands?and?enlarged spleen and liver. Schnitzler syndrome is considered an?autoinflammatory disorder?and is generally treated with?anakinra, which inhibits?interleukin 1. This treatment controls the condition but does not cure it. Around 15% of people develop complications, but the condition generally does not shorten life.
Cause of Schnitzler's Syndrome.
Schnitzler syndrome is a late-onset?autoinflammatory disorder. As of 2017 the cause of the disease was not understood.
Pathophysiology of Schnitzler's Syndrome.
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Schnitzler syndrome is an autoinflammatory disease for which the exact pathophysiology remains unclear. Dysfunction of several components of the innate immune system have been described, including the uncontrolled activation of interleukin 1-alpha (IL-1alpha). Increased levels of several members of the cytokine IL-1 family have been found, including IL-18.??Others hypothesize that the deposition of the IgM paraprotein, leading to the formation of immune complexes and the activation of the complement cascade, is responsible for the cutaneous manifestations of Schnitzler syndrome.
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Diagnosis of Schnitzler's Syndrome.
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Blood tests?show a high concentration of specific?gamma-globulins?(monoclonal gammopathy) of the?IgM?type. It almost always has?light chains?of the κ-type. A variant in which?IgG?is raised has been described, which appears to be one-tenth as common. The immunoglobulins may show up in the urine as?Bence Jones proteins. Signs of inflammation are often present: these include an increased?white blood cell?count (leukocytosis) and a raised?erythrocyte sedimentation rate?and?C-reactive protein. There can be?anemia of chronic disease.?Bone abnormalities can be seen on?radiological imaging?(often increased density or?osteosclerosis) or?biopsy.
There are two sets of diagnostic criteria, the Lipsker criteria published in 2001 and the Strasbourg criteria that were produced at a meeting in that city in 2012.
The Lipsker criteria require hives, the presence of monoclonal IgM, and at least 2 of the following: fever, joint pain or arthritis, bone pain, swollen lymph nodes, enlarged spleen or liver, elevated?erythrocyte sedimentation rate,?high levels of white blood cells, and findings of problems in bone imaging.[1][2]
In the Strasbourg criteria, the person must have hives and the presence of monoclonal IgM or IgG. Schnitzler's is diagnosed if the person has IgM and two of the following, or IgG and three of the following: recurrent fevers, abnormalities in bone imaging, with or without bone pain, findings of?neutrophil?infiltration in a?skin biopsy, high levels of white blood cells or?C-reactive protein.Other conditions?which can cause?periodic fevers,?paraproteins?or chronic hives that should be ruled out, include (and are not limited to)?autoimmune?or autoinflammatory disorders such as?adult-onset Still's disease,?angioedema, hematological disorders such as?lymphoma?or?monoclonal gammopathy of undetermined significance?(MGUS), other causes of hives,?cryoglobulinemia,?mastocytosis, chronic?neonatal onset multisystem inflammatory disease?or?Muckle–Wells syndrome.
?The typical onset is at around 55 years old, and the symptoms are recurrent?hives, mostly on the torso and limbs, often with recurring fever, joint pain, bone pain, muscle pain, headache, fatigue, and loss of weight.
Schnitzler Syndrome?Differential Diagnoses.
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Diagnostic Considerations.
Adult-onset Still disease is associated with fever, rash, arthralgias, and/or myalgias. The rash in Still disease is evanescent. The urticarial lesions in Schnitzler syndrome are chronically recurrent. In addition, monoclonal gammopathy does not occur in Still disease.
Systemic lupus erythematosus?(SLE) may be associated with urticaria, fever, arthralgia, and an elevated ESR. However, leukopenia, neutropenia, and thrombocytopenia are seen in SLE, compared with the leukocytosis and thrombocytosis in Schnitzler syndrome. Antinuclear antibodies are present in SLE, but not in Schnitzler syndrome. Monoclonal paraprotein would not be expected in SLE.
Urticarial vasculitis?can have features of nonpruritic urticaria persisting for more than 24 hours, myalgia, arthralgia, fever, an elevated ESR, and an increased white blood cell count. Skin biopsy of urticarial vasculitis shows fibrinoid necrosis of vessels and a perivascular neutrophilic infiltrate. Fibrinoid necrosis is rarely seen with Schnitzler syndrome.
Chronic idiopathic urticaria?often responds symptomatically to antihistamines and lacks the accompanying systemic features and paraprotein seen in Schnitzler syndrome.
Cryoglobulinemia?shows clinical signs and symptoms at cold temperatures and demonstrates the presence of cryoglobulins.
The cryoprin-associated periodic syndromes (CAPS), which include familial cold urticaria, Muckle-Wells syndrome, and chronic infantile neurologic cutaneous articular (CINCA) syndrome, all can have associated fever and rash. Patients with these disorders have onset before adulthood, lack a paraprotein, and have a family history of the disease. Muckle-Wells syndrome is often associated with amyloidosis and deafness. CINCA syndrome may be associated with chronic sterile meningitis and neurological deficits.?
Hyperimmunoglobulin D syndrome shows elevated polyclonal immunoglobulin D levels with onset of recurrent fever, usually in the first year of life.
Delayed?pressure urticaria?can occasionally be nonpruritic. However, it is not associated with an elevated ESR or an increased white blood cell count, although in severe cases, fever, myalgia, and arthralgias may occur. In addition, anemia is not seen with delayed pressure urticaria.
Waldenstr?m macroglobulinemia?shows a lymphoid proliferation in the bone marrow, and the monoclonal IgM gammopathy is found in large amounts, usually more than 10,000 mg/L. Often, it is associated with hepatosplenomegaly. In Schnitzler syndrome, the monoclonal gammopathy is less than that seen in Waldenstr?m macroglobulinemia.
Differential Diagnoses.
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Sign and Symptoms of Schnitzler's Syndrome.
?Schnitzler syndrome is characterized by the following signs and symptoms:
Chronic, recurrent, urticarial eruption: Occurs in all patients, usually as the first sign of the disease; primarily affects the trunk and the extremities and spares the palms, soles, and head and neck areas
Pruritus: Usually absent at disease onset, but lesions may become mildly pruritic in approximately 45% of patients after 3-4 years.
Recurrent fevers: In approximately 90% of patients.
Relapsing arthralgias: Concurrent with fever; reported in 80% of patients.
Bone pain: Concurrent with fever; reported in 70% of patients.
Myalgias: Concurrent with fever.
Lymphadenopathy.
Hepatomegaly.
Splenomegaly.
Fatigue.
Weight loss.
Angioedema: Very rare.
The urticarial rash is characterized as follows:
Pale-rose, slightly elevated papules and plaques.
Individual lesions are 0.5-3 cm in diameter.
New lesions appear daily.
Lesions last 12-24 hours and then disappear without sequelae.
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Prognosis of Schnitzler's Syndrome.
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Most Schnitzler syndrome patients have a chronic benign course. No spontaneous complete remissions have been reported. Overall, the prognosis for Schnitzler syndrome is good. However, approximately 10-15% of patients develop a lymphoplasmacytic malignancy.
Approximately 10-15% of patients eventually develop a lymphoproliferative disorder, including lymphoplasmacytic lymphoma,?Waldenstr?m macroglobulinemia, or IgM myeloma. Schnitzler's original patient died at age 88 years, with a diffuse lymphoplasmacytic infiltration of his liver and bone marrow. Thus, the initial workup of a Schnitzler syndrome patient should include an examination of the bone marrow, immunoelectrophoresis of serum, and a urinary protein level. A lymph node biopsy should be performed if the nodes are enlarged.?
Kidney involvement has been described as a rare complication, but it improved with treatment in the cases reported.?
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Complications of Schnitzler's Syndrome.
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Roughly 15-20% of patients develop an overt lymphoproliferative disorder.?
With Schnitzler syndrome, a lymphoplasmacytic malignancy, such as Waldenstr?m macroglobulinemia, lymphoplasmacytic lymphoma, or IgM myeloma, may occur.
The development of AA amyloidosis is a concern in untreated patients with Schnitzler syndrome.?
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If you have any questions?concerning?“Schnitzler's Syndrome ,Cause,Diagnosis, Differential Diagnosesand Symptoms”,?interactive clinical pharmacology?,?or any other?questions, please?inform?me .?
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??????Prof. Hayk S. Arakelyan
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