Background

Schnitzler syndrome, also known as Schnitzler’s syndrome, is a rare autoinflammatory disorder characterized by chronic urticaria (hives) and a monoclonal gammopathy (abnormal production of a specific type of antibody). It was first described by Dr. Liliane Schnitzler in 1972. The exact cause of Schnitzler syndrome is not yet fully understood, and the syndrome is considered idiopathic, meaning its underlying cause is unknown. 

Certain key features and characteristics of Schnitzler syndrome: 

• Urticaria: The hallmark symptom of Schnitzler syndrome is chronic, recurring urticaria. These hives typically last more than six weeks and are accompanied by intense itching. Urticaria can affect various body parts and often occurs daily or near daily. It tends to worsen with exposure to heat, exercise, or alcohol. 
• Monoclonal gammopathy: Nearly all individuals with Schnitzler syndrome have an abnormal increase in immunoglobulin M (IgM) or, less commonly, immunoglobulin G (IgG) antibodies. A clone of abnormal plasma cells, a white blood cell type, produces these antibodies. The monoclonal gammopathy may also lead to other complications, such as kidney problems or neuropathy. 
• Systemic symptoms: Besides urticaria, individuals with Schnitzler syndrome may experience various systemic symptoms, including recurrent fever, bone pain, joint pain (arthralgia), fatigue, weight loss, and swollen lymph nodes. These symptoms can fluctuate in intensity and frequency. 
• Laboratory findings: Besides the monoclonal gammopathy, blood tests may reveal elevated levels of acute-phase reactants, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Some individuals may also have increased levels of white blood cells and liver enzymes. 
• Overlap with other conditions: Schnitzler syndrome shares similarities with other autoinflammatory disorders, such as chronic urticarial syndromes, periodic fever syndromes, and monoclonal gammopathy of undetermined significance (MGUS). The presence of monoclonal gammopathy helps distinguish Schnitzler syndrome from other urticarial conditions. 
• Diagnostic criteria: The diagnosis of Schnitzler syndrome is primarily clinical, based on the characteristic symptoms and findings. However, specific criteria have been proposed, including chronic urticaria, monoclonal gammopathy, and at least two additional minor criteria, such as recurrent fever, bone pain, elevated inflammatory markers, or organ involvement. 

Epidemiology

• America 
• The number of reported cases of Schnitzler syndrome from America is limited, with only a few instances documented. 
• International 
• Schnitzler syndrome is a relatively rare condition, although more cases are reported in the medical literature. The first documented case originated in France, and the highest concentration of reported cases is primarily found in Western Europe. 
• Sex 
• Males exhibit a slight predominance in Schnitzler syndrome, with 1.76:1, indicating a slightly higher prevalence than females. 
• Race 
• It generally occurs in all types of races. 
• Age 
• Patients diagnosed with Schnitzler syndrome have shown a wide age range, spanning from 13 to 71 years old. It is typically regarded as a condition with “late onset,” with the mean age of onset being around 52 years; however, with an average delay of over five years from the onset of symptoms. 

Anatomy

Pathophysiology

The exact pathophysiology of Schnitzler syndrome still needs to be fully understood. However, based on the clinical and laboratory findings observed in affected individuals, several underlying mechanisms have been proposed.

Here are some critical aspects of the pathophysiology of Schnitzler syndrome: 

• Abnormal immune response: Schnitzler syndrome is considered an autoinflammatory disorder, suggesting that an abnormal immune response plays a role in its development. It is hypothesized that there is an inappropriate activation of the immune system, which causes to release of inflammatory mediators. 
• Monoclonal gammopathy: Almost all individuals with Schnitzler syndrome have a monoclonal gammopathy, primarily involving immunoglobulin M (IgM) antibodies. This abnormal increase in IgM is due to the clonal expansion of plasma cells, a type of white blood cell involved in antibody production. The cause of this clonal expansion is unclear, but it may be related to immune system dysregulation. 
• Inflammatory cytokines: It is believed that excessive production of inflammatory cytokines contributes to the symptoms and pathology of Schnitzler syndrome. Cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interleukin-18 (IL-18) have been implicated in the disease process. These cytokines play a role in initiating and sustaining the inflammatory response. 
• Activation of the inflammasome: The inflammasome is a multiprotein complex that activates inflammatory processes. In Schnitzler syndrome, there is evidence of inflammasome activation, particularly the NLRP3 inflammasome. This activation leads to the release of pro-inflammatory cytokines and contributes to persistent inflammation in the disease. 
• Neutrophil involvement: Neutrophils, a type of white blood cell, are thought to play a role in the pathophysiology of Schnitzler syndrome. Increased neutrophil counts and elevated levels of neutrophil activation markers have been observed in affected individuals. These activated neutrophils may release inflammatory substances and contribute to tissue damage. 
• Genetic factors: While the genetic basis of Schnitzler syndrome is not well understood, some evidence suggests a possible genetic component. Some studies have identified potential genetic mutations associated with the disorder, including mutations in genes involved in regulating the immune system and inflammation.  

Overall, Schnitzler syndrome appears to involve dysregulation of the immune system, including abnormal activation of immune cells and excessive production of inflammatory cytokines. The monoclonal gammopathy observed in affected individuals further contributes to the inflammatory processes.  

Etiology

The exact etiology (cause) of Schnitzler syndrome remains unknown. It is considered idiopathic, meaning the underlying cause is not fully understood. However, several theories and observations have been proposed to explain the development of Schnitzler syndrome. Here are some factors that have been suggested to contribute to the etiology of Schnitzler syndrome: 

• Genetic factors: Some evidence suggests a genetic predisposition to Schnitzler syndrome. Familial syndrome cases have been reported, indicating a potential genetic component. However, specific genetic mutations or markers associated with Schnitzler syndrome have yet to be definitively identified. 
• Abnormal immune system regulation: Dysfunction or dysregulation of the immune system is generally believed to play a role in developing Schnitzler syndrome. The exact mechanisms underlying this dysregulation have yet to be fully understood. An abnormal immune response may trigger chronic inflammation and the associated symptoms of the syndrome. This may involve abnormalities in the production and regulation of inflammatory cytokines and other immune system factors. 
• Monoclonal gammopathy: Monoclonal gammopathy, particularly an increase in immunoglobulin M (IgM) antibodies, is a consistent feature of Schnitzler syndrome. However, it is unclear whether monoclonal gammopathy is a cause/consequence of the syndrome. The clonal expansion of abnormal plasma cells that produce monoclonal gammopathy is believed to be related to dysregulation in the immune system, but the exact mechanisms are not yet understood. 
• Inflammatory pathways: In Schnitzler syndrome, dysfunction of specific inflammatory pathways, such as activating the inflammasome and increased production of pro-inflammatory cytokines. These abnormalities suggest a potential role for chronic inflammation in the condition’s etiology. However, the triggers and mechanisms underlying the dysregulated inflammatory pathways are still under investigation. 
• Environmental triggers: It has been suggested that certain environmental factors, like infections or exposure to specific allergens, may act as triggers or exacerbating factors for Schnitzler syndrome in susceptible individuals. However, specific triggers have not been identified, and their role in the syndrome’s etiology remains speculative. 

Notably, these proposed factors are based on current knowledge and understanding of the syndrome.  

Genetics

Prognostic Factors

The prognosis of Schnitzler syndrome can vary among individuals, and it is challenging to accurately predict the course of the disease. However, certain factors have been identified that may influence the prognosis and clinical outcomes in individuals with Schnitzler syndrome. These prognostic factors include: 

• Disease duration: The duration of symptoms and the delay in diagnosis and treatment may impact the prognosis. Prolonged untreated or undertreated Schnitzler syndrome may lead to the progression of organ involvement and increased morbidity. 
• Organ involvement: The presence and severity of organ involvement, such as kidney, liver, or neurological complications, can affect the prognosis. Schnitzler syndrome can lead to complications like renal amyloidosis, neuropathy, or liver abnormalities, impacting long-term outcomes. 
• Monoclonal gammopathy: The specific characteristics of monoclonal gammopathy, such as the type (IgM or IgG) and the monoclonal protein level, may influence the prognosis.  
• Response to treatment: The response to treatment can be a prognostic indicator. Schnitzler syndrome is typically responsive to certain medications, such as IL-1 inhibitors (e.g., anakinra) or IL-6 inhibitors (e.g., tocilizumab). Individuals who respond well to treatment and experience symptom improvement may have a more favorable prognosis. 
• Inflammatory markers: Elevated levels of inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), at the time of diagnosis may indicate more active and severe disease. Despite treatment, persistent elevation of these markers may suggest inadequate disease control and potentially impact the prognosis. 
• Renal involvement: Renal involvement, particularly the development of renal amyloidosis, is associated with a poorer prognosis. Renal amyloidosis can lead to progressive kidney dysfunction and complications. 
• Age and comorbidities: The age of onset and other underlying comorbidities can influence the prognosis. Older age and other health conditions may contribute to a higher risk of complications and poorer outcomes. 

It is important to note that Schnitzler syndrome is a rare and complex condition, and the prognosis can vary significantly among individuals.  

Clinical History

• Schnitzler syndrome can present with a variety of clinical features. General overview of the clinical presentation of Schnitzler syndrome: 
• Age group: Schnitzler syndrome typically presents in adulthood, usually between 40 and 70. However, cases have been reported in younger individuals as well. 

Physical Examination

During a physical examination of a person suspected to have Schnitzler syndrome, healthcare professionals may look for specific findings that can help support the diagnosis. Here are some key aspects that may be assessed during the physical examination: 

• Skin examination: Urticaria (hives) is a characteristic of Schnitzler syndrome. The healthcare provider may examine the skin for raised, red, and itchy lesions or hives. These hives may vary in size and shape and may appear in different locations on the body. The examination may also involve checking for any associated skin manifestations, such as angioedema (swelling of deeper layers of the skin). 
• Joint and musculoskeletal examination: Joint pain (arthralgia) and bone pain are common symptoms of Schnitzler syndrome. The healthcare provider may assess the joints for tenderness, swelling, or limitation of movement. The musculoskeletal system, including muscles, may also be evaluated for any signs of inflammation or pain. 
• Lymph node examination: Swollen lymph nodes may be present in Schnitzler syndrome, particularly in the neck, groin, or underarm areas. The healthcare provider may palpate these regions to assess for enlarged or tender lymph nodes. 
• Organomegaly assessment: In some cases, Schnitzler syndrome may be associated with hepatomegaly (enlarged liver) or splenomegaly (enlarged spleen). The healthcare provider may perform abdominal palpation to evaluate the size and texture of these organs. 
• Neurological assessment: Although less common, neurological symptoms, such as peripheral neuropathy, may occur in Schnitzler syndrome. The healthcare provider may conduct a neurological examination to assess for muscle strength, sensation, reflexes, or coordination abnormalities. 
• General assessment: The healthcare provider will also conduct a general physical examination to assess vital signs, overall appearance, and any additional signs or symptoms relevant to the diagnosis of Schnitzler syndrome. 

Age group

Associated comorbidity

• No specific associated comorbidity is commonly seen in Schnitzler syndrome. However, some individuals may have a history of other autoimmune or autoinflammatory conditions.
• It is important to note that Schnitzler syndrome is a distinct clinical entity not directly associated with other known diseases. 

Associated activity

Acuity of presentation

The onset of Schnitzler syndrome is usually gradual and chronic, with symptoms persisting for months or even years. The acuity of presentation can vary among individuals, ranging from mild and intermittent symptoms to more severe and persistent manifestations. 

The clinical presentation of Schnitzler syndrome typically includes the following features: 

• Chronic urticaria: The hallmark symptom of Schnitzler syndrome is chronic urticaria, characterized by recurrent episodes of hives. The urticaria is typically present daily or almost daily and can be accompanied by severe itching. The hives may affect different body parts and can vary in size and shape. 
• Systemic symptoms: Along with chronic urticaria, individuals with Schnitzler syndrome often experience systemic symptoms, including recurrent fever, fatigue, weight loss, bone pain, joint pain (arthralgia), muscle pain (myalgia), and swollen lymph nodes. 
• Monoclonal gammopathy: Almost all individuals with Schnitzler syndrome have a monoclonal gammopathy, primarily involving immunoglobulin M (IgM) antibodies. Monoclonal gammopathy is detected through blood tests and is an essential diagnostic criterion for Schnitzler syndrome. 
• Elevated inflammatory markers: Laboratory tests may reveal elevated levels of acute-phase reactants, like C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Increased white blood cell count and liver enzymes may also be observed. 
• Other potential features: Although less common, Schnitzler syndrome can also present with other manifestations, such as neurological symptoms (e.g., peripheral neuropathy), renal abnormalities, hepatomegaly (enlarged liver), or splenomegaly (enlarged spleen). These features are typically associated with more severe and prolonged disease. 

Differential Diagnoses

Schnitzler syndrome is a rare and unique condition, and its diagnosis requires careful consideration of clinical features and the exclusion of other possible causes. Certain conditions that may be considered in the differential diagnosis of Schnitzler syndrome: 

• Autoimmune urticaria: Autoimmune urticaria, such as chronic autoimmune urticaria or autoimmune progesterone dermatitis, can present with chronic urticaria similar to Schnitzler syndrome. However, autoimmune urticaria lacks the characteristic features of monoclonal gammopathy and associated systemic symptoms seen in Schnitzler syndrome. 
• Cryopyrin-associated periodic syndromes (CAPS): CAPS encompass a spectrum of autoinflammatory disorders, like the familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurological cutaneous and articular syndrome (CINCA). These syndromes may share some clinical features with Schnitzler syndrome, such as urticarial rash, fever, and systemic inflammation. However, unlike Schnitzler syndrome, CAPS is typically associated with mutations in the NLRP3 gene and demonstrates an autosomal dominant inheritance pattern. 
• Chronic infection: Certain chronic infections, such as hepatitis B or C, human immunodeficiency virus (HIV), or Helicobacter pylori infection, can cause chronic urticaria and systemic symptoms resembling Schnitzler syndrome. A thorough evaluation and appropriate testing for infectious agents should be performed to exclude these possibilities. 
• Autoinflammatory syndromes: Various autoinflammatory syndromes, such as adult-onset Still’s disease, systemic lupus erythematosus (SLE), or periodic fever syndromes (e.g., familial Mediterranean fever, TNF receptor-associated periodic syndrome), can present with recurrent fever, urticarial rash, and systemic symptoms. Detailed clinical assessment and additional laboratory investigations are necessary to differentiate Schnitzler syndrome from these conditions. 
• Lymphoproliferative disorders: Some lymphoproliferative disorders, such as lymphoma or monoclonal gammopathies (e.g., Waldenström macroglobulinemia), may be associated with chronic urticaria and monoclonal gammopathy. Differentiating Schnitzler syndrome from these disorders may require further investigations, including imaging studies and bone marrow biopsy. 
• Idiopathic chronic urticaria: In some cases, chronic urticaria without an identifiable cause may present symptoms similar to Schnitzler syndrome. The absence of associated monoclonal gammopathy and systemic features can help differentiate idiopathic chronic urticaria from Schnitzler syndrome. 

Due to the rarity and complexity of Schnitzler syndrome, its diagnosis often requires collaboration between various specialists, including dermatologists, rheumatologists, and immunologists. A thorough evaluation, including clinical assessment, laboratory tests, and, in some cases, genetic analysis, is necessary to differentiate Schnitzler syndrome from other similar conditions 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

• The treatment of Schnitzler syndrome aims to control symptoms, reduce inflammation, and improve the overall quality of life for individuals affected by the condition.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

• While there are no specific environmental modifications for Schnitzler syndrome, avoiding known triggers or exacerbating factors, such as certain medications or environmental allergens, may be beneficial in some cases.
• Identifying and avoiding potential triggers based on individual experiences and sensitivities can help minimize symptom flare-ups. 

• Medications are the mainstay of treatment for Schnitzler syndrome. The choice of drug may vary depending on the individual’s symptoms and disease severity. The following medications have shown efficacy in managing Schnitzler syndrome: 
• Interleukin-1 (IL-1) inhibitors: IL-1 inhibitors, such as anakinra, can effectively reduce symptoms, including urticarial rash, fever, and systemic inflammation. Anakinra is typically the first-line treatment for Schnitzler syndrome. 
• Interleukin-6 (IL-6) inhibitors: IL-6 inhibitors, such as tocilizumab, have also shown promise in managing Schnitzler syndrome, particularly in individuals who do not respond adequately to IL-1 inhibitors or have concurrent inflammatory arthritis. 
• Other immunomodulatory agents: In some cases, other immunomodulatory medications, such as corticosteroids (e.g., prednisone), may be used to control symptoms during acute flare-ups or as a bridge therapy until IL-1 or IL-6 inhibitors take effect.  

• There are no specific procedures or surgical interventions for Schnitzler syndrome. Treatment primarily focuses on medication management to control symptoms and inflammation. 

• The management of Schnitzler syndrome typically involves different phases: 
• Acute phase: During the acute phase, the goal is to control symptoms and reduce inflammation. Medications, such as IL-1 inhibitors or corticosteroids, may relieve symptoms and improve quality of life. 
• Maintenance phase: Once symptoms are under control, the treatment enters the maintenance phase. The aim is to maintain long-term disease control and prevent symptom recurrence. IL-1 or IL-6 inhibitors often continue during this phase, regularly monitoring symptoms and laboratory markers. 
• Follow-up and monitoring: Regular follow-up visits with healthcare providers are essential to assess treatment response, monitor disease activity, and manage any potential side effects or complications associated with medication use. Monitoring may involve laboratory tests to evaluate inflammatory markers, monoclonal gammopathy levels, and organ function. 

Medication

Future Trends

Media Gallary

References

• Schnitzler syndrome: Schnitzler syndrome – PubMed (nih.gov)