What is Schnitzler syndrome

Schnitzler syndrome is a rare autoinflammatory disorder characterized by a chronic reddish rash that resembles hives (urticaria) and elevated levels of a specific protein in the blood (most often monoclonal IgM gammopathy) ¹. Schnitzler syndrome is difficult to classify and some researchers have suggested that it is an acquired autoinflammatory syndrome. Autoinflammatory syndromes are a group of disorders characterized by recurrent episodes of inflammation due to an abnormality of the innate immune system. They are not the same as autoimmune disorders, in which the adaptive immune system malfunctions and mistakenly attacks healthy tissue. Schnitzler syndrome signs and symptoms vary but may include urticaria; repeated bouts of fever; joint pain (arthralgia) and joint inflammation (arthritis); bone pain, and other findings such as enlarged lymph nodes (lymphadenopathy); organomegaly (abnormally enlarged organs); and/or blood abnormalities ². A monoclonal IgM gammopathy refers to the uncontrolled growth of a single clone (monoclonal) of plasma cells, which results in the abnormal accumulation of M-proteins (also known as immunoglobulin M or IgM) in the blood. However, the specific role these proteins play and the exact cause of Schnitzler syndrome is unknown; however, most cases occur sporadically in people with no family history of the condition.

Schnitzler syndrome affects males slightly more often than females. However, only approximately 160 cases of this rare disorder have been reported in the medical literature so no definitive conclusions can be made about ethnic or gender predispositions. Because of the varied symptoms and rarity of Schnitzler syndrome, a diagnosis is usually delayed by several years and researchers believe that the disorder is underdiagnosed, making it difficult to determine its true frequency in the general population. Most individuals with Schnitzler syndrome are in their 50s when the characteristic symptoms develop.

Less often, symptoms have been noted in individuals in their 30s. In one reported case, symptoms were identified in an individual 12 years old. It is to be questioned whether these cases were classical Schnitzler syndrome (see Related Disorders below).

Schnitzler syndrome was first described in the medical literature in 1972, by a French dermatologist named Liliane Schnitzler. Most of the reported cases of Schnitzler syndrome have been from Europe, particularly France, but cases from Australia, Japan and the United States have been reported too.

Schnitzler syndrome treatment is focused on alleviating the signs and symptoms associated with the condition and may include various medications and/or phototherapy ¹.

Schnitzler syndrome causes

The exact cause of Schnitzler syndrome is unknown. Researchers believe that specific parts of the immune system may not function properly, eventually causing Schnitzler syndrome.

Individuals with Schnitzler syndrome also have a clinical finding called monoclonal IgM gammopathy, in which abnormalities affecting the production of immunoglobulins result in elevated levels of a specific immunoglobulin M (IgM) in the body. Immunoglobulins are proteins produced by certain white blood cells. There are five classes of immunoglobulins known as IgA, IgD, IgE, IgG, and IgM. Immunoglobulins play a role in defending the body against foreign substances or microorganisms by destroying them or coating them so they are more easily destroyed by white blood cells.

At the time of diagnosis, IgM levels may only be slightly elevated and may remain stable for years.

A variant form of Schnitzler syndrome has been reported in which individuals have a monoclonal gammopathy of IgG instead of IgM.

Certain cytokines (specialized proteins secreted from certain immune system cells that either stimulate or inhibit the function of other immune system cells) play a role in the development of Schnitzler syndrome. The cytokine interleukin-1 (IL-1), is an important mediator of the inflammation in Schnitzler syndrome. Abnormal clinical findings involving interleukin-1 have been found in some individuals with Schnitzler syndrome and therapy with drugs that block the activity of interleukin-1 have brought about complete remission.

Schnitzler syndrome signs and symptoms

The symptoms associated with Schnitzler syndrome can vary from one person to another. The symptoms can occur all at once or, because they often come and go, the symptoms can occur at different times. The symptoms tend to persist for many years (chronic disease).

A reddish, rash that resembles hives (urticaria) is the hallmark finding associated with Schnitzler syndrome. The distinctive rash usually consists of raised, reddish bumps (papules) and flatter, wider lesions (plaques). In most cases, a rash is the first symptom to appear in individuals with Schnitzler syndrome. The rash usually lasts for a day to two and then disappears without scarring. However, a new rash often develops each day so that a rash is a constant occurrence but the frequency of the rash can vary greatly from one person to another and some people only develop a rash a few times during the year.

When the rash first develops, it usually is not itchy (not pruritic). However, in approximately 45 percent of cases, the rash will become itchy within a few years. The trunk, arms and legs are most often affected. The head, neck, palms and soles are usually spared. Some affected individuals have reported that alcohol, spicy foods and stress have aggravated the rash.

Fevers that come and go over a period of time (chronic, intermittent fevers) are the second most common symptom in individuals with Schnitzler syndrome. The frequency of fevers varies greatly, ranging from being a daily occurrence to only a couple times per year. Fevers are usually unrelated to the skin rash, are well-tolerated and are rarely accompanied by chills.

Additional symptoms associated with Schnitzler syndrome include bone pain, most often affecting the lower legs and hips, and joint pain, most often affecting the large joints such as the hips, knees, wrists and ankles. In some cases, inflammation of the joints (arthritis) may develop with accompanying swelling, redness and a feeling of heat or warmth in the joint. Despite joint involvement, joint degeneration or destruction has not been reported in individuals with Schnitzler syndrome.

Abnormal enlargement of the lymph nodes (lymphadenopathy), the liver (hepatomegaly) and the spleen (splenomegaly) may also occur in some cases. Additional nonspecific symptoms that have been reported in individuals with Schnitzler syndrome include unintended weight loss, fatigue and a general feeling of poor health (malaise). Rapid swelling due to fluid accumulation just beneath the surface skin (angioedema) is very rare.

The main hematological (blood) abnormality of Schnitzler syndrome is monoclonal gammopathy. This usually means a raised level of immunoglobulin M (IgM) but raised immunoglobulin G (IgG) or combinations of IgM and IgA or IgM and IgG have also been reported. Bone marrow tests are normal in 80% at the time of diagnosis.

Other hematological abnormalities in Schnitzler syndrome may include:

• Elevated C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR)
• Lowered complement levels (C4)
• Anemia of chronic disease
• Thrombocytosis (raised platelet count)
• Neutrophilic leucocytosis (raised neutrophil white blood cells)

Most cases of Schnitzler syndrome have a chronic, benign course. However, over a period of 10 years, approximately 10-15 percent of affected individuals developed cancer, most often cancer caused by the overproduction of white blood cells (lymphoproliferative disorders) such as lymphoplasmacytic lymphoma, Waldenström macroglobulinemia or IgM myeloma ³.

Some individuals with Schnitzler syndrome have elevated levels of a different protein than individuals with classic Schnitzler syndrome. These individuals are classified as having variant Schnitzler syndrome and have very similar symptoms to classic Schnitzler syndrome.

The signs and symptoms of Schnitzler syndrome vary but may include ⁴:

• Red raised patches of skin (urticaria) that may become itchy. Chronic recurrent, urticarial eruption occurs in all patients, usually as the first sign of Schnitzler syndrome; primarily affects the trunk and the extremities and spares the palms, soles, and head and neck areas.
• Pruritus (itch): 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.
• Join pain and inflammation concurrent with fever; reported in 80% of patients.
• Organomegaly (enlarged internal organs) often involving the lymph nodes (lymphadenopathy), liver (hepatomegaly) and/or spleen (splenomegaly)
• Bone pain concurrent with fever; reported in 70% of patients.
• Blood abnormalities
• Muscle aches (myalgia) concurrent with fever
• Fatigue
• Weight loss
• Angioedema: Very rare

People affected by Schnitzler syndrome also have an increased risk of developing certain lymphoproliferative disorders ¹. A monoclonal IgM gammopathy refers to the uncontrolled growth of a single clone (monoclonal) of plasma cells, which results in the abnormal accumulation of M-proteins (also known as immunoglobulin M or IgM) in the blood. However, the specific role these proteins play in Schnitzler syndrome is unknown.

Schnitzler syndrome diagnosis

A diagnosis of Schnitzler syndrome is based upon a thorough clinical evaluation, a detailed patient history, exclusion of other disorders, and identification of characteristic findings, specifically a urticarial rash, an immunoglobulin M (IgM) protein and at least two of the following findings – fever, joint pain or inflammation, bone pain, palpable lymph nodes, enlargement of the liver or spleen, elevated numbers of white blood cells (leukocytosis), elevated red blood cell (erythrocyte) sedimentation rate or abnormalities on bone morphological study, which can reveal increased bone density (osteosclerosis).

Sedimentation rate measures how long it takes red blood cells to settle in a test tube over a given period. Many individuals with Schnitzler syndrome have an elevated sedimentation rate, which is an indication of inflammation.

In younger patients, careful attention should be paid because alternative diagnosis is much more likely and often overlooked – such as urticarial vasculitis, hematological disease or chronic idiopathic urticaria – which needs a different approach to treatment – so a diagnosis of Schnitzler’s syndrome in younger patients should only be made after extensive work on exclusion of other diagnoses.

Schnitzler syndrome treatment

The treatment of Schnitzler syndrome is aimed at alleviating the signs and symptoms associated with the condition. The following medications have been used with variable success ³:

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Corticosteroids
• Immunosuppressive agents
• Interleukin-1 receptor antagonists (medications that inhibit the cytokine IL-1)
• Colchicine
• Dapsone
• Thalidomide
• Rituximab

Some studies suggest that phototherapy may improve the rash in some affected people ³.

First-line treatment in mild cases is with nonsteroidal anti-inflammatory drugs (NSAIDs). But this is often not sufficient.

In more severe cases, the standard treatment is with therapy to inhibit the cytokine IL-1. Patients with Schnitzler syndrome are successfully treated with anakinra, an interleukin-1 receptor antagonist. Anakinra is a drug that blocks the activity of interleukin-1, which some researchers believe plays a key role in the development of Schnitzler syndrome. There have also been at least 2 studies showing the efficacy of the interleukin-1 beta antibody canakinumab.

High-dose regimens of corticosteroids have temporarily improved symptoms in some cases, but usually must be stopped due to side effects. In a small percentage of cases, colchicine (a medication used to suppress inflammation in acute gout) and dapsone were effective in treating some individuals with Schnitzler syndrome. Interleukin-6 is a cytokine that can be induced by interleukin-1; , anti-interleukin-6 therapy was also recently tried in three patients with Schnitzler syndrome, in which it was effective.

At least three individuals with Schnitzler syndrome have been successfully treated with thalidomide, a drug that affects how the immune system works (immunomodulatory drugs). Thalidomide induced a complete resolution of the rash and dramatic improvement of other symptoms in three individuals who received the drug as a therapy for Schnitzler syndrome. However, thalidomide is often associated with significant side effects including pain, numbness and a tingling sensation in the hands and feet (peripheral neuropathy). Two of the three patients had to stop thalidomide therapy because of side effects. In addition, two additional individuals with Schnitzler syndrome did not improve after treatment with thalidomide. More research is necessary to determine the long-term safety, effectiveness and role, if any, of thalidomide in treating individuals with Schnitzler syndrome.

A small study investigated the effectiveness of the antibiotic drug, pefloxacine, for the treatment of Schnitzler syndrome. Eleven affected individuals received pefloxacine, which caused rapid and dramatic improvement of both the rash and systemic symptoms associated with the disorder. More research is necessary to determine the long-term safety and effectiveness of pefloxacine in the treatment of individuals with Schnitzler syndrome.

Inhibitors of interleukin (IL)–1 (anakinra, rilonacept and canakinumab) appear to be particularly effective ⁵.

Anakinra

Anakinra is an effective treatment for Schnitzler syndrome. It is an interleukin 1 antagonist, registered to treat rheumatoid arthritis. In Schnitzler syndrome, anakinra 100 mg/day allows a complete control of all symptoms including ⁴:

• chronic urticarial rash with a monoclonal IgM component
• intermittent fever
• arthralgia or arthritis
• bone pain
• lymphadenopathy
• leukocytosis
• elevated ESR
• spleen or liver enlargement

Complete remissions have been reported in at least 10 patients with anakinra at a daily subcutaneous dose of 100 mg. Some patients have experienced a recurrence of signs and symptoms within 1 day of stopping treatment; anakinra must be given on a continuous basis. Localised painful erythematous injection site reactions may occur.

Other IL-1 antagonists are under investigation for the treatment of Schnitzler syndrome, including rilonacept and canakinumab. IL-6 anatoganists have been tried for non-responders to IL-1 responders.

Schnitzler syndrome is a chronic disease so discontinuing an effective treatment can be expected to lead to relapse of the disease.

Schnitzler syndrome prognosis

The long-term outlook (prognosis) for people with Schnitzler syndrome is generally good. Schnitzler syndrome does not affect lifespan in most cases, but requires periodic follow up because of the increased risk of developing cancer. Although the condition is chronic and symptoms can be a nuisance, it generally does not progress to severe disease in most affected people. However, approximately 10-15% of people with Schnitzler syndrome develop a lymphoproliferative disorder ³.

Schnitzler’s original patient died at age 88 years, with a diffuse lymphoplasmacytic infiltration of his liver and bone marrow ⁶. 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 ⁷.

References

1. Schnitzler Syndrome. https://rarediseases.org/rare-diseases/schnitzler-syndrome
2. Schnitzler syndrome. https://rarediseases.info.nih.gov/diseases/12390/schnitzler-syndrome
3. Schnitzler Syndrome. https://emedicine.medscape.com/article/1050761-overview
4. Schnitzler syndrome. https://www.dermnetnz.org/topics/schnitzler-syndrome/
5. Krause, K, Tsianakas A, Wagner, N, et al. Effectiveness of canakinumab treatment in Schnitzler’s syndrome: a multi-center randomized placebo controlled study. Pediatric Rheumatology. 2015. 13 (supplement 1):066.
6. Schnitzler L, Schubert B, Boasson M. Urticaire chronique, lons osseuses, macroglobuline IgM: maladie de Waldenstrom. Bull Soc Franc Derm Syph. 1974. 81:363.
7. Basile C, Rossi L, Casucci F, Teutonico A, Libutti P, Lisi P, et al. Kidney involvement in the Schnitzler syndrome, a rare disease. Clin Kidney J. 2017 Dec. 10(6):723-727.