Schnitzler syndrome: a rare autoinflammatory condition with a chronic rash

Schnitzler syndrome was first described in 1972 by a French dermatologist, Liliane Schnitzler. A UK case report describes it as a rare auto-inflammatory condition, one in which the innate immune system is overactive and produces inflammation without infection, with at least 300 cases documented worldwide at the time of writing, mostly in adult white people. The review states that it is almost certainly underrecognised.

The syndrome has two defining ingredients. One is a chronic, recurrent urticarial rash that looks like hives. In the UK case report the rash was non-itchy and only modestly helped by antihistamines. The other is a monoclonal protein in the blood, an antibody produced by a single clone of cells, most often of the IgM type. Around these are fever, bone and joint pain, enlarged lymph nodes, tiredness and raised markers of inflammation.

The review says the urticarial eruption is typically chronic and recurrent and generally difficult to treat, with a pale rose-coloured macular eruption that sometimes develops into raised papules and plaques, usually affecting the trunk and proximal limbs and very rarely the face, neck, hands and feet. Other features that are often present include malaise, fever, muscle ache, joint or bone pain and enlarged lymph nodes, and symptoms of peripheral neuropathy may also occur.

Musculoskeletal symptoms are common. The review reports arthralgia in 68% of patients in one series and bone pain in 63%, with the distal femur and proximal tibia the most commonly affected bones in a cohort of 22 patients. The UK case report described a woman with a progressive non-itchy rash spreading from trunk to limbs, drenching night sweats for years and small-joint pains, who was only partly helped by antihistamines.

A typical story is therefore years of apparent chronic hives, intermittent fevers or night sweats and aches, with several specialists each seeing one part of the picture, which is why pattern recognition matters.

There is no single diagnostic test, so doctors use the Strasbourg criteria. The review sets out the obligate criteria as a chronic urticarial rash and a monoclonal IgM or IgG. The minor criteria are recurrent unexplained fever above 38 degrees Celsius, abnormal bone remodelling with or without bone pain, a neutrophilic dermal infiltrate on skin biopsy, leukocytosis (a high neutrophil count) and a raised C-reactive protein. A definite diagnosis requires both obligate criteria and at least two minor criteria if the protein is IgM, or at least three if it is IgG.

Tests commonly include blood tests for inflammatory markers, a full blood count, serum protein electrophoresis and immunoglobulins to detect the monoclonal protein, a skin biopsy, and imaging of bones if there is bone pain. The review lists conditions that must be excluded, including Waldenstrom macroglobulinaemia, urticarial vasculitis, adult-onset Still disease, lupus, cryoglobulinaemia, C1 esterase inhibitor deficiency, chronic idiopathic urticaria and the inherited periodic fever syndromes such as Muckle-Wells syndrome.

The UK case report notes that an auto-inflammatory genetic screen in that patient showed no mutations, and that there are no known risk factors, and that family history is typically negative. In practice a diagnosis is often made by, or with advice from, rheumatology, immunology, haematology or a specialist autoinflammatory service.

Schnitzler syndrome has a reputation for being resistant to conventional treatment. The review says it has been resistant to most agents including glucocorticosteroids, antihistamines and rituximab, that responses to high-dose steroids tend to be incomplete with flares when tapered, and that immunosuppressants such as cyclophosphamide, azathioprine and methotrexate are ineffective.

The breakthrough has been anakinra, a medicine that blocks interleukin-1 and is given by daily injection under the skin. The review says anakinra provides a rapid, dramatic, sustained and complete resolution of the rash and the other symptoms and normalisation of inflammatory markers, though the monoclonal IgM remains detectable. Most patients who miss doses rapidly experience resurgence of symptoms, but they respond again when treatment is resumed. The UK case report likewise describes rapid improvement in rash and night sweats, and a recurrence of rash when a patient forgot her medication for a weekend.

The review adds that because the response is so typical, the diagnosis should be questioned in patients who do not respond. Anakinra is generally well tolerated apart from injection-site reactions, and patients are monitored regularly for a low neutrophil count, especially early on. Anyone considering pregnancy should discuss this with their specialist. Ask your specialist team how access to anakinra and monitoring will work for you.

The main long-term concern is the risk of a blood cancer arising from the monoclonal cell population. The review says the initial series reported that perhaps 20% of patients may develop a lymphoproliferative disorder within 10 years of diagnosis, whereas a more recent series found 12% with a median follow-up of 13 years. It is not known whether anakinra reduces this risk. The UK case report gives a figure of 15 to 20% and says the possibility prompts examination of lymph nodes and bone marrow and long-term surveillance.

The review advises following patients using standard guidelines for monoclonal gammopathy and monitoring for the development of Waldenstrom macroglobulinaemia, non-Hodgkin lymphoma, IgM myeloma or amyloidosis. It states that Schnitzler syndrome is a chronic condition, with only two documented patients achieving spontaneous sustained remission, and that median overall survival in one large single-centre series was 12.8 years from diagnosis. Rare complications include reactive (AA) amyloidosis with kidney involvement, which is another reason for regular checks.

You will typically be seen regularly by a haematologist or the specialist team, with blood tests for the monoclonal protein, inflammatory markers and blood counts. Report new lumps, drenching sweats, weight loss or worsening bone pain promptly.

See your GP if you have a persistent urticarial rash that does not respond to antihistamines, particularly alongside fevers, night sweats, bone or joint pain or enlarged glands. Ask about a referral to rheumatology or immunology, and mention that you would like the possibility of an autoinflammatory condition considered. A symptom diary and photographs of the rash during flares are very helpful.

Call 999 for swelling of the lips or tongue with difficulty breathing, or collapse. Contact your specialist team urgently if you are on anakinra and develop fever with signs of infection, since the medicine affects the immune system.

There is no NHS patient information page for Schnitzler syndrome at the time of writing. This page draws on a UK case report abstract and a review written by US authors. Because the condition is very rare, most evidence comes from case reports and small series, and there are no large trials. Your specialist team is the best source of advice for your own situation.