Schnitzler syndrome

# Overview
Schnitzler syndrome is a rare disease characterised by 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.
The urticarial rash is non-itching in more than half of cases, which is unusual for hives. It is most prominent on the trunk, arms and legs, sparing the palms, soles, head and neck. Associated angioedema has been reported in a few patients. A review of 94 cases found a mean age at onset of 51 years, and only four patients developed symptoms before the age of 35. The cause and disease mechanism of Schnitzler syndrome remain largely unknown.
Schnitzler syndrome is considered an autoimmune disorder. Chronic hives and a monoclonal gammopathy have been proposed as the major criteria, while the others represent minor criteria.

# Historical Perspective
The disease is named after the French dermatologist L. Schnitzler who first described this syndrome in 1972.

# Classification
-  may be classified according to  into  subtypes/groups:
- Other variants of  include , , and .

# Pathophysiology
- The pathogenesis of  is characterized by , , and .
- The  gene/Mutation in  has been associated with the development of , involving the  pathway.
- On gross pathology, , , and  are characteristic findings of .
- On microscopic histopathological analysis, , , and  are characteristic findings of .

# Causes
-  may be caused by either , , or .
-  is caused by a mutation in the , , or  gene.
- There are no established causes for .

# Differentiating  from other Diseases
-  must be differentiated from other diseases that cause , , and , such as:

# Epidemiology and Demographics
- The prevalence of  is approximately  per 100,000 individuals worldwide.
- In , the incidence of  was estimated to be  cases per 100,000 individuals in .

## Age
- Patients of all age groups may develop .
-  is more commonly observed among patients aged  years old.
-  is more commonly observed among .

## Gender
-  affects men and women equally.
-  are more commonly affected with  than .
- The  to  ratio is approximately  to 1.

## Race
- There is no racial predilection for .
-  usually affects individuals of the  race.
-  individuals are less likely to develop .

# Risk Factors
- Common risk factors in the development of  are , , , and .

# Natural History, Complications and Prognosis
- The majority of patients with  remain asymptomatic for .
- Early clinical features include , , and .
- If left untreated,  of patients with  may progress to develop , , and .
- Common complications of  include , , and .

## Prognosis
The life span in patients with Schnitzler syndrome has not been shown to differ much from the general population. Careful follow-up is advised, however. A significant proportion of patients develops a lymphoproliferative disorder as a complication, most commonly Waldenstrom's macroglobulinemia. This may lead to symptoms of hyperviscosity syndrome. AA amyloidosis has also been reported in people with Schnitzler syndrome.

# Diagnosis
Blood tests show a high concentration of specific gamma-globulins (monoclonal gammopathy) of the IgM type. It almost always has light chains of the -type. A variant in which IgG is raised has been described, which appears to be ten times as rare. 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.
Because it is such a rare condition (less than 100 cases reported in the literature worldwide before 2008), it is important to rule out other conditions which can cause periodic fevers, paraproteins or chronic hives. These include (and are not limited to) auto-immune or -inflammatory disorders such as adult-onset Still's disease, angioedema, hematological disorders such as lymphoma or monoclonal gammopathy of undetermined significance, other causes of hives, cryoglobulinemia, mastocytosis, chronic neonatal onset multisystem inflammatory disease or Muckle-Wells syndrome.
It is however possible to have more than one rare condition as seen by a patient with Schnitzler's syndrome and cold induced urticaria.

## Diagnostic Criteria
- The diagnosis of  is made when at least  of the following  diagnostic criteria are met:

## Symptoms
-  is usually asymptomatic.
- Symptoms of  may include the following:

## Physical Examination
- Patients with  usually appear .
- Physical examination may be remarkable for:

## Laboratory Findings
- There are no specific laboratory findings associated with .
- A    is diagnostic of .
- An  concentration of   is diagnostic of .
- Other laboratory findings consistent with the diagnosis of  include , , and .

## Imaging Findings
- There are no  findings associated with .
-  is the imaging modality of choice for .
- On ,  is characterized by , , and .
-  may demonstrate , , and .

## Other Diagnostic Studies
-  may also be diagnosed using .
- Findings on  include , , and .

# Treatment
Antihistamines are not effective in treating the hives in this condition. It may respond to immunosuppressant drugs such as corticosteroids, cyclooxygenase inhibitors, interferon alpha, interleukin 1 receptor antagonists (Anakinra), perfloxacin, colchicine, cyclosporine or thalidomide. The hives may respond to treatment with PUVA, and the bone pain may respond to bisphosphonates.
Because Schnitzler's syndrome is so rare, the efficacy of different treatments cannot be compared using statistics. Nevertheless, case studies provide evidence that anakinra (otherwise known as kinaret) is much more effective for Schnitzler's syndrome than any other drug, and that the improvement in symptoms associated with this treatment is dramatic. For example, Beseda and Nossent (2010)  reviewed the literature concerning IL1-RA treatment (i.e. anakinra) for Schnitzler's syndrome. They concluded that, Twenty-four patients with Schnitzler's syndrome... have been successfully treated with anakinra. They add that seven out of seven patients , that either interrupted or used anakinra every other day, had relapse of their symptoms within 24-48 h; anakinra was restarted in all patients with the same clinical efficiency. Kluger et al. (2008) investigated the effectiveness of anakinra for a range of conditions. They searched MEDLINE for English-language trials of anakinra and abstracts from rheumatologial scientific meetings. They conclude that, Over the last few years it has become increasingly evident that anakinra is highly effective and safe in patients with ... Schnitzlers syndrome. The year before, De Koning et al. (2007)  reviewed the disease characteristics of Schnitzler syndrome and collected follow-up information to gain insight into long-term prognosis and treatment efficacy. They used data from 94 patients, and their conclusions about treatment for the condition are that, There have been promising developments in therapeutic options, especially antiinterleukin-1 treatment, which induced complete remission in all 8 patients treated so far.
Reports of individual patients treated with anakinra illustrate its effectiveness. Beseda and Nossent (ibid.) report treating a longstanding multidrug resistant Schnitzlers syndrome patient with anakinra: Within 24 h after the first injection, both the urticaria and the fever disappeared and have not recurred. For the past 6 months, the patient has been in clinical and biochemical remission. Other authors report a complete resolution of symptoms (Dybowski et al., 2008). Crouch et al. (2007)   report the effective treatment of a 52 year old man who had been diagnosed with Schnitzlers syndrome 8 years earlier: On review, one week later, the patients systemic symptoms had resolved, and his previously elevated white cell count and inflammatory markers had normalised. The use of anakinra in our patient resulted in resolution of symptoms and has enabled cessation of oral prednisolone. Our patient remains symptom free on anakinra after 14 months of follow-up. Similar stories are reported by Frischmeyer-Guerrerio et al. (2008), Wastiaux et al. (2007), and Eiling et al. (2007), Schneider et al. (2007). De Koning et al. (2006)  treated three patients with Schnitzlers syndrome with thalidomide and anakinra. Thalidomide was only effective for one of the three patients and was discontinued because of polyneuropathy. In contrast, for all three patients, anakinra led to disappearance of fever and skin lesions within 24 hours. After a follow-up of 16-18 months, all patients are free of symptoms. The authors concluded that anakinra as a treatment for Schnitzlers syndrome is preferable to thalidomide... as it has fewer side effects.
As well as being more effective, anakinra is safer than the other treatments available for Schnitzler's syndrome. The Cochrane review entitled, Anakinra for rheumatoid arthritis (Mertens and Singh, 2009 ) evaluates the (clinical effectiveness and) safety of anakinra in adult patients with rheumatoid arthritis, using data from  2876 patients, from five trials which constituted 781 randomized to placebo and 2065 to anakinra. The authors conclude, There were no statistically significant differences noted in most safety outcomes with treatment with anakinra versus placebo - including number of withdrawals, deaths, adverse events (total and serious), and infections (total and serious). Injection site reactions were significantly increased, occurring in 1235/1729 (71%) versus 204/729 (28%) of patients treated with anakinra versus placebo, respectively. These injection site reactions last for no more than four months, and are trivial compared to the very debilitating symptoms of Schnitzler's syndrome.

## Medical Therapy
- There is no treatment for ; the mainstay of therapy is supportive care.
- The mainstay of therapy for  is  and .
-  acts by .
- Response to  can be monitored with  every .

## Surgery
- Surgery is the mainstay of therapy for .
-  in conjunction with  is the most common approach to the treatment of .
-  can only be performed for patients with  .

## Prevention
- There are no primary preventive measures available for .
- Effective measures for the primary prevention of  include , , and .
- Once diagnosed and successfully treated, patients with  are followed-up every . Follow-up testing includes , , and .

# Related Chapters
- Schinzel-Giedion syndrome
- List of cutaneous conditions