Schnitzler's syndrome: diagnosis, treatment, and follow-up

Authors


  • Edited by: Thomas Bieber

Correspondence

Dan Lipsker, Clinique Dermatologique, Hôpitaux Universitaires, 1, place de l'hôpital, F-67091 Strasbourg Cedex, France.

Tel.: + 33 3 88 11 61 79

Fax: + 33 3 88 11 59 62

E-mail: dan.lipsker@chru-strasbourg.fr

Abstract

Schnitzler's syndrome is characterized by recurrent urticarial rash and monoclonal gammopathy, associated with clinical and biological signs of inflammation and a long-term risk of AA amyloidosis and overt lymphoproliferation. An extensive literature review was performed, and the following questions were addressed during an expert meeting: In whom should Schnitzler's syndrome be suspected? How should the diagnosis of Schnitzler's syndrome be established? How should a patient with Schnitzler's syndrome be treated? How should a patient with Schnitzler's syndrome be followed up?. A diagnosis of Schnitzler's syndrome is considered definite in any patient with two obligate criteria: a recurrent urticarial rash and a monoclonal IgM gammopathy, and two of the following minor criteria: recurrent fever, objective signs of abnormal bone remodeling, elevated CRP level or leukocytosis, and a neutrophilic infiltrate on skin biopsy. It is considered probable, if only 1 minor criterion is present. In patients with monoclonal IgG gammopathies, diagnosis is definite if three minor criteria are present and possible if two are present. First-line treatment in patients with significant alteration of quality of life or persistent elevation of markers of inflammation should be anakinra. Follow-up should include clinical evaluation, CBC and CRP every 3 months and MGUS as usually recommended.

Abbreviations
AOSD

adult-onset Still's disease

CAPS

cryopyrin-associated periodic syndrome

CRP

C-reactive protein

ESR

erythrocyte sedimentation rate

HIDS

hyper-IgD syndrome

IL-1

interleukin-1

MGUS

monoclonal of undetermined significance (MGUS)

SAA

serum amyloid A

SD

standard deviation

TRAPS

TNF receptor-associated periodic syndrome

Schnitzler's syndrome was first reported in 1972 and then published as an autonomous entity in 1974 and 1989, by Liliane Schnitzler, a French dermatologist [1-3]. Its main clinical features include recurrent fever, an urticarial rash, muscle, bone, and/or joint pain, and enlarged lymph nodes. Monoclonal IgM or rarely IgG gammopathy is the biological hallmark of the disease. The physiopathological link between the features of the syndrome and the monoclonal gammopathy is still unknown, whereas interleukin-1 beta (IL-1β) crucially contributes to the symptoms and signs of systemic inflammation, and it is unknown whether it affects the paraprotein or vice versa [4-6]. Conventional therapies including antihistamines for the skin rash, as well as anti-inflammatory drugs and immunosuppressive drugs for the systemic manifestations, are usually ineffective or too toxic. The IL-1 (interleukin 1) receptor antagonist anakinra was found to rapidly control all the symptoms of this syndrome. However, the disease recurs as soon as treatment is stopped. About 15% to 20% of patients with Schnitzler's syndrome will develop an overt lymphoproliferative disorder, as would be expected in all patients who have monoclonal IgM gammopathy of undetermined significance (MGUS) [7]. The development of AA amyloidosis is a concern in untreated patients [5, 8].

Since Liliane Schnitzler's description of this syndrome, about 200 patients have been reported. To establish guidelines for the diagnosis, treatment, and follow-up of this syndrome, an expert meeting took place in Strasbourg, France, in May 2012. Although she is retired now, Liliane Schnitzler participated in the meeting and validated the conclusions. Here, we report the methodology and conclusions of this meeting.

Material and methods

A MEDLINE (National Library of Medicine, Bethesda, MD, USA) search using the key words ‘Schnitzler syndrome’ and ‘Schnitzler's syndrome’ was performed by two of the authors (DL and AS) in January 2012 to retrieve all cases. Relevant articles in English, French, and German were included. We also included cases known to us through the Schnitzler syndrome registry. This literature review was used to provide a factual basis to address the following four questions that were submitted to the experts before the meeting:

  1. In whom should Schnitzler's syndrome be suspected?
  2. How should the diagnosis of Schnitzler's syndrome be established?
  3. How should a patient with Schnitzler's syndrome be treated?
  4. How should a patient with Schnitzler's syndrome be followed up?

Only experts with recognized knowledge about Schnitzler's syndrome and who published on the topic participated in this meeting. During the first day, all issues were discussed. In the evening, two experts (DL and AS) wrote a synthesis summarizing each experts' intervention, which was submitted to second round of discussion on the second day when all points of disagreement were discussed to reach consensus, or to highlight disagreement between experts in the final paper (simplified Delphi technique).

Results

Literature review

More than 200 papers were reviewed. Cases published before 2007 were already summarized in De Koning et al.'s report of 94 patients with Schnitzler's syndrome [5]. The main clinical signs of the syndrome, including an additional 102 new cases [8-43] [because of space limitations, all references cannot be cited here]) since the De Koning report, thus totaling 196 patients, are shown in Table 1. Male/female ratio is 1.76, while mean and median age when first symptoms appeared were 51.6 years (SD 10 years) and 51 years, respectively. It should be highlighted that Schnitzler's syndrome is a recurrent disorder, with periods of spontaneous remission of variable duration. The rash is the most constant feature of the disorder. Detailed descriptions of this syndrome were published [4-6].

Table 1. Clinical and biological findings in patients with Schnitzler's syndrome
  1. a

    As usually assessed by conventional X-rays.

Urticarial rash100%
Elevated ESR (≥30)95%
Fever93%
Monoclonal IgM gammopathy89%
Kappa light chain89%
Arthralgia/arthritis77%
Leucocytosis (≥10 000)76%
Bone pain68%
Abnormal bone morphologya62%
Palpable lymph nodes47%
Pruritus45%
Liver and/or spleen enlargement34%

Expert consensus

In whom should diagnosis be suspected?

A chronic/recurrent urticarial rash is the hallmark feature of the disease. Together with the monoclonal gammopathy, it defines the syndrome. Patients with all signs of Schnitzler syndrome except the rash should be referred to as patients with Schnitzler-like syndrome.

Schnitzler's syndrome should be suspected in adult patients, usually older than 40 with a chronic urticarial rash associated with any of the other signs summarized in Table 2. When even one of these signs is present, appropriate tests should be performed in search of an associated monoclonal gammopathy, if not already known. Standard serum electrophoresis and immunofixation are mandatory. If negative, performing urine electrophoresis and immunofixation and serum-free light-chain measurements should be considered, as well as phenotype of blood mononuclear cells and immunoglobulin gene rearrangement study of circulating cells. Cytological, immunohistological, and molecular bone marrow studies may also be discussed in those rare cases with high clinical suspicion, no detectable monoclonal immunoglobulin, and no evidence for any differential diagnosis.

Table 2. When should Schnitzler's syndrome be suspected?
In an adult patient with a recurrent urticarial rash and any of thefollowing signs or symptoms
Fever
Fatigue, general malaise
Pain in joints, muscle, and/or bone
Enlarged lymph nodes, enlarged liver, or spleen
Leukocytosis and/or increased markers of inflammation
Monoclonal gammopathy
A neutrophilic infiltrate on skin biopsy

How should the diagnosis of Schnitzler's syndrome be established?

Diagnostic criteria

Since the 2001 publication of diagnostic criteria by Lipsker et al., authors have referred to those criteria in almost all subsequently published cases [4]. De Koning slightly expanded the criteria by including the possibility of an IgG variant of Schnitzler's syndrome [5].

There is unfortunately no biological or other confirmative examination to allow definite diagnosis at present.

The experts felt that it is necessary to distinguish between patients with definite Schnitzler's syndrome and probable Schnitzler's syndrome, as definition of homogenous patient groups will facilitate pathogenic and therapeutic studies. Therefore, and after applying those criteria to their own series of patients, the experts agreed upon the following criteria, referred to as the Strasbourg criteria, illustrated in Table 3.

Table 3. Schnitzler's syndrome: Strasbourg diagnostic criteria
  1. a

    A valid criterion if objectively measured. Must be >38°C, and otherwise unexplained. Occurs usually – but not obligatory – together with the skin rash.

  2. b

    As assessed by bone scintigraphy, MRI or elevation of bone alkaline phosphatase.

  3. c

    Corresponds usually to the entity described as ‘neutrophilic urticarial dermatosis’ (Medicine 2009;88:23–31); absence of fibrinoid necrosis and significant dermal edema.

  4. d

    Neutrophils >10 000/mm3 and/or CRP > 30 mg/l.

Obligate criteria
Chronic urticarial rash +
Monoclonal IgM or IgG
Minor criteria
Recurrent fevera
Objective findings of abnormal bone remodeling with or without bone painb
A neutrophilic dermal infiltrate on skin biopsyc
Leukocytosis and/or elevated CRPd
Definite diagnosis if
Two obligate criteria AND at least two minor criteria if IgM, and three minor criteria if IgG
Probable diagnosis if
Two obligate criteria AND at least one minor criterion if IgM, and two minor criteria if IgG

These criteria should be considered provisional until prospective validation. Their sensitivity and specificity should be established in a prospective series by comparison of patients with Schnitzler's syndrome to patients with other inflammatory diseases, including AOSD, cryoglobulinemia, chronic spontaneous urticaria, and cryopyrin-associated periodic syndrome (CAPS).

Attention should be paid to the following points:

  • Some diagnoses need to be excluded before application of the criteria, especially if patients are seen early in the course of the disease. They are summarized in Table 4. Some of those entities deserve a comment:
  • Adult-onset Still's disease can closely mimic Schnitzler's syndrome. Both syndromes are characterized by an urticarial rash, fever, joint pain, leukocytosis, and absence of a specific diagnostic marker. Some useful features to distinguish between the two entities is the initial pharyngitis, frequent in AOSD and absent in Schnitzler's syndrome, increase in transaminases usually absent in Schnitzler's syndrome, and very elevated (low-glycosylated) ferritin levels, which are characteristic of AOSD, while ferritin rarely, if ever, exceeds 1200 ng/ml in patients with Schnitzler's syndrome [4-6].
  • Urticarial vasculitis, especially the hypocomplementemic variant, can also resemble Schnitzler's syndrome because of rash, fever, and joint pain. Cutaneous biopsy shows features of true vasculitis, with fibrinoid necrosis of small vessel walls, which is usually not the case in Schnitzler's syndrome. Complement consumption and anti-C1q antibodies are present, which are not observed in Schnitzler's syndrome.
  • Cryopyrin-associated periodic syndrome (especially Muckle–Wells syndrome or familial cold auto-inflammatory syndrome) and other auto-inflammatory disorders, such as TRAPS or mevalonate kinase deficiency syndrome [(also known as hyper-IgD syndrome (HIDS)], are usually present at a young age (especially HIDS). Development of the first symptoms after the age of 50 years would be exceptional, although some patients do not present to medical attention until late in life. A family history can help, as CAPS is inherited in an autosomal dominant fashion. A monoclonal paraprotein would not be expected.
  • Finally, one should not forget that both chronic idiopathic urticaria and monoclonal gammopathy (MGUS) are relatively prevalent disorders, especially in the elderly. Thus, their combination is not exceptional, and their mere association is not enough to establish the diagnosis of Schnitzler's syndrome.
Table 4. Entities that should be ruled out before considering the diagnosis of Schnitzler's syndrome
  1. a

    As both these conditions are relatively common in the elderly, these are important to consider as their co-occurrence is not exceptional.

For the skin lesions and/or inflammatory phenotype
Adult-onset Still's disease
Cryopyrin-associated periodic syndrome (especially Muckle–Wells syndrome) and other monogenic auto-inflammatory syndromes
Urticarial vasculitis
Cryoglobulinemic vasculitis
Systemic lupus erythematosus
Chronic idiopathic urticariaa
For the monoclonal gammopathy
Monoclonal gammopathy of unknown significance (MGUS)a

How should patients with Schnitzler's syndrome be treated?

The following recommendations, summarized in Fig. 1, were agreed upon to treat patients with definite or probable Schnitzler's syndrome:

Figure 1.

Treatment and follow-up recommendations for patients with definite and probable Schnitzler's syndrome. 1As soon as patients are controlled, try to find lowest effective dosage either by administering anakinra every other day or by lowering administered dose. 2Currently, there is very little known about this subject. 3This may be considered, although data on its efficacy are sparse.

  1. Patients without significant alteration in quality of life and without persistent elevation of markers of inflammation.

Exacerbating factors, if identified, should be avoided if possible. In those patients, close observation is an acceptable option. Treatment potentially targeting the inflammasome, which is probably involved in the pathogenesis of the clinical signs, seems adequate (agreement among experts). Colchicine 1–2 mg/d seems to offer a good benefit/risk ratio and was beneficial in about 25% of treated patients [4]. A therapeutic trial to assess efficacy should be at least 6 months of duration. Colchicine should be ingested during a meal, because of poor digestive tolerance. Some drug interactions, especially with erythromycin and other macrolides, must be avoided.

Short-course treatments with nonsteroidal anti-inflammatory drugs, especially ibuprofen, can be used in case of time-limited exacerbations, especially of joint and bone pain (recommendation grade C).

The experts concluded that the benefit/risk ratio of thalidomide was unfavorable.

Pefloxacin was used successfully in a few patients [44, 45], but the risk of tendinopathy is significant, and the drug is not readily available in many countries. Although rarely effective, but because of low risk, a trial of hydroxychloroquine is reasonable in patients in whom joint pain is the main complaint (agreement among experts).

Experts draw attention to the fact that patients often underestimate the impact of their chronic condition on their quality of life, because of its slow onset with progression over a number of years. It is only when they are put on an effective treatment that they feel the difference.

  1. Patients with significant alteration in the quality of life, and/or patients with regularly elevated inflammation markers such as ESR or CRP above the upper limit of normal.

Even in the absence of significant symptoms, this is a risk factor for the development of complications, and such patients need to be treated adequately.

Those patients should be treated with anakinra 100 mg/d subcutaneously (recommendation grade C: numerous case reports, small series, [10-43], and with strong support by experts). Tapering to the lowest possible dose that controls symptoms should be tried secondarily. This can be achieved either by injecting 100 mg every other day or, if signs recur on the second day, by injecting every 36 h or only part of the syringe every day (lowering the injected dose). Monitoring should include neutrophil count, liver enzymes, cholesterol, and triglycerides.

Anakinra is contraindicated in patients with hypersensitivity to the drug and when renal clearance is less than 30 ml/min. In patients with impaired renal function, the benefit/risk ratio should be evaluated and the dose of anakinra reduced if treatment deemed necessary. Pregnancy is rare in patients with Schnitzler's syndrome, as the mean age of first symptoms is more than 50 years. In case of pregnancy, treatment should be interrupted. If not possible, the benefit/risk ratio should be evaluated and discussed; very limited data suggest that anakinra does not induce malformations and can be used safely during pregnancy [46].

Because a small number of long-term remissions have been described in Schnitzler's syndrome [6, 47], it seems reasonable to propose that after a complete remission of more than 2 years' duration, treatment should be stopped to assess whether symptoms still persist. This interruption should last at least 2 weeks as flares can occur directly after anakinra is stopped (because of compensatory regulation mechanisms). Some experts (JPF, BA, DL) feel that if an interruption is considered because of complete remission, patients should first be treated with colchicine for at least 3 months and colchicine treatment should then be continued – in the absence of recurrence – for another 3–6 months.

Longer-acting IL-1 inhibitors that do not need to be injected daily seem promising alternatives (e.g. canakinumab or rilonacept). However, these are more expensive, and data regarding Schnitzler's syndrome are scarce [48, 49]. Furthermore, we lack data on long-term safety.

In case of failure of anakinra, diagnosis should first be reconsidered (agreement of experts). If the diagnosis is verified, anakinra dosage should be increased (up to 3 × 100 mg/d) and colchicine and or pefloxacin added (agreement among experts). Tocilizumab could also be considered as an alternative [50].Experts point to the fact that they do not recommend systemic steroids or nonsteroidal immunosuppressive drugs or treatments targeting MGUS (if not otherwise indicated).

How should patients with Schnitzler's syndrome be followed up?

Both the clinical and biological signs of inflammation and the monoclonal gammopathy need follow-up.

Disease activity: inflammation

Parameters of inflammation and response to treatment should be monitored by serum CRP and leukocyte count. The aim of treatment should be normalization of these values, to prevent long-term complications. These parameters should be monitored at least every 3 months. Once the patient has been established on successful treatment, parameters should be monitored at least twice a year. Serum amyloid A (SAA) protein can also be used for monitoring, with the theoretical advantage that this combines monitoring of the acute phase response and the risk for AA amyloidosis, although the potential value of monitoring SAA in Schnitzler's syndrome has not been established.

Monoclonal gammopathy

The MGUS should be monitored as usually recommended, at a rate dependent on its serum level (once yearly if under 10 g/l, twice a year if <30 g/l, and every 3 months if >30 g/l). Blood count and differential, serum electrophoresis, creatinine, calcium (only if mIgG), LDH, and urine protein, should be measured. Changes in the characteristics of the gammopathy (such as clear increase in monoclonal Ig level) or development of lymphadenopathy should lead to consider the emergence of an overt lymphoid disorder. This should prompt to perform appropriate tests including bone marrow examination and lymph node biopsy.

Other investigations depend on comorbidities and specific treatments.

Discussion

Schnitzler's syndrome is a rare disorder with fewer than 250 known patients, although there is probably underreporting. It is considered as being a paradigm of a late-in-life-acquired auto-inflammatory syndrome. Here, we provide guidelines for diagnosis, treatment, and follow-up of patients with Schnitzler's syndrome, by using a simplified Delphi technique to reach consensus. The proposed diagnostic criteria should allow a simplified diagnosis. By separating patients in definite and probable Schnitzler's syndrome, more homogenous patient groups should be delineated. All experts agreed that IL-1 inhibition is the only regularly and completely efficient treatment for patients with Schnitzler's syndrome; patients with an alteration in their quality of life or persistent elevation of markers on inflammation should be treated with anakinra. The experts want, however, to underline the following points and unmet needs:

The here suggested Strasbourg diagnostic criteria of Schnitzler's syndrome should be evaluated prospectively, both in terms of sensitivity and specificity when applied to patients with related inflammatory disorders (AOSD, urticarial vasculitis) and in patients with chronic idiopathic urticaria.

Overall, the phenotypic characteristics of these patients should be more carefully assessed; especially, bone lesions should be more precisely investigated. We do not yet know whether they are already present in the ‘early’ patients (within 2 years after onset of first symptoms). The value of determining SAA as a prognostic marker should be evaluated.

Interleukin-1-neutralizing agents such as anakinra are clearly the treatment of choice in patients with Schnitzler's syndrome. These drugs should be licensed and be made available for this indication, whatever the healthcare system. Every physician taking care of patients with Schnitzler's syndrome, whatever her or his specialty, should be allowed to prescribe these drugs. A randomized controlled trial to obtain legal approval of an IL-1 inhibitor in Schnitzler's syndrome is encouraged.

Long-term efficacy of anakinra and potential secondary treatment failures must be assessed.

Delay to diagnosis is still often many years, and knowledge about this rare and sometimes debilitating syndrome should be increased.

Basic research on Schnitzler's syndrome should be encouraged, as the syndrome bears a significant impact on quality of life and probably is a paradigm of acquired diseases involving auto-inflammatory mechanisms, which are not yet understood.

To achieve some of those unmet needs, the experts encourage all clinicians who care for patients with Schnitzler's syndrome to include them in the Schnitzler syndrome database (www.schnitzlersyndrome.com). All patients with Schnitzler's-like syndrome should also be registered to increase the overall knowledge in this field.

Acknowledgments

Dan Lipsker organized the meeting. Dan Lipsker obtained a research grant from the French Dermatological Society (Société Française de Dermatologie) to support his research on causative factors and pathomechanism involved in Schnitzler's syndrome (http://clinicaltrialsfeeds.org/clinical-trials/show/NCT00933296). Dan Lipsker and Anna Simon performed the literature review and wrote the initial draft of this manuscript. All authors discussed content and contributed significantly to the input of the final paper, which reflects consensus.

Conflict of interest

Anna Simon received consultancy fees from Novartis and Biovitrum; Heleen de Koning received a research support from Novartis; Victor Matinez-Taboada participated in an advisory board for SOBI laboratories; Clive Grattan attended an advisory board for SOBI laboratories; SOBI laboratories covered travel expenses and hotel accommodation for the following experts: AS, BA, HdK, JPF, CG, KK, FR, RR, and LS.

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