Elsevier

Autoimmunity Reviews

Volume 13, Issue 10, October 2014, Pages 1035-1041
Autoimmunity Reviews

Review
Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: A french multicenter study

https://doi.org/10.1016/j.autrev.2014.08.031Get rights and content

Abstract

The aim of this study is to assess the long-term effectiveness and safety of IL1Ra in Schnitzler syndrome (SchS). Between 2010 and 2012, we performed a nationwide survey among French internal medicine departments to identify SchS patients. We retrospectively analyzed the long-term efficacy and safety of IL1Ra and the outcome of patients that did not receive this treatment. Forty-two patients were included in the study, 29 of whom received IL1Ra. The mean age at disease onset was 59.9 years. Disease manifestations included urticaria (100%), fever (76%), bone/joint pain (86%), bone lesions (76%), anemia (67%), and weight loss (60%). The monoclonal gammopathy was overwhelmingly IgM kappa (83%). The mean follow-up was 9.5 years (range: 1.6–35). Two patients developed Waldenström's macroglobulinemia and one developed AA amyloidosis. All of the 29 patients who received IL1Ra responded dramatically. After a median follow-up of 36 months (range: 2–79), the effectiveness remained unchanged. All patients remained on anti-IL-1 therapy. Twenty-four patients (83%) went into complete remission and five (17%) into partial remission. Three patients experienced grade 3–4 neutropenia. Six patients developed severe infections. No lymphoproliferative diseases occurred while on IL1Ra. When last seen, all patients without anakinra had an active disease with variable impact on their quality of life. Their median corticosteroids dosage was 6 mg/d (range: 5–25). IL1Ra is effective in SchS, with a sharp corticosteroid-sparing effect. Treatment failures should lead to reconsider the diagnosis. Long-term follow-up revealed no loss of effectiveness and a favorable tolerance profile. The long-term effects on the risk of hemopathy remain unknown.

Introduction

Schnitzler's syndrome (SchS) is a rare disease that manifests with a urticarial skin rash, monoclonal gammopathy (mostly IgM kappa), and a variable combination of recurrent fever, osteoarticular pain, sclerotic bone lesions, lymphadenopathy, and hepatosplenomegaly [1], [2] This disease was first described by the French dermatologist Liliane Schnitzler almost 40 years ago [3], [4], but even today it is still underdiagnosed [5].

Patients with SchS frequently exhibit an altered quality of life (QoL) because of recurrent fever, rash, pain, fatigue, and sometimes weight loss or anemia [1], [2]. As with other patients with monoclonal gammopathy of undetermined significance, SchS patients may develop a hematological malignancy (usually Waldenström's macroglobulinemia). More infrequently, they can develop AA amyloidosis [6], [7]. Conventional therapies, such as antihistamines, non-steroidal anti-inflammatory drugs (NSAID), corticosteroids, immunomodulating agents (colchicine and hydroxychloroquine), and pefloxacin, usually provide only partial or transient improvement of the symptoms [7]. Disease-modifying anti-rheumatic drugs are rarely useful [2], [7]. In recent years, several case reports have revealed the remarkable efficacy of the interleukin-1 (IL-1) receptor antagonist (IL1Ra) anakinra on this disease [8], [9]. Two small, open-label, non-comparative studies also demonstrated the short-term efficacy of the long-acting IL-1 blockers canakinumab [10] and rilonacept [11]. Given the efficacy of blocking IL-1 activity toward treatment of this disease, phenotypical similarities between SchS and cryopyrin-associated periodic syndrome, and biological data suggesting a dysfunction of the inflammasome [11], [12], [13], [14], [15], most physicians and scientists consider SchS an acquired, late-onset auto-inflammatory disease [1], [2], [7], [16]. However, the relationship between the systemic inflammation and the monoclonal component remains unknown.

Unfortunately, most data regarding the use of IL1Ra in SchS arise from case reports or very small study series. Therefore, long-term data regarding its efficacy, tolerance, and safety are scarce. Furthermore, the concern that some patients may not respond to IL-1 blockers has recently emerged [17], [18] and the possibility of secondary treatment failure remains unknown [2].

Herein we report on the long-term effectiveness and safety of the off-label use of IL1Ra in SchS through a retrospective analysis of a multicenter cohort of 42 patients with SchS, of whom 29 were treated with IL1Ra.

Section snippets

Patients

In this study, we included all of the SchS patients evaluated at Nantes University Hospital since 1998 (n = 17). Further, we conducted a nationwide survey among all of the departments of internal medicine in France through the French Internal Medicine Society (Société Nationale Française de Médecine Interne) from 2010 to 2012. To be included, patients had to fulfill the diagnostic criteria proposed by Lipsker et al. in 2001 [19], irrespective of the recourse or the effect of IL-1 blockers. This

Cohort characteristics

The cohort included 42 SchS patients from 16 centers. There were 30 men and 12 women. The mean age at disease onset was 59.9 ± 11.9 years (range: 34–79). The mean diagnostic delay was 43 ± 36 months (range: 1–141).

Aside from the urticarial rash, fever and bone and joint pain were the most frequent complaints (Table 1). In addition, 25 patients experienced weight loss and 28 developed inflammatory anemia, with a hemoglobin level at < 10 g/dL in 16 cases (38%).

Overall, 29 patients were treated with

Discussion

In this study we assessed the long-term effectiveness, tolerance, and safety of IL1Ra treatment in patients with SchS. To the best of our knowledge, this is the largest series focusing on the management of these patients since the advent of IL-1-targeted therapies.

A wide range of drugs has been used in patients with SchS [2], [7], [20]. However, none of these treatments were reported to induce a complete, durable remission of the disease until the first report of the successful use of IL1Ra [8]

Take-home messages

  • IL1Ra is dramatically effective in Schnitzler Syndrome.

  • Treatment failure should lead to reconsider the diagnosis.

  • In the long-term, no loss of effectiveness occurs.

  • The tolerance and safety profile of IL1Ra is satisfying.

  • IL1Ra has no impact on the natural history of the underlying monoclonal gammopathy.

Acknowledgments

The authors would like to thank the members of the Société Nationale Française de Médecine Interne that participated in the survey and Dr Jonathan Batchelor, Nottingham, for his advises.

Contributors: AN, BH, SB and MH conceived and designed the study. AN, BH and FP collected and interpreted the data. AN performed statistical analysis. TD performed serum electrophoresis re-analysis. AM, CB, XK, XP, PJW, OD, JN, AH, AA, LA, JMBe, FB, JMBr, BC, FCP, JDdK, RD, RF, BG, EH, PYH, HJ, DL, AL, PP, GM,

References (39)

  • I. Koné-Paut et al.

    Targeting interleukin-1β in CAPS (cryopyrin-associated periodic) syndromes: what did we learn?

    Autoimmun Rev

    (2012)
  • D. Lipsker

    The Schnitzler syndrome

    Orphanet J Rare Dis

    (2010)
  • A. Simon et al.

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

    Allergy

    (2013)
  • L. Schnitzler et al.

    Urticaire chronique, lésions osseuses, macroglobulinémie IgM: maladie de Waldenström

    Bull Soc Fr Dermatol Syphiligr

    (1974)
  • L. Schnitzler et al.

    Urticaire chronique-osteocodensation-macroglobulinemie. Cas princeps. Etude sur 20 ans

    Ann Dermatol Venereol

    (1989)
  • T. Jain et al.

    Schnitzler syndrome—an under diagnosed clinical entity

    Haematologica

    (2013)
  • K. Claes et al.

    Another devastating complication of the Schnitzler syndrome: AA amyloidosis

    Br J Dermatol

    (2008)
  • V.M. Martinez-Taboada et al.

    Successful treatment of refractory Schnitzler syndrome with anakinra: comment on the article by Hawkins et al

    Arthritis Rheum

    (2005)
  • J.T. Gran et al.

    Treatment of Schnitzler's syndrome with anakinra: report of three cases and review of the literature

    Scand J Rheumatol

    (2011)
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