Anakinra Treatment in Schnitzler Syndrome – Results of the First Retrospective Multi‑center Study in Six Patients from the Czech Republic
Authors:
P. Szturz 1; A. Šedivá 2; M. Žurek 3; Z. Adam 1; J. Štork 4; Z. Čermáková 5; P. Steyerová 6; A. Vokáčová 7; J. Hrbek 8; M. Sýkora 9; I. Špička 10; Z. Mechl 1; J. Mayer 1
Authors‘ workplace:
Interní hematologická a onkologická klinika LF MU a FN Brno
1; Ústav imunologie 2. LF UK a FN v Motole, Praha
2; III. interní klinika – nefrologická, revmatologická a endokrinologická LF UP a FN Olomouc
3; Dermatovenerologická klinika 1. LF UK a VFN v Praze
4; Oddělení klinické biochemie, FN Brno
5; Radiodiagnostická klinika 1. LF UK a VFN v Praze
6; Ústav nukleární medicíny 1. LF UK a VFN v Praze
7; Radiologická klinika LF UP a FN Olomouc
8; Oddělení klinické hematologie, Nemocnice České Budějovice
9; I. interní klinika – klinika hematologie 1. LF UK a VFN v Praze
10
Published in:
Klin Onkol 2014; 27(2): 111-126
Category:
Original Articles
Overview
Background:
Schnitzler syndrome is a very rare, acquired, autoinflammatory disease of mostly adult onset with characteristic combination of chronic recurrent urticaria and monoclonal immunoglobulin M or G gammopathy predisposing the patients to malignant lymphoproliferation. In this work, we analyzed the results of biological therapy with anakinra on a national level aiming to supply data for effective pharmacoeconomic estimates, lay the grounds of nationwide patient registry, raise awareness among professional public and optimize provided health care.
Patients and Methods:
The retrospective study (10/ 2006– 9/ 2013) included six males with definite Schnitzler syndrome verified by the new Strasbourg criteria. All patients were pretreated with antihistamines, nonsteroidal anti‑inflammatory drugs and glucocorticoids. Four patients underwent two or more treatment lines including intravenous bisphosphonates, 2- chlorodeoxyadenosine (cladribine), interferon‑α, PUVA photochemotherapy, cyclosporine A, thalidomide, bortezomib, chlorambucil, cyclophosphamide, colchicine and methotrexate. Anakinra monotherapy was initiated in standard dosing (100 mg subcutaneously daily).
Results:
Complete and partial remissions were achieved in five (83%) and one patients (17%), respectively. Complete remission was characterized by urticaria and pain regression (within hours), normalization of inflammatory markers (within days) and bone metabolism improvement assessed by the markers of osteoblastic osteoformation and osteoclastic osteoresorption in one case (within weeks). With normalized inflammatory markers (including interleukin‑6 and interleukin‑18), arthralgia and sporadic exacerbations of urticaria and fevers persist in the patient in partial remission with proven Q703K polymorphism in NLRP3 gene. The median treatment follow‑up was 30.5 months (37.2 ± 31.2 (n = 6)). The dosing interval was prolonged in one case of complete remission to 48 hours. No serious adverse reactions occurred during anakinra application.
Conclusion:
In Schnitzler syndrome, anakinra represents an effective, verified and safe medication with potentionally long‑term administration not compromising its original efficacy and subjective tolerance. Anakinra, blocking autonomous inflammatory reaction of the organism via interleukin‑1 pathway, is a generally accepted first line treatment that should be made available in standard dosing for all Schnitzler patients.
Key words:
Schnitzler syndrome – monoclonal gammopathy – interleukins – anakinra – acute‑ phase proteins – osteogenesis
Sources
1. Lipsker D. The Schnitzler syndrome. Orphanet J Rare Dis 2010; 5: 38.
2. Simon A, Asli B, Braun‑ Falco M et al. Schnitzler‘s syndrome: diagnosis, treatment, and follow‑up. Allergy 2013; 68(5): 562– 568.
3. Schnitzler L. Lésions urticariennes chroniques permanentes (érytheme pétaloıde?) Cas cliniques, n° 46 B. Journée Dermatologique d’Angers, 28 octobre 1972.
4. Schnitzler L, Schubert B, Boasson M et al. Urticaire chronique lesions osseuses macroglobulinémie IgM: Maladie de Waldenström? Bull Soc Fr Dermatol Syph 1974; 81: 363– 366.
5. de Koning HD, Bodar EJ, van der Meer JW et al. Schnitzler syndrome: beyond the case reports: review and follow‑up of 94 patients with an emphasis on prognosis and treatment. Semin Arthritis Rheum 2007; 37(3): 137– 148.
6. Jain T, Offord CP, Kyle R et al. Schnitzler syndrome: an under diagnosed clinical entity. Haematologica 2013; 98(10): 1581– 1585.
7. Szturz P, Adam Z, Šedivá A et al. Schnitzler‑ syndrom: diagnostika a léčba. Klin Onkol 2011; 24(4): 271– 277.
8. Lipsker D, Veran Y, Grunenberger F et al. The Schnitzler syndrome. Four new cases and review of the literature. Medicine (Baltimore) 2001; 80(1): 37– 44.
9. SanMartín O, Febrer I, Botella R et al. Urticarial lesions and monoclonal IgM gammopathy. Schnitzler’s syndrome. Arch Dermatol 1994; 130(9): 1195– 1198.
10. Kieffer C, Cribier B, Lipsker D. Neutrophilic urticarial dermatosis: a variant of neutrophilic urticaria strongly associated with systemic disease. Report of 9 new cases and review of the literature. Medicine (Baltimore) 2009; 88(1): 23– 31.
11. Besada E, Nossent H. Dramatic response to IL1- RA treatment in longstanding multidrug resistant Schnitzler‘s syndrome: a case report and literature review. Clin Rheumatol 2010; 29(5): 567– 571.
12. Loock J, Lamprecht P, Timmann C et al. Genetic predisposition (NLRP3 V198M mutation) for IL‑1- mediated inflammation in a patient with Schnitzler syndrome. J Allergy Clin Immunol 2010; 125(2): 500– 502.
13. Rowczenio DM, Trojer H, Russell T et al. Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature. Arthritis Res Ther 2013; 15(1): R30.
14. Terpos E, Asli B, Christoulas D et al. Increased angiogenesis and enhanced bone formation in patients with IgM monoclonal gammopathy and urticarial skin rash: new insight into the biology of Schnitzler syndrome. Haematologica 2012; 97(11): 1699– 1703.
15. Szturz P, Adam Z, Klabusay M et al. Schnitzler‑ syndrom: popis případu, zkušenosti s léčbou glukokortikoidy a preparátem anakinra (KineretTM) a sledování cytokinové odpovědi organizmu. Vnitř Lék 2011; 57(1): 97– 112.
16. Adam Z, Krejčí M, Pour L et al. Zhodnocení dvouleté léčby Schnitzlerova syndromu (kopřivkové velkoplošné morfy, monoklonální IgM gamapatie a osteolyticko‑osteosklerotické změny skeletu) preparátem anakinra (Kineret). Vnitř Lék 2009; 55(12): 1196– 1197.
17. Claes K, Bammens B, Delforge M et al. Another devastating complication of the Schnitzler’s syndrome: AA amyloidosis. Br J Dermatol 2008; 158(1): 182– 184.
18. Verret JL, Leclech C, Rousselet MC et al. Schnitzler syndrome and Waldenström disease. Fatal outcome of the original case. Ann Dermatol Venereol 1993; 120(6– 7): 459– 460.
19. Asli B, Brouet JC, Fermand JP. Spontaneous remission of Schnitzler syndrome. Ann Allergy Asthma Immunol 2011; 107(1): 87– 88.
20. Martinez‑ Taboada VM, Fontalba A, Blanco R et al. Successful treatment of refractory Schnizler syndrome with anakinra: comment on the article by Hawkins et al. Arthritis Rheum 2005; 52(7): 2226– 2227.
21. Flórez AF, Gallardo Agromayor E, García‑Barredo R et al. Radiological aid to clinical diagnosis of Schnizler’s syndrome: multimodality imaging approach. Clin Rheumatol 2008; 27(1): 107– 110.
22. Sedivá A, Poloučková A, Podrazil M et al. Characterization of the B‑ cell compartment in a patient with Schnitzler syndrome. Scand J Rheumatol 2011; 40(2): 158– 160.
23. Borradori L, Rybojad M, Puissant A et al. Urticarial vasculitis associated with monoclonal IgM gammopathy, Schnitzler’s syndrome. Brit J Dermatol 1990; 123(1): 113– 118.
24. Berdy SS, Bloch KJ. Schnitzler’s syndrome: A broader clinical spectrum. J Allergy Clin Immunol 1991; 87(4): 849– 854.
25. Olsen E, Forre O, Lea T et al. Unique antigenic determinants used as markers in a patient with macroglobulinemia urticaria. Similar idiotypes demonstrated in the skin and on peripheral blood lymphocytes. Acta Med Scand 1980; 207(5): 379– 384.
26. Lebbe C, Rybojad M, Klein F et al. Schnitzler’s syndrome with sensomotor neuropaty. J Amer Acad Dermatol 1994; 30(2 Pt 2): 316– 318.
27. Eiling E, Möller M, Kreiselmaier I et al. Schnizler syndrome: treatment failure to rituximab but response to anakinra. J Am Acad Dermatol 2007; 57(2): 361– 364.
28. Aikawa NE, Silva CA, Bonfá E et al. Schnitzler‘s syndrome improvement after anti‑TNF‑alpha therapy. Joint Bone Spine 2010; 77(5): 491.
29. de Koning HD, Bodar EJ, Simon A et al. Beneficial response to anakinra and thalidomide in Schnitzler‘s syndrome. Ann Rheum Dis 2006; 65(4): 542– 544.
30. Asli B, Bienvenu B, Cordoliani F et al. Chronic urticaria and monoclonal IgM gammopathy (Schnitzler syndrome): report of 11 cases treated with pefloxacin. Arch Dermatol 2007; 143(8): 1046– 1050.
31. Kastritis E, Katoulis A, Terpos E et al. Schnitzler‘s syndrome: increased levels of bone formation and angiogenesis factors are reduced after successful pefloxacin treatment. Clin Lymphoma Myeloma 2008; 8(6): 359– 362.
32. Janier M, Bonvalet D, Blanc MF et al. Chronic urtica and macroglobulinemia (Schnitzler’s syndrome): report of two cases. J Amer Acad Dermatol 1989; 20(2 Pt 1): 206– 211.
33. Asahina A, Sakurai N, Suzuki Y et al. Schnitzler‘s syndrome with prominent neutrophil infiltration misdiagnosed as Sweet‘s syndrome: a typical example of urticarial neutrophilic dermatosis. Clin Exp Dermatol 2010; 35(4): e123– e126.
34. Migliorini P, Del Corso I, Tommasi C et al. Free circulating interleukin‑18 is increased in Schnitzler syndrome: a new autoinflammatory disease? Eur Cytokine Netw 2009; 20(3): 108– 111.
35. Pizzirani C, Falzoni S, Govoni M et al. Dysfunctional inflammasome in Schnitzler‘s syndrome. Rheumatology (Oxford) 2009; 48(10): 1304– 1308.
36. Ryan JG, de Koning HD, Beck LA et al. IL‑1 blockade in Schnitzler syndrome: ex vivo findings correlate with clinical remission. J Allergy Clin Immunol 2008; 121(1): 260– 262.
37. Krause K, Feist E, Fiene M et al. Complete remission in 3 of 3 anti‑IL‑6‑treated patients with Schnitzler syndrome. J Allergy Clin Immunol 2012; 129(3): 848– 850.
38. Vitale A, Lucherini OM, Galeazzi M et al. Long‑term clinical course of patients carrying the Q703K mutation in the NLRP3 gene: a case series. Clin Exp Rheumatol 2012; 30(6): 943– 946.
39. Nuki G, Bresnihan B, Bear MB et al. Long‑term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin‑1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized, double‑blind, placebo‑ controlled trial. Arthritis Rheum 2002; 46(11): 2838– 2846.
40. Stahl N, Radin A, Mellis S. Rilonacept‑ CAPS and beyond. Ann N Y Acad Sci 2009; 1182: 124– 134.
41. Krause K, Weller K, Stefaniak R et al. Efficacy and safety of the interleukin‑1 antagonist rilonacept in Schnitzler syndrome: an open‑ label study. Allergy 2012; 67(7): 943– 950.
42. Church LD, McDermott MF. Canakinumab: a human anti‑IL‑1β monoclonal antibody for the treatment of cryopyrin‑associated periodic syndromes. Expert Rev Clin Immunol 2010; 6(6): 831– 841.
43. de Koning HD, Schalkwijk J, van der Meer JW et al. Successful canakinumab treatment identifies IL‑1β as a pivotal mediator in Schnitzler syndrome. J Allergy Clin Immunol 2011; 128(6): 1352– 1354.
44. Vanderschueren S, Knockaert D. Canakinumab in Schnitzler syndrome. Semin Arthritis Rheum 2013; 42(4): 413– 416.
45. Ščudla V, Budíková M, Petrová P et al. Analýza sérových hladin vybraných biologických ukazatelů u monoklonální gamapatie nejistého významu a mnohočetného myelomu. Klin Onkol 2010; 23(3): 171– 181.
46. Paglia F, Dionisi S, De Geronimo S et al. Biomarkers of bone turnover after a short period of steroid therapy in elderly men. Clin Chem 2001; 47(7): 1314– 1316.
47. Engvall IL, Svensson B, Tengstrand B et al. Impact of low‑dose prednisolone on bone synthesis and resorption in early rheumatoid arthritis: experiences from a two‑year randomized study. Arthritis Res Ther 2008; 10(6): R128.
Labels
Paediatric clinical oncology Surgery Clinical oncologyArticle was published in
Clinical Oncology
2014 Issue 2
Most read in this issue
- Renal Oncocytoma with Invasive Histopathologic Features – Case Report
- Psychoneuroimmunology in Context of Comprehensive Breast Cancer Treatment
- Lobular Breast Cancer in Man – Case Report and Review of the Literature
- Continuing Progress in Withdrawal of Axillary Dissection in Early Stage Breast Cancer