Schnitzler syndrome – report on a fourteen-year course of the disease and an overview of information on the disease

Czech version

Authors: Z. Adam ¹; M. Krejčí ¹; L. Pour ¹; J. Neubauer ²; J. Prášek ³; R. Hájek ¹
Authors‘ workplace: Interní hematoonkologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Vorlíček, CSc. ¹
Published in: Vnitř Lék 2008; 54(12): 1140-1153
Category: Reviews

Overview

Schnitzler syndrome is a rare disease characterised by chronic urticaria and the presence of monoclonal IgM immunoglobulin, and by other symptoms. We report our experience with 14-year treatment of a patient. The first medical examination in our workplace was at the beginning of 1995 and the patient was diagnosed with the disease in 1996 (at the age of 52). Antihistaminics, the first medication used to relieve the symptoms of urticaria, had no subjective or objective effect. After the detection of osteolytic-osteosclerotic changes in the pelvic region, in areas with intense pain, we started treatment with pamidronate (90 mg at 28-day intervals), and the pain disappeared completely within 3 months of application of the drug. When the bisphosphonate therapy was interrupted, the pain recurred and receded completely after renewal of bisphosphonate administration. After the diagnosis, we gave the patient high doses of dexametazone (40 mg day 1–4, 10–13 and 20–23, at 28-day cycles). However, the therapy suppressed urticaria only on the days dexametasone was administered and the effect did not last when the drug was discontinued. Therefore we moved to continuous daily doses of prednisone (10–30 mg, depending on the intensity of problems), which was the only therapy with a long-term effect which was relatively well tolerated at the same time. Based on the excellent effect of 2-chlordeoxyadenosine in Waldenström’s macroglobulinaemia, three cycles of this therapy were administered to the patient in 1996 (0.1 mg/kg/day, 7 days, at 28-day intervals). After the first infusion, urticarious lesions disappeared, but the positive effect on skin eruptions was limited in time and lasted only 14 days after the last infusion, i.e. the medication proved ineffective from a long-term point of view. The first improvement lasting for a longer period of time (partial remission) was achieved by regular application of interferon α (3 QU 3 times a week). However, adverse effects of interferon α prevailed after two years and the therapy was discontinued. Similarly phototherapy using the PUVA method resulted in partial regression of urticarious symptoms. Subsequently tested cyclosporine A (5 mg/kg/day) brought no benefit. Thalidomide (100 mg in the evening) administered on a continuous basis relieved pruritus and improved sleep disturbed by pruritus. However, adverse effects prevailed after 4 months and the therapy had to be discontinued, too. In 2005, we were hoping to achieve positive results with the most effective treatment for multiple myeloma of the time, a combination of bortezomib (1.3 mg/m² i.v. on day 1, 4, 8 and 11, thalidomide 100 mg daily and dexametazon 20 mg p.o. on days 1–4 and 8–11 in 21-day cycles – VTD). A total of 4 complete cycles and 4 cycles with bortezomib reduced by 50% were applied. Urticarious eruptions were reduced by at least 50% in the course of the therapy, and also the concentration of monoclonal immunoglobin decreased temporarily by more than 50%. However, after the therapy was discontinued, the symptoms returned with their original intensity, which means that VTD regime did not provide a long-term therapeutic response. In 2007, we started the anakinra (Kineret) therapy. Skin symptoms disappeared after the first injection and a dose of 100 mg/day has kept the patient free of skin symptoms for 12 months by now. Also the CRP value which had been constantly high returned to normal, and haemoglobin values increased to achieve physiological range. In the course of 14 years, we confirmed partial therapeutic effect of glucocorticoids administered on a continuous basis, as well as a partial therapeutic effect of interferon α, thalidomide and PUVA, but all the therapies had to be discontinued due to adverse effects. A major turn, i.e. the complete disappearance of skin symptoms and normalisation of CRP and haemoglobin values, only came with anakinra which has become the drug of the first choice for the above syndrome.

Key words:
anakinra – bortezomib – bisphosphonates – cyclosporine A  – interferon α  – thalidomide – 2-chlordeoxyadenosin – Schnitzler syndrome – monoclonal gammopathy – Waldenström’s macroglobulinaemia – multiple myeloma

Sources

1. Schnitzler L, Hurez D, Verret JL. Urticaire chronique osteoconcensation-macroglo-bulinemie. Cas Princeps Etude sur 20 ans Ann. Dermatol Venereol 1989; 116: 547–550.

2. Schnitzler L, Schubert B, Boasson M et al. Urticaire chronique lesions osseuses macroglobulinemie IgM: Maladie de Waldenström? Bull Soc Fr Dermatol Syph, 1974; 81: 363–366.

3. Altmeyer P, Welke S. Macroglobulinemiae Waldenström associirt mit einem chronisch rezidivierenden urtikariellen Exanthem. Akt Dermatol 1977; 3: 71–76.

4. Baty V, Hoen B, Hudziak H et al. Schnitzler’s syndrome. Two case reports and review of literature. Mayo Clin Proc 1995; 70: 570–572.

5. de Kleijn EM, Telgt D, Laan R. Schnitzler’s syndrome presenting as fever of unknown origin (FUO). The role of cytokines in its systemic features. Neth J Med 1997; 51: 140–142.

6. Puddu P, Cianchini G, Girardelli CR et al. Schnitzler’s syndrome: report of a new case and a review of the literature. Clin Exp Rheumatol 1997; 15: 91–95.

7. Kropp JD, Czarnetzki BM. Utica, vasculitis, und Schnitzler’s syndrome. Allergologie 1994; 17: S17–S20.

8. Shibolet O, Schata O, Krieger M et al. Schnitzler syndrome: chronic urticaria, fever and immunoglobulin M monoclonal gammopathy. Isr Med Assoc J 2002; 4: 466–467.

9. Verella TC, Nishimura MY, Machado MC et al. Schnitzler’s syndrome without monoclonal gammopathy. Acta Derm Venereol 2005; 85: 272–273.

10. Harati A, Brockmeyer NH, Altmeyer P et al. Skin disorders in association with monoclonal gammopathies. Eur J Med Res 2005; 10: 93–104.

11. Zuberbier T, Bindeslev-Jensen C, Canonica W et al. EAACI/GA2LEN/EDF Guidelines: definition, classification and diagnosis of urticaria. Allergy 2006; 61: 316–320.

12. Lipsker D, Veran Y, Grunenberger F et al. The Schnitzler’s syndrome. Four new cases and review of the literature. Medicine (Baltimore) 2001; 80: 37–44.

13. Lipsker D. The Schnitzler syndrome – a treatment at last? Dermatology 2002; 205: 1–2.

14. de Koning HD, Bodar EJ, van der Meer JW et al. Schnitzler’s Syndrome Study Group. Schnitzler’s syndrome: beyond the case reports: review and follow‑up of 94 patients with an emphasis on prognosis and treatment. Semin Arthritis Rheum 2007; 37: 137–148.

15. de Koning HD, van der Meer JW, Simon A. Comment on: Schnitzler’s syndrome – exacerbation after anti‑TNF treatment. Rheumatology (Oxford) 2007; 46: 1741.

16. Lipsker D, Boeckler P. Cutaneous manifestations of paraproteinemia and their mechanisms. Presse Med 2007; 36: 1135–1140.

17. Lipsker D, Cribier B, Maloisel F et al. Chronic urticaria and IgA myeloma. Acta Derm Venereol (Stockholm) 1998; 78: 395.

18. Lipsker D, Imrie K, Simon A et al. Hot and hobbling with hives: Schnitzler’s syndrome. Clin Immunol 2006; 119: 131–134.

19. Lipsker D, Spehner D, Drillien R et al. Schnitzler’s syndrome: heterogeneous immunopathological findings involving IgM-skin interactions. Br J Dermatol 2000; 142: 954–959.

20. de Castro FR, Masouyé I, Winkelmann RK et al. Urticarial pathology in Schnitzler’s syndrome. Dermatology 1996; 193: 94–99.

21. Berdy SS, Bloch KJ. Schnitzler’s syndrome: A broader clinical spectrum. J Allergy Clin Immunol 1991; 87: 849–854.

22. Borradori L, Rybojad M, Puissant A et al. Urticarial vasculitis associated with monoclonal IgM gammopathy, Schnitzler’s syndrome. Brit J Dermatol 1990; 123: 113–118.

23. Morita A, Sakakibara S, Yokota M et al. A case of urticarial vasculitis associated with macroglobulinemia (Schnitzler’s syndrome). J Dermatol 1995; 22: 32–35.

24. Lautenschlager S, Itin PH. Das Schnitzler Syndrom. Hautarzt 1993; 44: 781–784.

25. Janier M, Bonvalet D, Blanc MF et al. Chronic urtica and macroglobulinemia. Schnitzler’s syndrome. Report of two cases. J Am Acad Dermatol 1989; 20: 206–211.

26. Olsen E, Førre O, Lea T et al. Unique antigenic determinants (idiotypes) 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: 379–384.

27. Gallo R, Sabroe RA, Black AK et al. Schnitzler’s syndrome: no evidence for autoimmune basis in two patients. Clin Exp Dermatol 2000; 25: 281–284.

28. Eiling E, Schröder JO, Gross WL et al. The Schnitzler’s syndrome: Chronic urticaria and monoclonal gammopathy – an autoinflammatory syndrome? J Dtsch Dermatol Ges 2008; 6: 626–631 [Epub ahead of print].

29. Tomková H, Shirafuji Y, Arata J. Schnitzler’s syndrome versus adult onset Still’s disease. Eur J Dermatol 1998; 8: 118–121.

30. Sanmartín O, Febrer I, Botella R et al. Urticarial lesions and monoclonal IgM gammopathy. Schnitzler’s syndrome. Arch Dermatol 1994; 130: 1193–1198.

31. Almerigogna F, Giudizi MG, Cappelli F et al. Schnitzler’s syndrome: what’s new? J Eur Acad Dermatol Venereol 2002; 16: 214–219.

32. Clauvel JP, Brouet JC, Danon F et al. Chronic urticaria with monoclonal IgM Reprot of five cases. Clin Immunol Immunopathol 1982; 25: 348–353.

33. Sánchez G, Añó M, García-Avilés C et al. Schnitzler syndrome: a case study. J Investig Allergol Clin Immunol 2000; 10: 41–43.

34. deKleijn EM, Telg D, Laan R. Schnitzler’s syndrome presenting as a fever of unknown origin. The role of Cytokines in its systemic features. Neth J Med 1997; 51: 140–142.

35. Winckelmann G, Nagel HG, Maier R et al. The Schnitzler’s syndrome as a cause of recurrent fever of unknown origin. Dtsch Med Wochenschr 1996; 121: 860–864.

36. Nashan D, Sunderkötter C, Bonsmann G et al. Chronic urticaria, arthralgia, raised erythrocyte sedimentation rate and IgG paraproteinemia? A variant of Schnitzler’s syndrome? Brit J Dermatol 1995; 133: 132–135.

37. Akimoto R, Yoshida M, Matsuda R et al. Schnitzler’s syndrome with IgG κ gammopathy. J Dermatol 2002; 29: 735–738.

38. Husak R, Nestoris S, Goerdt S et al. Severe course of chronic urticaria, arthralgia, fever and elevation of erythrocyte sedimentation rate: Schnitzler’s syndrome without monoclonal gammopathy? Br J Dermatol 2000; 142: 581–582.

39. Rybojad M, Moraillon I, Cordoliani F et al. Schnitzler syndrome with genetic C4 deficiency. 2 cases. Ann Dermatol Venereol 1993; 120: 783–785.

40. Ščudla V, Adam Z, Ščudlová M. Současné možnosti diagnostiky a léčby anémie chronických chorob. Vnitř Lék 2001; 47: 400–406.

41. Lecompte M, Blais G, Bisson G et al. Schnitzler’s syndrome. Skeletal Radiol 1998; 27: 294–296.

42. De Saint-Pierre V, Ehrhart A, Baron D et al. Systemic urticaria, sclerosing osteopathy, monoclonal gammopathy (Schnitzler’s syndrome). Apropos of a case. Rev Rheum Mal Osteoartic 1992; 59: 288–292.

43. De Waele S, Lecouvet FE, Malghem J et al. Schnitzler’s syndrome: an unusual cause of bone pain with suggestive imaging features. AJR Am J Roentgenol 2000; 175: 1325–1327.

44. Flórez AF, Gallardo Agromayor E, García‑Barredo R et al. Radiological aid to clinical diagnosis of Schnitzler’s syndrome: multimodality imaging approach. Clin Rheumatol 2008; 27: 107–110.

45. Ferrando FJ, Pujol J, Hortells JL et al. Schnitzler’s syndrom: Report of a case with bone osteolysis. J Invest Allergol Clin Immunol 1994; 4: 203–205.

46. Bertrand A, Feydy A, Belmatoug N et al. Schnitzler’s syndrome: 3-year radiological follow‑up. Skeletal Radiol 2007; 36: 153–156.

47. Dupuy O, Pinede L, Coppere B et al. Schnitzler’s syndrome with stable course over a 18-year period. Report of a case. Presse Med 1995; 24: 1402.

48. Germain P, Fach J, Bui N et al. Schnitz-ler’s syndrome: a rare cause of systemic urticaria. Rev Med Interne 2000; 21: 285–289.

49. Singh B, Ezziddin S, Rabe E et al. Bone scan appearance supportive of Schnitzler’s syndrome: report of two new cases. Clin Nucl Med 2006; 31: 151–153.

50. Soubrier M. Schnitzler syndrome. Joint Bone Spine 2008; 75: 263–236 [Epub ahead of print].

51. Doutre MS, Beylot C, Bioulac P et al. Monoclonal IgM and chronic urticaria: two cases. Ann Allergy 1987; 58: 413–414.

52. Welsh B, Tate B. Schnitzler’s syndrome: report of a case with progression to Waldenström’s macroglobulinaemia. Australas J Dermatol 1999; 40: 201–203.

53. Barriere M, Schnitzler L, Moulin G et al. Lesions uricariennes chroniques at macroglobulinemie. Sem Hop Paris 1976; 52: 221–227.

54. Goupille P, Pizzuti P, Diot E et al. Schnitzler’s s syndrome (urticaria macroglobulinemia) dramatically improved with corticosteroids. Clin Exp Rheumatol 1995; 13: 95–98.

55. Machet L, Vaillant L, Machet MC et al. Schnitzler’s syndrome and associated with pseudoxanthoma elasticum. Acta Derm Venereol (Stockholm) 1992; 72: 22–24.

56. Machet L, Wattier H, Vaillant L. Urticaria and systemic diseases. Ann Dermatol Venereol 2001; 128: 1156–1160.

57. Adam Z, Šmardová J, Ščudla V. Waldenströmova makroglobulinémie: klinické projevy a diferenciální diagnostika a prognóza nemoci. Vnitř Lék 2007; 53: 1325–1337.

58. Wilhelmi ML, Wilhelmi J, Sierra J. Schnitzler syndrome and pseudoxanthoma elasticum 3rd Congress EADV 26–30 Sept. 1993 Kopenhagen, Abstract FC 20 159.

59. Lebbe C, Rybojad M, Klein F et al. Schnitzler’s syndrome with sensomotor neuropathy. J Amer Acad Dermatol 1994; 30: 316–318.

60. Blaise S, Vallat JM, Tabaraud F et al. Sensitive chronic inflammatory demyelinating polyradiculoneuropathy in Schnitzler’s syndrome. Ann Dermatol Venereol 2003; 130: 348–351.

61. Gossrau G, Pfeiffer C, Meurer M et al. Schnitzler’s syndrome with neurological findings. J Neurol 2003; 250: 1248–1250.

62. Nagy L, Hannema A, Swaak A. Acquired C1 inhibitor deficiency associated with systemic lupus erythematosus, secondary antiphospholipid syndrome and IgM monoclonal paraproteinaemia. Clin Rheumatol 1999; 18: 56–58.

63. Famularo G, Barracchini A, Minisola G. Severe thrombophilia with antiphospholipid syndrome and hyperhomocysteinemia in a patient with Schnitzler’s syndrome. Clin Exp Rheumatol 2003; 21: 366–368.

64. Lauwers A, Chouvy V, Mosnier JF et al. A case of Schnitzler’s syndrome with nodular regenerative hyperplasia of the liver. Rev Rhum Engl Ed 1999; 66: 281–283.

65. Doutre MS, Beylot C. Chronic urticaria and monoclonal IgM: Treatment with ibuprofen. J Am Acad Dermatol 1990; 22: 143–144.

66. Bonnetblanc JM, Drouet M, Laplaud P et al. Urticaria with macroglobulinaemia. Disease activity associated alterations in immunoglobulins profile and bone marrow hypodiploidy. Dermatologica 1990; 181: 41–43.

67. Lewicki M, Lewicka K, Kotyla PJ et al. Schnitzler’s syndrome. Pol Arch Med Wewn 2004; 111: 735–741.

68. Lozano GF, Aquirre PA, Rivera Civico JM et al. The Schniztler’s syndrome. A case report. Med Clin (Barc) 1999; 112: 158–159.

69. Obořilová A, Adam Z. Schnitzler’s syndrome. Vnitř Lék 1998; 44: 423–427.

70. Peterlana D, Puccetti A, Tinazzi E et al. Schnitzler’s syndrome treated successfully with intravenous pulse cyclophosphamide. Scand J Rheumatol 2005; 34: 328–330.

71. Schartz NE, Buder S, Sperl H et al. Report of a case of Schnitzler’s syndrome treated successfully with interferon α 2b. Dermatology 2002; 205: 54–56.

72. Kuenzli S, Buchet S, Saurat JH. Successful treatment of Schnitzler’s syndrome with interferon α-2b. Dermatology 2002; 205: 74.

73. Martinez-Taboada VM, Fontalba A, Blanco R et al. Successful treatment of refractory Schnitzler’s syndrome with anakinra. Arthritis Rheum 2005; 52: 2226–2227.

74. de Koning HD, Bodar EJ, Simon A et al. Beneficial response to anakinra and thalidomide in Schnitzler’s syndrome. Ann Rheum Dis 2006; 65: 542–544.

75. Worm M, Kolde G. Schnitzler’s syndrome: successful treatment of two patients using thalidomide. Br J Dermatol 2003; 148: 601–602.

76. Dalle S, Balme B, Sebban C et al. Schnitzler’s syndrome associated with systemic marginal zone B-cell lymphoma. Br J Dermatol 2006; 155: 827–829.

77. Modiano P, Bauraud-Laveine E et al. Efficacite de la puva therapei das um syndrome de Schnitzler. Nouv Dermatol 1995; 14: 362–363.

78. Cianchini G, Colonna L, Bergamo F et al. Efficacy of Psoralen-UV-A therapy in 3 cases of Schnitzler’s syndrome. Arch Dermatol 2001; 137: 1536–1537.

79. 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: 1046–1050.

80. Blasum J, Wozel G, Patzak A et al. Schnitzler’s syndrome successful treatment with extracorporal immunoadsorption. Ann Dermatovenereol 1997; 124 (Suppl): 117.

81. Carbone J, Paravisini A, Sarmiento E et al. Partial response to cyclosporine in a patient with Schnitzler’s syndrome. Allergol Immunopathol (Madr) 2007; 35: 71–73.

82. Pascual-López M, Hernández-Núñez A, Sánchez-Pérez J et al. Schnitzler’s syndrome with monoclonal IgG κ gammopathy: good response to cyclosporin. J Eur Acad Dermatol Venereol 2002; 16: 267–270.

83. Thonhofer R, Uitz E, Graninger W. Schnitzler’s syndrome-exacerbation after anti‑TNF treatment. Rheumatology (Oxford) 2007; 46: 1041–1042.

84. Eiling E, Möller M, Kreiselmaier I et al. Schnitzler syndrome: treatment failure to rituximab but response to anakinra. J Am Acad Dermatol 2007; 57: 361–364.

85. Ramadan KM, Eswedi HA, El-Agnaf MR. Schnitzler syndrome: a case report of successful treatment using the anti‑CD20 monoclonal antibody rituximab. Br J Dermatol 2007; 156: 1072–1074.

86. Gilson M, Abad S, Larroche C et al. Treatment of Schnitzler’s syndrome with anakinra. Clin Exp Rheumatol 2007; 25: 931.

87. Klemmer N, Lenain P, Balguerie X et al. Effectiveness of anti‑IL1 in Schnitzler’s syndrome. Joint Bone Spine 2007; 74: 509–510.

88. Kozel MM, Sabroe RA. Chronic urticaria: aetiology, management and current and future options. Drugs 2004; 64: 2515–2536.

89. Ryan JG, de Koning HD, Beck LA et al. IL‑1 blockade in Schnitzler’s syndrome: ex vivo findings correlate with clinical remission. J Allergy Clin Immunol 2008; 121: 260–262.

90. Schneider SW, Gaubitz M, Luger TA et al. Prompt response of refractory Schnitzler’s syndrome to treatment with anakinra. J Am Acad Dermatol 2007; 56 (Suppl 5): S120–S122.

91. Treudler R, Kauer F, Simon JC. Striking effect of the IL‑1 receptor antagonist anakinra in chronic urticarial rash with polyclonal increase in IgA and IgG. Acta Derm Venereol 2007; 87: 280–281.

92. Wastiaux H, Barbarot S, Gagey-Caron V et al. Schnitzler syndrome: a dramatic improvement with anakinra. J Eur Acad Dermatol Venereol 2008 [Epub ahead of print].

93. Carlioz R, Haas C, Jauber F et al. Maladie de Waldenstöm avec lymphome diffuse et urticarie chronique. Ann Med Interne 1989; 140: 51–78.

94. Claes K, Bammens B, Delforge M et al. Another devastating complication of the Schnitzler’s syndrome: AA amyloidosis. Br J Dermatol 2008; 158: 182–184.

95. Govindaraju S, Brochot P, Ringot AC et al. Chronic urticaria-macroglobulinemia (Schnitzler syndrome): developing to IgM myeloma. Apropos of a case. Rev Med Interne. 1993; 14: 780–783.

96. Machet L, Vaillant L, Machet MC. Schnitzler’s syndrome: Evolution to Waldenström’s disease is non uncommon. Acta Derm Venereol (Stockholm) 1996; 76: 413.

97. Karakelides M, Monson KL, Volcheck GW et al. Monoclonal gammopathies and malignancies in patients with chronic urticaria. Int J Dermatol 2006; 45: 1032–1038.

98. Lim W, Shumak KH, Reis M et al. Malignant evolution of Schnitzler’s syndrome – chronic urticaria and IgM monoclonal gammopathy: report of a new case and review of the literature. Leuk Lymphoma 2002; 43: 181–186.

99. Pujol RM, Barnadas MA, Brunet S. Urticarial dermatosis associated with Waldenström’s macroglobulinemia. J Am Acad Dermatol 1989; 20: 588–857.

100. Verret JL, Leclech C, Rousselet MC et al. Schnitzler’s syndrome and Waldenström disease. Fatal outcome of the original case. Ann Dermatol Venereol 1993; 120: 459–460.

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Internal Medicine

2008 Issue 12