The interleukin 1 inhibitor canakinumab in the treatment of cryopyrin-associated periodic syndromes (CAPS): clinical experience

Interleukin (IL) 1βis a major mediator of cryopyrin-associated periodic syndrome (CAPS). In this connection, the experience with IL-1 inhibitors used in patents with CAPS is being accumulated worldwide. Canakinumab was approved by FDA and EMEA in 2009 to treat CAPS and registered in the Russian Federation for this in 2011. The drug has been shown to be highly effective and well tolerated by patients with CAPS.

Objective: to present Russia's experience in using the IL-1 inhibitor canakinumab in children with CAPS.

Subjects and methods. The trial enrolled 6 CAPS patients, including 4 with Muckle-Wells Syndrome (MWS) and 4 with chronic infantile onset neurologic cutaneous articular/neonatal onset multisystem inflammatory disease (CINCA/NOMID), among whom there were 5 female patients aged 3.5 to 40 years and 1 male patient aged 17 years. Two patients (a 17-year-old daughter and her 40-year-old mother) were stated to have a familial MWS case. The duration of the disease was 3.5 to 33 years. All the patients underwent a molecular genetic analysis for mutations in the NLRP3 (CIAS1) gene. Four patients with MWS were found to have Thr436Ile and Thr438Ile mutations; the mother and her daughter had Thr350Met mutations; no mutations were detected in 2 patients with CINCA/NOMID. At the study, one female patient with MWS took gluco-corticoids (GC) in a dose of 0.1 mg/kg; the others received symptomatic therapy with nonsteroidal antiinflammatory drugs. Canakinumab was injected subcutaneously every 8 weeks in a dose of 4 mg/kg for patients with a body weight of <15 kg and in a dose of 2 mg/kg for those with a body weight of >15 kg. By now, 2 patients with MWS received 7 injections of the drug (a 48-week follow-up); 2 patients with CINCA/NOMID had its 6 injections (a 40-week follow-up) and 2 patients with MWS had 2 injections (a 10-week follow-up).

Results. All the patients showed a significant clinical improvement: recovery; elimination of fever, rash, and eye symptoms; and a reduction in the levels of acute-phase markers. The effect retained throughout the follow-up. GC could be completely discontinued in the female patient with MWS. No adverse events were observed in any case.

Conclusion. The experience in using canakinumab in the patients with CAPS showed the high efficacy and good tolerability of the drug. The decrease in acute-phase markers was slower in the patients with CINCA/NOMID, the most severe form of CAPS.

1. Kuijk LM, Hoffman HL, Neven B, Frenkel J. Episodic autoinflammatory disorders in children. In: Handbook of systemic autoimmune disease, v. 6 pediatrics in systemic autoimmune disease. Cimas R, Lehman T, editors. Elsevier; 2008. P. 119–35.

2. Barron K, Athreya B, Kastner D. Periodic fever syndromes and other inherited autoinflammatory diseases. In: Textbook of pediatric rheumatology. Cassidy JT, editor. 6th ed. Elsevier Saunders; 2011. P. 642–60.

3. Кузьмина НН, Салугина СО, Федоров ЕС. Аутовоспалительные заболевания и синдромы у детей. Учебно-методическое пособие. Москва: ИМА-ПРЕСС; 2012. 104 с. [Kuz'mina NN, Salugina SO, Fedorov ES. Autovospalitel'nye zabolevaniya i sindromy u detei. Uchebno-metodicheskoe posobie [Autovospalitelny diseases and syndromes at children. Educational and methodical grant]. Moscow: IMA-PRESS; 2012. 104 p.]

4. Kuemmerle-Deschner J, Haug I. Canakinumab in patients with cryopyrinassociated periodic syndrome: an update for clinicians. Ther Adv Musculoskel Dis. 2013;5(6):315–9. DOI: http://dx.doi.org/10.1177/1759720X13502629.

5. Cuisset L, Jeru I, Dumont B, et al. Mutation in the autoinflammatory cryopyrin-associated periodic syndrome gene: epidemiological study and lessons from eight years of genetic analysis in France. Ann Rheum Dis. 2011;70:495–9. DOI: http://dx.doi.org/10.1136/ard.2010.138420.

6. Lainka E, Bielak M, Hilger V, et al. Translational research network and patient registry for auto-inflammatory diseases. Rheumatology (Oxford). 2011;50:237–42. DOI: http://dx.doi.org/10.1093/rheumatology/keq270.

7. Stych B, Dobrovolny D. Familial cold auto-inflammatory syndrome (FCAS): characterization of symptomatology and impact on patients' lives. Curr Med Res Opin. 2008;24:1577–82. DOI:http://dx.doi.org/10.1185/03007990802081543.

8. Toplak I, Rihtaric D, Hostnik P, et al. Identification of a genetically diverse sequence of porcine reproductive and respiratory syndrome virus in Slovenia and the impact on the sensitivity of four molecular tests. J Virol Methods. 2012;179:51–6. DOI: 10.1016/j.jviromet.2011.09.019. Epub 2011 Oct 1.

9. Dollfus H, Hafner R, Hoffmann H, et al. Chronic infantile neurological cutaneous and articular/ neonatal onset mutisystem inflammatory disease syndrome: ocular manifestations in a recently recognized chronic inflammatory disease of childhood. Arch Ophthalmol. 2000;118:1386–92. DOI:http://dx.doi.org/10.1001/archopht.118.10.1386.

10. Kuemmerle-Deschner J, Koitschev A, Ummenhofer K, et al. Hearing loss in Muckle-Wells syndrome. Arthritis Rheum. 2013;65:824–31. DOI:http://dx.doi.org/10.1002/art.37810.

11. Hill S, Namde M, Dwyer A, et al. Arthropathy of neonatal onset mutisystem inflammatory disease (NOMID/CINCA). Pediatr Radiol. 2007;37:145–52. DOI:http://dx.doi.org/10.1007/s00247-006-0358-0.

12. Goldbach-Mansky R. Current status of understanding the pathogenesis and management of patients with NOMID/CINCA. Curr Rheumatol Rep. 2011;13:123–31. DOI: 10.1007/s11926-011-0165-y.

13. Dode C, Cuisset L, Delpech M, Grateau G. TNFRSF1A-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS) and renal amyloidosis. J Nephrol. 2003;16:435–7.

14. Hashkes P, Lovell D. Recognition of infantile-onset multisystem inflammatory disease as a unique entity. J Pediatrics. 1997;130:513–5.

15. Муравьев ЮВ, Лебедева ВВ. Кальций-связывающие белки при ревматических заболеваниях. Научно-практическая ревматология. 2012;50(1):60–4. [Murav'ev YuV, Lebedeva VV. Kal'tsiy-svyazyvayushchie belki pri revmaticheskikh zabolevaniyakh. Nauchno-prakticheskaya revmatologiya =Rheumatology Science and Practice. 2012;51(1):60–4. (In Russ.)]. DOI:http://dx.doi.org/10.14412/1995-4484-2012-506.

16. Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules. J Leukocyte Biol. 2007;81:28–37. DOI: http://dx.doi.org/10.1189/jlb.0306170.

17. Wittkowski H, Kuemmerle-Deschner J, Austermann J, et al. MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes. Ann Rheum Dis. 2011;70:2075–81. DOI: http://dx.doi.org/10.1136/ard.2011.152496.

18. Glaser R, Goldbach-Mansky R. The spectrum of monogenic autoinflammatory syndromes: understanding disease mechanisms and use of targeted therapies. Curr Allergy Asthma Rep. 2008;8:288–98. DOI: http://dx.doi.org/10.1007/s11882-008-0047-1.

19. Lovell DJ, Bowyer SL, Solinger AM. Interleukine-1 Blockade by Anakinra Improves Clinical Symptoms in Patients With Neonatal-Onset Mutisystem Inflammatory Disease. Arthritis Rheum. 2005;52:1283–6. DOI: http://dx.doi.org/10.1002/art.20953.

20. Hawkins PL, Lachmann HJ, McDermott MF. Interleikin-1 receptor antagonist in the Muckle-Wells syndrome. N Engl J Med. 2003;348:2583–4. DOI: http://dx.doi.org/10.1056/NEJM200306193482523.

21. Kuemmerle-Deschner G, Fizaribacliev N. Muckle-Wells syndrome effective treatment with anakinra. Arthritis Rheum. 2007;56(9):290.

22. Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrinassociated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58(8):2443–52. DOI: http://dx.doi.org/10.1002/art.23687.

23. Federici S, Martini A, Gattorno M. The central role of anti-IL-1 blockade in the treatment of monogenic and multi-factorial autoinflammatory diseases. Front Immunol. 2013;4:351. DOI: 10.3389/fimmu.2013.00351.

24. Салугина СО, Федоров ЕС, Кузьмина НН. Опыт применения ингибитора ИЛ-1β (анакинра) у пациента с CINCA/NOMID синдромом. Современная ревматология. 2012;(3):60–5. [Salugina SO, Fedorov ES, Kuz'mina NN. Experience with an IL-1β inhibitor (anakinra) in a patient with CINCA/NOMID syndrome. Sovremennaya revmatologiya = Modern Rheumatology Journal. 2012;(3):60–5. (In Russ.)]. DOI: http://dx.doi.org/10.14412/1996-7012-2012-749.

25. Bonner J, Lloyd P, Lowe P, et al. PK/PD, safety and tolerability of a human anti-IL-1β monoclonal antibody (ACZ885) in healthy subjects. In Annual Congress of the European Respiratry Society. 2006.

26. Lachmann H, Kone-Paut I, Kuemmerle-Deschner GB, et al.; Canakinumab in CAPS Study Group. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360:2416–25. DOI:http://dx.doi.org/10.1056/NEJMoa0810787.

27. Toker O, Hashkes PJ. Critical appraisal of canakinumab in the treatment of adults and children with cryopyrin-associated periodic syndrome (CAPS). Biologics. 2010;4:131–8.

28. Kuemmerle-Deschner JB, Hachulla E., Gartwright R, et al. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of Canakinumab in pts with cryopyrin associated periodic syndrome across different severity phenotypes. Ann Rheum Dis. 2011;70(12):2095–102. DOI: http://dx.doi.org/10.1136/ard.2011.152728.

29. Goldbach-Mansky R, Sibley C, Felix S, et al. Efficacy and safety of canacinumab in patients with NOMID/CINCA. Ann Rheum Dis. 2012;1(Suppl 3):291. DOI: http://dx.doi.org/10.1136/annrheumdis-2012-eular.2367.

30. Caorsi R, Lepore L, Zulian F, et al. The schedule of administration of Canakinumab in cryopyrin associated periodic syndrome is driven by the phenotype severity rather than the age. Arthritis Res Ther. 2013;15(1):R33. DOI: http://dx.doi.org/10.1186/ar4184.

31. Aksentijevich I, Putman D, Remmers E, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56:1273–85.http://dx.doi.org/10.1002/art.22491.

32. Hoffman H, Kuemmerle-Deschner J, Hawkins P, et al. Safety of canacinumab in a large cohort of patients with cryopirin-associated periodic syndrome: results from the confident registry. Arthritis Rheum. 2012;64(10):S78.