Article Text

other Versions

Download PDFPDF

Prolonged treatment with Tadekinig alfa in adult-onset Still’s disease
Free
  1. Uta Kiltz1,
  2. David Kiefer1,
  3. Jürgen Braun1,
  4. Eduardo Jorge Schiffrin2,
  5. Charlotte Girard-Guyonvarc'h3,
  6. Cem Gabay3
  1. 1 Rheumazentrum Ruhrgebiet, Herne, Germany
  2. 2 AB2 Bio Ltd, Lausanne, Switzerland
  3. 3 Division of Rheumatology, Department of Internal Medicine Specialties, University of Geneva, Geneva, Switzerland
  1. Correspondence to Professor Cem Gabay, Division of Rheumatology,Department of Internal Medicine Specialties, University Hospitals of Geneva, Geneva 1211, Switzerland; cem.gabay{at}hcuge.ch

Statistics from Altmetric.com

Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease, the treatment of which is still not well defined. Biological disease modifying antirheumatic drugs (bDMARDs), including interleukin (IL)-1 and IL-6 antagonists are used empirically in patients refractory to conventional DMARDs.1 This 12-week open-label clinical trial with Tadekinig (recombinant IL-18 binding protein, IL-18BP) showed promising results.2 Herein, we report two patients with AOSD treated successfully with Tadekinig during several months.

Case 1. A 50-year-old patient was diagnosed with AOSD in August 2014 when presenting with arthritis, recurrent fever episodes, sore throat and skin rash. C reactive protein (CRP, 22.9 mg/dL) and ferritin (3568 ng/mL) levels were markedly elevated. Since the initial treatment with prednisolone starting with 100 mg/day and oral methotrexate (MTX) 15 mg/week was insufficient, anakinra was started with 100 mg sc/day and MTX dose was augmented to 25 mg sc/week. High disease activity persisted and prednisolone tapering below 15 mg/day was impossible. As a side effect of the long-term high-dose prednisolone therapy, the patient developed a type 2 diabetes. In June 2015, the patient was recruited in a clinical trial to receive Tadekinig 80 mg sc three times weekly, which was subsequently increased to 160 mg three times weekly. The patient experienced a rapid decrease of disease activity accompanied by a marked decrease of CRP levels to 0.3–1.0 mg/dL (normal:<0.5 mg/dL), and ferritin between 300 and 450 ng/mL (normal:<400 ng/mL). No side effects, except for one upper airway infection, occurred. The daily dose of prednisolone decreased to 8.75 mg/day at the end of the study in November 2015. After completing the trial, Tadekinig was provided by the company as compassionate use for the patient until May 2017. During this time, AOSD was in sustained clinical remission and the prednisolone dose could be tapered to <5 mg/day. Since May 2017, the patient receives MTX (25 mg sc/week) in combination with prednisone 4.5 mg/day. and is in clinical remission up to July 2018.

Case 2. A 49-year-old obese patient with a history of type 2 diabetes was diagnosed with AOSD in April 2015 when presenting with arthritis, fever, sore throat and skin rash. The serum levels of CRP (114 mg/dL) and ferritin (9653 ng/mL) were elevated. Prednisone starting at 60 mg/day in combination with MTX 15 mg sc/week was insufficient to control his condition. In July 2016, Tadekinig 160 mg sc three times weekly was started in combination with prednisone 20 mg/day and MTX 15 mg sc/week. Elevated serum levels of free IL-18 during the course of AOSD decreased to almost undetectable levels 2 hours after the first Tadekinig injection and remained low up to 48 hours thereafter (figure 1A). The clinical manifestations as well as the laboratory test abnormalities (figure 1B) resolved rapidly. The clinical response was maintained but prednisone could not be tapered below 5 mg/day. In May 2017, due to limited drug availability, Tadekinig had to be discontinued and was replaced by canakinumab 150 mg sc/month. The patient experienced disease flares at each attempt to taper prednisone dosage. Currently, his disease is controlled with a combination of canakinumab, leflunomide and prednisone 15 mg/day.

Figure 1

Evolution of biomarkers before and after Tadekinig administration. Free IL-18 levels were measured at different time points during the course of the disease. On the first Tadekinig injection (arrow), free IL-18 levels dropped to almost undetectable levels within 2 hours (magnified picture) and remained low (A). Evolution of CRP, ferritin and haemoglobin levels before and after Tadekinig therapy (B). CRP, C reactive protein; IL, interleukin.

IL-18 is a member of the IL-1 family, the activity of which is controlled by its natural inhibitor IL-18BP that inactivates IL-18 by forming high affinity complexes.3 Thus, free unbound IL-18 represents the only bioactive form of IL-18 and is detected in the serum of patients with AOSD.4 Accordingly, the administration of Tadekinig was associated with a marked decrease in circulating levels of free IL-18 and improvement of disease manifestations, thus providing a strong rational for the mechanism of action of Tadekinig in AOSD.

References

Footnotes

  • Handling editor Josef S Smolen

  • Contributors All authors took part in drafting and revising the manuscript. CG-G performed the free IL-18 assays and drew figure 1. All authors approved the submitted version of the article.

  • Funding This study was funded by AB2 Bio.

  • Competing interests CG-G’s salary was supported by an unrestricted grant from AB2 Bio. EJS is an employee of AB2 Bio. CG has received consultant fees and a research grant from AB2 Bio and owns shares in AB2 Bio. All other authors have declared no conflicts of interest.

  • Patient consent Not required.

  • Ethics approval Geneva Ethics Committee on Research Involving Humans.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data sharing statement Should readers be interested in getting some additional unpublished data, they are asked to contact the authors.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.