Most patients included in this study had MWS, a moderately severe form of CAPS, and four patients had more-severe disease. This was reflected in the severity of symptoms at baseline, with almost all patients having arthralgia, conjunctivitis, urticarial skin rash, headache, and fatigue. In addition, myalgia, pyrexia, and deafness were reported in more than 50% of patients. In this study, we report the effects of canakinumab on these CAPS-related symptoms (except for amyloidosis, for which the duration of follow-up was insufficient for significant changes to be observed, and deafness, for which the potential for significant recovery of hearing has not been established). These results are in agreement with previous reports of the symptoms associated with the more-severe forms of CAPS [13
], and give a measure of how debilitating this disorder is and the need for effective treatment.
The results of this study indicate that a single dose of canakinumab induces rapid remission of symptoms in patients with CAPS; on day 8 (the first assessment), 89% of patients had no or minimal disease activity, according to the physician global assessment, and 82% of patients rated their symptoms as absent or minimal. Rapid remission was observed for all individual symptoms of CAPS assessed, and responses were sustained at week 8, the end of part 1 of the study. Remission of symptoms was accompanied by suppression of inflammation, as indicated by decreases in median levels of CRP, SAA, and IL-6. Furthermore, decreases in platelet counts and WBC counts and increases in hemoglobin levels were observed over the course of part 1 of the study, consistent with suppression of chronic inflammation.
Effective suppression of inflammation and symptoms of CAPS was maintained during treatment with canakinumab every 8 weeks during parts 2 and 3 of the study. At the end of part 3, 97% of all patients had no or minimal disease activity; the median IL-6 level was low (< 1 pg/ml); and CRP and SAA levels were below the ULN. For patients randomized to placebo, symptoms returned during part 2, with only four (25%) patients having no or minimal disease activity at the end of part 2. In addition, median IL-6, CRP, and SAA levels increased over the course of part 2. On resuming canakinumab in part 3, remissions were regained in all patients from the placebo group, and CRP and SAA levels returned to levels similar to those seen in patients randomized to canakinumab in part 2.
CAPS can have a profound impact on HRQoL, as was previously demonstrated in a study involving in-depth interviews with patients with FCAS, the mildest form of this disorder [3
]. In this study in patients with FCAS, patients reported that their disease had affected their employment, with one third reporting that they had left their job because of the need to accommodate their condition, and more than 95% reported to have limited participation in or avoided outdoor activities and sports. Subjects also reported that their disease had adverse effects on social activities, including socializing and personal relationships.
In our study, we used validated questionnaires to assess in detail the impact of CAPS on HRQoL in pediatric and adult patients, and the changes in HRQoL observed in response to canakinumab therapy. At baseline, SF-36 PCS and MCS, as well as FACIT-F scores, were all below those of the U.S. general population, as we previously reported for a phase 2 study with canakinumab [15
]. In addition, HRQoL scores for our patient population were comparable to or well below those reported for patients with musculoskeletal diseases, including rheumatoid arthritis, gout, osteoporosis, and fibromyalgia, in a recent survey of the Dutch general population [16
]. Results suggest that the individual SF-36 domains most affected by CAPS in adults are role-physical, bodily pain, and general health, as would be expected from the nature of the symptoms.
Within 8 days of receiving canakinumab, improvements were evident in all SF-36 domains and especially in those that were more than 20 points lower than those of the general U.S. population at baseline. This is in agreement with the rapid remission of symptoms observed in this study. Eight weeks after receiving the first dose of canakinumab, scores for FACIT-F, SF-36 PCS, and SF-36 MCS approached or exceeded scores for the U.S. general population, and improvements were mostly sustained throughout therapy with canakinumab. Moreover, further improvements in scores for all the SF-36 individual domains were observed at 8 weeks after the dose, compared with day 8. These results are in agreement with those reported for the phase 2 study, in which scores for SF-36 PCS, SF-36 MCS, and FACIT-F all approached or exceeded those of the general population by 5 weeks after the dose, and considerable improvements over baseline for all measures were observed at 1 week after the dose [15
]. Reductions in functional disability were also observed over the course of the study.
HRQoL results for the five pediatric patients included in the present study also demonstrated an improvement over the course of the study. In these patients, the physical component of HRQoL was well below that expected for healthy children at baseline and exceeded that of healthy children at the end of part 1 and at the end of the study. Although these data are based on only a small patient population, they suggest that the HRQoL benefits reported for adults are also achieved in pediatric patients.
As reported previously [6
], the results of this study indicate that canakinumab is generally well tolerated and is not associated with an increased risk of any particular AE, other than a slightly increased risk of infections. Only one patient discontinued the study owing to AEs, and only two serious AEs were reported during the course of the study. Because it is envisaged that patients with CAPS will require life-long therapy, long-term follow-up of patients treated with canakinumab is required to assess more fully the safety profile of this therapy.
This study has a number of limitations. First, the physician and patient global assessments and assessments of the individual symptoms used are not standardized, and hence results cannot be compared with those from other studies that have used different measures. Second, symptoms were assessed on a 5-point scale, which may bias results because it is difficult to detect small variations by using such a scale. Third, the patient's and physician's assessments of severity of symptoms scales are not validated instruments in this disease, which might have led to the differences in results observed between the two at baseline.
The dramatic resolution of symptoms and improvements in HRQoL observed in this study in patients with CAPS is tremendously encouraging and raises the possibility that IL-1β blockade may also benefit patients with other hereditary autoinflammatory disorders in which overproduction of IL-1β is implicated in the pathology. This is supported by promising results that have been reported for IL-1β blockade in individual patients with various autoinflammatory disorders and warrants further investigation [17