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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Objective

Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin-1β (IL-1β), which is associated with cold-induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL-1 Trap), a long-acting IL-1 receptor fusion protein, in patients with FCAS.

Methods

Five patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA], and IL-6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values.

Results

In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug–related serious adverse events were seen.

Conclusion

In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.

Familial cold autoinflammatory syndrome (FCAS) is a rare autosomal-dominant disorder caused by mutations in the CIAS1 (NLRP3) gene, which encodes a pyrin-related protein called “cryopyrin” (also known as NALP3 and PYPAF1) (1). FCAS (MIM no. 120100) is characterized by episodes of rash, arthralgia, and fever that are induced after exposure to cold temperatures (2, 3). Symptoms begin within the first 6 months of life, and disease flares develop ∼2.5 hours after exposure to cold and last, on average, 12 hours. Renal amyloidosis is seen infrequently (∼2% of patients) (4). FCAS is at the less-severe end of a spectrum of CIAS1-associated periodic fever syndromes known as cryopyrin-associated periodic syndromes (CAPS), which includes Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) (5, 6).

Cryopyrin is expressed in peripheral blood leukocytes (5, 7) and has structural similarities to pyrin, which is mutated in patients with familial Mediterranean fever (FMF) (8, 9). Cryopyrin mutations are gain-of-function mutations that lead to constitutive activation of the inflammasome (10, 11), a multimolecular complex with pro–interleukin-1β (proIL-1β)–processing activity that is involved in the regulation of inflammation (10) and macrophage necrosis (12, 13). Models of the structural basis for the activation of the inflammasome have been suggested (14, 15), and cryopyrin is essential for the ATP-driven activation of caspase 1 in lipopolysaccharide-stimulated macrophages and for the efficient secretion of the caspase 1–dependent cytokine IL-1β (16, 17), and possibly IL-18 (18) and IL-33 (19).

While fine-structure mapping of CIAS1 identified an ancestral haplotype carrying the mutation L353P that is common to a large kindred of North American patients with FCAS (20), de novo mutations can also account for new cases of FCAS, and more recently, patients with clinical FCAS, but without a mutation in the CIAS1 gene, have been identified (21).

Previous clinical studies in patients with CAPS have suggested that most of the disease manifestations are associated with oversecretion of IL-1β and rapidly respond to blockade of IL-1β signaling with the IL-1 receptor antagonist anakinra (22–24). Although effective, anakinra needs to be administered daily, and withdrawal of the drug leads to an immediate disease flare (24). In the present study, we evaluated the efficacy and safety of the long-acting IL-1 inhibitor rilonacept (IL-1 Trap), a fusion molecule comprised of the extracellular component of the IL-1 receptor (IL-1 receptor type I and IL-1 receptor accessory protein) and the Fc portion of IgG1, which binds circulating IL-1β and IL-1α with very high affinity. Rilonacept can be administered once weekly by subcutaneous injection.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Study patients.

Five adult Caucasian patients with CIAS1 mutation–positive FCAS were screened and enrolled in the study. All patients had classic features of FCAS, including cold-induced fevers, rash, and joint pain and swelling. All patients had at least 1 disease flare per week, as indicated by self-report and as documented by the clinical signs and symptoms recorded in a diary, which was completed daily for a minimum of 2 weeks prior to enrollment. All patients had elevations of acute-phase reactants at baseline: erythrocyte sedimentation rate (ESR; analyzed by the Westergren method), high-sensitivity C-reactive protein (hsCRP), and serum amyloid A (SAA). Two of the patients were related: patient 1 is the son of patient 3 and has the same CIAS1 mutation. All patients were naive to disease-modifying antirheumatic drugs and prednisone; and no patients had been treated with the IL-1β–blocking agent anakinra. Other medical conditions affecting the study patients are listed in Table 1. The patients' ages ranged from 20 years to 64 years at the time of enrollment.

Table 1. Demographic, clinical, and laboratory characteristics of the FCAS patients at baseline*
 Patient 1Patient 2Patient 3Patient 4Patient 5
  • *

    All patients had attacks that were typical of familial cold autoinflammatory syndrome (FCAS), with cold-induced fever, conjunctivitis, joint pain, and malaise. MWS = Muckle-Wells syndrome.

  • Missense mutations in exon 3 of the NACHT domain of cryopyrin.

  • These features were present in addition to cold-induced rash, fever, migratory arthralgias, and conjunctivitis, which occurred in all patients with each disease flare.

MutationE627GM659K (de novo mutation)E627GL353PL353P
Family history of FCASSon of patient 3No family historyFather of patient 1Several family members affectedHas a son with FCAS
SexMaleFemaleMaleMaleMale
RaceCaucasianCaucasianCaucasianCaucasianCaucasian
Age at enrollment4220645840
Frequency of attacks5 times/week1–2 times/week; rash only: 4 times/week1–2 times/week2–3 times/month in winter; 1–2 times/month in summer1–2 times/week
Features of flaresFatigue, morning stiffness, tinnitus; prodrome: uncomfortable “chill in the bones,” headachesHeadaches, oral ulcersChills, arthritis (knees)Prodrome: difficulty getting warm, chills, joint pain and swelling
Other disease featuresMild bilateral high-frequency hearing loss (left > right), uveitis, lymphadenopathy, clubbing, increased fatpads on hands and feetAnterior uveitis, mild-to-moderate high-frequency sensorineural hearing loss (right > left), clubbingInjected sclera, corneal opacity in right eye, scleredema over both calves, tissue laxity over both thighs, clubbing, extra fatpads on feet, axillary lymphadenopathyMild-to-moderate bilateral high-frequency hearing lossRecurrent aphthous ulcers, clubbing
Symptoms unrelated to FCAS/MWSVaricose veins, pitting edema, allergies, hypertension, rosacea, gastroesophageal reflux diseaseSubcapsular cataracts, history of “viral” meningitis, β-thalassemia, keratosis pilaris, depressionGout, glaucoma, diabetes, hypertension, calcified lung granuloma in right lower lobe, thyroid nodulesExposure to “agent orange” with history of basal cell and squamous cell carcinoma, ganglion cyst right wrist, actinic keratosis, mechanical back painCongenital fusion of cervical spine C2–C3

The Institutional Review Board of the National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (NIH) approved this study. Written informed consent was obtained from all study participants.

Study design.

After a baseline evaluation, all patients received an initial loading dose of 300 mg of rilonacept (Regeneron Pharmaceuticals, Tarrytown, NY) beginning on day 1 (100 mg/day for 3 consecutive days). All patients were observed thereafter and did not receive further study medication until a disease flare occurred.

The primary outcomes were drug safety and clinical efficacy (improvement in the patient's daily diary score and in the levels of the acute-phase reactants hsCRP, SAA, and ESR) on days 6 and 10 after rilonacept administration.

A disease flare was defined as an elevation of the acute-phase reactant levels by >50% from the time of maximum efficacy (day 10 for patients 1, 2, 4, and 5, and day 6 for patient 3). At the time of disease flare, patients were again given 300 mg of rilonacept, followed by weekly subcutaneous injections of 100 mg of rilonacept. If a complete remission of the signs and symptoms of inflammation (defined as an hsCRP level <0.5 mg/dl and/or an SAA level <10 mg/liter and a daily diary score of <0.5) had not occurred after reinitiating rilonacept postflare, patients were eligible for dosage escalation during the extension phase of the study. Two intrapatient dosage-escalation steps were allowed if remission criteria were not met. The first dosage increase was to 160 mg/week (dosage escalation A), and if remission as defined above had not occurred after 4 weeks at the higher dose or at any time thereafter, patients were eligible for a further escalation to 320 mg/week (dosage escalation B). Once the dosage of 160 mg/week was reached, the patient was continued in the study for an additional 2 years.

Blood sampling for analysis of drug safety (chemistry profile) and markers of inflammation (levels of acute-phase reactants and a complete blood cell count) was scheduled at baseline, on days 6 and 10, at the time of disease flare, and then monthly thereafter for the first year and every 2 months for the second year of the extension phase of the study.

Assessment of efficacy.

Baseline assessment included a prestudy daily diary score (daily diary information collected under a natural history study between 15 days and 45 days prior to initial study drug administration). The primary efficacy end point was improvement in the levels of acute-phase reactants (ESR, hsCRP, and SAA) and in the clinical daily diary scores (a composite score that included fever, rash, and arthritis/arthralgia, with each of the 3 symptoms scored from 0 [no symptom] to 4 [worst symptom], with an overall range score of 0–12).

On day 10 after drug administration, patients returned to the clinic for evaluation. Diary data for the efficacy evaluation on day 10 included a mean of the scores collected for 5 calendar days (prior to and including the day 10 data). Patient 3 experienced a disease flare on day 10; his maximum clinical and laboratory improvement was seen on day 6. For this patient, maximum benefit data were collected for the day 6 data, and he fulfilled flare criteria on day 10. Flare diary data included the means of the data collected for 3 calendar days (prior to and including the flare date). Diary data collected when the patient was receiving a dosage of 100 mg/week included the means of the data collected starting 10 days after retreatment with 300 mg of rilonacept and after each dosage escalation (this was considered steady-state at each dosage level). The designated 3-month visit refers to 3 months after dosage escalation to 160 mg of rilonacept per week; the 6-month visit refers to 6 months after dosage escalation to 160 mg/week, and so on.

Secondary efficacy end points included the development of, and time to, a disease flare after the first dose of rilonacept. This was aimed at assessing the duration of clinical and biochemical responses following discontinuation of rilonacept treatment. Other end points measured were the patient's and physician's global health assessments and the patient's assessment of pain and fatigue (all by visual analog scale [VAS; range 0–10 cm]), tender and swollen joint counts, quality of health assessments (using the Short Form 36 [SF-36] health survey questionnaire physical and mental component scores [range 0–100 for each] [25]), the Health Assessment Questionnaire (HAQ; range 0–3) (26), and measurements of IL-6 levels by enzyme-linked immunosorbent assay (Rules Based Medicine, Austin, TX).

Assessment of safety.

Adverse events were identified from the daily diaries, the medical history and physical examination findings, and the results of clinical laboratory tests performed during and between visits to the NIH.

Statistical analysis.

This was an exploratory pilot study of an investigational agent in the treatment of patients with FCAS. Summary statistics were determined, including means and standard deviations, as well as frequency distributions where appropriate. All statistical analyses were performed using paired t-tests. The optimal Box-Cox power transformation technique was used to achieve normal distribution of the data. During the initial phase of the study, comparisons were made between baseline and the day of maximum efficacy and between the day of maximum efficacy and the day of disease flare. During the extension phase of the study, comparisons were made between baseline data and the subsequent time points at which the same parameter was assessed. For analysis of secondary end points, P values were not adjusted for multiple comparisons. P values less than 0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Disease characteristics at baseline.

All enrolled patients were CIAS1 mutation positive and had reported cold-induced episodes of fever, rash, and arthralgia; patients 1–3 also had mild-to-moderate bilateral high-frequency hearing loss. All but 1 patient had a family history of FCAS; patient 2 had a de novo mutation that was previously reported in a familial case of FCAS (27) (Table 1). All patients had active disease at baseline, as indicated by their daily diary scores, as well as by elevations of acute-phase reactant values.

Response to the 300-mg loading dose of rilonacept during the initial study phase.

Within hours of administration of the initial dose of rilonacept, all patients reported benefit, with a decrease in cold-induced attacks of FCAS and improvement in symptoms (mainly, rash, fever, and arthralgia), as indicated by a reduction in daily diary scores. Although improvement in eye redness and fatigue was also seen, these symptoms were not suitable measures of FCAS disease activity in 2 of the 5 patients (patients 2 and 3), who had confounding medical conditions. These 2 symptoms were therefore not included in the calculation of the daily diary primary clinical efficacy score for all patients. (Data obtained for the individual disease variables recorded in each patient's daily diary during phase 1 of the study are available upon request from the corresponding author.)

Maximum clinical improvement occurred in 4 patients on day 10 and in 1 patient on day 6 (patient 3). Patient 3 fulfilled the criteria for a disease flare, with recurrence of symptoms and elevation of acute-phase reactant levels, on day 10. Interestingly, plasma levels of rilonacept measured on day 10 were lowest in the patient who experienced a disease flare and were comparable to the plasma drug level at which 1 other patient experienced a return of symptoms (data not shown). The improvement in daily symptoms from a mean ± SEM baseline score of 3.48 ± 0.93 by a mean of 3.09 ± 1.03 (81% mean reduction; P < 0.05) was paralleled by improvements in all 3 primary laboratory parameters of inflammation that were measured: the ESR decreased by a mean of 32.20 ± 7.31 mm/hour (58% mean reduction; P < 0.01), hsCRP by a mean of 4.22 ± 0.98 mg/dl (88% mean reduction; P < 0.001), and SAA by a mean of 216.10 ± 92.14 mg/liter (95% mean reduction; P < 0.001).

A disease flare occurred at a range of 10–28 days after the initial loading regimen. The daily diary scores increased by a mean of 1.51 ± 0.14 (P < 0.01), again paralleled by an increase in the levels of acute-phase reactants: the ESR increased by a mean of 12.20 ± 4.52 mm/hour, the hsCRP by 2.01 ± 0.95 mg/dl, and the SAA by a mean of 71.62 ± 39.76 mg/liter (P < 0.01 for each comparison) (Figure 1).

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Figure 1. A, Left arm of patient 5, showing a skin rash that occurred during a physical examination conducted in an air-conditioned examination room (left) and the absence of a rash 10 days after the initial loading dose of 300 mg of rilonacept, when exposure to the air-conditioned examination room did not trigger an attack (right). B, Changes in clinical symptoms, as measured by the mean daily diary score (range 0–12 for the daily mean of scores for rash, fever, and joint pain, each of which was scored on a 0–4 scale, where 0 = no symptom and 4 = worst symptom), and in levels of acute-phase reactants (high-sensitivity C-reactive protein [hsCRP], erythrocyte sedimentation rate [ESR], and serum amyloid A [SAA]) over the entire period of rilonacept treatment. The optimal Box-Cox power transformation technique was used to achieve normal distribution of the data. a = post–loading dose (300 mg of rilonacept at baseline) measurements were obtained on day 10 in 4 patients and on day 6 in 1 patient; b = comparisons were made between day 10 and the day of disease flare; c = data points represent the mean of all values obtained while the patient was receiving a dosage of 100 mg/week, a period that varied from 8 weeks to 42 weeks; at 3 months, 4 of the patients were receiving 160 mg/week and 1 patient was receiving 320 mg/week, and from month 6 to month 24, 1 patient was receiving 160 mg/week and 4 patients were receiving 320 mg/week. ∗ = P < 0.05; ∗∗ = P < 0.01; ∗∗∗ = P < 0.001 versus baseline, by paired t-test.

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Changes in other secondary end points included significant improvements in the physician's and patient's global assessments (by VAS), the patient's assessment of pain (by VAS), and the tender joint count. (Data obtained for the individual changes in the primary end point measures analyzed by rilonacept dosage are available upon request from the corresponding author.) A nonsignificant trend toward improvement was seen in the swollen joint count; however, the swollen joint score, which measures the degree of swelling in each affected joint on a scale of 0–3, was not >1 in any patient at baseline, and most joints were chronically thickened and, often, had no associated tenderness or warmth. The baseline health assessment score, as determined by the HAQ (range 0–3), was low, with a mean of 0.35 and a median of 0.13, and did not significantly change with therapy (data not shown).

Response to rilonacept during the extension phase of the study.

All patients entered the extension phase of the study and completed 24 months of followup at a rilonacept dosage of 160 mg/week or higher. The clinical and laboratory responses are summarized in Table 2 and indicate a persistent response to weekly administration of rilonacept. The SAA, hsCRP, and ESR values remained low at all measurements up to 24 months. This response was also seen in the reduction of the overall daily diary score, which indicates a persistent suppression of disease symptoms (Figure 1).

Table 2. Other clinical outcomes over 2 years in the FCAS patients*
MeasureBaselineChange from baseline
Month 3Month 6Month 9Month 12Month 16Month 20Month 24
  • *

    FCAS = familial cold autoinflammatory syndrome; VAS = visual analog scale (0–10 cm); SF-36 = Short Form 36 health survey (range 0–100 for each component score).

  • Statistically significant.

Patient's global assessment, by VAS        
 Mean ± SEM5.29 ± 0.67−2.69 ± 1.01−2.56 ± 1.27−2.63 ± 1.19−2.86 ± 1.24−3.40 ± 0.98−2.78 ± 1.13−2.33 ± 1.30
 Median (minimum, maximum)5.20 (3.70, 6.90)−3.02−3.50−2.65−3.60−3.60−3.60−3.55
 P 0.0725950.0912450.0795710.0536410.0209930.0527700.093472
Physician's global assessment, by VAS        
 Mean ± SEM5.19 ± 0.78−4.15 ± 0.89−4.27 ± 1.01−4.71 ± 0.75−4.30 ± 0.90−4.85 ± 0.95−4.79 ± 0.66−4.54 ± 0.99
 Median (minimum, maximum)5.10 (2.95, 6.95)−4.38−4.43−4.50−4.10−5.05−4.95−4.45
 P 0.0114010.0098510.0005620.0067480.0040110.0005680.007832
Patient's assessment of pain, by VAS        
 Mean ± SEM6.25 ± 0.98−5.43 ± 1.20−4.24 ± 1.24−3.93 ± 1.28−3.08 ± 2.28−5.65 ± 1.13−5.01 ± 1.22−4.82 ± 1.22
 Median (minimum, maximum)7.55 (3.60, 8.25)−6.58−3.25−2.70−2.80−7.20−4.80−4.15
 P 0.0074940.0248200.0444990.1639550.0039500.0171880.022074
Patient's assessment of fatigue, by VAS        
 Mean ± SEM5.96 ± 0.86−3.12 ± 1.04−2.27 ± 1.15−2.41 ± 1.10−2.04 ± 1.17−3.16 ± 0.67−2.38 ± 0.89−3.19 ± 1.63
 Median (minimum, maximum)5.55 (3.25, 8.00)−4.58−1.75−1.55−2.25−2.95−2.75−3.70
 P 0.0669750.1780830.1542690.2357290.0452830.0943280.120674
Tender joint count        
 Mean ± SEM9.60 ± 5.71−5.70 ± 3.49−4.30 ± 4.47−4.80 ± 4.73−7.40 ± 5.33−9.60 ± 5.71−8.40 ± 4.77−6.80 ± 5.53
 Median (minimum, maximum)6.00 (1.00, 32.00)−3.00−1.00−1.00−4.00−6.00−5.00−2.00
 P 0.0608720.4149000.3827630.1071230.0182590.0047750.288289
Swollen joint count        
 Mean ± SEM10.20 ± 4.35−7.90 ± 4.64−2.50 ± 3.66−2.30 ± 3.33−6.10 ± 2.82−9.00 ± 4.09−9.40 ± 3.59−4.20 ± 4.45
 Median (minimum, maximum)8.00 (3.00, 27.00)−6.00−4.00−4.00−4.00−5.00−8.00−4.00
 P 0.0878500.3693160.2797390.0180760.0046820.0004620.180822
SF-36 physical component score        
 Mean ± SEM36.60 ± 1.7911.11 ± 3.7413.09 ± 3.1910.38 ± 4.4513.28 ± 3.8412.58 ± 3.2310.12 ± 5.4810.22 ± 4.59
 Median (minimum, maximum)35.20 (33.00, 42.90)14.0014.4014.2016.8015.2016.5014.90
 P 0.0424320.0152350.0867410.0229310.0166510.2170700.098381
SF-36 mental component score        
 Mean ± SEM40.02 ± 4.647.56 ± 4.975.95 ± 4.018.80 ± 4.009.76 ± 3.4611.74 ± 6.4212.98 ± 3.9611.46 ± 6.46
 Median (minimum, maximum)36.60 (31.60, 56.50)6.655.205.509.2021.0016.9017.30
 P 0.2006650.1868390.0899400.0452730.1569000.0353060.159666

The duration of weekly doses of 100 mg of rilonacept varied between 8 weeks and 42 weeks. Dosage escalation to 160 mg of rilonacept per week was indicated in all patients, since none reached the stringent criteria for remission of inflammation: a daily diary score of ≤0.5, an hsCRP level of <0.5 mg/dl, and an SAA level of <10 mg/liter. Symptoms and markers of inflammation improved at the higher dosage in all patients, and the changes in markers of inflammation at the different dosage levels are shown in Figure 2. At the higher dosages, a statistically significant improvement was seen in the ESR (P = 0.0225), as well as a trend toward further improvement in the levels of hsCRP (P = 0.135) and the SAA (P = 0.083). The improvement was most pronounced with a dosage increase from 100 mg/week to 160 mg/week, but this did not significantly change with a further dosage increase from 160 mg/week to 320 mg/week (Figure 2). Four of the 5 patients did not fulfill the remission criteria for hsCRP and daily diary scores at the 160 mg/week dosage, and their rilonacept dosages were subsequently increased to 320 mg/week.

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Figure 2. Individual levels of A, serum amyloid A (SAA), B, high-sensitivity C-reactive protein (hsCRP), and C, the erythrocyte sedimentation rate (ESR) in the 4 patients who underwent dosage escalation up to 320 mg of rilonacept per week (patients 1, 2, 3, and 5). Values are plotted on a logarithmic scale at the different dosage levels of 100 mg/week (open circles), 160 mg/week (solid red circles), and 320 mg/week (solid blue circles). The mean of all plotted values at each dosage level is indicated as a solid line of the corresponding color.

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Although fevers had disappeared in all patients at a rilonacept dosage of 100 mg/week, mild joint pain and mild skin rashes persisted on occasion. The skin rash was difficult to completely suppress in 4 of the patients. While patient 4 had an almost complete resolution of skin rashes during treatment, with scores ranging from 0.07 to 0.17 at a dosage of 100 mg/week and scores of 0 throughout the study at a dosage of 160 mg/week, the other 4 patients had improvement in their rashes compared with baseline, but had persistent skin scores of >0. Interestingly, when the rash scores were plotted relative to the day of injection, there was an increase in the scores toward the end of the week before the next injection at a dosage of 100 mg/week, but this did not occur when the dosage was increased to 160 mg/week (Figure 3). Fevers and joint pain were well controlled at drug levels of 100 mg/week, and no further improvement was seen at the higher dosages (Figure 3). One patient with a history of gout had no such symptoms during the time of his study participation. Although patients reported subjective improvement at a dosage of 320 mg/week over the levels achieved with a dosage of 160 mg/week, fluctuations in the levels of acute-phase reactants were still present, although the variability was somewhat reduced.

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Figure 3. Mean daily diary scores for skin rash, joint pain, and fever were plotted for the respective days after injection of rilonacept (Interleukin-1 [IL-1] Trap), with day 1 indicating the day of initial injection, in the 4 patients who had persistent symptoms while taking 100 mg/week (patients 1, 2, 3, and 5). Values are the mean ± SEM daily diary scores for each of the symptoms while patients were receiving a rilonacept dosage of 100 mg/week, 160 mg/week, and 320 mg/week.

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Patient's assessment of pain and physician's global assessment were significantly and durably improved while receiving treatment. Patient's global assessment and patient's assessment of fatigue improved in all patients temporarily, but were influenced by factors unrelated to FCAS and were not robust outcome measures over the long term (Table 2). Tender and swollen joint counts improved as well, but the differences were not statistically significant. For the quality of health assessment, as measured by the SF-36, improvement in the physical component score was significant for most time points, but improvement in the mental component score was not significant (Table 2). (Data obtained for the individual changes in the physical and mental component scores of the SF-36 are available upon request from the corresponding author.) All 5 patients opted to continue with drug treatment therapy. IL-6 levels measured at baseline and at a dosage of 160 mg/week were elevated in 3 of the 5 patients at baseline (10.6–54.7 pg/ml) and decreased to undetectable levels (<5 pg/ml) in all patients (data not shown).

Drug safety and tolerability.

All 5 patients had 100% treatment compliance, as recorded in their diaries, over the study period. Treatment with rilonacept was well tolerated. No injection site reactions occurred during the course of the study. All adverse events that were classified as being at least possibly associated with the study drug are shown in Table 3. The events were classified as mild or moderate, and none required discontinuation of the study drug. Infections that occurred during therapy resolved as expected. One patient with preexisting basal cell carcinoma had 2 new lesions removed during the study, and 1 patient with preexisting oral ulcers indicated an increased frequency and prolonged healing of these ulcers while receiving the study drug. Significant weight gain of 11.3 kg and 13 kg, respectively, was seen in 2 patients. We could not detect an increase in adverse events at the higher dosage levels, but the number of patients treated was very small. No serious adverse events occurred in these 5 patients.

Table 3. Adverse events over 2 years of treatment with rilonacept*
System, conditionAffected patient (severity of event) and rilonacept dose
  • *

    No serious adverse events occurred during the study. Other adverse events that were thought to be unlikely to be related or not related to the study drug included flushed skin, toothache, folliculitis on the chest/back, recurring basal cell carcinoma in 1 patient with preexisting disease, worsening acne rosacea, diarrhea, intermittent stomachache/gastritis, nausea, hematuria, recurrence of preexisting oral herpes simplex virus stomatitis, foot pain, noncardiac chest pain, lower back pain, neck pain, groin pain, transitory traumatic hearing loss in left ear, allergic sinusitis, hypogonadism, increased urinary urgency, left eye pain, and nasal congestion. No events involving the hematologic system were reported. TSH = thyroid-stimulating hormone; AST = aspartate aminotransferase.

Cardiovascular system 
 HypercholesterolemiaPatient 1 (mild) at 320-mg dose
 HypertensionPatient 1 (moderate) at 100-mg dose
 Weight gainPatient 1 (moderate) and patient 3 (moderate) at 100-mg dose
 DyslipidemiaPatient 3 (mild) and patient 4 (mild) at 100-mg dose
Dermatologic system 
 Hordeolum in left eyePatient 1 (mild) at 320-mg dose
 Contact dermatitis on footPatient 4 (mild) at 100-mg dose
 Worsening aphthous ulcersPatient 5 (moderate) at 100-mg dose; patient 5 (mild) at 320-mg dose
Endocrine system 
 Inhomogeneous thyroidPatient 3 (mild) at 160-mg dose
 Low TSH levelPatient 3 (mild) at 320-mg dose
 Worsening diabetesPatient 3 (mild) at 320-mg dose
Gastrointestinal system 
 Elevated liver enzyme levelsPatient 4 (mild) at 160-mg dose; patient 5 (mild) 1× at 100-mg dose and 1× only an elevated AST level at 100-mg dose
Infections 
 Upper respiratory tract infectionPatient 1 (mild) 3× at 320-mg dose; patient 3 (mild) at 320-mg dose; patient 4 (mild) at 100-mg dose
 SinusitisPatient 1 (mild) and patient 5 (mild) at 160-mg dose
 Viral gastroenteritisPatient 2 (mild to moderate) at 160-mg dose
 BronchitisPatient 4 (mild) at 100-mg dose
 Infection of left first toenail bedPatient 4 (mild) at 100-mg dose and at 160-mg dose
 Infection of toothPatient 4 (moderate) at 160-mg dose
 Viral illnessPatient 5 (mild) at 160-mg dose
Neurologic system 
 XerostomiaPatient 1 (mild) at 100-mg dose
 Spongy/metallic taste in mouthPatient 1 (mild) at 100-mg dose
 Intermittent insomniaPatient 2 (moderate) at 320-mg dose and (severe) at 320-mg dose
 HeadachePatient 3 (mild) and patient 5 (severe) at 320-mg dose
 Memory impairmentPatient 5 (mild) at 160-mg dose
Respiratory system 
 Sore throatPatient 1 (mild) 1× at 100-mg dose and 3× at 320-mg dose; patient 6 (mild) 2× at 320-mg dose
 Nasal congestionPatient 4 (mild) at 100-mg dose

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

This pilot study of 5 patients with FCAS provides safety data as well as short-term and long-term clinical and laboratory responses to treatment with the long acting IL-1 inhibitor rilonacept (IL-1 Trap). This study allowed us to obtain data on the magnitude of the clinical and laboratory responses at different dosage levels and served to help design a larger phase III study in patients with FCAS and MWS, a study population that had not previously been treated with rilonacept. This is the first study of rilonacept therapy in patients with FCAS and for a duration of up to 2 years.

The spectrum of diseases associated with CIAS1 mutations, the cryopyrin-associated periodic fever syndromes, spans from patients with FCAS, a less-severe disease that presents as urticarial rashes, fevers, and joint pain upon exposure to cold temperatures, to patients with MWS, a disease that presents as more-persistent attacks that are unrelated to cold exposure and that carries a higher risk of the development of amyloidosis. The most severe phenotype seen in patients with NOMID/CINCA syndrome also presents with aseptic meningitis and increased intracranial pressure, with ∼70% of patients developing bony overgrowth with disabilities from joint contractures and mental retardation. These diseases form a continuous spectrum, with clinical overlaps between the classically described syndromes; however, the clinical description is important regarding disease prognosis. While patients with FCAS have normal lifespans, the mortality rate is ∼20% in children with NOMID/CINCA syndrome before they reach adulthood (28).

Many of the disease manifestations of CAPS are caused by excessive secretion of IL-1β and are highly responsive to IL-1 blockade with the inhibitor anakinra (22–24). The disease spectrum of CAPS presents an ideal model for testing the effect of other agents that block the IL-1 secretion pathway. The rapid and impressive response to IL-1 blockade in all patients with the disease allowed a study design that required only a few patients and close monitoring to obtain data on the efficacy of a new IL-1–blocking agent; the drug withdrawal phase was designed to determine drug serum levels at which the patients' symptoms recurred. All of the enrolled patients had typical attacks of FCAS induced by exposure to cold temperatures. Among the 3 patients who also presented with mild high-frequency hearing loss, 1 had a history of long-term exposure to noise, but the hearing loss in the other 2 patients was likely associated with the underlying disease, and these 2 patients had clinical features consistent with MWS. As expected, all patients experienced clinical benefit within several hours of drug administration and the 3 patients with hearing loss showed no deterioration over the 2 years of observation. However, a longer observation period is needed to determine if slowly progressive hearing loss continues to occur.

Interestingly, significant improvements in disease control were seen at a rilonacept dosage of 100 mg/week. However, remission of clinical signs and symptoms and markers of inflammation, as determined by normalization of acute-phase reactant levels and a daily diary score of <0.5, was not achieved at that dosage. At a dosage of 160 mg/week, clinical and inflammatory remission was seen in 1 patient, who also had the lowest values for markers of inflammation at baseline. The 4 patients with higher values for markers of inflammation at baseline reported further improvements in disease control at a dosage of 320 mg/week, but this subjective improvement did not result in statistically measurable improvement over the values obtained when they were receiving 160 mg/week. For these and other reasons, the dosage of 160 mg/week was chosen for a subsequent confirmatory phase III study in patients with FCAS/MWS (29). Although much improved, the levels of acute-phase reactants continued to fluctuate in individual patients, indicating that minor flares of inflammation could still be seen, although clinical symptoms, if they recurred during treatment, remained mild.

The response to rilonacept therapy was sustained over the trial period of 24 months while taking dosages of at least 160 mg/week. Drug compliance was high in these patients. Although this pilot study is limited by the small number of patients enrolled, the magnitude and uniformity of the clinical response and the relatively high degree of inflammation at baseline in 4 of the 5 patients allowed us to conclude that continued treatment with rilonacept was effective in rapidly suppressing the IL-1–mediated inflammation and in sustaining the response for up to 2 years in all patients. Even at dosages of 320 mg/week, no increase in adverse events was observed over those with the lower dosages. Daily injections of the IL-1–blocking agent anakinra have resulted in significant reductions in inflammation and in symptom control in patients with FCAS; however, no direct comparisons of the efficacy and safety of the 2 drugs are currently available.

Rilonacept therapy has not been used in patients with NOMID/CINCA syndrome who have inflammation of the central nervous system. Since this trial was designed as a pilot study to obtain initial safety and efficacy data on this new long-acting IL-1 inhibitor, and no pediatric pharmacokinetic data were available at the time the study was designed, pediatric patients with NOMID/CINCA syndrome were not eligible to enroll. Additional studies are ongoing in patients with other diseases that have been associated with IL-1 overstimulation and/or oversecretion, such as systemic-onset juvenile idiopathic arthritis, adult-onset Still's disease, gout, and some periodic fever syndromes including FMF, where elevated IL-1 secretion plays a role in causing and maintaining systemic and organ-specific inflammation. Results of these investigations may help to determine the benefit of this drug in the wider spectrum of autoinflammatory diseases.

The magnitude of the clinical and laboratory response and the sustained effect in controlling clinical symptoms and markers of inflammation (SAA, hsCRP, and ESR) suggest a potential benefit of using rilonacept in patients with FCAS/MWS and provide a promising option in these patients. These findings led to the conduct of a randomized controlled phase III trial in patients with FCAS/MWS, the results of which are reported elsewhere in this issue of Arthritis & Rheumatism (29).

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

Drs. Goldbach-Mansky and Wesley had full access to all of the data in the study and take full responsibility for the integrity of the data and the accuracy of the data analysis.

Study design. Goldbach-Mansky, Pucino, Wesley, Mellis, Kastner.

Acquisition of data. Goldbach-Mansky, Shroff, Wilson, Snyder, Plehn, Barham, Pham, Papadopoulos, Weinstein, Mellis.

Analysis and interpretation of data. Goldbach-Mansky, Shroff, Wilson, Snyder, Pham, Pucino, Wesley.

Manuscript preparation. Goldbach-Mansky, Shroff, Kastner.

Statistical analysis. Goldbach-Mansky, Wesley.

Sponsor's medical monitor. Weinstein.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

This study was conducted under a Cooperative Research and Development Agreement between the US Public Health Service and Regeneron Pharmaceuticals, Inc. Regeneron Pharmaceuticals, Inc. provided the study drug (rilonacept), partial financial support for study coordination, and financial support for intervisit central laboratory safety assessments, and was involved in the process of the study design, data monitoring, and manuscript preparation. Regeneron Pharmaceuticals, Inc. reviewed the content of the manuscript and agreed to submit the manuscript for publication.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES

The authors would like to thank Cedric McClinton (National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH) for help in preparing the manuscript and Judith Starling (Pharmaceutical Development Section, NIH) for assistance with investigational drug management.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
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