SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

Objective

Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS.

Methods

A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis.

Results

A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5–14 months). The median followup was 11 months (range 5–14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed.

Conclusion

Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.

Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease that belongs to the group of cryopyrin-associated periodic syndromes (CAPS). At the molecular level, CAPS are characterized by mutations in the NLRP3/CIAS1 gene, which encodes the protein cryopyrin (1). The clinical phenotype of CAPS encompasses the mild familial cold autoinflammatory syndrome (FCAS), the moderately severe MWS, and the devastatingly severe neonatal-onset multisystem inflammatory disease (NOMID), which is also known as chronic infantile neurologic, cutaneous, articular (CINCA) syndrome (2, 3).

Patients with MWS commonly present with acute attacks of fever, rash, musculoskeletal symptoms, and conjunctivitis. These characteristic features occur episodically and can last between 1 day and 2 weeks. The MWS-associated rash can be cold-induced, urticarial, or erythematous. Musculoskeletal symptoms include arthralgia, arthritis, and myalgia. Conjunctivitis and progressive sensorineural hearing loss are the pathognomonic clinical findings that support the diagnosis of MWS (4). Constitutional features of severe, persistent fatigue are commonly found and have a significant impact on the quality of life. Sequelae of MWS may include deafness and amyloidosis, requiring renal transplantation. Markers of inflammation are commonly elevated, particularly during fever episodes (5).

The NLRP3 mutations underlying MWS result in an altered function of the gene product cryopyrin, which is essential for the activation of intracellular caspase 1 and the processing of interleukin-1β (IL-1β) (6–9). Macrophages from MWS patients show a constitutively increased production of IL-1β (3, 10, 11). Excessive amounts of IL-1β lead periodically to the characteristic inflammatory features of MWS. Case reports and small case series have demonstrated the efficacy of IL-1 inhibition with the IL-1 receptor antagonist (IL-1Ra) anakinra (5). Anakinra is a recombinant, nonglycosylated form of the human IL-1Ra. It blocks the biologic activity of IL-1 by competitively binding to the IL-1 receptor type I (IL-1RI), which is expressed on a wide variety of tissues (12). However, no standardized assessment of the long-term efficacy, safety, and use of anakinra in pediatric patients has been reported so far.

The aims of this study were therefore 1) to describe a cohort of MWS patients with a severe disease course requiring IL-1 blockade, 2) to report the short-term efficacy of treatment with the IL-1Ra anakinra in MWS patients, and 3) to determine the long-term response, including the effect on disease sequelae such as hearing loss and amyloidosis, and the safety of anakinra therapy in MWS.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

Study design.

A single-center open-label observational study of anakinra therapy for consecutive patients diagnosed as having active MWS between April 1, 2004 and December 31, 2007 was performed. Informed individual consent was obtained from all patients for DNA sequence analysis of their NLRP3 gene. The study was approved by the Local Ethics Committee (REB no. 326/2007B01).

Patients.

Consecutive patients with MWS were eligible for study if they met the following criteria: 1) clinical features of active MWS requiring medical intervention and 2) carriage of an NLRP3 mutation. Patients were excluded if they were concurrently treated with immunomodulatory agents such as methotrexate or had evidence of a preexisting underlying infection or a significant medical condition(s) not related to MWS. Female patients of child-bearing age were required to start an effective method of contraception.

All MWS patients were followed up according to a standardized protocol at the institutional interdisciplinary Hereditary Periodic Fevers Clinic in a tertiary care center led by an experienced pediatric and adult rheumatologist (JBK-D and IK). Clinical and laboratory features and disease scores were recorded from standardized assessments obtained for all patients at baseline, after 2 weeks and 4 weeks, and then monthly thereafter.

Demographics and family history.

Demographic information included sex, ethnicity, age at diagnosis and at start of anakinra therapy, and duration of followup. Family history assessment determined parental consanguinity and identified family members diagnosed as having autoinflammatory syndromes and a history of possible organ involvement, such as hearing loss.

Clinical characteristics.

Review of systems included constitutional symptoms of fever (pattern and duration) and fatigue. Organ-specific clinical characteristics, such as headache, ocular symptoms (conjunctivitis, uveitis, optic disk edema, etc.), sensorineural hearing loss, oral ulcers, abdominal pain, arthralgia, arthritis, myalgia, and skin symptoms, including erythematous and cold-induced rashes, were evaluated. Associated conditions, disease complications, and sequelae, including hearing impairment or loss, renal impairment, or delayed puberty, also were recorded.

Disease Activity Score (DAS) for MWS.

The previously developed DAS for MWS captures active disease in 10 domains: 9 domains reflect the organ involvement in MWS (fever, headache, eye involvement, hearing impairment, oral ulcers, abdominal pain, renal disease, musculoskeletal disease, and rash), and the tenth is the patient's global assessment score (13). The DAS for MWS assigns 0, 1, or 2 points to each level of disease activity: 2 points for severe symptoms, 1 point for mild symptoms, and 0 points for absence of symptoms in each domain (maximum possible score 20). As previously determined, a score of <10 points reflects overall mild activity, whereas a score of ≥10 points reflects severe activity of the disease.

Global measures of disease activity.

Three patient-derived measures of health were determined at each visit: 1) patient's global assessment, which was scored using a 10-cm visual analog scale (VAS), where 0 represents no disease activity and 10 represents maximum disease activity; 2) patient's mood score, which was recorded on a 3-point Likert scale, where 1 represents excellent mood and 3 represents the lowest mood possible; and 3) patient's performance score, which was scored using a 10-cm VAS, where 0 represents inability to perform and 10 represents the best possible performance level. The physician's global assessment, which was scored using a 10-cm VAS, where 0 represents no disease activity and 10 represents maximum disease activity, was also recorded at each visit.

Laboratory measures and additional tests.

Standardized laboratory testing of blood, serum, and urine was conducted at each visit. Classic markers of inflammation assessed were the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Hematologic assessments included a complete blood cell count with differential cell count, neutrophil count, hemoglobin value, and platelet count. Novel MWS biomarkers assessed were serum amyloid A (SAA), IL-1β, IL-6, and tumor necrosis factor α (TNFα), as well as the serum concentration S100A12, as determined by enzyme-linked immunosorbent assay (14). Assessments of renal function included serum levels of creatinine, urea, and uric acid, a standard urinalysis, a urine dipstick test for blood and albumin levels, a spot urine collection for protein levels (α1-microglobulin and β2-microglobulin), and a 24-hour urine collection for creatinine and protein levels. In addition, creatinine clearance and the protein-to-creatinine ratio were calculated.

Audiologic assessment.

A clinical examination and an audiogram were performed prior to initiation of anakinra and every 6 months thereafter to evaluate hearing status. The audiologic examination included an air-conduction threshold for pure tone frequencies of 250–8,000 Hz, bone conduction threshold, and tympanometry. Hearing was graded on a scale of 0–4, where 0 = normal (≤20% hearing loss), 1 = mild impairment (>20–40% hearing loss), 2 = moderate impairment (>40–60% hearing loss), 3 = severe impairment (>60–80% hearing loss), and 4 = profound deafness (>80% hearing loss). Percentages of hearing loss were calculated from the measurements of pure tone audiologic threshold (15).

Ophthalmologic examination.

A standardized ophthalmologic evaluation was performed prior to initiation of anakinra, at 2 weeks, and every 6 months thereafter. Emphasis was on visual changes as sensitive indicators of optic nerve function, conjunctivitis, and uveitis.

Magnetic resonance imaging (MRI).

A gadolinium-enhanced MRI of the brain and inner ear was performed prior to the start of anakinra therapy and then every 12 months thereafter. Inflammatory changes affecting the meninges and the inner ear were the primary focus of the MRI.

Scintigraphic scan for amyloidosis.

In all patients with amyloidosis diagnosed by renal biopsy, a scintigraphic scan for amyloidosis was performed with 123I-labeled serum amyloid P component (16).

Treatment.

All MWS patients were treated with the chimeric monoclonal IL-1Ra anakinra (Kineret; Amgen). Anakinra was administered at doses of 1–2 mg/kg in patients weighing <40 kg and 100 mg for patients weighing ≥40 kg. The drug was self-administered by subcutaneous injection once a day. In children with persistent disease activity, the anakinra dose was increased stepwise to a maximum of 8 mg/kg. Concurrent treatment with a nonsteroidal antiinflammatory drug was added if required.

Outcomes.

The primary study outcome was response to anakinra therapy at 2 weeks of treatment. A good response was defined as control of the MWS disease activity, with a DAS for MWS of <10 at 2 weeks.

Secondary outcomes included efficacy at the primary study end point (2 weeks) and long-term efficacy. To determine efficacy at the primary study end point, the following parameters were assessed: the disease activity in all single domains of the DAS for MWS, the patient-derived and physician-derived global measures of disease activity and overall health, the classic markers of inflammation, and the novel biomarkers at 2 weeks. To determine long-term efficacy, the following parameters were assessed: the overall response, as determined by the DAS for MWS and its single domains, the patient-derived and physician-derived global measures, and the classic and novel markers of inflammation at the last followup visit at a median of 11 months (range 5–14 months). In addition, MWS sequelae, including delayed puberty and amyloidosis, were evaluated. Treatment safety assessments included adverse events and severe adverse events. Adverse events captured signs of local injection reaction, local and systemic infections, and organ disease. Severe adverse events were defined as signs and symptoms requiring hospitalization or as death.

Statistical analysis.

Demographic characteristics, clinical and laboratory measures, scores for the different domains of the DAS for MWS, and patient-derived and physician-derived measures of health (by VAS) were collected in a designated Arthritis and Rheumatology Documentation and Information System (ARDIS) research database. Summary statistics were determined. Comparisons were made for each variable at baseline and at the primary study end point using paired analysis: McNemar's exact test for categorical variables and Student's paired t-test or Wilcoxon's signed rank test, when appropriate, for continuous variables. P values less than 0.05 were considered significant. All analyses were performed with SAS for Windows software, version 9.3 (SAS Institute).

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

Patient characteristics.

A total of 21 Caucasian patients (9 males and 12 females) with the clinical diagnosis of MWS and an underlying NLRP3 exon 3 mutation were included in the study. The patients came from 4 different families; all had a family history of MWS. The median age at diagnosis was 33.5 years (range 3.0–72 years) (Table 1).

Table 1. Baseline characteristics, disease activity, and followup of the patients with MWS*
 Total MWS population at study center (n = 21)Anakinra-treated MWS inception cohort (n = 12)
  • *

    MWS = Muckle-Wells syndrome; NA = not applicable; DAS = Disease Activity Score.

Demographics  
 No. male/female9/123/9
 Age, median (range) years  
  At diagnosis of MWS33.5 (3.0–72)19.1 (3.0–65.5)
  At start of anakinra therapyNA21.0 (3.0–66.9)
 Pediatric MWS patients  
  No. of pediatric patients receiving anakinra therapyNA5
  No. male/femaleNA1/4
  Age at start of anakinra therapy, median (range) yearsNA6.4 (3.0–15.3)
 Adult MWS patients  
  No. of patients ≥18 years old at start of anakinra therapyNA7
  No. male/femaleNA2/5
  Age at start of anakinra therapy, median (range) yearsNA39.0 (20.6–66.9)
 Ethnicity, no. (%) Caucasian21 (100)12 (100)
NALP3 mutation, no. (%) of patients  
 Patients with confirmed mutation21 (100)12 (100)
 Mutation subtype  
  E311K13 (62)7 (58)
  T348M3 (14)3 (25)
  V198M5 (24)2 (17)
MWS disease activity at diagnosis, no. (%)  
 Mild (<10 on the DAS for MWS)5 (24)0 (0)
 Severe (≥10 on the DAS for MWS)16 (76)12 (100)
Followup, median (range) months  
 Total followup51 (22–114)51 (22–114)
 Followup after start of anakinra therapyNA11 (5–14)

Study inception cohort.

Of the 21 MWS patients, 16 (76%) had severe disease activity, and 4 of these 16 patients were excluded from the study: 1 required dialysis, 1 had multiple sclerosis, and 2 refused the daily subcutaneous injections. Thus, 12 patients (3 males and 9 females) were included in the inception cohort. Five patients (42%) were children under 18 years of age, with a median age of 6.4 years (range 3.0–15.3 years), whereas 7 patients were adults, with a median age of 39.0 years (range 20.6–66.9 years). The median age at diagnosis of MWS was 19.1 years (range 3.0–65.5 years). The median age at the start of anakinra therapy was 21.0 years (range 3.0–66.5 years).

Three different NLRP3 gene mutations were found: 7 of the 12 patients carried the E311K mutation (17). The remaining mutations were T348M in 3 of the 12 patients (25%) and V198M in 2 (17%). The median followup time was 51 months (range 22–114 months) (Table 1).

Baseline characteristics.

Clinical features.

All patients had clinically active MWS. Severe fatigue was seen in all patients. The most common organ system features were musculoskeletal and ocular manifestations (Table 2). Arthralgias were present in all 12 of the patients (100%), arthritis in 8 (67%), and myalgia in 6 (50%). Ocular symptoms were seen in 12 patients (100%), with conjunctivitis in 11 (92%) and anterior uveitis in 2 (17%). No optic disk edema was found in the cohort. At baseline, hearing loss was present in 10 patients (83%). Recurrent episodes of headache and oral ulcers were found in 10 patients (83%). Erythematous rash independent of cold exposure was described by 8 patients (67%). Only 1 patient had cold-induced rash (8%). Febrile episodes were reported by 6 patients (50%), lasting an average of 3–5 days. The maximum temperature per episode ranged between 39°C and 40°C. A total of 6 patients (50%) experienced abdominal pain during a disease flare. Disease sequelae were present in 3 patients: amyloidosis in 2 patients and delay of puberty in 1 female patient.

Table 2. Clinical efficacy of anakinra therapy in the patients with MWS*
 Baseline (n = 12)Study end point (n = 12)Last followup (n = 12)P
Baseline vs. study end pointBaseline vs. last followup
  • *

    The primary study end point was 2 weeks. The median followup was 11 months (range 5–14 months). P values less than 0.05 were considered significant. MWS = Muckle-Wells syndrome; NS = not significant; NA = not applicable; DAS = Disease Activity Score; VAS = visual analog scale; ND = not done.

Constitutional symptoms, no. (%)     
 Fever6 (50)0 (0)1 (8)0.030.02
MWS symptoms by organ system, no. (%)     
 Headache10 (83)2 (17)1 (8)0.0080.0004
 Ocular symptoms12 (100)1 (8)4 (33)<0.00010.008
  Conjunctivitis11 (92)1 (8)4 (33)0.0020.04
  Uveitis2 (17)0 (0)1 (8)NSNS
  Optic disk edema0 (0)0 (0)0 (0)NANA
 Sensorineural hearing loss10 (83)10 (83)9 (75)NSNS
 Oral ulcers10 (83)1 (8)1 (8)0.0040.004
 Abdominal pain6 (50)3 (25)1 (8)NSNS
 Renal disease9 (75)4 (33)3 (25)NS0.03
  Proteinuria7 (58)4 (33)2 (17)NSNS
  Hematuria2 (17)0 (0)0 (0)NSNS
  Renal failure1 (8)1 (8)1 (8)NSNS
 Musculoskeletal symptoms12 (100)0 (0)3 (25)<0.00010.004
  Arthralgia12 (100)0 (0)3 (25)<0.00010.004
  Arthritis8 (67)0 (0)0 (0)0.0080.008
  Myalgia6 (50)0 (0)0 (0)0.030.03
 Skin symptoms8 (67)1 (8)2 (17)0.020.04
  Erythematous rash8 (67)1 (8)2 (17)0.020.04
  Cold-induced rash1 (8)0 (0)0 (0)NSNS
Disease activity, mean ± SD     
 DAS for MWS12.8 ± 2.23.2 ± 1.03.9 ± 3.20.0005<0.0001
Global measures of health status, mean ± SD     
 Patient-derived global measures     
  Patient's global assessment, by 10-cm VAS6.3 ± 2.02.8 ± 1.62.5 ± 0.80.0005<0.0001
  Patient's mood score, by 3-point Likert scale2.2 ± 0.51.8 ± 0.61.4 ± 0.50.030.0004
  Patient's performance score, by 10-cm VAS5.9 ± 2.18.2 ± 1.68.3 ± 1.2NS0.01
 Physician's global assessment, by 10-cm VAS7.3 ± 1.11.9 ± 1.31.9 ± 1.10.0005<0.0001
Sequelae, no. (%)     
 Amyloidosis2 (17)1 (8)1 (8)NDND
 Delay of puberty1 (8)1 (8)0NDND
Scores on the DAS for MWS.

The mean DAS for MWS was 12.8 (maximum possible score 20) and was therefore in the range of severe disease activity (≥10 points) in all patients at baseline. All patient-derived scores confirmed the presence of active disease. The mean score on the patient's global assessment was high at 6.3 (on a 10-cm VAS). The patient's mood score was 2.2 (on a 3-point Likert scale), reflecting poor mood, and the patient's performance score was low at 5.92 (on a 10-cm VAS), indicating a decreased performance level. The physician's global assessment score mirrored that of the patient's global assessment, with a high mean score of 7.25 (on a 10-cm VAS), confirming high levels of disease activity.

Markers of inflammation.

The majority of patients had elevated levels of the classic markers of inflammation at baseline (Table 3). ESR elevation was seen in 9 patients (75%), and the CRP was raised in 11 (92%). Five patients had leukocytosis (42%), 3 were anemic (25%), and 1 had neutrophilia. Levels of novel biomarkers of MWS were raised in all patients at baseline. High serum levels of SAA were seen in 11 of the 12 patients (92%). There were marked increases in proinflammatory cytokine levels, with increased IL-6 in 7 of the 12 patients (58%), TNFα in 5 of the 12 patients (42%), and IL-1β in 7 of the 11 patients tested (64%). S100A12 was elevated above the upper limit of normal (>120 ng/ml) in 6 of the 11 patients tested (55%).

Table 3. Laboratory findings in MWS patients treated with anakinra*
 Baseline (n = 12)Study end point (n = 12)Last followup (n = 12)P
Baseline vs. study end pointBaseline vs. last followup
  • *

    The primary study end point was 2 weeks. The median followup was 11 months (range 5–14 months). P values less than 0.05 were considered significant. MWS = Muckle-Wells syndrome; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; NS = not significant; age/sex-adj. = adjusted for age and sex; SAA = serum amyloid A; IL-1β = interleukin-1β; ND = not done; TNFα = tumor necrosis factor α.

Classic markers of inflammation     
 ESR     
  No. (%) with elevated ESR9 (75)1 (8)2 (17)
  Mean ± SD ESR, mm/hour (normal <22)32 ± 1713 ± 1613 ± 80.020.0005
 CRP     
  No. (%) with elevated CRP11 (92)5 (42)3 (25)
  Mean ± SD CRP, mg/dl (normal <0.5)2.11 ± 1.330.87 ± 1.860.44 ± 0.7NS0.0005
Hematologic abnormalities     
 Leukocytes     
  No. (%) with leukocytosis5 (42)1 (8)0 (0)
  Mean ± SD leukocytes/μl (normal 4-10)9,906 ± 2,8146,949 ± 1,7086,016 ± 1,4090.0001<0.0001
 Neutrophils     
  No. (%) with neutrophilia1 (8)0 (0)0 (0)
  Mean ± SD neutrophils/μl (normal 2.5–7.5)6,918 ± 3,2093,930 ± 1,7453,506 ± 1,5720.0001<0.0001
 Hemoglobin     
  No. (%) with anemia3 (25)0 (0)0 (0)
  Mean ± SD hemoglobin, gm/dl (age/sex-adj.)12.7 ± 213.6 ± 1.413.7 ± 2NSNS
Novel biomarkers of inflammation     
 SAA     
  No. with elevated SAA/no. evaluated (%)11/12 (92)4/12 (33)3/12 (25)
  Mean ± SD SAA, mg/liter (normal <10)36.5 ± 26.127.5 ± 70.56.6 ± 5.2NS0.001
 IL-1β     
  No. with elevated IL-1β/no. evaluated (%)7/11 (64)ND5/7 (72)
  Mean ± SD IL-1β, pg/ml (normal <0.5)1.4 ± 2.4ND0.8 ± 0.5NDNS
 IL-6     
  No. with elevated IL-6/no. evaluated (%)7/12 (58)ND1/12 (8)
  Mean ± SD IL-6, pg/ml (normal <5)15.0 ± 16.0ND3.2 ± 3.9ND0.03
 TNFα     
  No. with elevated TNFα/no. evaluated (%)5/12 (42)ND6/12 (50)
  Mean ± SD TNFα, pg/ml (normal <8)9.42 ± 5.1ND8.8 ± 4.3NDNS
 S100A12     
  No. with elevated S100A12/no. evaluated (%)6/11 (55)5/11 (42)5/11 (42)
  Mean ± SD S100A12, ng/ml (normal <130)240 ± 172142 ± 57273 ± 330NSNS

Efficacy of anakinra therapy.

Primary outcome.

All 12 patients reached the primary study end point of 2 weeks of anakinra therapy. A good response, defined as control of disease activity (score of <10 on the DAS for MWS), was noted in all patients. The mean DAS for MWS at 2 weeks was 3.2, which was a statistically significant improvement compared to baseline (P = 0.0005) (Table 2).

Secondary outcomes at 2 weeks of therapy.
Disease activity in the domains of the DAS for MWS.

Treatment with anakinra led to a complete resolution of constitutional symptoms, such as fatigue and fever, in all patients at 2 weeks. Musculoskeletal manifestations, including arthralgias, arthritis, and myalgia, also completely resolved in all patients. Ocular symptoms in general (P < 0.0001) and conjunctivitis in particular (P = 0.002) were significantly reduced. Uveitis, which was present in only 2 patients, resolved in both. Skin manifestations of MWS resolved in the majority of patients (P = 0.02). In addition, there was a significant reduction of headaches and oral ulcers. There was also a decrease in the number of patients reporting abdominal pain. Proteinuria improved and hematuria resolved in all affected patients (Table 2).

Patient-derived and physician-derived global measures.

All patient- and physician-derived measures of health status significantly improved in all patients. Scores for the patient's global assessment of overall disease activity decreased from 6.3 to 2.8 (P = 0.0005). Simultaneously, the patient's performance score increased from 5.9 to 8.2 (P = 0.05). The patient's mood score also decreased from 2.2 to 1.8 (P = 0.03), indicating better mood. The physician's global assessment score was reduced from 7.3 to 1.9 (P = 0.0005) (Table 2).

Classic markers of inflammation.

Classic markers of inflammation improved in all but 1 patient. The ESR normalized in 11 of the 12 patients (P = 0.02). CRP levels normalized in 5 of the 11 individuals with CRP elevation at baseline. Only 1 patient became worse. Hematologic abnormalities resolved in all but 1 patient (Table 3).

Novel biomarkers of MWS.

At 2 weeks of anakinra therapy, the mean levels of the novel neutrophil activation marker S100A12 significantly decreased (P = 0.05). In contrast, SAA levels improved overall but the difference was not statistically significant (Table 3).

Long-term efficacy.
Overall disease control at the last followup visit.

Ninety-two percent of the patients experienced sustained disease control, with a score of <10 on the DAS for MWS. However, there was a slight increase from 3.2 to 3.9. One patient experienced a disease flare, with a score of 13 on the DAS for MWS at the last followup visit. Two children age 3.0 years and 6.4 years, respectively, required a dosage adjustment of anakinra in order to maintain disease control. The dosage had to be increased stepwise to 8 mg/kg/day. Both children were found to carry the V198M mutation. The highest score on the DAS for MWS at the last followup was 13 and was measured in the second youngest patient. No adjustment of the anakinra dosage was needed in adult patients with MWS.

Disease activity in the domains of the DAS for MWS.

At the last followup visit, all but 1 patient remained afebrile. Musculoskeletal manifestations also remained well controlled in all but 3 patients, who reported a recurrence of arthralgia. Ocular symptoms were present in 5 of the 12 patients. Conjunctivitis had recurred in 4 of the 11 patients who had this manifestation at baseline. Skin manifestations flared in 1 patient who did not have skin manifestations at baseline. Sustained disease control was seen for headache, oral ulcers, and renal disease, including proteinuria and hematuria. There was a further increase in the number of patients reporting resolution of abdominal pain. Hearing loss subjectively resolved in 1 patient who previously had significant hearing loss. The audiogram demonstrated persistent, but nevertheless improved, mild impairment in this patient (Figure 1).

thumbnail image

Figure 1. Improvement in hearing loss in a 15-year-old patient with Muckle-Wells syndrome following treatment with anakinra. Serial bilateral audiograms demonstrate a 10–30-dB improvement in the 250–4,000-Hz frequency range. Air-conducted sounds at baseline (○) and the last followup (●) and bone-conducted sounds at baseline (□) and the last followup (▪) were recorded.

Download figure to PowerPoint

Patient-derived and physician-derived global measures.

All global measures of health status further improved at the last followup visit in all patients. The score on the patient's global assessment of overall disease activity decreased from 2.8 at 2 weeks to 2.5 at last followup. The patient's mood score also decreased, from 1.8 to 1.4, indicating improved mood. The patient's performance score remained stable at 8.2. The physician's global assessment confirmed stable disease control (Table 2).

Classic markers of inflammation.

Values for the classic markers of inflammation remained stable at the last followup visit. There was a slight increase in the number of patients with an elevated ESR; however, the mean value for the ESR was stable at 13 mm/hour. CRP levels further improved compared to the 2-week primary end point and normalized in the majority of patients. Hematologic abnormalities completely resolved in all patients (Table 3).

Novel biomarkers of MWS.

Mean SAA levels further decreased from 27.5 mg/liter to 6.6 mg/liter. Simultaneously, the proinflammatory cytokine levels significantly decreased. The S100A12 concentration, in contrast, increased compared to the 2-week assessment, reaching and exceeding baseline levels (Table 3).

Sequelae of MWS.

Amyloidosis, which was confirmed by kidney biopsy in 2 patients at baseline, resolved in one and improved in the other, as documented by repeat scintigraphic scans (data not shown). Delayed puberty in 1 patient had resolved at the time of the last followup visit. Sensorineural hearing loss was documented in 10 of the 12 patients at baseline, and improved in 2 patients with treatment. It completely resolved in one patient and significantly improved in the other. In the latter individual, initial hearing impairment was found to be the most severe (grade 4). Subsequent testing revealed only grade 3 impairment. Hearing loss became worse during anakinra treatment in 2 patients: from grade 1 to grade 2 in one and from grade 2 to grade 3 in the other.

Safety.

Overall, anakinra therapy was well tolerated. There were no serious adverse events during the study period. Adverse events included mild injection site reactions in 5 patients (42%), mild infections in 5 (42%), and hyperactivity and weight gain in 4 patients each (33%).

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

Our study determined the short- and long-term efficacy and safety of anakinra therapy in children and adults with genetically confirmed MWS. All 12 patients included in this observational cohort had severe MWS requiring IL-1 blockade. Patients were followed up in a designated periodic fever clinic according to a standardized protocol. Clinical features as well as classic and novel markers of inflammation were evaluated at defined intervals. Anakinra proved to be efficacious and safe in all MWS patients studied, with a rapid clinical response after only 2 weeks. At the primary end point (2 weeks), anakinra therapy resulted in complete resolution of fever, fatigue, and musculoskeletal symptoms. In fact, the vast majority of MWS organ manifestations had resolved. The mean DAS for MWS also significantly improved, reflecting excellent disease control. The treatment response was sustained in the majority of patients, as documented at the last followup visit. Disease sequelae, including hearing loss and amyloidosis, were shown to be reversible in individual patients. All patient-derived measures of disease activity, mood, and performance improved significantly at 2 weeks as compared to baseline and, at the last followup visit, had continued to improve.

The short-term efficacy of anakinra was documented after 2 weeks of therapy. Rapid resolution of all constitutional symptoms, most importantly, the disease-associated severe fatigue, was seen in all individuals. MWS patients consistently reported that the inflammation-associated fatigue negatively affected their performance and mood. With resolution of the constitutional features of the disease, scores on the patient-derived health status, performance, and mood measures improved in all patients. Organ manifestations were equally responsive to anakinra therapy. Musculoskeletal symptoms completely resolved, and skin and eye symptoms significantly improved, following IL-1 blockade. This rapid response to anakinra was first reported by Hawkins et al (5), who studied 3 severely ill family members carrying the NALP3 V198M mutation. In that patient series, clinical features of rash, fever, conjunctivitis, and arthralgia improved within 4 hours after the first injection, and serologic remission was achieved within 1 week (5). Leslie et al (18) described 22 patients with CAPS, 15 of whom were treated with anakinra. The authors reported that the clinical features resolved within 4–12 hours, and the laboratory markers normalized within 1 week (18). Similar observations were reported by Hoffman et al (19) for FCAS patients, Goldbach-Mansky et al (20) for NOMID patients, and Maksimovic et al (21) for MWS/FCAS overlap patients.

The long-term efficacy of anakinra therapy was determined at the last followup visit. There was a sustained response to anakinra in the majority of patients. Adults did not require any dosage adjustment to maintain disease control; however, all patients had mild features of MWS at the last followup. In contrast, 2 of 5 children needed a significant dosage augmentation, to 8 mg/kg/day. One child who did not have a dosage adjustment had severe disease including fever at the last followup (score of 13 on the DAS for MWS). It appeared that younger children required higher doses of anakinra as compared to adults.

Recurrence of MWS organ manifestations was observed in 50% of our patients, comparing the data at the primary study end point at 2 weeks with the data at the last followup visit. These symptoms were mainly conjunctivitis and arthralgia, less commonly rash. Improvement and/or stability of organ manifestations was seen in the other 50% of patients. The latter group included the 2 children, who had a dosage adjustment. Headaches, oral ulcers, abdominal pain, and renal disease, including proteinuria and hematuria, remained well controlled in all patients.

Sensorineural hearing loss was reversible in 1 patient, who was 15 years old at the start of therapy. One adult, who was 44 years of age, had a gradual improvement. In 2 other adult patients, hearing worsened during anakinra therapy. In all of the remaining patients, anakinra appeared to stabilize the hearing loss. The two children who required dosage adjustment never developed hearing loss.

Long-term followup data for anakinra therapy in children and adults with MWS are limited. Leslie et al (18) reported the outcome of 15 MWS patients, including 2 children, who were followed up for a median of 17 months (range 1–39 months). All patients showed a sustained response to drug therapy. No dosage adjustment was needed to prevent the recurrence of symptoms. Significant improvement in renal disease, as determined by proteinuria and amyloidosis (measured by scintigraphic scan for amyloidosis), was recorded (5). Three patients described by Hawkins et al (5) in 2004 were followed up for 3 months and were also reported to have experienced a sustained response to anakinra.

Single cases of MWS in whom hearing loss was reversed following anakinra treatment have recently been described (22–24). These patients were ages 8–22 years, similar to the individuals in our cohort. These data suggest that there may be a window of opportunity at a younger age for reversing hearing loss, although Rynne et al (25) reported reversibility of sensorineural deafness in a 59-year-old woman with MWS.

Classic markers of inflammation improved in the majority of patients. The ESR normalized in all but 1 patient (92%) and the CRP value in 45% of those who had an elevation at baseline. While significant improvement in the ESR was detectable as early as 2 weeks and then plateaued, CRP levels improved further until the last followup visit. Hematologic abnormalities also completely resolved and did not recur as of the last followup visit.

The novel markers of inflammation in patients with MWS had distinct kinetics. The SAA levels mirrored the CRP and IL-6 concentrations, improving at 2 weeks and significantly decreasing over the long term. The S100A12 levels, in contrast, rapidly decreased at 2 weeks (P = 0.05), but had increased again by the time of the last followup visit. These data indicate that MWS may be associated with abnormal activation of neutrophils, which is not completely alleviated by IL-1β blockade. In this cohort, serum levels of IL-1β and TNFα did not correlate significantly with clinical features and other markers of inflammation.

Classic markers of inflammation have been measured in previous series of MWS patients treated with anakinra. Hawkins et al (5) and Leslie et al (18) reported a rapid decrease in CRP levels and a resolution of hematologic abnormalities in all patients. Lovell et al (26), in contrast, noted an improvement in the ESR in 2 NOMID patients; however, the CRP levels appeared to be “unstable” and remained abnormal at all times. Goldbach-Mansky et al (20) reported significantly decreased SAA, CRP, and ESR values in NOMID patients at month 3, all of which remained low at month 6. The novel markers of inflammation have not been systematically studied in most series. Goldbach-Mansky et al (20), Hawkins et al (5), and Leslie et al (18) reported SAA levels. Goldbach-Mansky also reported IL-1, Il-6, and TNFα concentrations in NOMID patients, which have not been reported in MWS patients until now.

The most promising biomarker of MWS in our series was S100A12, a neutrophil-specific protein belonging to the group of damage-associated molecular patterns. This marker may indicate subclinical disease activity, as has already been shown in other inflammatory disorders (27) and may possibly be associated with subclinical disease progression and risk of the development of disease sequelae such as amyloidosis.

Subcutaneous injections of anakinra were reasonably well tolerated in all patients, including the children. Local injection site reactions, including itchiness, swelling, and redness, occurred in 42% of the patients. Similar rates of local reactions in other series of patients have been reported (5, 18, 20). Increasing the dosages and the corresponding drug volumes resulted in increased local discomfort and pain, particularly in small children. However, the benefit of clinical improvement outweighed the injection site discomfort in all participating MWS patients.

The overall safety of anakinra in our cohort was excellent. No serious adverse events were observed. No discontinuation of therapy was necessary. Hyperactivity, which was seen in 4 individuals, may be a result of the increased energy level reported by all patients. Weight gain was observed in 4 female MWS patients (33%).

This study has limitations, however. It was an observational cohort study, which inevitably suffers from incompleteness of the data. Since the patients were followed up according to a standardized protocol, however, the percentage of missing data was <5%, indicating robustness of the results. Only 12 MWS patients were recruited. Nevertheless, since MWS is a newly recognized, rare disease, this study reflects the largest experience with IL-1 blockade in patients with severe MWS published to date. Also, no previous study has enrolled a comparable number of children with MWS, making this the largest pediatric experience with anakinra thus far.

In conclusion, anakinra was an effective and safe therapy for children and adults with severe MWS. Rapid resolution of constitutional symptoms and organ manifestations was observed. Most noticeably, anakinra had a significant and sustained positive impact on the quality of life, as documented by all patient-derived measures. Disease sequelae were possibly prevented and even reversed in some patients. Novel markers of inflammation, such as the S100A12, appear to be promising, sensitive measures of disease activity.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Benseler had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Kuemmerle-Deschner, Tyrrell, Koetter, Wittkowski, Tzaribachev, Lohse, Koitchev, Benseler.

Acquisition of data. Kuemmerle-Deschner, Tyrrell, Koetter, Wittkowski, Bialkowski, Tzaribachev, Lohse, Koitchev, Deuter, Foell, Benseler.

Analysis and interpretation of data. Kuemmerle-Deschner, Tyrrell, Koetter, Wittkowski, Lohse, Koitchev, Foell, Benseler.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. REFERENCES