Muckle-Wells syndrome (MWS) is a dominantly inherited autoinflammatory disease characterized by rashes, fever, arthralgia, sensorineural deafness, and the possible development of systemic AA amyloidosis. We used anakinra to treat a 22-year-old patient with MWS who had deafness and a high serum level of C-reactive protein (CRP). Following treatment with anakinra, the patient's CRP level normalized, and she recovered from deafness. The fact that this occurrence has never been previously reported strengthens the role of anakinra in MWS but also raises new questions about the physiopathology of such deafness.
Autoinflammatory diseases are defined as recurrent attacks of generalized inflammation for which neither infectious nor systemic causes can be identified. Familial Mediterranean fever (MIM no. 249100), hyperimmunoglobulinemia D with periodic fever syndrome (MIM no. 260920), tumor necrosis factor receptor–associated periodic syndrome (MIM no. 142680), familial cold autoinflammatory syndrome (FCAS; MIM no. 120100), neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular (CINCA) syndrome (MIM no. 607115), and Muckle-Wells syndrome (MWS; MIM no. 191900) are the different subsets of the autoinflammatory diseases.
In 1962, Muckle and Wells (1) described a new heredofamilial syndrome (urticaria, hearing loss, and amyloidosis) with autosomal-dominant transmission, in 9 members of a Derbyshire family. MWS is characterized by chronic recurrent urticaria, fever, chills, arthralgia, and recurrent bouts of transient synovitis, progressive sensorineural deafness, and, in approximately one-fourth to one-third of patients, amyloidosis. The finding of genetic linkage of MWS to chromosome 1q44 (2), followed by the discovery of missense mutations in the CIAS1/NALP3/PYPAF1 gene (3), opened the area of a molecular approach to MWS. The CIAS1/NALP3/PYPAF1 gene encodes cryopyrin, a member of the NALP family and the PYPAF1 family, which contains a PYRIN domain. Actually, mutations of the same gene, CIAS1, have been associated with FCAS and the CINCA syndrome (4, 5). Overlap between these syndromes is associated with a mutation in CIAS1 (6, 7), and the term CAPS (cryopyrin-associated periodic syndromes) has been proposed to describe these cryopyrin-related diseases.
Coexpression and selective interaction between cryopyrin and apoptosis-associated speck-like protein result in potent synergistic activation of NF-κB (8) and up-regulation of interleukin-1β (IL-1β), via procaspase 1. Cryopyrin is thus involved in apoptotic and inflammatory pathways, and IL-1β probably plays a large role in the pathophysiology of these diseases (9). Moreover, IL-1 is already known to increase synthesis of serum amyloid A protein by hepatocytes during the acute-phase response. Therefore, IL-1 inhibition should be beneficial in CAPS.
Anakinra, a recombinant nonglycosylated homolog of human IL-1 receptor, is at present the only drug that competitively inhibits binding of IL-1α and IL-1β to IL-1 receptor type I. Anakinra has been tested in studies involving several patients with MWS (10, 11). A successful response was observed in 2 patients with the R260W variant and in 3 patients with the V198M variant of the CIAS1/NALP3/PYPAF1 gene. Indeed, cessation of symptoms of inflammation and normalization of the plasma level of SAA protein were rapidly and steadily obtained, which had never been reported with other therapeutic agents. To our knowledge, however, anakinra had no effect on MWS-related deafness. Here, we report the first case of dramatic improvement of deafness with anakinra in a patient with MWS.
The patient, a 22-year-old white woman, was hospitalized for the treatment of MWS, which had been diagnosed 3 months previously. Her medical history began with hospitalization at age 8 years, when arthritis in her right great toe developed, along with a transient urticarial rash. A biologic inflammatory syndrome was observed, with a C-reactive protein (CRP) level of 60 mg/liter (normal <3) and a white blood cell count of 19,000/mm3. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) for 4 days was effective.
Approximately 1 year after the first articular manifestation, the patient reported progressive high-frequency hearing loss. Repeated audiographic examinations confirmed the presence of bilateral sensorineural deafness when she was 12 years of age and its worsening thereafter. At age 19 years, the patient required hearing aids. A flare of urticarial rashes, conjunctivitis, arthralgia, and (sometimes) synovitis occurred every 3–4 years. Short periods of treatment with NSAIDs (<7 days) reduced the intensity of the symptoms and permitted her to recover normal mobility. The patient did not receive any steroids or immunosuppressive treatment. Nevertheless, the deafness and the inflammatory syndrome were still present. Indeed, the elevated CRP level and high white blood cell count that were present at the beginning of the disease persisted. Exhaustive explorations failed to establish any diagnosis of immunologic, infectious, or neoplastic disease.
A genetic study, which was undertaken after the patient provided written informed consent according to the recommendations of the Declaration of Helsinki, revealed a heterozygous E311K mutation in the CIAS1/NALP3/PYPAF1 gene. The diagnoses of CAPS and, especially, MWS were therefore retained with regard to the bouts of arthralgia and arthritis, the deafness, and the absence of other neurologic symptoms, meningitis, or cold-induced urticaria. Because an inflammatory syndrome and deafness were still present, treatment with anakinra (100 mg once daily by subcutaneous injection) was started, based on data in the literature (10, 11).
The patient's serum CRP level was reduced by half after 1 month of treatment (from 55.3 mg/liter to 24 mg/liter) and nearly normalized after 2 months (to 6.9 mg/liter). A decrease in the number of polymorphonuclear neutrophils followed the same pattern (Figure 1). At the third month, the patient reported that she did not need her hearing aids. Comparison of the audiogram obtained after 3 months of anakinra treatment against the audiogram obtained before treatment confirmed the nearly complete regression of deafness (Figure 2). No bouts of rash, fever, or arthralgia were observed. The treatment was well tolerated. A reduction in the dosage of anakinra, from 100 mg daily to 100 mg every other day, resulted in an increase in the serum CRP level. Treatment with the initial dosage (100 mg daily) was therefore reinstituted, resulting in complete resolution of the inflammatory syndrome. After 18 months, the patient's CRP level remained normal, and no recurrence of deafness has been observed.
The patient with MWS described herein recovered from deafness following anakinra treatment. To the best of our knowledge, this occurrence has not been reported previously.
The first part of our discussion concerns the genetic aspect of this case. Although the E311K mutation has never been reported in the literature, several arguments favor the clinical significance of E311K. First, data obtained from a sequencing analysis of the region (the CIAS1 gene exon where the E311K mutation was found) in both of the unaffected parents and the unaffected brother (who were examined and provided informed written consent for genetic studies) revealed that the transition has appeared de novo in the proband. De novo mutations are typically observed in the CINCA syndrome but have also been previously reported in MWS (4, 6). Second, the E311K mutation causes a dramatic change in the protein, because it converts a glutamic acid into the basic amino acid lysine and because it is located in a highly conserved region of the protein, near the Walker B motif (12). In addition, causal mutations of amino acids that are in close proximity to the glutamic acid (position 311) that is converted into a lysine (amino acids 301, 303, 305, 306, 309 have been reported), suggesting that they all may belong to a functional domain of the protein (12).
The second part of the discussion concerns the phenotype. As reported by Feldmann et al (13), the association between chronic inflammation and recurrent fever, cutaneous rash, and joint symptoms is a common characteristic within the group of autoinflammatory diseases. The CINCA syndrome could have been suggested in the case of our patient. However, the CINCA syndrome is partly defined by neonatal onset, chronic meningitis, and severe symmetric cartilage manifestations. Our patient had no evidence of these features, although no imaging of the central nervous system was performed. Typically, patients with MWS present with persistent mild urticaria, fever, transient arthritis, and a permanent elevation of the CRP concentration. In contrast, our patient presented with symptom flares, which could be considered uncommon. Nonetheless, it is known that the clinical manifestations and severity of MWS can be variable according to the genetic mutation (11, 12). Thus, the E311K mutation may be involved in this particular phenotype of MWS. Moreover, the association between urticaria, arthralgia, and progressive sensorineural deafness is highly suggestive of MWS.
In our patient, a noticeable effect of treatment with anakinra was the improvement of her deafness, as demonstrated through all successive audiograms. To our knowledge, such an effect has never been reported in association with anakinra or any other drug. However, we did not find results of followup audiograms in other reports. In the cases described by Hawkins et al (11), the patients' deafness was not influenced by anakinra. This lack of effect suggests that patients have different susceptibility to anakinra treatment. The improvement of the deafness observed in our patient, with near normalization of the audiogram findings, raises new questions about the pathophysiology of the hearing loss associated with MWS. First, necropsy showed the absence of a Corti organ and atrophy of the cochlear nerve, which seem to be irreversible lesions. Moreover, amyloidosis was never found in the Corti organ or the cochlear nerve (1, 14).
Another hypothesis was proposed by Gerbig et al (15), who measured elevations in the IL-6 level in a patient with MWS. IL-6 can act as an osteoclast-activating factor, which could explain the destruction of the Corti organ and therefore a sensorineural deafness. However, increased plasma levels of IL-6 have been previously reported in patients with several different acute and chronic inflammatory diseases that are not characterized by an increased prevalence of sensorineural hearing loss. It is therefore probable that IL-6 alone is not sufficient to cause deafness, and that other pathophysiologic pathways are involved. For example, CIAS1 was found to be expressed in chondrocytes (13), and the role of the mutation of CIAS1 in the pathophysiology of deafness in MWS could be suggested. The different results in terms of deafness also suggest that hearing could degenerate gradually, step by step, with an inflammatory phase and with reversible loss of hearing occurring first, followed by irreversible destruction of the anatomic structures.
Because anakinra had a dramatic effect in our patient and no effect in the patients described by Hawkins and colleagues, we can hypothesize that IL-1 plays a role in the pathophysiology of the deafness in some, but not all, patients with MWS. As other investigators have already reported, the severity of MWS and CAPS may be influenced by the CIAS1 mutation (11, 12), and we can also suggest that response to anakinra may be variable according to capture of the mutation. Followup of MWS with repeat audiograms and perhaps imaging, before and after treatment with anakinra, could increase our knowledge of the pathophysiology of MWS-related deafness. Neither functional studies nor ear imaging was performed in our patient, and we have not found reports of such studies in the literature.
The third part of our discussion concerns the biologic aspect. A dramatic response of MWS to anakinra has already been described (10, 11). Such a response favors the central role of IL-1 in the pathogenesis of this syndrome. In the study by Hawkins et al (11), the CRP level normalized very quickly (<1 week) after the start of anakinra therapy. In our patient, the CRP level reached near-normal values only after 2 months. There is no obvious explanation for this. We suggest that the response to anakinra can be different in some patients according to the different genetic mutations, as mentioned above. This must be confirmed in further studies.
Finally, it is remarkable that anakinra was well tolerated (i.e., no side effects or severe infections were observed) within 18 months of treatment. As for other biologic therapies, data on long-term tolerance are missing. However, the risks associated with long-term therapy must counterbalance the tremendous improvement in the quality of life and perhaps the long-term risk of AA amyloidosis.
In conclusion, anakinra seems to be the most efficacious treatment of MWS, not only for the biologic inflammatory syndrome, but also for the clinical symptoms. However, further studies are required to confirm these promising results, to evaluate long-term tolerance to anakinra and the effect of treatment on the incidence of AA amyloidosis, and to understand the pathophysiology of the deafness.