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Diagnosis of Muckle-Wells Syndrome — 33 Years Later

To the Editor:

As medical information is rapidly expanding, it is incumbent on the clinician to continually reevaluate every patient, looking for new diagnostic and therapeutic opportunities. We describe our experience with a woman who developed her disease at 4 months of age but in whom the diagnosis and appropriate therapy were delayed until she was 33 years old. The diagnosis was originally missed, because 30 years ago the syndrome was not widely recognized, the tools necessary for diagnosis had not yet been developed, and effective therapy had not yet been devised. Three decades of accumulating medical experience, creation of new diagnostic techniques, and development of new effective therapies resulted in diagnosis and successful treatment of her disorder.

The patient was a 33-year-old Caucasian woman referred to the University of California, San Francisco, with a chronic syndrome characterized by recurrent urticaria, migratory polyarthritis, progressive hearing loss, intermittent anterior eye disease (episcleritis, scleritis, uveitis, and iridocyclitis), headaches, intermittent fevers, lymphadenopathy, and episodic diarrhea. Her disease had begun when she was 4 months of age, and over 30 years she had been evaluated by an army of pediatricians, internists, rheumatologists, otolaryngologists, and ophthalmologists, with no definitive diagnosis. Therapeutic interventions included various nonsteroidal antiinflammatory agents, antihistamines, prednisone, and colchicine, all of which were of limited benefit or associated with unacceptable side effects.

At presentation her therapeutic regimen included diclofenac, 75 mg bid, and colchicine, 0.6 mg tid. Physical examination revealed bilateral conjunctivitis, hearing loss requiring the use of hearing aids in both ears, synovitis of the left wrist, and urticaria of the shoulders, trunk and thighs. Laboratory evaluation revealed a hematocrit of 30.4%, white blood cell count 8.8 ´ 109/l, and platelet count 333 ´ 109/l. Erythrocyte sedimentation rate was 45 mm/h and C-reactive protein was 28.1 mg/l (normal < 6.3). Liver function studies, electrolytes, creatinine, blood urea nitrogen, antinuclear antibody, rheumatoid factor, antineutrophil cytoplasm antibodies, complement levels (C3 and C4), quantitative immunoglobulins, hepatitis C antibody, thyroid function studies, antithyroid antibodies, cryoglobulins, creatine phosphokinase, and urinalysis were all normal. Chest radiograph and magnetic resonance imaging of the brain were unremarkable. A previous biopsy of one of the skin lesions revealed urticarial vasculitis.

Because the constellation of signs and symptoms was consistent with a diagnosis of Muckle-Wells syndrome, a buccal swab was sent for genetic testing. Gene sequencing revealed a heterozygous cytosine to thiamine substitution in exon 3 of the CIAS1 gene, leading to a methionine for threonine substitution at amino acid position 348 in the cryopyrin protein. This mutation is seen in patients with the Muckle-Wells syndrome or with familial cold urticaria. After the diagnosis was confirmed, treatment with the interleukin 1 (IL-1) receptor antagonist anakinra (100 mg subcutaneously per day) was begun. Within 24 hours of the first injection she noted a dramatic improvement. Since initiation of therapy 1 year ago, ocular inflammation and arthritis have recurred only once, when she went on a 3 day vacation and forgot her anakinra.

Muckle-Wells syndrome is a heritable autoinflammatory disorder characterized by progressive deafness, inflammatory eye disease, recurrent urticaria, cutaneous vasculitis, arthritis, lymphadenopathy, abdominal pain and bloating, and recurrent fevers1. Some patients will eventually develop AA amyloidosis. The disease begins during infancy, so generally patients are diagnosed and treated by pediatricians. The disorder is due to some of over 20 defects in the CIAS1 gene (also termed NALP3 or PYPAF1) that codes for the production of cryopyrin, a protein that modulates a platform of proinflammatory cytokines important in the innate immune system2. Related disorders with defects at the same locus include familial cold-induced urticaria, neonatal-onset multisystem inflammatory disease (NOMID), and the CINCA (chronic infantile neurologic, cutaneous, articular) syndrome. Specific gene sequencing, available commercially and done with a simple cheek swab, now offers clinicians the capability of a definitive diagnosis.

Prednisone, antihistamines, dapsone, minocycline, azathioprine, chlorambucil, mycophenolate mofetil, and infliximab have all been used to treat the inflammatory components of the disorder, and colchicine has been prescribed in hope of preventing the development of amyloidosis. None of these therapies has been particularly helpful in the long term. The defect at CIAS1 results in unregulated activation of a number of humoral inflammatory mediators, including IL-1a, IL-1ß, tumor necrosis factor-a, IL-3, IL-5, IL-6, and IL-183,4.

The proinflammatory cytokine IL-1ß is felt to be the major mediator of the clinical manifestations of Muckle-Wells syndrome. Therefore, development of the IL-1 receptor antagonist anakinra that could block the ability of IL-1ß to mediate the inflammatory process offered patients a potentially valuable therapeutic modality. Anakinra has proven to be dramatically effective in short-term treatment of Muckle-Wells syndrome2. There is even evidence that anakinra can normalize serum amyloid A protein5, suggesting that it could prevent the development of AA amyloidosis in these patients. Certainly, our patient's dramatic response to anakinra appears to be typical of patients with this disorder.

This case is an example of just how much our diagnostic and therapeutic capability has improved in the last 30 years. It is a reminder that physicians should try to view every new patient interaction as if it were the patient's first experience with a medical professional. Without an open, unbiased assessment of even longstanding chronic problems there is always the risk that incorrect diagnoses or inadequate therapies will be perpetuated for decades, and that new diagnostic and therapeutic modalities will be wasted for lack of consideration.

KENNETH H. FYE, MD, Professor of Clinical Medicine, Division of Rheumatology, Department of Medicine, University of California, San Francisco; DAWN H. SIEGEL, MD, Resident in Dermatology, Department of Dermatology, University of California,San Francisco; M. KARI CONNOLLY, MD, Professor of Dermatology and Medicine, Departments of Dermatology and Medicine, University of California, San Francisco. Address reprint requests to Dr. Fye; E-mail: Ken.Fye@ucsf.edu.

REFERENCES

Search PubMed for:

1. Hawkins PN, Lachman HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 2004;50:607-12. [MEDLINE]

2. Aksentijevich I, Nowak M, Mallah M, et al. De novo mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum 2002;46:3340-8. [MEDLINE]

3. Sutterwala FS, Ogura Y, Szczepanik M, et al. Critical role for NALP3/CIAS1/cryopyrin in innate and adaptive immunity through its regulation of caspase-1. Immunity 2006;24:241-3. [MEDLINE]

4. Mariathasan S, Weiss DS, Newton K, et al. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 2006;440:228-32. [MEDLINE]

5. Hawkins PN, Lachman HJ. Interleukin-1 receptor antagonist in the Muckle-Wells syndrome. N Engl J Med 2003;348:2583-4. [MEDLINE]



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