A 60 year old woman was seen in our primary care clinic with a long history of unusual symptoms.
For the past 15 years she has been experiencing intermittent outbreaks of oral and genital ulcers for which she received multiple courses of acyclovir with good clinical response. In addition she has intermittent erythema with urticarial like rash over her entire body. The rash is raised, usually non-pruritic and often associated with low grade fevers. When the hives resolve they leave purplish bruise like marks on her skin. Biopsy showed urticarial dermatitis, with no evidence of vasculitis. She experiences daily fatigue and generalized weakness. She also has migratory joint pains and occasional myalgias.
An extensive endocrine and rheumatological workup was unrevealing. She also states that she has had hearing difficulty over the past 1-2 years. She was evaluated by a hearing center and was told she had mild hearing loss. She denies any history of pneumonias, skin infections or frequent diarrhea. She does report chronic sinusitis.
She was sent for genetic testing for Muckle-Wells syndrome (MWS) and found to be positive.
Muckle-Wells is part of a group of genetic diseases termed cryopyrin-associated periodic syndromes. While diseases in this category tend to present during childhood, the age of onset in MWS is variable—in some studies ranging from 3-75 years of age. It is a rare condition characterized by periodic skin rash, fever and joint pains. It is caused by a defect in the NLRP3 gene that transcribes the protein cryopyrin which causes its activity to be upregulated. This leads to excessive production of interleukin 1B by macrophages leading to diffuse inflammation. Chronic inflammation overtime in this disease leads to progressive sensorineural hearing loss due to nerve damage, and may also lead to renal failure via amyloid deposition in the kidneys. Intermittent episodes may be provoked by stresses such as cold or heat or fatigue, but often no inciting factors are found. The rash tends to be non-pruritic, associated with mild to moderate fevers and painful, swollen joints.
While our patient’s symptoms invoked a high degree of suspicion for a vasculitic process, her symptoms did not seem to fit one particular type of vasculitis. Biopsy findings of the skin lesions also did not support this diagnosis. This led us to the rare circumstance of a nonvasculitic, vasculitis type illness. While our patient was not able to give us a detailed family history, MWS in general tends to be genetic in an autosomal dominant pattern. She was recently started on Canakinumab which is a monoclonal antibody against interleukin 1B. She has noted improvement in her symptoms with this therapy.
In conclusion, in patients with rash, fever and joint pains of unknown origin, with vasculitis ruled out as a cause, consider MWS especially if associated with hearing loss and a positive family history.