Cryopyrin-Associated Periodic Syndromes: Difficult to Recognize, Diagnose, Treat

CASE 1: Recently, I (RML) received an e-mail from a 32-year-old father of a 21-month-old girl who appeared to have developed an ongoing “rash” that was identical to one he had had for the past 14 years (see Figure 1). He had seen multiple physicians and specialists, including a dermatologist, rheumatologist, allergist, ophthalmologist and otolaryngologist, but no diagnosis had been made. Seeing her with what he described as a non-itchy urticarial eruption caused him to spend the year reading extensively about diagnostic possibilities. He stumbled across Muckle‑Wells syndrome, and it seemed to explain many of his symptoms. These included episodes of arthritis beginning when he was a school-aged child, which lessened in severity as he got older. He also suffered from “migraine” headaches, which similarly lessened in severity as he grew older. He had had a non-itchy urticarial rash and bloodshot eyes (see Figure 2) from the age of 17, and at age 30 he discovered he had significant hearing loss.

His daughter had recently experienced two bouts of severe pain in her legs, and she had the same, consistent urticarial eruption that he has. She also has had an occasional bloodshot eye and a fever.

Both father and daughter were found to carry the R260W pathogenic variant on one allele of the NLRP3 gene.

Several days after commencing treatment with the monoclonal interleukin (IL) 1β antibody, canakinumab, the father wrote: “I went to the store tonight wearing shorts and a T-shirt. Neither one of us had a single spot on our bodies for the past two days (see Figure 3). My daughter has been very cheerful, with a great appetite and is as happy as can be. Two more days like this and I will probably start falling asleep at night in a puddle of my own happy tears.”

Figure 1: Case 1 with multiple urticarial lesions on both thighs prior to treatment.

Figure 2: Case 1 showing conjunctivitis, which was recurrent.

Figure 3: Case 1 two weeks after canakinumab injection showing complete absence of urticarial lesions.

CASE 2: In 2012, a 12-year-old female of North African-Jewish origin was referred for evaluation of frequent episodes of rash, arthritis (mainly ankle), fever, “red” eyes, “migraine” headaches and mouth sores that she had experienced from the first year of her life. Acute-phase reactants were elevated, even between episodes. She had short stature and weight for her age, and was still in the pubertal developmental stage of Tanner I. She was absent from school ~80% of days. Twelve other family members (see Figure 4), including a deceased grandfather, mother, four aunts and four cousins (and since diagnosis, another two first cousins once removed), had short episodes of fever, accompanied by headache, myalgia, arthralgia and an urticarial skin rash. Prior workup found no mutations in the MEFV gene (for familial Mediterranean fever), although she was positive for the HLA-B51 antigen. The provisional diagnosis was familial Behçet’s disease, although there was no response of symptoms to colchicine and azathioprine, and only a mild improvement when corticosteroids were used.