Emerging clinical spectrum of tumor necrosis factor receptor–associated periodic syndrome: Comment on the articles by Hull et al and Dodé et al


Emerging Clinical Spectrum of Tumor Necrosis Factor Receptor–Associated Periodic Syndrome: Comment on the Articles by Hull et al and Dodé et al

To the Editor:

We read with interest the recent reports by Hull et al (1) and Dodé et al (2). We herein describe a family with the R92Q TNFRSF1A mutation, thereby widening the debate initiated by Hull and colleagues regarding the pathologic cause of myalgia in tumor necrosis factor receptor–associated periodic syndrome (TRAPS). Our report also demonstrates a wide spectrum of inflammation manifestations compatible with the proposed enlarging clinical spectrum of TRAPS reported by Dodé et al. However, we suggest the need to clarify diagnostic criteria for TRAPS, particularly in patients with low-penetrance TNFRSF1A mutations.

The patient, a 37-year-old man (index case), presented with a 15-year history of inflammation symptoms of unknown cause. At age 22 years he developed bilateral synovitis of the knees. Seven years later, he developed recurrent abdominal pain, testicular pain, breathlessness, myalgia, and fevers, followed by an erythematous rash. Analysis of the TNFRSF1A gene revealed the R92Q mutation, confirming the diagnosis of TRAPS. Muscle biopsy revealed thickening of small blood vessel walls only, without evidence of myositis or fasciitis. Corticosteroid treatment was ineffective, although twice-weekly administration of subcutaneous etanercept improved the patient's recorded symptoms.

The patient's 64-year-old father, who also had the R92Q TNFRSF1A mutation, was subsequently evaluated. He reported a 16-year history of increasingly severe but constant lower limb muscle cramps and pain, but no history of recurrent fever. Clinical examination revealed tense hard quadriceps muscles and difficulty with hand grip and walking. A complete blood cell count, the erythrocyte sedimentation rate, the C-reactive protein level, serologic evaluation of autoimmunity, and levels of antineutrophil cytoplasmic antibody, immunoglobulins (including IgD), and creatine kinase were normal. Electromyographic studies and magnetic resonance imaging (MRI) of the quadriceps were also normal, but muscle biopsy revealed lymphocytic vasculitis (Figure 1). A dramatic clinical response was achieved with intravenous methylprednisolone, but symptoms were unresponsive to both intravenous cyclophosphamide and etanercept. Repeat muscle biopsy revealed foci of interstitial lymphocytes, one of which was centered around a blood vessel. Subsequent treatment with infliximab was unsuccessful, although oral etoposide produced symptom relief and improved the patient's mobility.

Figure 1.

Lymphocytic vasculitis of muscle with the TNFRSF1A mutation.

The sister of the index case patient was a 36-year-old female with the R92Q TNFRSF1A mutation; she had no history of recurrent fever. At age 14 years, she developed bilateral tenosynovitis of the tibialis anterior that responded to tendon release but was followed by tenosynovitis of the extensor tendons in the foot. By age 17 years, she had developed intermittent cramps in her toes and arthralgia in her fingers and wrists, which has persisted. The acute-phase response, serologic evaluation of autoimmunity, and rheumatoid factor were negative during episodes of tenosynovitis.

Two additional family members with the R92Q TNFRSF1A mutation included a healthy 62-year-old man who had calf pain and cramps on most days, and a healthy 39-year-old man with a history of childhood inguinal hernia repair (a feature previously described in some families with TRAPS). Three family members were negative for TNFRSF1A mutations and had no history of inflammatory disease. The 3 subjects with the R92Q TNFRSFA1 mutation and symptoms of inflammation also reported intervertebral disc prolapse requiring surgery before age 40 years, which was not apparent in the R92Q-negative patients.

We agree with Hull et al that myalgia represents a common finding in TRAPS, but its etiology may be variable. We previously described myalgia in a man with C33Y TRAPS (3). In that patient, muscle biopsy revealed thick-walled small vessels with a focus of interstitial edema only, while MRI of the forearm demonstrated edema in the deep musculature and overlying skin. Dodé et al previously suggested myositis as the cause of myalgia in C30S TRAPS, and we now broaden the spectrum of muscle involvement in patients with TNFRSF1A mutations with our description of lymphocytic vasculitis in muscle. Of particular note, MRI scanning was normal in our subject, despite the fact that he was symptomatic.

The index case patient in this family has a typical history of TRAPS, illustrated by recurrent fever, myalgia, abdominal pain, and breathlessness. The 2 other subjects with inflammation symptoms, however, have histories that are atypical of TRAPS (e.g., absence of fever and, for the patient with lymphocytic vasculitis, a lack of periodicity and late onset of symptoms). Although both subjects had the R92Q TNFRSF1A mutation and no other cause of their symptoms was apparent, we suggest that the diagnosis of TRAPS could be inappropriate for these subjects. We suggest that Dodé and colleagues should exercise the same caution when enlarging the clinical spectrum of TRAPS (i.e., diagnosing TRAPS based on late-onset pericarditis in patients with low- or variable-penetrance mutations, including R92Q and P46L).

The diagnosis of TRAPS is currently based on clinical features associated with TNFRSF1A mutations. Other laboratory indicators, e.g., reduced circulating soluble TNFRSF1A receptor levels and reduced in vitro cleavage of TNFRSF1A from the cell surface, are variable and in isolation are not indicative of TRAPS. We propose that the presence of low-penetrance mutations (e.g., R92Q) in 1% of the normal population (4) requires that the clinical and laboratory diagnostic criteria for TRAPS be refined. This family study, the increased incidence of R92Q in early arthritis, and our finding of 1 of 21 patients with systemic vasculitis (predominantly Wegener's granulomatosis) having the R92Q mutation suggests that R92Q TNFRSF1A predisposes to a wide spectrum of inflammatory disease as a whole, and represents a low-penetrance mutation for TRAPS.

E. Drewe MBBS*, P. C. Lanyon MBBS, DM*, R. J. Powell MBBS, DM*, * Queens Medical Center, Nottingham, UK.