Clinical Immunology Unit, Queens Medical Centre, Nottingham NG7 2UH, UK
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Abstract |
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Methods. Seven patients with a clinical and genetic diagnosis of TRAPS received subcutaneous etanercept for 24 weeks. One of these patients had previously received an intravenous infusion of p55TNFr-Ig. Therapeutic response was assessed by comparing corticosteroid requirement, acute-phase response and an established scoring system over 20 weeks, both on and off etanercept.
Results. Etanercept was well tolerated. The five corticosteroid-responsive patients required significantly less corticosteroids and demonstrated reductions in acute-phase reactants on etanercept. The two patients not requiring corticosteroids had small reductions in disease activity scores. The effect of p55TNFr-Ig in a single patient with TRAPS remains unclear.
Conclusions. Etanercept does not abolish inflammatory attacks but improves disease activity allowing corticosteroid reduction. Etanercept may be clinically useful in replacing or reducing steroid requirements in the treatment of TRAPS. A formal trial of etanercept to establish its role in clinical management is indicated.
KEY WORDS: Tumour necrosis factor associated periodic syndrome, Etanercept, p55TNFr-Ig.
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Introduction |
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Patients and methods |
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p55TNFr-Ig treatment in patient 1
He was treated with a single 100 mg i.v. infusion of a p55TNFr-Ig chimeric molecule containing the extracellular domain of the human TNFRSF1A coupled to the hinge CH2 and CH3 constant regions of human IgG1 heavy chain (gift from Professor H. Waldmann and Dr G. Hale, Oxford Therapeutic Antibody Centre). The patient had received no immunosuppressive agents except corticosteroids in the 3 months prior to p55TNFr-Ig and was given an infusion of p55TNFr-Ig on the fourth day of an acute attack of TRAPS. The patient had discontinued corticosteroids to facilitate assessment of benefit due to p55TNFr-Ig. Acute-phase response and corticosteroid use was documented for 3 months prior to and after p55TNFr-Ig.
Patient details
Patient 1 was a 48-yr-old male with a C33Y TNFRSF1A mutation (C33Y TRAPS) with recurrent episodes of fevers, myalgias, lymphadenopathy, ptosis, migratory erythematous rash, arthralgia, and chest and abdominal pain since 2 yr of age. Over the last 7 years his condition had deteriorated with increasing frequency and severity of attacks resulting in regular high-dose corticosteroid use. His persistent poor health had resulted in him being unable to sustain regular employment. Previous treatments including oral azathioprine, methotrexate, cyclosporin, thalidomide and i.v. cyclophosphamide gave no benefit. He initially received i.v. p55TNFr-Ig. Following p55TNFr-Ig therapy he was found to have developed hypoadrenalism, presumed secondary to prolonged corticosteroid use, and thereafter received at least 5 mg of prednisolone daily. Following a 3-month washout period he underwent two repeat cycles of 24 weeks on and off etanercept. A subsequent course of two doses of i.v. infliximab at 5 mg/kg was unhelpful.
Patient 2 was a 25-yr-old female with C33Y TRAPS with fever, abdominal pain and vomiting since 18 months of age, regularly requiring 2030 mg of prednisolone daily. In May 1999, her TRAPS became complicated by the development of nephrotic syndrome and a serum amyloid P (SAP) scan confirmed type AA amyloidosis [3].
Patient 3 was a 55-yr-old male with C33Y TRAPS characterized by abdominal pain, myalgias and rashes approximately every 6 weeks. Previous unsuccessful treatments included colchicine, azathioprine, cyclosporin and thalidomide.
Patient 4 was a 33-yr-old female with C33Y TRAPS comprising fevers, myalgias and rash requiring intermittent, albeit frequent, doses of oral prednisolone. This was associated with persisting anaemia and high acute-phase response. The birth of her first child created increased problems with activities of daily living such as lifting. Her attacks had not been improved by colchicine, i.v. immunoglobulin, cyclosporin or tacrolimus.
Patient 5 was a 31-yr-old female with C33Y TRAPS since 20 yr of age and has had regular attacks with fever, abdominal pain, myalgia and lymphadenopathy. Colchicine produced no benefit and was withdrawn owing to gastrointestinal side-effects and cyclosporin resulted in unacceptable hirsutism.
Patient 6 was a 37-yr-old male with R92Q TRAPS. At the age of 29 yr he developed severe attacks of fevers, rigors and abdominal pain recurring every few years. Other frequent symptoms have included calf pain, breathlessness, testicular pain, fatigue and the development of a rash for the first time at 37 yr. He was unresponsive to corticosteroids including a trial of three 1000 mg methylprednisolone infusions. CRP and ESR were often normal during symptomatic attacks.
Patient 7 was a 5-yr-old boy with R92Q TRAPS since 1 yr of age and has suffered with frequent febrile attacks with abdominal pain, diarrhoea, vomiting, conjunctival injection, ptosis, calf pain and lymphadenopathy. His symptoms are not steroid responsive. Owing to problems with venesection, CRP only was measured five times on etanercept and on three occasions off treatment.
Statistical analysis
Corticosteroid use in 20-week periods on and off etanercept in C33Y TRAPS (all corticosteroid-responsive patients) was compared using the Wilcoxon Pair Signed Rank test. The MannWhitney test (two-tailed) was used to compare ESR and CRP values in study periods on and off etanercept for C33Y TRAPS, and also for patient scoring systems in all patients. All tests were performed by SPSS.
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Results |
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p55TNFr-Ig treatment
Patient 1 received p55TNFr-Ig (day 1) on the fourth day of a flare of TRAPS comprising fevers maximally up to 38.8°C and myalgia. No side-effects were apparent although his attack continued with fevers, rigors, sweating, myalgia, conjunctivitis, nausea and abdominal pain. On days 4 and 5 he received 30 mg of oral prednisolone daily without benefit. On day 6 his severe and persisting symptoms were improved by a 1000 mg methylprednisolone infusion. Three days later, however, he developed further myalgia and abdominal pain and commenced 35 mg of oral prednisolone daily. Oral prednisolone was reduced over the next 8 weeks to 10 mg daily whilst he described less severe but continued myalgia and abdominal pain. After 1 week on 10 mg of prednisolone daily (11 weeks after p55TNFr-Ig), he developed a further flare of TRAPS. His acute-phase response reflected his clinical attacks with a CRP of 242 mg/l and ESR >100 mm/h peaking on day 3 (Fig. 1).
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Discussion |
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Etanercept appears to be safe in the short term in TRAPS. We have also demonstrated significantly reduced corticosteroid use in the five C33Y TRAPS patients with etanercept. Response to etanercept was harder to assess in the two R92Q TRAPS patients not using corticosteroids.
Any study of a periodic fever syndrome is problematic owing to its low prevalence and the unpredictable frequency and severity of attacks. A 24-week interval on etanercept was selected to enable inclusion of patients with differing attack frequencies. Patient 1 demonstrated marked differences in corticosteroid use on etanercept during cycle 1 and 2. This could reflect fluctuation in disease activity, although declining responsiveness to etanercept over time cannot be excluded. This case series evaluated corticosteroid intake that may conceivably alter natural history of disease and hence affect scoring systems, acute-phase response and days of fever. The clinical need for methylprednisolone, only off etanercept, could mask greater differences between these parameters on and off treatment.
The availability of a p55TNFr-Ig fusion protein for patients with a mutation in this receptor resulted in us initially giving a single infusion of p55TNFr-Ig to our most severely affected TRAPS patient. The p55TNFr-Ig infusion appeared well tolerated, although administration during an attack could potentially mask side-effects. Following p55TNFr-Ig treatment the patient continued with one of his severest attacks of TRAPS. The subsequent finding that he had become steroid dependent raises the possibility that this attack could have been exacerbated or even precipitated by discontinuation of corticosteroids immediately prior to the p55TNFr-Ig infusion. Once the patient was established on permanent oral corticosteroids (day 10 onwards), he continued to experience TRAPS-related symptoms. Figure 1 suggests improvement in CRP following the resolution of the initial severe attack, although these results need to be interpreted in the context of concurrent corticosteroid use. A single infusion of p55TNFr-Ig may improve symptoms for up to 8 weeks in rheumatoid arthritis (unpublished data J.D. Isaacs). The p55TNFr-Ig could therefore have provided some benefit to this patient in weeks 210 when corticosteroid withdrawal was not a complicating factor. The effect of p55TNFr-Ig given during an acute attack of TRAPS is inconclusive and p55TNFr-Ig has also not been studied on a prophylactic basis in TRAPS.
This small case series reflects severe TRAPS, with p55TNFr-Ig being assessed in our most severely affected patient. The use of p55TNFr-Ig could be considered for other patients with TRAPS, although possibly using prophylactic administration. Our data demonstrating reduction in corticosteroid use support the use of etanercept in TRAPS. This could be of great value to patients who have failed with multiple immunosuppressive strategies. Different TNFRSF1A mutations may affect treatment response, but a larger study is warranted to assess the place of etanercept in the treatment of TRAPS.
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Acknowledgments |
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Notes |
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References |
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