Adult-onset tumour necrosis factor receptor-associated periodic syndrome presenting as transfusion-dependent refractory haemophagocytosis

Adult-onset tumour necrosis factor receptor-associated periodic syndrome presenting as... Rheumatology key message Tumour necrosis factor receptor-associated periodic syndrome may have an adult onset and present with haemophagocytosis requiring IL-1 inhibition. Sir, A 31-year old Caucasian male presented in 2006 with fatigue, night sweats and fever. His symptoms displayed no diurnal variation but worsened with exercise and cold exposure. There was mild splenomegaly without other lymphadenopathy. A full blood count was abnormal: Hb 65 g/l, MCV 91.5 fl, WBC 3.2 × 109/l, platelets 289 × 109/l. Bone marrow biopsy demonstrated haemophagocytosis, hypercellularity and red cell activity with prominent macrophages. Cytogenetics were normal. Following extensive negative investigations, including autoimmune and infectious serology, two fluorodeoxyglucose-CT-PET scans and a lymph node biopsy, he was prescribed prednisolone 60 mg daily with excellent clinical response. However, reduction in steroid dose to below 20 mg daily precipitated return of symptoms, inflammation and anaemia. After 5 years he had developed arthritis of the knees, ankles and small joints of the hands and was steroid and transfusion dependent, receiving >150 U of blood in total. In 2015 a further haematological opinion was sought; repeat bone marrow biopsy showed persistent haemophagocytosis. Rheumatology review confirmed synovitis in both knees and oral MTX (15 mg weekly) was initiated. However, the CRP remained >200 mg/l and anaemia continued. The treatment refractory nature of the illness, fever and arthritis and lack of family history due to adoption raised the possibility of an auto-inflammatory syndrome and the patient was referred to the periodic fever clinic at the UK National Amyloidosis Centre. Genetic sequencing revealed the presence of a mutation in intron 4 of the gene for TNF receptor superfamily 1A (TNFRSF1A), c.473-72 G > A, suggesting the diagnosis of tumour necrosis factor-associated periodic fever syndrome (TRAPS). A trial of the IL-1 antagonist anakinra was instigated (100 mg daily) and within 2 days there was symptomatic improvement, CRP and serum amyloid A levels began to normalize and there was no further transfusion requirement (Fig. 1). Ferritin was statically elevated secondary to presumed transfusional iron overload (1567 μg/l, from 1632 μg/l at anakinra initiation). A repeat bone marrow analysis at 6 months revealed a normocellular marrow, with normal granulopoiesis, megakaryocytes and lymphocytes and considerable reduction in macrophage activity. Continued daily use of anakinra over a 14-month period has led to a sustained complete response, allowing complete corticosteroid withdrawal. Fig. 1 View largeDownload slide Changes in CRP, serum amyloid A protein and haemoglobin before and after initiation of anakinra Hb: haemoglobin; SAA: serum amyloid A protein. Fig. 1 View largeDownload slide Changes in CRP, serum amyloid A protein and haemoglobin before and after initiation of anakinra Hb: haemoglobin; SAA: serum amyloid A protein. This is the first reported case of adult-onset TRAPS presenting with haemophagocytosis. The TRAPS phenotype is broad and diagnosis relies on clinical suspicion supported by evidence of biochemical inflammation and genetic testing. Thirty-three per cent are diagnosed in adulthood and 9.1% reported their first symptoms after the age of 30 [1]. There are no validated diagnostic criteria [2]. Although recurrent discrete inflammatory episodes are commonest, 5% of patients experienced continuous symptoms with exacerbations as in our case. The most common presenting symptom is fever with rigors at onset, with abdominal pain, myalgia, arthralgia, cervical lymphadenopathy, maculopapular rash and periorbital oedema in decreasing order. In the largest published series of 158 cases and elsewhere in the literature haemophagocytic lymphohistiocytosis (HLH) has not previously been reported as a presenting feature in adult-onset TRAPS [1]. There is a single published paediatric case of TRAPS presenting as a refractory HLH in an 11-year-old Turkish girl [3]. She was treated with dexamethasone, ciclosporin A and etoposide with initial recovery but over the subsequent 3 years developed intermittent episodes of remitting fevers and arthralgia and she was referred for rheumatology opinion aged 14 years. Sequencing of the TNFRSF1A gene revealed a known pathogenic mutation and anakinra was started with sustained complete clinical and biochemical remission. Most pathogenic sequence variants of the TNFRSF1A gene are found within exons 2–4 and are missense substitutions disrupting cysteine–cysteine disulphide bonds in the extracellular domain [4]. Intronic mutations within the TNFRSF1A gene causing TRAPS account for 3% of pathogenic mutations in the EUROTRAPS registry [1]. The c.473-72 G > A mutation has been previously reported in association with TRAPS in a mother and son [5]. The mutation is at a splice site leading to a conformational change in the TNFR1 protein. In vivo functional consequences were demonstrated by reduced serum and cell surface TNFR1 levels, increased pro-inflammatory cytokine production, and elevated basal NF-κB activation in peripheral blood mononuclear cells. The mechanisms by which mutations in the TNFRSF1A gene result in inflammation remain poorly understood. Pathogenic mutations appear to lead to misfolding of the TNFR1 protein, which accumulates in the endoplasmic reticulum, leading to defective autophagy, which in turn induces excessive IL-1β secretion via activation of the NLRP3 inflammasome [6, 7]. This case suggests that the diagnosis of TRAPS should be considered in cases of unexplained refractory HLH and highlights the fact that rheumatologists should be alert to the adult onset of heritable auto-inflammatory diseases. Acknowledgements Author contributions: T.Y.: wrote the manuscript and designed the figure; M.B.K.: edited the manuscript; J.R.S.: revised the manuscript, and helped to design the figure; D.R.: edited the manuscript and performed genetic sequencing; H.T.: edited the manuscript and performed genetic sequencing; H.L.: supervised and edited the manuscript; N.S.: supervised and edited the manuscript. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Lachmann HJ, Papa R, Gerhold K et al.   The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis  2014; 73: 2160– 7. Google Scholar CrossRef Search ADS PubMed  2 Kallinich T, Gattorno M, Grattan CE et al.   Unexplained recurrent fever: when is autoinflammation the explanation? Allergy  2013; 68: 285– 96. Google Scholar CrossRef Search ADS PubMed  3 Horneff G, Rhouma A, Weber C, Lohse P. Macrophage activation syndrome as the initial manifestation of tumour necrosis factor receptor 1-associated periodic syndrome (TRAPS). Clin Exp Rheumatol  2013; 31(3 Suppl 77): 99– 102. 4 McDermott MF, Aksentijevich I, Galon J et al.   Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell  1999; 97: 133– 44. Google Scholar CrossRef Search ADS PubMed  5 Churchman SM, Church LD, Savic S et al.   A novel TNFRSF1A splice mutation associated with increased nuclear factor kappaB (NF-kappaB) transcription factor activation in patients with tumour necrosis factor receptor associated periodic syndrome (TRAPS). Ann Rheum Dis  2008; 67: 1589– 95. Google Scholar CrossRef Search ADS PubMed  6 Bachetti T, Chiesa S, Castagnola P et al.   Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann Rheum Dis  2013; 72: 1044– 52. Google Scholar CrossRef Search ADS PubMed  7 Simon A, Park H, Maddipati R et al.   Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A  2010; 107: 9801– 6. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Adult-onset tumour necrosis factor receptor-associated periodic syndrome presenting as transfusion-dependent refractory haemophagocytosis

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Oxford University Press
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© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
1462-0324
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1462-0332
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10.1093/rheumatology/kex427
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Abstract

Rheumatology key message Tumour necrosis factor receptor-associated periodic syndrome may have an adult onset and present with haemophagocytosis requiring IL-1 inhibition. Sir, A 31-year old Caucasian male presented in 2006 with fatigue, night sweats and fever. His symptoms displayed no diurnal variation but worsened with exercise and cold exposure. There was mild splenomegaly without other lymphadenopathy. A full blood count was abnormal: Hb 65 g/l, MCV 91.5 fl, WBC 3.2 × 109/l, platelets 289 × 109/l. Bone marrow biopsy demonstrated haemophagocytosis, hypercellularity and red cell activity with prominent macrophages. Cytogenetics were normal. Following extensive negative investigations, including autoimmune and infectious serology, two fluorodeoxyglucose-CT-PET scans and a lymph node biopsy, he was prescribed prednisolone 60 mg daily with excellent clinical response. However, reduction in steroid dose to below 20 mg daily precipitated return of symptoms, inflammation and anaemia. After 5 years he had developed arthritis of the knees, ankles and small joints of the hands and was steroid and transfusion dependent, receiving >150 U of blood in total. In 2015 a further haematological opinion was sought; repeat bone marrow biopsy showed persistent haemophagocytosis. Rheumatology review confirmed synovitis in both knees and oral MTX (15 mg weekly) was initiated. However, the CRP remained >200 mg/l and anaemia continued. The treatment refractory nature of the illness, fever and arthritis and lack of family history due to adoption raised the possibility of an auto-inflammatory syndrome and the patient was referred to the periodic fever clinic at the UK National Amyloidosis Centre. Genetic sequencing revealed the presence of a mutation in intron 4 of the gene for TNF receptor superfamily 1A (TNFRSF1A), c.473-72 G > A, suggesting the diagnosis of tumour necrosis factor-associated periodic fever syndrome (TRAPS). A trial of the IL-1 antagonist anakinra was instigated (100 mg daily) and within 2 days there was symptomatic improvement, CRP and serum amyloid A levels began to normalize and there was no further transfusion requirement (Fig. 1). Ferritin was statically elevated secondary to presumed transfusional iron overload (1567 μg/l, from 1632 μg/l at anakinra initiation). A repeat bone marrow analysis at 6 months revealed a normocellular marrow, with normal granulopoiesis, megakaryocytes and lymphocytes and considerable reduction in macrophage activity. Continued daily use of anakinra over a 14-month period has led to a sustained complete response, allowing complete corticosteroid withdrawal. Fig. 1 View largeDownload slide Changes in CRP, serum amyloid A protein and haemoglobin before and after initiation of anakinra Hb: haemoglobin; SAA: serum amyloid A protein. Fig. 1 View largeDownload slide Changes in CRP, serum amyloid A protein and haemoglobin before and after initiation of anakinra Hb: haemoglobin; SAA: serum amyloid A protein. This is the first reported case of adult-onset TRAPS presenting with haemophagocytosis. The TRAPS phenotype is broad and diagnosis relies on clinical suspicion supported by evidence of biochemical inflammation and genetic testing. Thirty-three per cent are diagnosed in adulthood and 9.1% reported their first symptoms after the age of 30 [1]. There are no validated diagnostic criteria [2]. Although recurrent discrete inflammatory episodes are commonest, 5% of patients experienced continuous symptoms with exacerbations as in our case. The most common presenting symptom is fever with rigors at onset, with abdominal pain, myalgia, arthralgia, cervical lymphadenopathy, maculopapular rash and periorbital oedema in decreasing order. In the largest published series of 158 cases and elsewhere in the literature haemophagocytic lymphohistiocytosis (HLH) has not previously been reported as a presenting feature in adult-onset TRAPS [1]. There is a single published paediatric case of TRAPS presenting as a refractory HLH in an 11-year-old Turkish girl [3]. She was treated with dexamethasone, ciclosporin A and etoposide with initial recovery but over the subsequent 3 years developed intermittent episodes of remitting fevers and arthralgia and she was referred for rheumatology opinion aged 14 years. Sequencing of the TNFRSF1A gene revealed a known pathogenic mutation and anakinra was started with sustained complete clinical and biochemical remission. Most pathogenic sequence variants of the TNFRSF1A gene are found within exons 2–4 and are missense substitutions disrupting cysteine–cysteine disulphide bonds in the extracellular domain [4]. Intronic mutations within the TNFRSF1A gene causing TRAPS account for 3% of pathogenic mutations in the EUROTRAPS registry [1]. The c.473-72 G > A mutation has been previously reported in association with TRAPS in a mother and son [5]. The mutation is at a splice site leading to a conformational change in the TNFR1 protein. In vivo functional consequences were demonstrated by reduced serum and cell surface TNFR1 levels, increased pro-inflammatory cytokine production, and elevated basal NF-κB activation in peripheral blood mononuclear cells. The mechanisms by which mutations in the TNFRSF1A gene result in inflammation remain poorly understood. Pathogenic mutations appear to lead to misfolding of the TNFR1 protein, which accumulates in the endoplasmic reticulum, leading to defective autophagy, which in turn induces excessive IL-1β secretion via activation of the NLRP3 inflammasome [6, 7]. This case suggests that the diagnosis of TRAPS should be considered in cases of unexplained refractory HLH and highlights the fact that rheumatologists should be alert to the adult onset of heritable auto-inflammatory diseases. Acknowledgements Author contributions: T.Y.: wrote the manuscript and designed the figure; M.B.K.: edited the manuscript; J.R.S.: revised the manuscript, and helped to design the figure; D.R.: edited the manuscript and performed genetic sequencing; H.T.: edited the manuscript and performed genetic sequencing; H.L.: supervised and edited the manuscript; N.S.: supervised and edited the manuscript. Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest. References 1 Lachmann HJ, Papa R, Gerhold K et al.   The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis  2014; 73: 2160– 7. Google Scholar CrossRef Search ADS PubMed  2 Kallinich T, Gattorno M, Grattan CE et al.   Unexplained recurrent fever: when is autoinflammation the explanation? Allergy  2013; 68: 285– 96. Google Scholar CrossRef Search ADS PubMed  3 Horneff G, Rhouma A, Weber C, Lohse P. Macrophage activation syndrome as the initial manifestation of tumour necrosis factor receptor 1-associated periodic syndrome (TRAPS). Clin Exp Rheumatol  2013; 31(3 Suppl 77): 99– 102. 4 McDermott MF, Aksentijevich I, Galon J et al.   Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell  1999; 97: 133– 44. Google Scholar CrossRef Search ADS PubMed  5 Churchman SM, Church LD, Savic S et al.   A novel TNFRSF1A splice mutation associated with increased nuclear factor kappaB (NF-kappaB) transcription factor activation in patients with tumour necrosis factor receptor associated periodic syndrome (TRAPS). Ann Rheum Dis  2008; 67: 1589– 95. Google Scholar CrossRef Search ADS PubMed  6 Bachetti T, Chiesa S, Castagnola P et al.   Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann Rheum Dis  2013; 72: 1044– 52. Google Scholar CrossRef Search ADS PubMed  7 Simon A, Park H, Maddipati R et al.   Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A  2010; 107: 9801– 6. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

RheumatologyOxford University Press

Published: Mar 1, 2018

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