Autologous stem cell transplantation in juvenile idiopathic
arthritis : regaining immunological tolerance and arresting
disease progression
Brinkman, D.M.C.
Citation
Brinkman, D. M. C. (2007, November 14). Autologous stem cell
transplantation in juvenile idiopathic arthritis : regaining immunological
tolerance and arresting disease progression. Retrieved from
https://hdl.handle.net/1887/12432
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thesis in the Institutional Repository of the University
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Chapter 5
Macrophage activation syndrome after
autologous stem cell transplantation for
systemic juvenile idiopathic arthritis.
R. ten Cate1, D.M.C. Brinkman1 M.A.J. van Rossum1, A.C. Lankester1, R.G.M. Bredius1, R.M. Egeler1, M.J.D. van Tol2, J.M. Vossen1
1 Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
2 Laboratory ofImmunology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
Eur J Pediatr. 2002;161:685-686.
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The macrophage activation syndrome (MAS) (1) represented by haemophagocytosis can develop as a secondary phenomenon in systemic juvenile idiopathic arthritis (sJIA), induced by viral infections or medication (2). It is associated with sudden deterioration of clinical condition, persistent fever, lymphadenopathy, hepatosplenomegaly, depression of all blood cell lines, sudden decrease of erythrocyte sedimentation rate (ESR), raised liver enzymes, high triglycerides, hypofibrinogenaemia and fibrin degradation products. Haemophagocytosis in bone marrow or other tissues/organs confirms the diagnosis. High dose steroids, cyclosporin and recently etanercept (3) have been used as treatment for MAS in individual patients but mortality remains high.
A 3-years-old boy with sJIA had persistent disease activity despite indomethacin (2.5 mg/kg per day), prednisone (1 mg/kg per day), methotrexate (up to 1 mg/kg subcutaneously once a week) and cyclosporin (5 mg/kg per day) over time resulting in stunted growth and decreased bone mineral density. Two years after disease onset, an experimental autologous stem cell transplantation (ASCT) was performed. Bone marrow was enriched for CD34 positive cells and cryopreserved.
Throughout the conditioning and during myelo-reconstitution corticosteroids and indomethacin were continued. Conditioning was performed using antithymocyte globulin (rabbit ATG, Merieux, 5 mg/kg i.v.) for four days, i.v. cyclophosphamide (50 mg/kg) for four days and unfractionated total body irradiation (4 Gy). The re-infused graft contained 1.5 x 106 /kg CD34 positive cells and 2.0 x 104 /kg T cells. On day 9, sepsis therapy was started because of fever and an elevated CRP (300 mg/l).
A coagulase-negative staphylococcus was cultured from the peripheral blood. Although clinically improved the patient remained febrile. Consecutive cultures were negative. Adenovirus type 3 was cultured from the stools, but adenovirus-specific PCR on serum was negative. On day 18 his clinical condition abruptly deteriorated: he developed oedema, cyanosis and dyspnoea. The chest X-ray film was normal. Haemoglobin dropped from 7.0 mmol/l to 5.6 mmol/l, platelets from 57x 109/l to 11 x 109/l, leukocytes were 0.7 109/l day 16 with 6% lymphocytes. ASAT and ALAT were both raised as was serum LDH (over 4000 IU/l). Hypofibrinogenaemia and hypertriglyceridaemia were present.
Within an hour he became respiratory and circulatory insufficient. Reanimation was unsuccessful.
Autopsy showed a hypertrophic heart with an influx of CD8 positive T cells, chronic pericarditis and a subendocardial infarction. In the enlarged spleen extensive haemophagocytosis was observed.
At autopsy the bone marrow was hypoplastic showing focal repopulation. Haemophagocytosis was observed in the bone marrow, however in a lesser extent compared to the spleen. PCR for adenovirus and other viruses was negative in several organs. No bacteria or fungi could be cultured.
The clinical picture evolved so fulminantly that therapeutic measures failed.
The pathophysiology of MAS is still unclear. It has been described after allogeneic bone marrow transplantation for leukaemia (4). In primary Familial Hemophagocytic Lymphohistiocytosis (FHL) (5) a genetic cause is found (in approximately 30 % of the patients there is a mutation in the perforin gene). Similarly in sJIA, a genetic abnormality (a polymorphism of the macrophage migration inhibitory factor) might explain the loss of cytokine regulation (6).
Continuous active systemic disease, bacteraemia and ASCT performed with a strong (4.5 log) T-cell depleted graft (no natural killer and cytotoxic T cells) might have contributed to the development of MAS in our patient. Although no detailed data on immune reconstitution of the patient are available,
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leukocyte counts at day 16 were 0.7 x 109/l, consisting of only 6 % lymphocytes. Subsequently, T cells that eventually might regulate macrophage (de)activation (1) were low to absent. However, no phenotyping of the lymphocytes was performed in this stage. Immunoglobulins pre-ASCT were normal. No data post-ASCT are available. In view of the fatal course of our patient and a similar patient in another hospital with biological features of MAS, the protocol for ASCT in children with JIA was adapted.
References.
1. Sawhney S, Woo P, Murray KJ. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders. Arch Dis Child 2001; 85:421-426.
2. Stephan JL, Kone-Paut I, Galambrun C, Mouy R, Bader-Meunier B, Prieur AM. Reactive haemophagocytic syndrome in children with inflammatory disorders. A retrospective study of 24 patients. Rheumatology (Oxford) 2001; 40(11):1285-92.
3. Prahalad S, Bove KE, Dickens D, Lovell DJ, Grom AA. Etanercept in the treatment of macrophage activation syndrome. J Rheumatol 2001;28(9):2120-2124.
4. Sato M, Matsushima T, Hatsumi N, Kim K, Sakuraya M, Saito T et al. Fulminant, CMV-associated, hemophagocytic syndrome following unrelated bone marrow transplantation. Bone Marrow Transplan- tation 1998; 22:1219-1222.
5. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 1999; 286(5446):1957-1959.
6. Donn RP, Shelley E, Ollier WER, Thomson W and the British Paediatric Rheumatology Study Group. A novel 5’-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic- onset juvenile idiopathic arthritis. Arthritis Rheum 2001; 44(8):1782-1785.
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