Myeloid related protein 8 and 14 secretion reflects phagocyte activation and correlates with disease activity in juvenile idiopathic arthritis treated with autologous stem cell transplantation. (Extended Report).

Objectives: To determine whether myeloid related proteins (MRP8/MRP14), a complex of two S100 proteins related to neutrophil and monocyte activation, might be used as a marker for disease activity, and as an early indicator of relapse in juvenile idiopathic arthritis.

Patients and methods: A group of 12 patients who underwent an autologous haematopoietic stem cell transplantation (ASCT) for refractory juvenile idiopathic arthritis (JLA) were studied. MRP8/MRP14 serum concentrations were determined by a sandwich enzyme linked immunosorbent assay (ELISA) as described. Improvement from baseline was described by a definition of improvement employing a core set of criteria as detailed previously by Giannini.

Results: After ASCT, MRP8/MRP14 serum concentrations in JIA showed a positive correlation with the Child Health Assessment Questionnaire (CHAQ; r=0.80) and erythrocyte sedimentation rate (r=0.45), but not with the total leucocyte count (r=0.26). Mean MRP8/MRP14 serum concentrations dropped markedly in the first three months after ASCT (p=0.0039) and clinical parameters of disease activity such as CHAQ markedly improved (p=0.0039). During a transient relapse there was an increase in MRP8/MRP 14.

Conclusions: MRP8/MRP14 serum concentration can be used as a marker for disease activity in patients who receive an ASCT for refractory JIA. This indicates a role of macrophage activation in the pathogenesis of JIA. The occurrence of MAS in three patients in this study was not preceded by significant changes in MRP8/MRP14 concentration.

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Myeloid related proteins 8 (MRP8) and MRP14 are two S100 proteins specific to myeloid cells and expressed in neutrophils and monocytes. Although their exact function is not yet known, MRP8 and MRP14 may play a part in immobilising myeloid cells to endothelium. It has been suggested that the MRP8/MRP14 complex may modulate myeloid cell maturation. (1) MRP8 and MRP14 have a distinct role in neutrophil and monocyte activation. (2-5) Recently, Frosch et al found that MRP8 and MRP14 are specifically released during the interaction of monocytes with inflammatory activated endothelium, probably at sites of local inflammation. They showed that the serum concentrations represent a useful marker for monitoring local inflammation in oligoarticular juvenile idiopathic arthritis (JIA). (6) We extended this study to other forms of JIA--namely, the polyarticular and systemic subtypes.

Autologous haematopoietic stem cell transplantation (ASCT) has been described as a possible treatment for severe autoimmune disease refractory to conventional treatment, such as combinations of non-steroidal anti-inflammatory drugs, anti-inflammatory drugs such as methotrexate (MTX), cyclosporin A, cyclophosphamide, prednisone, and tumour necrosis factor (TNF) receptor blocking agents. (7-16) A recent study reported a follow up of 3-34 months of 12 children with severe and longstanding JIA refractory to conventional treatment who received an ASCT. (9) These patients showed a marked and sustained decrease in arthritis severity as expressed in core set criteria for JIA activity and were therefore also included in this study.

We here report the results of serial determination of MRP serum concentrations and disease activity in a group of 12 patients with JIA (nine with systemic JIA and three with polyarticular JIA) before and after ASCT.

PATIENTS AND METHODS

Patients and ASCT

The inclusion criteria for an ASCT in patients with JIA are as described by Wulffraat et al. (9 10) These criteria were failure to respond to at least two disease modifying antirheumatic drugs (DMARDs; including high dose MTX intramuscularly 1 mg/kg/wk), failure to respond to TNF[alpha] blocking agents, steroid dependency (> 0.3 mg/kg/day needed to control symptoms), unacceptable toxicity to DMARDs or corticosteroids. Exclusion criteria were cardiorespiratory insufficiency, chronic active infection such as Epstein-Barr virus, cytomegalovirus, toxoplasmosis, spiking fever despite steroids, end stage disease (Steinbrocker IV), or poor compliance. All patients met the described inclusion criteria.

The conditioning regimen and ASCT have been described previously. (9 10) Haematopoietic stem cells were taken by conventional bone marrow aspiration. In patients 1-7 and 11 the graft was purged by two cycles of T cell depletion with anti-CD2 and anti-CD3 antibodies, yielding a final suspension with a CD34 positive stem cell count of 0.5-6.5x[10.sup.6] CD34 cells/kg and <5x[10.sup.5] CD3 cells/kg. In patients 8-10 and 12 the graft …