An unusual presentation of purine nucleoside phosphorylase deficiency mimicking systemic juvenile idiopathic arthritis complicated by macrophage activation syndrome

Abstract

Background: Systemic juvenile idiopathic arthritis (sJIA) is an inflammatory condition that presents with fever, rash and arthritis. At onset systemic features are predominant and the diagnosis may be a challenge. Secondary hemophagocytic lymphohistiocytosis (sHLH) forms may be associated with different disorders, including rheumatic diseases, and this form is called macrophage activation syndrome (MAS). CXCL9 levels, a chemokine induced by IFNγ, are significantly elevated in patients with sHLH or MAS and are correlated with laboratory features of disease activity. High levels of IL-18 have been reported in patients with MAS during sJIA, as well as in some patients with sHLH and IL-18 is indeed known to induce IFNγ production.

Findings: We report a patient with a clinical presentation highly suggestive for systemic juvenile idiopathic arthritis (sJIA) onset complicated by MAS, and was later diagnosed with purine nucleoside phosphorylase (PNP)-deficiency with HLH. Some unusual features appeared when HLH was controlled and further investigations provided the correct diagnosis. Serum CXCL9 and IL-18 levels were found markedly elevated at disease onset, during the active phase of MAS and decreased progressively during the course.

Conclusion: The reported case underlines the potential difficulties in discriminating sJIA from other causes of systemic inflammation. Furthermore, this supports the notion that especially in young children with a sJIA-like disease other mimicking conditions should be actively sought for. CXCL9 and IL-18 levels suggested that patients with PNP-deficiency may have a subclinical activation of the IFNγ pathway and indeed they are predisposed to develop sHLH.

Keywords: Chemokines; Interferons; Interleukins; Juvenile idiopathic arthritis; Macrophage activation syndrome.

Fig. 1

Immunological functional tests of the patient. Intracellular expression of perforin in CD56⁺ NK cells was assessed by flow cytometry (a). Degranulation potential of CD56⁺ NK cells was assessed by flow cytometry after overnight co-culture with target cells K562. Plots show the surface expression of CD107a on unstimulated and stimulated NK cells (b). Lymphocytes subsets were analysed by flow cytometry: T cells were identified as CD3⁺ CD56⁻ CD19⁻; within the CD3⁺ gate, γδ-T cells were gated as CD3⁺ γδ-TCR⁺ αβ-TCR⁻ (c). T cell proliferation was assessed by a standard [³H]-thymidine incorporation assay following stimulation with anti-CD3 (OKT3) or PHA (d). The results are shown for first determination while on 2 mg/Kg of methylprednisolone. They were repeated on a lower dose of oral prednisone (0.25 mg/Kg) with similar results