Distinguishing between the innate immune response due to ocular inflammation and infection in a child with juvenile systemic granulomatous disease treated with anti-TNF- monoclonal antibodies

Abstract

Sir, Early-onset sarcoidosis (EOS) is often diagnosed if there is granulomatous involvement of an organ or sometimes as a diagnosis of exclusion in a child presenting with fever, rash and swollen joints. Recent evidence points to the fact that EOS is synonymous with juvenile systemic granulomatous disease (JSGD), also eponymously known as Blau syndrome (BS) or Jabs disease [1, 2]. They share clinical features of uveitis, dermatitis and arthritis, and are caused by inherited (BS) or sporadic (EOS) mis-sense mutations in the NACHT [NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC Class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein)] protein domain of the NOD2 (CARD15) gene, a major orchestrator during innate immune responses [1, 3]. Granulomatous disease of any origin may cause a panuveitis characterized by inflammation in the anterior and vitreous chambers and also the choroid or retina. We report a case of JSGD with a novel mutation and highlight the difficulty in distinguishing between granulomatous inflammation and infection in ocular inflammation. The importance of this is magnified when anti-TNF-α agents are implicated. We also speculate on mechanisms by which infection and inflammation may share a similar clinical profile. A 15-month-old Caucasian male, C.P., presented with a 2-week history of spiking fevers, a follicular, erythematous rash and symmetrical polyarthritis affecting the small joints of hand, ankles, knees and wrists and hips (Fig. 1). He had normocytic anaemia (7 g/dl), normal ferritin and elevated ESR and CRP (100 mm; 200 mg/l). Autoantibodies including RF and ANA were negative and infection was excluded. Biopsies were not taken from skin or SF. Fig. 1 Synovitis of the ankles and follicular rash. A clinical diagnosis of systemic-onset JIA was made initially followed by treatment with MTX, IVIG and anakinra alongside frequent, intermittent courses of oral, IA and i.v. CS therapy for recurrences of rash and arthritis over the next 4 years. Consequently, etanercept and MTX were instituted when C.P. was 6 years old. Etanercept was stopped upon developing bilateral anterior uveitis [4]. In order to control both ocular disease and arthritis, adalimumab was started but 8 weeks later, C.P. was admitted as an emergency with papilloedema, headache and raised CSF pressure, CSF leucocyte count and protein. Investigations for tuberculosis were negative including CSF PCR, CSF and blood culture, ELISpot™ (Mabtech, Nacka, Sweden) IFN-γ-release assay (IGRA) and TST (tuberculin skin test). Despite negative results, he was treated empirically with a full course of quadruple therapy for tuberculous meningitis and adalimumab was stopped. Ocular inflammation relapsed during anti-tuberculous therapy with reduction of vision attributable to panuveitis [4] with choroidal infiltrate; this responded to oral CS and MTX. Aqueous fluid was sampled under general anaesthetic for MTb PCR but the sample volume was insufficient. At this stage, we revised the differential to consider inflammatory granulomatous diseases as neither granulomatous ocular disease nor recurrent rash are consistent with a diagnosis of JIA. Venous blood samples from C.P. and his biological parents were obtained for genomic DNA extraction and genotyping of the NOD2 exonic regions. This analysis revealed a novel, de novo heterozygous mutation at position c.1558 C > T in exon 4 encoding the amino acid substitution H520Y in C.P., confirming a diagnosis of JSGD. Following reported success with infliximab and its more potent TNF-α blockade, C.P. was restarted on infliximab after 9 months of anti-tuberculous therapy normal lung imaging and repeated negative ELISpot™. C.P. is now 8 years old, he remains in drug-induced remission for joint and ocular disease and has vision of 6/5 in both eyes.