Reliable detection of subtypes of nailfold capillary haemorrhages in childhood-onset systemic lupus erythematosus.

OBJECTIVES: In systemic lupus erythematosus (SLE), it is necessary to obtain biomarkers that predict cardiovascular complications due to premature atherosclerosis, which is related to endothelial dysfunction. Nailfold capillary abnormalities might be a biomarker for endothelial dysfunction. In adults and children with SLE, nailfold capillary haemorrhages have shown to be significantly correlated with disease activity. Recently, different subtypes of capillary haemorrhages have been described in childhood-onset SLE (cSLE). The aim of the current study was to assess the inter- and intra-rater reliability of observations of different subtypes of haemorrhages in cSLE patients. METHODS: Five raters blindly evaluated 140 capillaroscopy images from 35 cSLE-patients (diagnosed according to the 2012 SLICC criteria). The images were assessed qualitatively (present or absent) and quantitatively (total number) on four different subtypes of haemorrhages: 1) punctate extravasations, 2) perivascular haemorrhage, 3) large confluent haemorrhage and 4) non-definable. As subgroups 1) and 2) were interpreted as a continuous spectrum, a post-hoc analysis with "merged" (mean) kappa/ICC was additionally calculated as one sub-group. RESULTS: Qualitative assessment showed a kappa 0.65 (95% CI: 0.60-0.70) for "punctate extravasations and perivascular haemorrhages merged" and a kappa 0.78 (95% CI: 0.72-0.83) for large confluent haemorrhages. For the quantitative assessment, ICC was 0.82 (95% CI: 0.76-0.87) for the "merged groups" and ICC 0.93 (95% CI: 0.91-0.95) for large confluent haemorrhages. CONCLUSIONS: Our study shows that different subtypes of capillary haemorrhages in cSLE-patients could be reliably reproduced by different raters. This confirms our recent observation of perivascular extravasations as a subgroup of capillary haemorrhage in cSLE that might reflect endothelial dysregulation.

Prostaglandin E2 synthesizing enzymes in rheumatoid arthritis B cells and the effects of B cell depleting therapy on enzyme expression.

INTRODUCTION: B cells may play an important role in promoting immune activation in the rheumatoid synovium and can produce prostaglandin E(2) (PGE(2)) when activated. In its turn, PGE(2) formed by cyclooxygenase (COX) and microsomal prostaglandin E(2) synthase 1 (MPGES1) contributes to the rheumatoid arthritis (RA) pathological process. Therapeutic depletion of B cells results in important improvement in controlling disease activity in rheumatoid patients. Therefore we investigated the expression of PGE(2) pathway enzymes in RA B cells and evaluated the effects of B cell depleting therapy on their expression in RA tissue. METHODS: B cells expressing MPGES1 and COX-2 were identified by flow cytometry in in vitro stimulated and control mononuclear cells isolated from synovial fluid and peripheral blood of RA patients. Synovial biopsies were obtained from 24 RA patients before and at two consecutive time points after rituximab therapy. Expression of MPGES1, COX-1 and COX-2, as well as interleukin (IL)-1ß and IL-6, known inducers of MPGES1, was quantified in immunostained biopsy sections using computerized image analysis. RESULTS: Expression of MPGES1 or COX-2 was significantly upregulated upon stimulation of B cells from blood and synovial fluid while control cells displayed no detectable enzymes. In synovial biopsy sections, the expression of MPGES1, COX-1 or COX-2 was resistant to rituximab therapy at 8 or 16 weeks after start of treatment. Furthermore expression of IL-1ß in the synovial tissue remained unchanged, while IL-6 tended to decrease after therapy. CONCLUSIONS: Therapy with B cell depleting agents, although efficient in achieving good clinical and radiographic response in RA patients, leaves important inflammatory pathways in the rheumatoid synovium essentially unaffected.

Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis.

OBJECTIVE: Peripheral spondylarthritis (SpA) is characterized by macrophages that express CD163, a marker of alternative activation (M2). The purpose of this study was to assess whether this differential infiltration with macrophage subsets was associated with a different local inflammatory milieu in SpA as compared with rheumatoid arthritis (RA). METHODS: The effect of SpA and RA synovial fluid (SF) on macrophage polarization was tested in vitro on normal peripheral blood monocytes. SF levels of classically activated macrophage (M1)-derived and alternatively activated macrophage (M2)-derived mediators were analyzed by enzyme-linked immunosorbent assay and multiparameter Luminex bead assay in 47 patients with non-psoriatic SpA, 55 with RA, and 15 with psoriatic arthritis (PsA). Paired synovial biopsy samples were analyzed histologically. RESULTS: SF from SpA patients promoted preferential expression of the M2 markers CD163 and CD200R in vitro, even if SF levels of the prototypical M2-polarizing factors (interleukin-4 [IL-4], IL-13, and IL-10) were not increased as compared with those in RA SF. Despite a similar degree of overall joint inflammation in SpA and RA, SpA synovitis displayed strongly reduced SF levels of M1-derived, but not M2-derived, mediators, such as tumor necrosis factor alpha (TNFalpha), IL-1beta, IL-12p70, and interferon-gamma-inducible protein 10. SF levels of M1-derived mediators correlated well with peripheral joint inflammation in RA, but neither these mediators nor IL-1alpha and IL-17 did so in SpA. Of interest, the SF cytokine profile in PsA, a more destructive subtype of SpA, was similar to that in non-psoriatic SpA. CONCLUSION: The local inflammatory milieu is clearly different in SpA as compared with RA peripheral arthritis. Synovitis in SpA, including that in PsA, is characterized by a selective decrease in M1-derived proinflammatory mediators, such as TNFalpha and IL-1beta.