Autoinflammatory Disease Reloaded: A Clinical Perspective

Our understanding of the etiology of autoinflammatory disease is growing rapidly. Recent advances offer new opportunities for therapeutic intervention and suggest that the definition of what constitutes an autoinflammatory disease should be reassessed

The histological and immunohistochemical features of the skin lesions in CANDLE syndrome

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a newly characterized autoinflammatory disorder, caused by mutations in PSMB8. It is characterized by early-onset fevers, accompanied by a widespread, violaceous and often annular, cutaneous eruption. While the exact pathogenesis of this syndrome is still obscure, it is postulated that the inflammatory disease manifestations stem from excess secretion of interferons. Based on preliminary blood cytokine and gene expression studies, the signature seems to come mostly from type I interferons, which are proposed to lead to the recruitment of immature myeloid cells into the dermis and subcutis. In this study, we systematically analyzed skin biopsies from 6 CANDLE syndrome patients by routine histopathology and immunohistochemistry methods. Skin lesions showed the presence of extensive mixed dermal and subcutaneous inflammatory infiltrate, composed of mononuclear cells, atypical myeloid cells, neutrophils, eosinophils and some mature lymphocytes. Positive LEDER and myeloperoxidase staining supported the presence of myeloid cells. Positive CD68/PMG1 and CD163 staining confirmed the existence of histiocytes and monocytic macrophages in the inflammatory infiltrate. CD123 staining was positive, demonstrating the presence of plasmacytoid dendritic cells. Uncovering the unique histopathologic and immunohistochemical features of CANDLE syndrome provides tools for rapid and specific diagnosis of this disorder as well as further insight into the pathogenesis of this severe, life-threatening conditionThis work was supported in part by the NIAMS Intramural Research Program (IRP) at the National Institutes of Health (NIH); The Authority for Research and Development, Hebrew University of Jerusalem (to A.Z.), and the Young clinician’s grant, Hadassah – Hebrew University Medical Center (to Y.R.

MRP8 and MRP14, phagocyte-specific danger signals, are sensitive biomarkers of disease activity in cryopyrin-associated periodic syndromes

To assess the sensitivity of the phagocyte-specific molecules myeloid-related protein (MRP) 8 and MRP14 (calprotectin) for monitoring disease activity during anti-interleukin (IL)-1 therapies in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological, cutaneous and articular (CINCA) syndrome

Alterations in peripheral blood memory B cells in patients with active rheumatoid arthritis are dependent on the action of tumour necrosis factor

INTRODUCTION: Disturbances in peripheral blood memory B cell subpopulations have been observed in various autoimmune diseases, but have not been fully delineated in rheumatoid arthritis (RA). Additionally, the possible role of tumour necrosis factor (TNF) in regulating changes in specific peripheral blood memory B cell subsets in RA is still unclear. METHODS: The frequency and distribution of B cell subsets in the peripheral blood and synovial membrane of active RA patients with long-standing disease have been analysed. Additionally, the possible role of TNF in causing disturbances in memory B cell subsets in RA patients was assessed in a clinical trial with the specific TNF-neutralising antibody, infliximab. RESULTS: RA patients, independent of disease duration, have a significantly lower frequency of peripheral blood pre-switch IgD+CD27+ memory B cells than healthy individuals, whereas post-switch IgD-CD27+ accumulate with increased disease duration. Notably, both pre-switch IgD+CD27+ and post-switch IgD-CD27+ memory B cells accumulate in the synovial membrane of RA patients. Finally, anti-TNF therapy increased the frequency of pre-switch IgD+CD27 memory B cells in the peripheral blood. CONCLUSIONS: The data suggest that decreases in peripheral blood IgD+CD27+ pre-switch memory B cells in RA reflect their accumulation in the synovial tissue. Moreover, the significant increase in the peripheral blood pre-switch memory B cells in patients who underwent specific TNF-blockade with infliximab indicates that trafficking of memory B cells into inflamed tissue in RA patients is regulated by TNF and can be corrected by neutralising TN

Diurnal secretion of growth hormone, cortisol, and dehydroepiandrosterone in pre- and perimenopausal women with active rheumatoid arthritis: a pilot case-control study

Rheumatoid arthritis (RA) is associated with neuroendocrine and immunologic dysfunction leading to rheumatoid cachexia. Although excess proinflammatory cytokines can decrease somatotropic axis activity, little is known about the effects of RA on growth hormone/insulin-like growth factor-1 (GH/IGF-I) axis function. We tested the hypothesis that patients with active RA exhibit decreased GH/IGF-I axis activity. To do so, we conducted a pilot case-control study at a clinical research center in 7 pre- and perimenopausal women with active RA and 10 age- and body mass index-matched healthy women. Participants underwent blood sampling every 20 minutes for 24 hours (8 a.m. to 8 a.m.), and sera were assayed for GH, cortisol, and dehydroepiandrosterone (DHEA). Sera obtained after overnight fasting were assayed for IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3, C-reactive protein (CRP), interleukin-6 (IL-6), glucose, insulin, and lipids. Body composition and bone mineral density were evaluated by DEXA (dual emission x-ray absorptiometry) scans. In patients with RA, mean disease duration was 7.6 ± 6.8 years, and erythrocyte sedimentation rate, CRP, and IL-6 were elevated. GH half-life was shorter than in control subjects (p = 0.0037), with no other significant group differences in GH deconvolution parameters or approximate entropy scores. IGF-I (p = 0.05) and IGFBP-3 (p = 0.058) were lower, whereas IGFBP-1 tended to be higher (p = 0.066), in patients with RA, with nonsignificantly increased 24-hour total GH production rates. There were no significant group differences in cortisol or DHEA secretion. Lean body mass was lower in patients with RA (p = 0.019), particularly in the legs (p = 0.01). Women with active RA exhibit a trend toward GH insensitivity and relatively diminished diurnal cortisol and DHEA secretion for their state of inflammation. Whether these changes contribute to rheumatoid cachexia remains to be determined