Arthritis Research & Therapy

Schnitzler’s syndrome (SchS) is a disabling autoinflammatory disorder, characterized by a chronic urticarial rash, an M-protein, arthralgia, and other signs of systemic inflammation. Anti-interleukin-1 (IL-1) beta antibodies are highly effective, but the pathophysiology is still largely unknown. Here we studied the effect of in-vivo IL-1 inhibition on serum markers of inflammation and cellular immune responses. Eight patients with SchS received monthly subcutaneous (s.c.) injections with 150 mg canakinumab for six months. Blood was drawn for measurement of serum markers of inflammation (12 times per patient) and for functional and phenotypic analysis of both freshly isolated and toll-like receptor (TLR)-ligand-stimulated peripheral blood mononuclear cells (PBMCs) (five times per patient). All data were compared to results of healthy controls. IL-6 levels in serum and in lysates of freshly isolated PBMCs and serum myeloid-related protein (MRP8)/14 and S100A12 levels correlated with disease activity. In vitro, LPS stimulation resulted in higher IL-6 and IL-1 beta production in PBMCs from symptomatic SchS patients compared to healthy controls, whereas patient cells were relatively hyporesponsive to poly:IC and Pam3Cys. The mRNA microarray of PBMCs showed distinct transcriptomes for controls, symptomatic patients and anti-IL-1-treated patients. Numbers of T- and B-cell subsets as well as M-protein concentrations were not affected by IL-1 inhibition. Free light chain levels were elevated in 4 out of 8 patients. In conclusion, patient PBMCs are hyperresponsive to LPS, and clinical efficacy of IL-1 beta inhibition in patients with SchS is associated with in-vivo and ex-vivo suppression of inflammation. Interestingly, patient PBMCs showed divergent responses to TLR2/6, TLR3 and TLR4 ligands. Our data underscore that IL-1 beta plays a pivotal role in SchS.

Hình ảnh Doppler laser (LDI) là một phương pháp tương đối mới để đánh giá khía cạnh chức năng của lưu lượng máu ở bề mặt da trong bệnh xơ cứng hệ thống (SSc) và hiện tượng Raynaud. Nghiên cứu hiện tại đã điều tra hành vi động học của lưu lượng máu vi mạch ở da các đầu ngón tay trước và sau khi kích thích lạnh (CS) ở bệnh nhân SSc và nhóm đối chứng khỏe mạnh thông qua một cách tiếp cận toàn diện gồm các thành phần vi tuần hoàn chức năng (LDI), hình thái (nội soi mạch máu ở vùng nếp gấp móng tay (NFC)) và hóa sinh (kỹ thuật đo lacticemy ở đầu ngón tay (FTL)). Bốn mươi bốn bệnh nhân SSc và 40 đối chứng khỏe mạnh đã được đưa vào nghiên cứu. Sau khi thích nghi, tất cả các đối tượng đã trải qua NFC, tiếp theo là đo LDI và FTL. NFC được thực hiện bằng một kính hiển vi lập thể dưới độ phóng đại từ 10× đến 20× trên 10 đầu ngón tay của bàn tay. Lưu lượng máu ở da tại mu bốn đầu ngón tay (không bao gồm ngón cái) của bàn tay trái đã được đo bằng LDI tại thời điểm cơ sở và trong 30 phút sau khi CS. Lưu lượng máu trung bình ở các đầu ngón tay (FBF) của bốn đầu ngón tay được thể hiện dưới dạng các đơn vị tưới máu tùy ý. FTL được xác định trên ngón tay trái thứ tư trước (pre-CS-FTL) và 10 phút sau khi CS. LDI cho thấy lưu lượng máu FBF trung bình cơ sở trong bệnh nhân SSc thấp hơn đáng kể so với nhóm đối chứng (296.9 ± 208.8 so với 503.6 ± 146.4 đơn vị tưới máu; P < 0.001) và cũng thấp hơn ở tất cả các thời điểm sau CS (P < 0.001). Có một sự giảm đáng kể trên FBF trung bình sau CS so với cơ sở ở bệnh nhân SSc và ở nhóm đối chứng, tiếp theo là sự hồi phục lưu lượng máu sau 27 phút sau CS ở nhóm đối chứng khỏe mạnh, nhưng không xảy ra ở bệnh nhân SSc. FBF có xu hướng thấp hơn ở bệnh nhân có sẹo kỹ thuật số và đã từng bị loét/cắt cụt (P = 0.06). Không có mối tương quan giữa FBF trung bình cơ sở và các tham số NFC. Điều thú vị là có sự tương quan nghịch giữa FTL và FBF đo bằng LDI trong các điều kiện cơ sở và 10 phút sau CS ở bệnh nhân SSc. LDI cho thấy lưu lượng máu kỹ thuật số thấp hơn ở bệnh nhân SSc so với đối chứng khỏe mạnh và có sự tương quan tốt với FTL cả ở cơ sở và sau CS, cho phép đo lường khách quan về tưới máu ở bệnh nhân SSc. Việc thiếu tương quan giữa các bất thường vi mạch chức năng và hình thái, được đo bằng LDI và NFC, cho thấy chúng là những công cụ bổ sung cho việc đánh giá các khía cạnh độc lập của vi mạch trong bệnh nhân SSc.

Broad-range rDNA PCR provides an alternative, cultivation-independent approach for identifying bacterial DNA in reactive and other form of arthritis. The aim of this study was to use broad-range rDNA PCR targeting the 16S rRNA gene in patients with reactive and other forms of arthritis and to screen for the presence of DNA from any given bacterial species in synovial fluid (SF) samples. We examined the SF samples from a total of 27 patients consisting of patients with reactive arthritis (ReA) (n = 5), undifferentiated arthritis (UA) (n = 9), rheumatoid arthritis (n = 7), and osteoarthritis (n = 6) of which the latter two were used as controls. Using broad-range bacterial PCR amplifying a 1400 bp fragment from the 16S rRNA gene, we identified and sequenced at least 24 clones from each SF sample. To identify the corresponding bacteria, DNA sequences were compared to the EMBL (European Molecular Biology Laboratory) database. Bacterial DNA was identified in 20 of the 27 SF samples (74, 10%). Analysis of a large number of sequences revealed the presence of DNA from more than one single bacterial species in the SF of all patients studied. The nearly complete sequences of the 1400 bp were obtained for most of the detected species. DNA of bacterial species including Shigella species, Escherichia species, and other coli-form bacteria as well as opportunistic pathogens such as Stenotrophomonas maltophilia and Achromobacter xylosoxidans were shared in all arthritis patients. Among pathogens described to trigger ReA, DNA from Shigella sonnei was found in ReA and UA patients. We also detected DNA from rarely occurring human pathogens such as Aranicola species and Pantoea ananatis. We also found DNA from bacteria so far not described in human infections such as Bacillus niacini, Paenibacillus humicus, Diaphorobacter species and uncultured bacterium genera incertae sedis OP10. Broad-range PCR followed by cloning and sequencing the entire 16S rDNA, allowed the identification of the bacterial DNA environment in the SF samples of arthritic patients. We found a wide spectrum of bacteria including those known to be involved in ReA and others not previously associated with arthritis.

HLA-B*35 is associated with increased risk of developing pulmonary hypertension in SSc patients. We previously reported that HLA-B*35 induces endothelial cell dysfunction via activation of ER stress/UPR and upregulation of the inflammatory response. Because PBMCs from lcSSc-PAH patients are also characterized by activation of ER stress/UPR and inflammation, the goal of this study was to assess whether the presence of HLA-B*35 contributes to those characteristics. PBMCs were purified from healthy controls (n = 49 HC) and lcSSc patients, (n = 44 with PAH, n = 53 without PAH). PBMCs from each group were stratified for the presence of HLA-B*35. Global changes in gene expression in response to HLA-B*35, HLA-B*8 or empty lentivirus were investigated by microarray analysis in HC PBMCs. Total RNA was extracted and qPCR was performed to measure gene expression. ER stress markers, in particular the chaperones BiP and DNAJB1 were significantly elevated in PBMC samples carrying the HLA-B*35 allele. IL-6 expression was also significantly increased in HLA-B*35 lcSSc PBMCs and positively correlated with ER stress markers. Likewise, HMGB1 was increased in HLA-B*35-positive lcSSc PBMCs. Global gene expression analysis was used to further probe the role of HLA-B*35. Among genes downregulated by HLA-B*35 lentivirus were genes related to complement (C1QB, C1QC), cell cycle (CDNK1A) and apoptosis (Bax, Gadd45). Interestingly, complement genes (C1QC and C1QB) showed elevated expression in lcSSc without PAH, but were expressed at the low levels in lcSSc-PAH. The presence of HLA-B*35 correlated with the decreased expression of the complement genes. Furthermore, HLA-B*35 correlated with decreased expression of cyclin inhibitors (p21, p57) and pro-apoptotic genes (Bax, Gadd45) in lcSSc B35 subjects. FYN, a tyrosine kinase involved in proliferation of immune cells, was among the genes that were positively regulated by HLA-B*35. HLA-B*35 correlated with increased levels of FYN in lcSSc PBMCs. Our study demonstrates that HLA-B*35 contributes to the dysregulated expression of selected ER stress, inflammation and proliferation related genes in lcSSc patient PBMCs, as well as healthy individuals, thus supporting a pathogenic role of HLA-B*35 in the development of PAH in SSc patients.

Recent guidelines pertaining to exercise for individuals with osteoarthritis have been released. These guidelines have been based primarily on studies of knee-joint osteoarthritis. The current study was focused on the hip joint, which has different biomechanical features and risk factors for osteoarthritis and has received much less attention in the literature. The purpose was to conduct a systematic review of the literature to evaluate the exercise programs used in intervention studies focused solely on hip-joint osteoarthritis, to decide whether their exercise regimens met the new guidelines, and to determine the level of support for exercise-therapy interventions in the management of hip-joint osteoarthritis. A systematic literature search of 14 electronic databases was undertaken to identify interventions that used exercise therapy as a treatment modality for hip osteoarthritis. The quality of each article was critically appraised and graded according to standardized methodologic approaches. A 'pattern-of-evidence' approach was used to determine the overall level of evidence in support of exercise-therapy interventions for treating hip osteoarthritis. More than 4,000 articles were identified, of which 338 were considered suitable for abstract review. Of these, only 6 intervention studies met the inclusion criteria. Few well-designed studies specifically investigated the use of exercise-therapy management on hip-joint osteoarthritis. Insufficient evidence was found to suggest that exercise therapy can be an effective short-term management approach for reducing pain levels, improving joint function and the quality of life. Limited information was available on which conclusions regarding the efficacy of exercise could be clearly based. No studies met the level of exercise recommended for individuals with osteoarthritis. High-quality trials are needed, and further consideration should be given to establishing the optimal exercises and exposure levels necessary for achieving long-term gains in the management of osteoarthritis of the hip.