Abstract Introduction Spondyloarthritis (SpA), an interrelated group of rheumatic diseases, has been suggested to be triggered by bacterial infections prior to the development of an autoimmune response that causes inflammation of the spinal and peripheral joints. Because human heat shock protein 60 (HSP60), recently renamed HSPD1, and bacterial HSP60 are highly homologous, immunological cross-reactivity has been proposed as a mechanism of disease initiation. However, previous investigations of the humoral immune response to HSP60 in SpA patients have lacked determination of immunoglobulin G (IgG) subclasses and patient follow-up. In this study, we have focused on these parameters in a cohort of axial SpA patients with a well-established set of clinical characteristics, including MRI changes and human leukocyte antigen B27. Methods IgG subclass antibodies (IgG1, IgG2, IgG3 and IgG4) against recombinant HSP60 of three reactive arthritis-related bacteria; human HSP60; and the microorganisms Chlamydia trachomatis and C. pneumoniae were determined by ELISA. Serum samples collected from 2004 to 2006 and in 2010 and 2011 from 39 axial SpA patients were analyzed and compared with samples from 39 healthy controls. The Mann-Whitney U test and Wilcoxon matched pairs test were used to compare the antibody levels in different and paired groups, respectively. P < 0.01 was considered significant. The Spearman nonparametric correlation was used to determine correlation between antibody levels and between antibody levels and the disease parameters. Results Elevated levels of IgG1 and IgG3 to human HSP60 and IgG1 to HSP60 of Salmonella enterica Enteritidis were observed in SpA patients compared with healthy controls at both time points. The antibody levels were almost constant over time for IgG1, whereas high levels of IgG3 to human HSP60 tended to decrease over time. The antibody response to human HSP60 was predominantly of the IgG3 subclass, and patients with high levels of IgG3 to this antigen had low levels of IgG1, indicating an inverse association. Different IgG subclasses were produced against bacterial and human HSP60 in the same serum sample, IgG1 and IgG3, respectively, indicating that there was no cross-reaction. Conclusions A significant association was observed between axial SpA and the presence of IgG1/IgG3 antibodies to human HSP60 and of IgG1 to S. enterica Enteritidis and C. trachomatis . Generation of antibodies to human HSP60 was independent of the presence of antibodies to bacterial HSP60. No association was observed between clinical and MRI changes with antibodies over time. Altogether, such antibodies do not reflect the disease activity in these patients. This study has been approved by the Regional Research Ethics Committee of Central Jutland, Denmark. Trial registration numbers: 20050046 and 20100083
Background: Recent studies suggest dysregulation in T cell activation in systemic sclerosis (SSc). Co-inhibitory-receptors (Co-IRs) such as TIM-3, PD-1 and LAG-3 play a crucial role in controlling excessive T cell activation and in maintaining immune homeostasis. Engagement of these receptors by their ligand’s limits cytokine production in response to TCR or activating NK receptor stimulation and hence limit tissue damage from excessive immune activation. However, chronically increased expression of multiple Co-IRs is a hallmark of immune exhaustion. We evaluate the role of these soluble Co-IRs in diffuse SSc (dcSSc). Objectives: Establish the role of CiR and their ligands in diffuse systemic sclerosis. Understand how immune regulatory mechanisms influence the development of fibrosis. Provide a better understanding of the disease and fibrosis in general. Methods: PBMC’s(Peripheral blood mononuclear cells) and dermal fibroblasts from SSc patients were isolated and investigated for markers of T cell inhibition. These cells were analysed using flow cytometry in a 10 colour panel. Cells were stained for PD1, TIM3, TIGIT, LAG3, CD3, CD8, CD4 and CD19 along with a Live/dead marker. Co-cultures of fibroblasts and PBMCs will be setup, and treated with various drugs that act on the Co-IRs. Results: The proportion of CD4+ T cells expressing PD1 were markedly increased in SSc patients compared to healthy volunteers and Rheumatoid Arthritis patients. There was increased expression of both TIGIT and TIM3 in the CD4+ T cells. (Figure 1) Similarly, the co-expression of these receptors on the CD4+ T cell population was elevated compared to healthy volunteers. (figure 2) Conclusion: Soluble co-inhibitors are differentially expressed in early dcSSc compared to healthy volunteers and other autoimmune diseases. Our preliminary data indicates that these co inhibitors could play an important role in unravelling the pathogenesis of systemic sclerosis. Inhibition or activation of these receptors through different treatment modalities can be utilized as a novel patient centric treatment strategy. References: [1]Fukasawa, T., Yoshizaki, A., Ebata, S., Nakamura, K., Saigusa, R., Miura, S., … Sato, S. (2017). Contribution of Soluble Forms of Programmed Death 1 and Programmed Death Ligand 2 to Disease Severity and Progression in Systemic Sclerosis. Arthritis & Rheumatology , 69 (9), 1879–1890. [2]Greisen S, Rasmussen T, Stengaard-Pedersen K, Hetland M, Hørslev-Petersen K, Hvid M, et al. Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis. Scand J Rheumatol 2014; 43:101-8. [3]de Paoli, F., Nielsen, B., Rasmussen, F., Deleuran, B., & Søndergaard, K. (2014). Abatacept induces clinical improvement in patients with severe systemic sclerosis. Scandinavian Journal of Rheumatology , 43 (4), 342–345. [4]Kwon, B. (2010). Intervention with costimulatory pathways as a therapeutic approach for graft-versus-host disease. Experimental and Molecular Medicine . Nature Publishing Group. Acknowledgments: FOREUM: Foundation of Research in Rheumatology Disclosure of Interests: None declared
The vagal nerve exerts an essential pathway in controlling the cholinergic anti-inflammatory reflex. Thus, the study is aimed at investigating the acute effect of a noninvasive transcutaneous vagus nerve stimulation on clinical disease activity and systemic levels of inflammation in patients with psoriatic arthritis or ankylosing spondylitis.Twenty patients with psoriatic arthritis (PsA) and 20 patients with ankylosing spondylitis (AS) were included and stimulated bilaterally with a handheld vagal nerve stimulator for 120 seconds 3 times a day for 5 consecutive days. All patients were in remission. Cardiac vagal tone, clinical scores, CRP, and cytokine levels were assessed.In PsA and AS, decreased heart rate was observed, confirming compliance. Furthermore, in PsA, a clear reduction of clinical disease activity associated with a 20% reduction in CRP was shown. In AS, a reduction in interferon-γ, interleukin- (IL-) 8, and 10 was shown. No side effects were described.This open-label study provides support for an anti-inflammatory effect of transcutaneous vagus nerve stimulation in patients with psoriatic arthritis and ankylosing spondylitis. The modulated immune response and reduced disease activity and CRP-levels raise the fascinating possibility of using neuromodulation as an add-on to existing pharmacological treatments.
Using monoclonal antibodies and immunohistochemical techniques we have investigated the presence and distribution of interleukin-1α (IL-1α), type 1 IL-1 receptor (IL-1R1) and of interleukin-1 receptor antagonist (IL-1ra) in synovial tissue from 18 rheumatoid arthritis (RA) and eight osteoarthritis (OA) patients and in eight normal synovial tissue samples. IL-1α and IL-1R1 were found in all of the samples examined. In RA, there were a large number of synovial cells expressing IL-lα and IL-1Rl, with 85 and 90% positive cells in the lining layer, 45 and.80% in the interaggregate area, and 90% of the vascular endothelial cells. In the lymphoid aggregates, 20% of the cells contained IL-lα and 70% expressed IL-1R1. IL-1α and IL-1R1 expressing cells showed a similar distribution in OA synovial membrane, but there was a smaller number of positive cells in the deeper area; and the staining intensity was lower. In contrast to IL-1α and IL-1R1, IL-1ra was found only in 10/18 RA, 5/8 OA and 2/8 normal tissue samples. IL-1ra was detected in 35% of RA and 45% OA lining layer cells; 25% RA and 35% OA vascular endothelium; 10% RA and 15% OA interstitial cells and 30% cells in RA lymphoid aggregate. The staining intensity in both RA and OA tissues was comparably low. The presence of IL-1ra in RA and OA tissues was confirmed by Northern blot analysis for IL-1ra mRNA. At the RA cartilage/pannus junction, up to 90% of the pannus cells expressed IL-1α and IL-1R1, whereas IL-1ra was present in less than 10% of the cells. Some chondrocytes also expressed IL-1α and IL-1R1. In the normal cartilage/synovium junction fewer cells expressed IL-1α, IL-1R1 and IL-1ra. These results provide histological evidence that IL-1α, IL-1R1 and IL-1ra are present in the inflamed synovium, indicating that the IL-1 pathway is expressed and regulated within diseased joints.
Objective This is the first randomized double-blinded, placebo-controlled pilot trial to investigate the efficacy of pamidronate in reducing radiological and clinical disease activity in chronic non-bacterial osteomyelitis (CNO).Method Patients received pamidronate or placebo at baseline and weeks 12 and 24. Whole-body magnetic resonance imaging was performed at baseline and weeks 12 and 36, and computed tomography of the anterior chest wall (ACW) at baseline and week 36. Radiological disease activity was systematically scored in the ACW and spine. Patient-reported outcomes [visual analogue scale (VAS) pain, VAS global health, Health Assessment Questionnaire (HAQ), EuroQol-5 Dimensions (EQ-5D), and 36-item Short-Form Health Survey (SF-36)] and biomarkers of bone turnover and inflammation were assessed at baseline and weeks 1, 4, 12, 24, and 36. Data are expressed as median [interquartile range].Results Fourteen patients were randomized and 12 were analysed. From baseline to week 36, the radiological disease activity score in the ACW decreased from 5 [4–7] to 2.5 [1–3] in the pamidronate group, but did not change in the placebo group (p = 0.04). From baseline to week 36, VAS pain and VAS global health tended to decrease more in the pamidronate than in the placebo group (p = 0.11, p = 0.08). Physical functioning (HAQ) and health-related quality of life (EQ-5D, SF-36) did not change. Biomarkers of bone turnover decreased only in the pamidronate group (p ≤ 0.02).Conclusion Pamidronate may improve radiological and clinical disease activity in CNO. Methods to score radiological disease activity in adult CNO were suggested.Clinical Trials: NCT02594878
Anifrolumab is a new therapeutic approach for individuals with systemic lupus erythematosus (SLE) directed at blocking the type 1 interferon pathway. Despite the expanding body of literature on Anifrolumab, an essential aspect remains absent: the subjective patient experience of treatment effects and implications on patients’ health-related quality of life (HRQoL). The present study aimed to fill this void by elucidating the nuanced perspectives of SLE patients receiving Anifrolumab treatment by conducting qualitative in-depth interviews (IDIs). SLE patients at Aarhus University Hospital who had received at least three infusions of Anifrolumab were approached for inclusion in the study, which comprised two main elements: (1) qualitative IDIs and (2) collection of patient data from electronic medical records (EMRs). The IDIs were semi-structured and based on a discussion guide that included open-ended and close-ended questions. Verbatim transcripts were coded and analysed using qualitative software to understand concepts important to patients and to understand patients’ own experiences before and after Anifrolumab therapy. A clinical chart review was conducted using EMR data at baseline, 3 months, and 6 months after Anifrolumab initiation. IDIs were completed with 14 patients, and EMR data was collected from 16 patients (treatment days range: 62-474). Of the 23 symptoms spontaneously reported by patients prior to Anifrolumab treatment, fatigue, joint pain, sun sensitivity, joint stiffness, skin rashes, and hair loss were the most common. Most symptoms improved, and none worsened during treatment. Patients reported significant impacts of disease on daily life before treatment: day-to-day activities, social life, emotional aspects, physical activity, concentration/memory, work/employment, and family/romantic relationships. Patients reported improvements in all aspects after treatment but were still impacted. From the EMR data, we observed a fall in disease activity after treatment initiation with a concomitant reduction in the use of corticosteroids. This study provides valuable insights into the subjective experiences of SLE patients treated with Anifrolumab, and the findings collectively contribute to a comprehensive understanding of the treatment’s efficacy from the patients’ perspective and its tangible effects on both subjective and objective parameters in SLE patients.
