The Usefulness of Serological Inflammatory Markers in Patients with Rotator Cuff Disease-A Systematic Review.

Background and Objectives: Rotator cuff disease (RCD) is a prominent musculoskeletal pain condition that spans a variety of pathologies. The etiology and precise diagnostic criteria of this condition remain unclear. The current practice of investigating the biochemical status of RCD is by conducting biopsy studies but their invasiveness is a major limitation. Recent biochemical studies on RCD demonstrate the potential application of serological tests for evaluating the disease which may benefit future clinical applications and research. This systematic review is to summarize the results of available studies on serological biochemical investigations in patients with RCD. Methods: An electronic search on databases PubMed and Virtual Health Library was conducted from inception to 1 September 2021. The inclusion criteria were case-control, cross-sectional, and cohort studies with serological biochemical investigations on humans with RCD. Methodological quality was assessed using the Study Quality Assessment Tool for Observational Cohort and Cross-sectional studies from the National Heart, Lung, and Blood Institute. Results: A total of 6008 records were found in the databases; of these, 163 full-text studies were checked for inclusion and exclusion criteria. Nine eligible studies involving 984 subjects with RCD emerged from this systematic review. The quality of the studies found ranged from poor to moderate. In summarizing all the studies, several fatty acids, nonprotein nitrogen, interleukin-1 ß, interleukin-8, and vascular endothelial growth factor were found to be significantly higher in blood samples of patients with RCD than with control group patients, while Omega-3 Intex, vitamin B12, vitamin D, phosphorus, interleukin-10, and angiogenin were observed to be significantly lower. Conclusions: This is the first systematic review to summarize current serological studies in patients with RCD. Results of the studies reflect several systemic physiological changes in patients with RCD, which may prove helpful to better understand the complex pathology of RCD. In addition, the results also indicate the possibility of using serological tests in order to evaluate RCD; however, further longitudinal studies are required.

A brief report on the clinical trial on neural mobilization exercise for joint pain in patients with rheumatoid arthritis.

BACKGROUND: In rheumatoid arthritis (RA) synovitis, activation of synoviocytes and infiltration of adaptive immune cells leads to synovial hyperplasia and joint swelling. Under the elevated extra-neural pressure, free nerve endings release neuropeptides, calcitonin gene-related peptide, and substance P, thus promoting neurogenic inflammation. OBJECTIVE: This study aimed to assess the effect of therapeutic neural mobilization (NM) exercises targeting the nervous system on disease impact in RA patients. METHODS: A total of 21 RA patients were randomized into NM (n = 11) and control (n = 10) groups. NM group patients performed NM exercises targeting the median, musculocutaneous, femoral, and saphenous nerve, as well as the entire nervous system twice daily for 4-8 weeks. Control RA patients performed gentle joint mobilization exercises targeting the same joints. Primary outcome was the change in pre-/post-treatment score in the validated Rheumatoid Arthritis Impact of Disease (RAID). Secondary outcome was erythrocyte sedimentation rate (ESR). RESULTS: There were no significant differences between the groups at baseline. No adverse events were observed and compliance was over 90%. Post-treatment, favorable changes were observed in the NM group RAID score: -5.1 vs. -0.8; weighted RAID score: -0.79 vs. -0.15. ESR was reduced in the NM group, albeit non-significantly. Regarding the RAID score domains, the NM group demonstrated significant improvements in pain and coping. CONCLUSION: The current data indicate a beneficial effect of NM exercises on pain and self-efficacy in our RA patients. Larger clinical studies are warranted to determine the clinical effectiveness of NM as a treatment for pain for RA patients and simultaneously address immune and neuropeptide modulation through NM.

The major pain source of rotator cuff-related shoulder pain: A narrative review on current evidence.

BACKGROUND: Rotator cuff-related shoulder pain (RCRSP) was proposed to have a complex pain mechanism, but the exact aetiology is still unclear. A recent review summarised the updated research to analyse the traditional concept of shoulder impingement which may not be accurate. Current studies have demonstrated that mechanical factors including a reduction in subacromial space, scapular dyskinesia and different acromial shapes are unlikely directly contributing to RCRSP. AIMS: Since the precise RCRSP pain mechanism remains unclear, the aim of this narrative review is to discuss possible sources of pain contributing to RCRSP according to the mechanisms-based pain classifications. RESULTS AND DISCUSSION: Research findings on potential mechanical nociceptive factors of RCRSP are conflicting; investigations of neuropathic and central pain mechanisms of RCRSP are limited and inconclusive. Overall, available evidence has indicated moderate to strong correlations between RCRSP and chemical nociceptive sources of pain. CONCLUSION: Results from current research may provide new directions for future studies on the aetiology of RCRSP and its clinical management towards a biochemical view instead of the traditional mechanical hypothesis.

Immune and coagulation profiles in 3 adults with multisystem inflammatory syndrome.

INTRODUCTION: There is a paucity of information on the cytokine, complement, endothelial activation, and coagulation profiles of multisystem inflammatory syndrome in adults (MIS-A), a rare but serious complication following recovery from SARS-CoV-2 infection. We aim to examine the immune biomarker and coagulation profiles in association with the clinical presentation and course of MIS-A. METHOD: The clinical features of MIS-A patients admitted to our tertiary hospital were documented. Their levels of interleukin (IL)-1ß, IL-6, IL-10, IL-17, IL-18, interferon-α (IFN-α), IFN-γ, interferon gamma-induced protein 10 (IP-10), tumour necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, complement activation product (complement 5a [C5a]), and endothelial biomarker intercellular adhesion molecule-1 (ICAM-1) levels were assayed. The haemostatic profile was assessed with standard coagulation testing and thromboelastography. RESULTS: Three male patients were diagnosed with MIS-A at our centre from January to June 2022 with a median age of 55 years. All had tested positive for SARS-CoV-2 12-62 days prior to MIS-A presentation, with gastrointestinal and cardiovascular systems as the most commonly involved. Levels of IL-6, IL-10, IL-18, IP-10 and MCP-1 were raised whereas IL-1ß, IFN-α, IFN-γ, IL-17 and TNF-α remained normal. Markedly elevated levels of C-reactive protein (CRP), ferritin and ICAM-1 were present in all. C5a was elevated in 2 patients. A hypercoagulable state was demonstrated by raised levels of D-dimer, factor VIII, von Willebrand factor antigen, and ristocetin cofactor with corresponding raised parameters in thromboelastography in the 2 patients who had their coagulation profile assessed. CONCLUSION: MIS-A patients demonstrate activation of pro-inflammatory cytokines, endotheliopathy, complement hyperactivation and hypercoagulability.

Anaphylatoxin Complement 5a in Pfizer BNT162b2-Induced Immediate-Type Vaccine Hypersensitivity Reactions.

The underlying immunological mechanisms of immediate-type hypersensitivity reactions (HSR) to COVID-19 vaccines are poorly understood. We investigate the mechanisms of immediate-type hypersensitivity reactions to the Pfizer BNT162b2 vaccine and the response of antibodies to the polyethylene glycol (PEG)ylated lipid nanoparticle after two doses of vaccination. Sixty-seven participants, median age 35 and 77.3% females who tolerated two doses of the BNT162b2 vaccine (non-reactors), were subjected to various blood-sampling time points. A separate group of vaccine reactors (10 anaphylaxis and 37 anonymised tryptase samples) were recruited for blood sampling. Immunoglobulin (Ig)G, IgM and IgE antibodies to the BNT162b2 vaccine, biomarkers associated with allergic reaction, including tryptase for anaphylaxis, complement 5a(C5a), intercellular adhesion molecule 1 (ICAM-1) for endothelial activation and Interleukin (IL)-4, IL-10, IL-33, tumour necrosis factor (TNF) and monocyte chemoattractant protein (MCP-1), were measured. Basophil activation test (BAT) was performed in BNT162b2-induced anaphylaxis patients by flow cytometry. The majority of patients with immediate-type BNT162b2 vaccine HSR demonstrated raised C5a and Th2-related cytokines but normal tryptase levels during the acute reaction, together with significantly higher levels of IgM antibodies to the BNT162b2 vaccine (IgM 67.2 (median) vs. 23.9 AU/mL, p < 0.001) and ICAM-1 when compared to non-reactor controls. No detectable IgE antibodies to the BNT162b2 vaccine were found in these patients. The basophil activation tests by flow cytometry to the Pfizer vaccine, 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG) and PEG-2000 were negative in four anaphylaxis patients. Acute hypersensitivity reactions post BNT162b2 vaccination suggest pseudo-allergic reactions via the activation of anaphylatoxins C5a and are independent of IgE-mechanisms. Vaccine reactors have significantly higher levels of anti-BNT162b2 IgM although its precise role remains unclear.

Evaluation of Patients with Vaccine Allergies Prior to mRNA-Based COVID-19 Vaccination.

During the initial rollout of coronavirus disease 2019 (COVID-19) vaccination in Singapore, the Ministry of Health (MOH) issued a recommendation that patients with a history of any previous vaccine allergy be referred to an allergist for further review of their suitability to proceed with mRNA-based COVID-19 vaccines. Patients fulfilling the above criterion were divided into three groups: immediate reaction (Group A), delayed reaction (Group B) and no/irrelevant reaction (Group C). They were subjected to either a skin prick test (SPT) and intradermal test (IDT) with polyethylene glycol (PEG) or polysorbate-containing products; direct injection with the Pfizer BNT162b2 vaccine in the allergy clinic; or injection at community vaccination centres, respectively. Groups A and B were also invited to complete a questionnaire survey on post-vaccination reactions, and blood sampling pre-vaccination and 1 h after the first dose of the BNT162b2 vaccine to measure immunoglobulin (Ig) G, IgM and IgE antibodies to the Pfizer BNT162b2 vaccine via ELISA assays immobilised with the BNT162b2 vaccine, as well as levels of allergic cytokines interleukin (IL)-4 and IL-33, complement C5a and the endothelial activation marker intercellular adhesion molecule-1 (ICAM-1). Groups A and B comprised 62 (20.5%) patients each. In Group A, two subjects (3.2%) with equivocal IDT results tolerated both doses of the BNT162b2 vaccine without major allergic reactions. The remaining 60 (96.8%) in Group A and 62 (100%) in Group B completed both doses of BNT162b2 vaccination without major adverse reactions. Among the 99 who completed the questionnaire survey, 13 (13%) patients reported mild allergic reactions after the first dose of the vaccine. Immunoglobulin (Ig) G and M antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine were detected in 67 subjects prior to vaccination. The presence of anti-Pfizer BNT162b2 IgG and IgM prior to vaccination did not result in major allergic reactions nor increases in Th2-related cytokines (IL-4, IL-33), complement activation products (C5a) or endothelial activation (ICAM-1). The majority of those with suspected reactions to non-COVID-19 polysorbate-containing vaccines tolerated the BNT162b2 vaccine. Excipient skin tests for PEG and polysorbate prior to vaccination are unnecessary.

Pseudo-Anaphylactic Reactions to Pfizer BNT162b2 Vaccine: Report of 3 Cases of Anaphylaxis Post Pfizer BNT162b2 Vaccination.

Anaphylactic reactions were observed after Singapore's national coronavirus disease 2019 (COVID-19) vaccination programme started in December 2020. We report the clinical and laboratory features of three patients in our institution who developed anaphylactic reactions after receiving the Pifzer BNT162b2 vaccine. IgM and IgG antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine, were detected in all subjects. Similarly, mild to high elevated levels of anti-polyethylene glycol (PEG) IgG (1035-19709 U/mL, vs. vaccine-naive < 265 U/mL, vaccine-tolerant < 785 U/mL) and IgM (1682-5310 U/mL, vs. vaccine-naive < 1011 U/mL, vaccine-tolerant < 1007 U/mL) were detected in two out of three patients via commercial ELISA. High levels of serum anaphylatoxin C3a (79.0 ± 6.3 µg/mL, mean ± SD, vs. normal < 10 µg/mL) were observed in all three patients during the acute phase of the reaction, while tryptase levels, a marker of mast cell activation, were not elevated. Finally, one patient with the highest levels of anti-PEG IgG, IgM, and anti-Pfizer BNT162b2 IgG and IgM exhibited an enhanced Th2 cytokine serum profile during an acute reaction, with high levels of IL-4 (45.7 pg/mL, vs. vaccine-naive/tolerant < 2.30 pg/mL), IL-33 (86.4 pg/mL, vs. vaccine-naive/tolerant < 5.51 pg/mL) and IL-10 (22.9 pg/mL, vs. vaccine-naive/tolerant < 12.49 pg/mL) diminishing over time following corticosteroid treatment. Taken together, we propose these cases of anaphylaxis described are driven by a complement activation-related pseudoallergy (CAPRA), rather than classical IgE-mediated mechanisms.

Anti-Cytokine Autoantibodies in Systemic Lupus Erythematosus.

Cytokine dysregulation is characteristic of systemic lupus erythematosus (SLE), a systemic autoimmune disease of considerable heterogeneity. Insights gained about the cytokine dysregulation in SLE have the potential for identifying patient subsets before the onset of clinical disease and during established disease. Clustering patients by cytokine and disease activity subsets is more informative than isolated cytokine studies, as both pro inflammatory and immunoregulatory cytokines contribute to the cytokine dysregulated state in SLE. Endogenous anti-cytokine autoantibodies (ACAAs) may be involved in the regulation of cytokine biology by reducing excessive production or by prolonging their half-life in the circulation through the formation of cytokine-antibody immune complexes. Although endogenous ACAAs may have deleterious effects such as contributing to immunodeficiency states, their role in the pathophysiology of autoimmune conditions such as SLE has yet to be clearly elucidated. The aim of the present article is to provide a focused review of the current knowledge of ACAAs in SLE.