Forms Of Chronic Inflammatory Arthritis Research Articles

Advantages of ultrasound imaging for the early diagnosis of psoriatic arthritis in patients with moderate to severe psoriasis

BackgroundPsoriatic arthritis (PsA) is an immune-mediated form of chronic inflammatory arthritis associated with psoriasis (PsO). It constitutes a significant comorbidity of PsO and is distinguished by the presence of widespread musculoskeletal inflammation. ObjectiveThe aim of this study is to precisely detect asymptomatic PsA using ultrasound (US) examinations and to distinguish between various stages of PsO. MethodsAll patients with moderate-to-severe PsO, who consented to undergo musculoskeletal US examinations during their hospitalization between September 2020 and January 2022, were enrolled in the study. We compared patients' demographic characteristics, comorbidities, disease duration, relevant laboratory parameters, and musculoskeletal US findings. ResultsA total of 547 patients with PsO were included in the study, and 114 of them received a diagnosis of PsA. Furthermore, 16.45 % of patients with moderate to severe PsO displayed subclinical PsA. We observed a significantly higher frequency of abnormal US findings in patients with PsA compared to those without PsA, with a sensitivity of 95.61 % and a specificity of 79.22 %. Additionally, the incidence of enthesitis and synovitis varied significantly between PsA and non-PsA patients, and they were identified as independent variables predicting the presence of PsA. Furthermore, the interphalangeal joint, knee joint, and calcaneal tendon were the most frequently affected areas in PsA, as indicated by the observed US changes. ConclusionUltrasound examination proves to be a valuable tool for detecting subclinical PsA, facilitating early screening of the condition. Particular attention should be directed towards changes in the interphalangeal joint, knee joint, and calcaneal tendon when reviewing ultrasound images of asymptomatic patients.

Evidence-based modalities in the management of Psoriasis and Psoriatic arthritis.

Psoriasis is a waxing and waning skin disorder, often associated with a plethora of co-morbidities, including psoriatic arthritis (PsA), a severe form of chronic inflammatory arthritis. All forms of psoriasis and PsA are immune-mediated diseases where the patient's immune system is overactive in the production of certain factors that stimulate and activate the function of certain immune cells. Recent evidence has uncovered an important role for cell-mediated immunity in the aetiology and course of psoriasis and PsA, with a critical role played by the pro-inflammatory IL-23/TH17 axis. Taken together, these new lines of evidence suggest new and improved therapeutic interventions for patients with psoriasis and PsA. The hypothesis-driven process of inquiry of the best available evidence and its implication, application and evaluation in the context of clinical practice pertains to the meta-science of evidence-based health care (EBHC). EBHC consists in the initial step of research synthesis and generation of the systematic review of the best available evidence, estimated both qualitatively and quantitatively (i.e., meta-analysis). Evidence-based decision-making, a process driven and controlled by the expertise of the clinician and by the clinical needs and personal wants of the patient, is the principal, most timely and critical aspect of evidence-based practice. Recent and systematic reviews for the treatment of psoriasis and PsA consistently updated for emerging new and revised data (i.e., living systematic reviews) confirm the efficacy and the effectiveness of methotrexate (MTX) in containing and controlling psoriasis. The outcomes of MTX intervention for PsA remain mixed and inconclusive.

Diagnostic Challenges and Management of Patients with Overlapping Rheumatoid Arthritis with Psoriatic Arthritis: A Case Report

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) have key differences in clinical presentation, radiographic findings, and pathogenesis to distinguish between these common forms of chronic inflammatory arthritis. Several case reports report the occurrence of overlapping syndromes of RA with PsA. However, until now, the cases are still very rare. We report A 33-year-old woman, complaining of pain in the joints of her fingers, toes, and her back since eight years ago. The patient also complained of red, silvery-white patches on the abdomen and spread all over the body. On the left hand, there is a swan neck deformity on the fifth finger of the left hand. On the right hand, there is a boutonniere deformity on the second and fourth fingers of the right hand and ulnar deviation of the first finger. On skin examination, it was found with multiple silvery-white erythematous plaques, varying in size, geographical shape, covered with fine white scales spread all over the body skin. The patient was diagnosed with Rheumatoid Arthritis based on the 2010 ACR/EULAR diagnostic criteria, overlapping with Psoriatic Arthritis syndrome based on the 2010 ASAS diagnostic criteria for spondyloarthropathy 2006 CASPAR for PsA. The right diagnosis process speeds up the time for initiation of appropriate therapy to improve quality of life and improve disease prognosis. Keywords: Rheumatoid arthritis, psoriatic arthritis, overlapping syndrome.

Psoriatic arthritis: prospects for the future.

Psoriatic arthritis (PsA) is a form of chronic inflammatory arthritis associated with psoriasis and a multitude of other symptoms, most commonly arthritis, dactylitis, enthesitis and axial involvement. PsA is significantly heterogeneous, with a highly variable clinical course of PsA. Patients may experience significant or mild skin and joint symptoms, with some patients developing rapidly progressing joint destruction and skin symptoms. Despite the range of symptom severity, PsA is frequently associated with significantly impaired quality of life from joint destruction, as well as chronic pain and a range of comorbidities such as depression and cardiovascular disease. Currently, there are no definitive diagnostic tests for PsA, with diagnosis remaining challenging owing to the heterogeneous presentation and course of the disease. Presently, the CASPAR criteria are often used to aid rheumatologists in distinguishing PsA from other inflammatory arthritides. Treatment options for patients have been expanded over the last two decades with the emerging clinical utility of biological therapies. However, early identification and diagnosis of patients and effective disease control remain unmet medical needs within the PsA community. In addition, predicting response to treatment also remains a challenge to rheumatologists. This review highlights the current hurdles faced by healthcare professionals in the diagnosis and management of PsA patients and provides future action points for consideration by the members of the multidisciplinary team who treat PsA patients.

Th1 polarization defines the synovial fluid T cell compartment in oligoarticular juvenile idiopathic arthritis.

Oligoarticular juvenile idiopathic arthritis (oligo JIA) is the most common form of chronic inflammatory arthritis in children, yet the cause of this disease remains unknown. To understand immune responses in oligo JIA, we immunophenotyped synovial fluid T cells with flow cytometry, bulk RNA-Seq, single-cell RNA-Seq (scRNA-Seq), DNA methylation studies, and Treg suppression assays. In synovial fluid, CD4+, CD8+, and γδ T cells expressed Th1-related markers, whereas Th17 cells were not enriched. Th1 skewing was prominent in CD4+ T cells, including Tregs, and was associated with severe disease. Transcriptomic studies confirmed a Th1 signature in CD4+ T cells from synovial fluid. The regulatory gene expression signature was preserved in Tregs, even those exhibiting Th1 polarization. These Th1-like Tregs maintained Treg-specific methylation patterns and suppressive function, supporting the stability of this Treg population in the joint. Although synovial fluid CD4+ T cells displayed an overall Th1 phenotype, scRNA-Seq uncovered heterogeneous effector and regulatory subpopulations, including IFN-induced Tregs, peripheral helper T cells, and cytotoxic CD4+ T cells. In conclusion, oligo JIA is characterized by Th1 polarization that encompasses Tregs but does not compromise their regulatory identity. Targeting Th1-driven inflammation and augmenting Treg function may represent important therapeutic approaches in oligo JIA.

New Insights in Physical Therapy and Rehabilitation in Psoriatic Arthritis: A Review.

Psoriatic arthritis (PsA) is a complex, multiform and chronic inflammatory disease characterized by the association of psoriasis and arthritis with other musculoskeletal and extra-articular manifestations. The treatment of PsA is rapidly evolving due to the introduction of new biologic and small-molecule drugs, and the aim of treatment is to induce a condition of remission or low disease activity in all disease domains. However, unmet treatment needs still persist for those patients with impaired function, reduced quality of life or comorbidities. In this context, physical therapy and rehabilitation could provide additional benefits by reducing disease activity and improving function. Although a large number of studies have assessed the role of physical therapy and exercise in other forms of chronic inflammatory arthritis, such as axial spondyloarthritis and rheumatoid arthritis, evidence on their effect on persons with PsA is still lacking. However, some studies have reported the potential positive role of physical therapy on the different disease domains of PsA, in helping to improve disease activity, prevent or improve articular impairment, improve pain management and improve quality of life. Here, we review current evidence on physical therapy, exercise and rehabilitation in patients with PsA. In particular, we review the literature focusing on each domain, to provide evidence of efficacy and effectiveness of exercise and rehabilitation on skin, peripheral arthritis, axial involvement, dactylitis, enthesitis and comorbidities.

Biophoton Imaging Evaluation of the Process of Rheumatoid Arthritis in Rats

Rheumatoid arthritis (RA) is a common form of chronic inflammatory arthritis, and it mainly causes the destruction of small joints. The development of this disease is a relatively secret and repeated process, and therefore early diagnosis and evaluation of the disease is usually difficult. In this study, an arthritis model was successfully induced by injecting complete Freund’s adjuvant (CFA) into the toes of lower limbs of Wistar rats. Seven days after injection of CFA, obvious redness and swelling appeared at the toe joints of lower limbs accompanied by more sensitivity to thermal stimulation. Using the ultraweak bio-photon imaging system (UBIS) established by us, the toe joint area of the lower limbs of rats was imaged 7 days after injection of CFA. It was found that the volar part of lower limbs of arthritis rats showed significantly higher biophoton emissions compared with the control group. The results of this study may provide a basis for further research and devel-opment of early diagnosis and assessment of lesion progression of rheumatoid arthritis.

Abatacept: A Review of the Treatment of Polyarticular-Course Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) encompasses several forms of chronic inflammatory arthritis of unknown etiology presenting in children < 16years of age, with a minimum symptom duration of 6weeks. Approximately half of affected children have polyarticular-course JIA (pJIA), a functional concept related to several clinically and genetically heterogeneous JIA categories (systemic, extended oligoarthritis, polyarticular rheumatoid factor-positive or rheumatoid factor-negative, enthesitis-related arthritis, and psoriatic arthritis), which has as its defining feature the involvement of five or more joints during the disease course. Chronic inflammation and joint damage lead to the manifestations of JIA such as pain, limitation of motion, and loss of physical function, all of which negatively impact patients' quality of life. The American College of Rheumatology recommends initial treatment with a conventional synthetic disease-modifying antirheumatic drug (csDMARD), such as methotrexate (MTX) and, in patients with pJIA who have an inadequate response or intolerance to MTX, the use of a biologic DMARD (bDMARD) such as a tumor necrosis factor inhibitor, abatacept, or tocilizumab. Abatacept selectively modulates the CD80/CD86:CD28 co-stimulatory signal required for full T cell activation, and thus has a distinct mechanism of action upstream of that of other currently available bDMARD treatments for rheumatic diseases. To enable physicians to make informed treatment decisions, it is important to review available data for the existing therapeutic agents. Here, we summarize the current evidence from phase III pivotal trials of intravenous (IV) and subcutaneous (SC) abatacept and from an ongoing registry of patients with JIA treated with abatacept. In the pivotal trials for IV and SC abatacept, either with or without MTX, both formulations demonstrated clinical efficacy, with a high proportion of patients achieving stringent clinical responses, as well as improvements in patient-reported outcomes and a favorable safety profile, particularly with regard to infections.

Tendon and ligament mechanical loading in the pathogenesis of inflammatory arthritis.

Mechanical loading is an important factor in musculoskeletal health and disease. Tendons and ligaments require physiological levels of mechanical loading to develop and maintain their tissue architecture, a process that is achieved at the cellular level through mechanotransduction-mediated fine tuning of the extracellular matrix by tendon and ligament stromal cells. Pathological levels of force represent a biological (mechanical) stress that elicits an immune system-mediated tissue repair pathway in tendons and ligaments. The biomechanics and mechanobiology of tendons and ligaments form the basis for understanding how such tissues sense and respond to mechanical force, and the anatomical extent of several mechanical stress-related disorders in tendons and ligaments overlaps with that of chronic inflammatory arthritis in joints. The role of mechanical stress in 'overuse' injuries, such as tendinopathy, has long been known, but mechanical stress is now also emerging as a possible trigger for some forms of chronic inflammatory arthritis, including spondyloarthritis and rheumatoid arthritis. Thus, seemingly diverse diseases of the musculoskeletal system might have similar mechanisms of immunopathogenesis owing to conserved responses to mechanical stress.

Distinguishing rheumatoid arthritis from psoriatic arthritis

Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) have key differences in clinical presentation, radiographic findings, comorbidities and pathogenesis to distinguish between these common forms of chronic inflammatory arthritis. Joint involvement...

A spontaneous model of spondyloarthropathies that develops bone loss and pathological bone formation: A process regulated by IL27RA-/- and mutant-p53.

Spondyloarthropathies, the second most frequently occurring form of chronic inflammatory arthritis, affects young adults in particular. However, a proper model with which to study the biology of this disease and to develop therapeutics is lacking. One of the most accepted animal models for this disease uses HLA-B27/Hu-β2m transgenic rats; however, only 30%-50% of male HLA-B27/Hu-β2m rats develop spontaneous, clinically apparent spondylitis and have a variable time until disease onset. Here, we report a high-incidence, low-variation spontaneous mouse model that delineates how the combination of inflammatory cytokine interleukin-27 (IL-27) signaling deficiency and mitogenic signaling (mutant p53R172H) in vivo, leads to bone loss in the vertebral bodies and ossification of the cartilage in the intervertebral discs. In this human disease–like mouse model, bone loss and pathogenic bone development are seen as early as 4 months of age in the absence of inflammatory aggregates in the enthesis or intervertebral disc.

The relationship between serum levels of lipid profile and activity of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology marked by a symmetric, peripheral polyarthritis. It is the most common form of chronic inflammatory arthritis and often results in joint damage and physical disability. As it is a systemic disease, it may result in variety of extra-articular manifestations, including fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities. Aim of the work: Show changes of serum lipid profile in patients with rheumatoid arthritis. Patients and Methods: Fifty patients with rheumatoid arthritis who diagnosed according to (EULAR/ ACR2010) criteria for rheumatoid arthritis, 47 females and 3 males with a mean age of 36.80 ±6.03 years. Fifty control healthy subjects included 43 females and 7 males with a mean age of 36.14 ±7.73 years were examined for their lipid profile parameters and disease activity. Lipid profile parameters (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and atherogenic index ratio), erythrocyte sedimentation rate and C-reactive protein; all were determined for both the patients and control groups. Results: The results of the present study revealed that rheumatoid arthritis patients exhibited a highly significant increase in total cholesterol and low-density lipoprotein cholesterol (p=0.0001), with a significant increase in high-density lipoprotein cholesterol (p= 0.002). As a consequence, the atherogenic index ratio was significantly higher (p=0.0001). The rheumatoid factor, CRP and ESR were higher in patients with RA than in control group with very highly significant difference (p=0.0001). There is a significant correlation between disease activity score (DAS 28) and different parameters of lipid profile which was a highly significant with LDL and TC/HDL (0.9-0.8) respectively and was less significant with other parameters. The disease duration for rheumatoid arthritis patients was significantly correlated with Das28 score (p=0.01). Conclusion: Rheumatoid arthritis patients are characterized by an atherogenic lipid profile in comparison with the healthy controls. Recognition and treatment of early rheumatoid arthritis and reduction of cardiac risk factor has greater impact on the course of the disease.

Celecoxib for the Treatment of Ankylosing Spondylitis

Ankylosing spondylitis is a debilitating form of chronic inflammatory arthritis which primarily affects the spine. Treatment is based on non-pharmacological therapy, largely exercise, and pharmacological therapy, with non-steroidal anti-inflammatory drugs (NSAIDs) recommended as first-line treatment.

Effects of β-d-mannuronic acid, as a novel non-steroidal anti-inflammatory medication within immunosuppressive properties, on IL17, RORγt, IL4 and GATA3 gene expressions in rheumatoid arthritis patients.

Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis characterized by pain, swelling and destruction of joints, with a resultant disability. Disease-modifying anti-rheumatic drugs (DMARDs) and biological drugs can interfere with the disease process. In this study, the effect of β-d-mannuronic acid (M2000) as a novel non-steroidal anti-inflammatory drug (NSAID) with immunosuppressive and anti-inflammatory effects together with antioxidant effects was evaluated on IL17, RORγt, IL4 and GATA3 gene expression in 12 RA patients. Previously, M2000 driven from sodium alginate (natural product; patented, DEU: 102016113018.4) has shown a notable efficacy in experimental models of multiple sclerosis, RA and nephrotic syndrome. This study was performed on 12 patients with RA who had an inadequate response to conventional treatments. During this trial, patients were permitted to continue the conventional therapy excluding NSAIDs. M2000 was administered orally at a dose of 500 mg twice daily for 12 weeks. The peripheral blood mononuclear cells (PBMCs) were collected before and after treatment to evaluate the expression levels of IL4, GATA3, IL17 and RORγt. The gene expression results showed that M2000 has a potent efficacy, so that it could not only significantly decrease IL17 and RORγt levels but also increase IL4 and GATA3 levels after 12 weeks of treatment. Moreover, the gene expression results were in accordance with the clinical and preclinical assessments. In conclusion, M2000 as a natural novel agent has therapeutic and immunosuppressive properties on RA patients (identifier: IRCT2014011213739N2).

Role of Hijama’ (Cupping Therapy) in the Management of Niqras (Gouty Arthritis)

Gout is a potentially progressive and debilitating form of chronic inflammatory arthritis caused by the deposition of monosodium urate crystals in synovial fluid and other tissues, characterized by sudden & severe episode of pain, warmth and swelling in a joint. People suffering from recurrent attacks frequently experience pain and disability, reduced health-related quality of life and productivity and increased morbidity. NSAIDs, colchicines, glucocorticoids, uric acid lowering agent like uricostatic drugs (allopurinol, a xanthine oxidase inhibitor), Uricosuric drugs (Probenecid) are very effective but risky in patients having pre-existing renal, cardiovascular, gastrointestinal and metabolic disorders. Cupping (Al-Hijama) is a widely used therapeutic regimen of Unani system of medicine with high acceptance in Egypt and Arab countries. It is used for the treatment of various inflammatory and painful conditions like sciatica, gout, rheumatoid arthritis, pain of knee, removal of deep swelling, disease of liver and skin etc. It is a minor surgical excretory procedure related scientifically to the principles of renal glomerular filtration and abscess evacuation where a pressure-dependent excretion of causative pathological substances occurs. Cupping is thought to act mainly by increasing local blood circulation and relieving the painful muscle tension. It acts by improving microcirculation, promoting capillary endothelial cell repair, accelerating granulation, and angiogenesis in the regional tissues. It is the best deep tissue massage which normalizes the patient’s functional state and progressive muscle relaxation. In Unani system of Medicine, this is a simple and economic treatment, effectively treating diseases with different etiologies and pathogenesis.

Rheumatoid Arthritis: Etiology and Pathogenesis

Rheumatoid arthritis (RA) is among the most common forms of chronic inflammatory arthritis. It affects approximately 1% of adults and is two to three times more prevalent in women than in men. There are no specific laboratory tests for RA; diagnosis depends on a constellation of signs and symptoms that can be supported by serology and radiographs. The disease evolves over many years as a consequence of repeated environmental stress causing inflammation and immune activation followed by a breakdown of tolerance in individuals with a specific genetic background. This review describes the definition of RA; its etiology, including genetics, infections, the role of smoking and citrullination of proteins, and epigenetic mechanisms; and its pathogenesis, including synovial histopathology, bone and cartilage damage, adaptive and innate immunity, and the role of cytokines and intracellular signaling. Tables include the 1987 American Rheumatism Association criteria for the classification of RA and the 2010 American College of Rheumatology/European League Against Rheumatism classification for RA. Figures show citrullinated proteins in airway cells, a section of a proliferative synovium from a patient with a classic RA, and scalloped regions of erosion at the junction between a proliferative inflamed rheumatoid synovium and the bone. This review contains 3 highly rendered figures, 2 tables, and 71 references.

Antibodies to Endothelial Cell Growth Factor and Obliterative Microvascular Lesions in the Synovium of Patients With Antibiotic‐Refractory Lyme Arthritis

Endothelial cell growth factor (ECGF) was recently identified as the first autoantigen known to be a target of T cell and B cell responses in ~20% of patients with antibiotic-refractory Lyme arthritis. The goal of the current study was to look for a pathologic correlate between ECGF autoantibody responses and histologic findings in synovial tissue. Synovial tissue was examined from 14 patients with antibiotic-refractory Lyme arthritis and 6 patients with other forms of chronic inflammatory arthritis, primarily rheumatoid arthritis. The tissue sections were subjected to chemical and immunostaining, and IgG antibody responses to ECGF were determined by enzyme-linked immunosorbent assay (ELISA). Each finding was ranked for statistical analysis. In each disease, synovial tissue showed synovial hypertrophy, vascular proliferation, immune cell infiltrates, and fibrosis. However, among the 14 patients with antibiotic-refractory arthritis, 8 (57%) had obliterative microvascular lesions in the tissue, compared with none of the 6 patients with other forms of chronic inflammatory arthritis (P = 0.04). Among the patients with Lyme arthritis, 5 (36%) had autoantibody responses to ECGF, and all 5 had obliterative lesions, as compared with only 3 of 9 patients who lacked ECGF antibody responses (P = 0.009). Moreover, the magnitude of ECGF antibody responses correlated directly with the extent of obliterative lesions (P = 0.02) and with greater vascularity in the tissue (P = 0.05). The correlations of ECGF autoantibody reactivity with obliterative microvascular lesions imply that these autoantibodies may be involved in the obliterative process, suggesting that anti-ECGF antibodies have specific pathologic consequences in the synovial tissue of patients with antibiotic-refractory Lyme arthritis.

Circulating miRNA-125b is a potential biomarker predicting response to rituximab in rheumatoid arthritis.

Although biologic therapies have changed the course of rheumatoid arthritis (RA), today's major challenge remains to identify biomarkers to target treatments to selected patient groups. Circulating micro(mi)RNAs represent a novel class of molecular biomarkers whose expression is altered in RA. Our study aimed at quantifying miR-125b in blood and serum samples from RA patients, comparing healthy controls and patients with other forms of rheumatic diseases and arthritis, and evaluating its predictive value as biomarker for response to rituximab. Detectable levels of miR-125b were measured in total blood and serum samples and were significantly elevated in RA patients compared to osteoarthritic and healthy donors. The increase was however also found in patients with other forms of chronic inflammatory arthritis. Importantly, high serum levels of miR-125b at disease flare were associated with good clinical response to treatment with rituximab three months later (P = 0.002). This predictive value was not limited to RA as it was also found in patients with B lymphomas. Our results identify circulating miR-125b as a novel miRNA over expressed in RA and suggest that serum level of miR-125b is potential predictive biomarker of response to rituximab treatment.

Inflammatory pathways in spondyloarthritis

Spondyloarthritis is the second most common form of chronic inflammatory arthritis and a unique hallmark of the disease is pathologic new bone formation. Several cytokine pathways have been genetically associated with ankylosing spondylitis (AS), the prototypic subtype of SpA, and additional evidence from human and animal studies support a role of these pathways in the disease. TNF has a key role in SpA as blockade significantly reduces inflammation and destruction, however the treatment does not halt new bone formation. New insights into the TNF pathway were recently obtained from an animal model specifically overexpressing the transmembrane form of TNF. This model leads to axial and peripheral new bone formation which is not seen in soluble TNF overexpression models, indicating different pathogenic roles of soluble and transmembrane TNF in arthritis development. Besides TNF, the IL-23/IL-17 axis is emerging as an important inflammatory pathway in SpA, as a SNP in the IL-23R locus has been associated with developing AS, mice overexpressing IL-23 develop SpA-like features and IL-17 blockade has been shown to be efficacious for AS patients in a phase II trial. In this review, we focus on the cytokine pathways that have recently been genetically associated with SpA, i.e. TNF, IL-1, IL-6 and IL-23/IL-17. We review the current genetic, experimental and human in vivo data available and discuss how these different pathways are involved in the pathophysiology of SpA. Additionally, we discuss how these pathways relate to the pathogenic new bone formation in SpA.

AB0483 Cutaneous adverse events related to TNFα blockers in patients with chronic inflammatory arthritis

BackgroundTNFα blockers are effective options for the treatment of different forms of chronic inflammatory arthritis (CIA). However, these drugs are associated with a greater frequency of adverse events, especially infectious...