Long-standing Inflammatory Disease Research Articles

Multi-failure psoriasis patients: characterization of the patients and response to biological therapy in a multicenter Italian cohort.

Patients with psoriasis who have failed multiple biologic drugs have been defined as "multi-failure," although there are no clear data on the characteristics, comorbidities, and best treatment strategies for this population. Nowadays, given the next generation and the number of biologics available, patients are considered multi-failure when ≥4 biologics fail to achieve a good response. Demographic characteristics and efficacy of anti-interleukin drugs in multi-failure patients were compared to a cohort of general psoriatic patients treated with IL-23 or IL-17 inhibitors. In total 97 multi-failure patients (≥4 lines of biologics) were compared with 1,057 patients in the general cohort. The current drugs in the multi-failure group were risankizumab (34), ixekizumab (23), guselkumab (21), brodalumab (7), tildrakizumab (5), ustekinumab (4), secukinumab (2), and certolizumab pegol (1). A significant difference was found in the multi-failure cohort for age of psoriasis onset (mean 29.7 vs. 35.1, P < 0.001), concurrent psoriatic arthritis (45.4 vs. 26.9%, P < 0.001), diabetes mellitus (30.9 vs. 10.9%, P < 0.001), and cardiovascular comorbidity (54.6 vs. 39.8%, P = 0.005). In multi-failure patients, current biological therapy showed a good initial response (PASI 90 and 100 of 41.24 and 27.84%, respectively, at 16 weeks); the response tended to decline after 40 weeks. Anti-IL-17 agents showed clinical superiority over IL-23 agents in terms of achieving PASI90 at 28 weeks (P < 0.001) and 40 weeks (P = 0.007), after which they reached a plateau. In contrast, IL-23 agents showed a slower but progressive improvement that was maintained for up to 52 weeks. A similar trend was also seen for PASI100 (28 weeks P = 0.032; 40 weeks P = 0.121). The multi-failure patient is characterized by many comorbidities and longstanding inflammatory disease that frequently precedes the introduction of systemic biologic therapy. Further studies are needed to identify more specific criteria that could be applied as a guideline by clinicians.

Penile Lichen Sclerosis: A Surgical Perspective of its Aetiology and Treatment.

Penile lichen sclerosis is a longstanding inflammatory disease of the skin with a controversial aetiology. Penile lichen sclerosis (PLS) is a growing, inflammatory dermatitis of the anogenital region, which involves the meatus, prepuce, penile shaft, and glans penis. Although the accurate aetiology of PLS is contentious, multiple factors including genetics, autoimmunity, infections of human papillomavirus, hepatitis C, Epstein-Barr virus, risk factors (hormonal and trauma), etc., can be considered to be a part of the etiopathogenesis of PLS. The initial clinical presentations of penile lichen sclerosis are white plaques, atrophied skin, erythema, erosions, and sclerosis in the anogenital region. When the disease advances, the following can occur, including meatal constraints, telangiectasia, petechiae, soreness, papular lesions, tightness of the foreskin, difficulties in passing urine, itching, tenderness on erections, pain, cracking, bleeding, redness, rashes, tightness at frenulum, and dysuria. This disease has a dangerous course of action and if untreated it may be linked with severe urologic and sexual morbidities. PLS is usually treated with medical and surgical interventions like topical or intralesional steroids and circumcision. The role of circumcision is very critical in the course of action and prognosis of PLS, and its treatment is dependent on the stage of the disease. This review brings up the knowledge regarding epidemiology, etiopathology, clinical presentation, and management of PLS with an emphasis on the role of circumcision.

Evaluation of Serum Apelin-13 in Acne Vulgaris Patients

Acne is a longstanding inflammatory disease of the pilosebaceous unit resulting from androgen-induced increased sebum production, altered keratinization, inflammation, and bacterial colonization of hair follicles by Propionibacterium acne [1]. Apelin is a newely discovered adipocytokine secreted by white adipose tissue and couples with the APJ receptor with the highest affinity. Apelin and the APJ receptor are found in pancreatic islet cells and found to have a role in energy metabolism. Many researches show that apelin has a role in glucose homeostasis regulation, insulin secretion, and increasing insulin sensitivity [2].The aim of the work was to evaluate the serum level of Apelin-13 in patients with acne vulgaris .Serum apelin was measured in 40 patients with moderate to severe acne vulgaris and 30 healthy controls using enzyme-linked immunosorbent assay (ELISA). Serumlevels of apelin13 in patients with acne vulgaris was found to be higher than in healthy controls (p value <0.005).In Conclusion Serum apelin13 has a role in the pathophysiology of acne vulgaris patients.

Obesity is a significant susceptibility factor for idiopathic AA amyloidosis

Background: To investigate obesity as susceptibility factor in patients with idiopathic AA amyloidosis.Methods: Clinical, biochemical and genetic data were obtained from 146 patients with AA amyloidosis. Control groups comprised 40 patients with long-standing inflammatory diseases without AA amyloidosis and 56 controls without any inflammatory disease.Findings: Patients with AA amyloidosis had either familial Mediterranean fever (FMF) or long-standing rheumatic diseases as underlying inflammatory disease (n = 111, median age 46 years). However, in a significant proportion of patients with AA amyloidosis no primary disease was identified (idiopathic AA; n = 37, median age 60 years). Patients with idiopathic AA amyloidosis were more obese and older than patients with AA amyloidosis secondary to FMF or rheumatic diseases. Serum leptin levels correlated with the body mass index (BMI) in all types of AA amyloidosis. Elevated leptin levels of more than 30 µg/l were detected in 18% of FMF/rheumatic + AA amyloidosis and in 40% of patients with idiopathic AA amyloidosis (p = .018). Finally, the SAA1 polymorphism was confirmed as a susceptibility factor for AA amyloidosis irrespective of the type of the disease.Conclusions: Obesity, age and the SAA1 polymorphism are susceptibility factors for idiopathic AA amyloidosis. Recent advances in treatment of FMF and rheumatic disorders will decrease the incidence of AA amyloidosis due to these diseases. Idiopathic AA, however, might be an emerging problem in the ageing and increasingly obese population.

Effects of vitamin D deficiency on the relapse, severity, and disability of multiple sclerosis

Background Multiple sclerosis (MS) is a long-standing inflammatory disease of the white matter and affects more than two million people worldwide. Upcoming evidence proposed that 25-hydroxy-vitamin D 3 (25HVD 3 ) deficiency could be one of the most crucial environmental elements for the pathogenesis of MS. Objective The aim of this study was to compare 25HVD 3 levels in MS patients and controls and to detect the association with relapse, severity, and disability in MS patients. Patients and methods Mansoura Neurology Department data sheet was collected and all patients were assessed using the Expanded Disability Status Scale (EDSS) at the onset. 25HVD 3 levels in the blood were evaluated for all patients and controls using the chemiluminescent immunoassay test. Results A total of 50 MS patients were included in this work and matched with 25 controls. There was a statistically significantly lower mean serum 25HVD 3 level in MS patients in comparison with the controls (20.5 ± 16.8 and 42.9 ± 17.9 ng/ml, respectively; P = 0.002). In addition, there was a statistically significantly lower level of 25HVD 3 (18.4 ± 17.7) in severe cases of MS (EDSS ≥ 6; P P P 3 deficiency ( Conclusion Our results showed that there is an inverse correlation between 25HVD 3 level and EDSS score. In addition, lower 25HVD 3 levels are associated with increased relapse risk in MS.

Risk factors for AA amyloidosis in Germany

Objective: To identify risk factors for serum amyloid-A (AA) amyloidosis in patients living in Germany.Methods: Clinical and genetic data were obtained from 71 patients with AA amyloidosis. SAA1 genotypes were analyzed in 231 individuals. Control groups comprised 45 patients with long-standing inflammatory diseases without AA amyloidosis and 56 age-matched patients without any inflammatory disease.Results: The most frequent underlying diseases of AA amyloidosis were familial Mediterranean fever (FMF) (n = 24, 34%) and inflammatory rheumatic diseases (n = 30, 42%). Patients without any known underlying disease (n = 11, 16%) were considered as having idiopathic AA amyloidosis. Patients with FMF were significantly younger at disease onset and younger at diagnosis of AA amyloidosis compared with patients with rheumatic diseases. Patients with idiopathic AA amyloidosis were older than patients with definite rheumatic diseases. Patients with FMF and high penetrance MEFV gene mutations had a relative risk of 1.73 for AA amyloidosis. Patients with FMF or a rheumatic disease and the SAA1 α/α genotype had a relative risk of 4.86 and 2.53, respectively, for developing an AA amyloidosis. The prevalence of this risk genotype was 36% in German patients without an inflammatory disease, 92% in German patients with AA amyloidosis and 100% in German patients with idiopathic AA amyloidosis.Conclusions: Risk factors for AA amyloidosis are the presence of a hereditary autoinflammatory or chronic rheumatic disease, elevated C-reactive protein and SAA serum levels, a long delay of a sufficient therapy, an advanced age and the SAA1α/α genotype.

AA amyloidosis: pathogenesis and targeted therapy.

The understanding of why and how proteins misfold and aggregate into amyloid fibrils has increased considerably during recent years. Central to amyloid formation is an increase in the frequency of the β-sheet structure, leading to hydrogen bonding between misfolded monomers and creating a fibril that is comparably resistant to degradation. Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules. In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver. A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood. Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease. This review summarizes current knowledge about AA amyloidosis. The systemic amyloidoses have been regarded as intractable conditions, but improvements in the understanding of fibril composition and pathogenesis over the past decade have led to the development of a number of different therapeutic approaches with promising results.

Animal Models of Carcinogenesis in Inflamed Colorectum: Potential Use in Chemoprevention Study

Inflammation is a risk factor for cancer development in several tissues. In the colorectum, inflammatory bowel disease (ulcerative colitis and Crohn's disease) is a longstanding inflammatory disease with increased risk for colorectal cancer (CRC). Several molecular events involving in chronic inflammatory process contribute to multi-stage carcinogenesis of CRC in the inflamed colon. They include alterations in production of reactive oxygen and nitrogen species, upregulation of pro-inflammatory cytokines and inflammatory enzymes, and intestinal immune system. In this short review, experimental animal models of inflammation-associated CRC are described. Also, some preclinical data on chemoprevention of inflammation-associated CRC by astaxanthin and a specific inhibitor of nitric oxide synthase using these inflammation-related CRC models is briefly introduced.

AA-Amyloid is cleared by endogenous immunological mechanisms

Objective: AA amyloidosis is a complication to longstanding inflammatory diseases, but reduction of amyloid mass has been reported as the inflammation ceases. Not much is known about the endogenous factors that contribute to this amyloid resolution. Herein, we describe the dynamics of amyloid degradation and resolution in experimental murine AA-amyloidosis. Methods: AA-amyloidosis was induced in mice with injections of amyloid enhancing factor (AEF) and by inflammation induced with injections of silver nitrate. Resolution of amyloid deposits was monitored over time. Results: Virtually all amyloid was cleared within 34 weeks. Using the ELISA-technique, antibodies directed against protein AA were detected in animals during amyloid clearance phase and macrophages were shown to internalize amyloid. Also, passive immunization with an amyloid specific monoclonal antibody, produced by a B-cell clone recovered from an animal with advanced AA-amyloidosis, reduced amyloid development in murine AA-amyloidosis. Conclusion: Immunoglobulins co-localize with amyloid deposits and can contribute to amyloid degradation by Fc-receptor mediated phagocytosis, and should be considered key players in the degradation process.

Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

Development of an Inflammation-Associated Colorectal Cancer Model and Its Application for Research on Carcinogenesis and Chemoprevention

Chronic inflammation is a well-recognized risk factor for development of human cancer in several tissues, including large bowel. Inflammatory bowel disease, including ulcerative colitis and Crohn's disease, is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer development. Several molecular events involved in chronic inflammatory process may contribute to multistep carcinogenesis of human colorectal cancer in the inflamed colon. They include overproduction of reactive oxygen and nitrogen species, overproduction and upregulation of productions and enzymes of arachidonic acid biosynthesis pathway and cytokines, and intestinal immune system dysfunction. In this paper, I will describe several methods to induce colorectal neoplasm in the inflamed colon. First, I will introduce a protocol of a novel inflammation-associated colon carcinogenesis in mice. In addition, powerful tumor-promotion/progression activity of dextran sodium sulfate in the large bowel of Apc Min/+ mice will be described. Finally, chemoprevention of inflammation-associated colon carcinogenesis will be mentioned.

Fibromyalgi

Unexplained pain and aches have been well known for centuries. In the modern time the concept fibrositis/ fibromyalgia has been applied to the phenomenon of idespread pain without known aetiology. Fibromyalgia (FM) is characterised by widespread, diffuse pain that is moving around. Typical for this condition is also morning stiffness and non restorative sleep, positive tender points (TP) and a number of associated, unspecific symptoms as feeling of swollenness, headache, depression etc.Positive TP are defined anatomic locations that feel painful when being palpated with a pressure of 4 kg/cm2. The TP have been considered as the hallmark of FM and is central in the classification criteria constructed to identify the disease (ACR-90 criteria).FM is not considered as a specific disease entity, but rather a continuum with respect of pain distribution, number of positive TP and number and intensity of associated symptoms. Nevertheless, due to the often overwhelming impact of pain and fatigue in those who fulfil the criteria, it is appropriate to keep FM as a diagnosis.During the last two decades about a dozen epidemiological studies has been performed to describe the prevalence in the general population. The average results lie between three and four percent with a range from 1.2% to 6.6%. The differences is probably mainly due to discrepancies in applied methodology, but one cannot rule out that some populations may have more FM than others. Incidence is not well known, one study performed on women indicates a high incidence.Mortality has until recently not been studied. There are now some few studies with somewhat scattered results. However, the major finding is higher mortality among individuals with FM, especially due to cancer.Whether this is a function of lifestyle or the presence of pain remains to be clarified. The main risk factor is the female gender; only about 10-30% of the FM population are men. Studies have shown that depression, longstanding localised pain especially in the back and the presence of a relatively large number of associated symptoms also are risk factors. FM develops in the majority of cases over many years. This knowledge may contribute to prevent FM before it actually manifests as such. FM has a large co-morbidity, especially with inflammatory rheumatological diseases. It is important to be aware of this to avoid overtreatment in patients with longstanding inflammatory diseases that have developed FM in addition. On the other hand it is also important to know that patients with FM also may get inflammatory diseases. It is an especially big overlap between FM and Sjögren’s syndrome. FM is a frequent condition that has a big impact on working ability. In Norway about five present of all who are receiving disability pension do have the diagnosis of FM. In spite of that approximately 50% of females’ application for disability pension are refused, FM is the most common diagnosis among those who are receiving pension. The development of the criteria has opened for international research on a considerable scale. This has lead to better understanding of the aetiopathogenesis and promising treatment possibilities in the future.

Susceptibility to AA amyloidosis in rheumatic diseases: A critical overview

Introduction Reactive systemic AA amyloidosis is one of the most severe complications of several chronic rheumatic disorders, particularly rheumatoid arthritis (RA), juvenile idiopathic arthritis, ankylosing spondylitis (AS), and the hereditary autoinflammatory syndromes. Organ and tissue damage results from the extracellular aggregation of proteolytic fragments of the circulating acute-phase reactant protein serum amyloid A (SAA) as insoluble amyloid fibrils. The kidneys, liver, and spleen are mostly targeted by AA amyloid deposits, and AA amyloidosis becomes clinically overt mainly when renal damage occurs, manifesting either as proteinuria, nephrotic syndrome, or derangement in renal function (1). Due to the risk of progression to end-stage renal disease and possible gastrointestinal and bladder bleeding, the occurrence of AA amyloidosis severely impacts the prognosis of patients with rheumatic disorders (2). In recent studies, amyloidosis has been reported as the cause of death in 5–17% of patients with RA (3). A sustained high concentration of SAA is the prerequisite for AA amyloidogenesis (Figure 1). However, AA amyloidosis actually develops in only a minority of patients with active, longstanding inflammatory diseases, indicating that significant disease-modifying factors might play a role in modulating either the occurrence, the rate of tissue deposition, or the induction of tissue damage in this form of amyloidosis. Here, we review genetic, biologic, and clinical factors underlying susceptibility to the development of AA amyloidosis in patients with chronic rheumatic disorders and provide a critical interpretation that also is supported by the well-characterized mouse model of the disease.

Review article: safety of infliximab in clinical trials.

Infliximab, a chimeric monoclonal antibody to tumour necrosis factor-alpha, contains murine protein elements and targets the immune system, raising concerns about the potential for immune sensitization and immunosuppressive sequelae. However, long-standing inflammatory disease with high activity and chronic immunosuppressant therapy can also predispose patients to immunosuppressive sequelae. Patients with Crohn's disease, rheumatoid arthritis and other indications received single or multiple doses of infliximab and their condition was followed for up to 3 years. Adverse events, most frequently headache, nausea, and upper respiratory tract infection, were generally mild and occurred in 76% of infliximab-treated patients vs. 57% of placebo-treated recipients. Human antichimeric antibodies developed in 13% of patients, increasing the potential for subsequent infusion reactions. Antibodies to double-stranded DNA developed in a small percentage of patients. Other antinuclear antibodies characteristic of serum lupus erythematosus were not found; no patient developed a true lupus syndrome and no other autoimmune disorders were reported. Infliximab is not associated with typical immunosuppressive sequelae, such as infections and malignancy, or with autoimmune disorders. Infliximab therapy was well tolerated, serious adverse events were infrequent, successfully managed with medication and without sequelae, and overall mortality was within the expected incidence for this patient population.