Chronic Systemic Inflammatory Disease Research Articles

Dupilumab Efficacy in Children With Atopic Dermatitis Aged 6 Months to 5 Years With and Without Atopic Comorbidities

Atopic dermatitis (AD) is a chronic inflammatory systemic disease that frequently occurs with atopic comorbidities. Here, we evaluate the efficacy of dupilumab with concomitant topical corticosteroids (TCS) for moderate-to-severe AD in children with and without asthma, allergic rhinitis, and food allergies.

Investigating the Interplay Between Gut Microbiome and Immune Landscape in Sarcoidosis

Sarcoidosis is a chronic systemic inflammatory disease characterized by granulomatous infiltration of affected organs, predominantly the lungs, with unclear etiology. Prior studies implicate microbial antigens as a trigger for inflammation driving granuloma formation. Considering potential cross-interactions along the lung-gut axis, we examine the relationship between gut microbiome and host immunity in sarcoidosis.

Effect of a combination of Atractylodes macrocephala extract with strychnine on the TLR4/NF-κB/NLRP3 pathway in MH7A cells.

Rheumatoid arthritis (RA) is now widely recognized as a chronic systemic inflammatory autoimmune disease characterized by swelling, pain and stiffness, which are often disabling. Although the number of drugs available for the treatment of RA has increased in recent years, they are generally expensive, leave patients prone to relapse and can result in severe effects when discontinued. Thus, there is a need for an inexpensive drug with fewer side effects that can be adhered to relieve pain and slow down the progression of the disease. Strychnine, a traditional Chinese medicine, was often used in ancient times to treat swollen and painful joints; however, because of its somewhat toxic nature, it is often combined with Atractylodes macrocephala to reduce its toxicity for safer therapeutic action. The present study performed high-performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) analysis to confirm whether the use of strychnine with Atractylodes macrocephala had the effect of reducing strychnine content. MH7A cells were induced using IL-1β to study the effect of strychnine with Atractylodes macrocephala on the Toll-like receptor 4 (TLR4)/NF-κB/NLR family pyrin domain-containing 3 (NLRP3) pathway in order to verify its role in the treatment of RA. The results indicated that the combined application of HPLC-MS/MS strychnine and Atractylodes macrocephala had a reducing effect on the strychnine content. From the subsequent experimental results, it can be inferred that Strychnine combined with Atractylodes macrocephala extract could promote the apoptosis of synovial cells, and could inhibit the expression levels of TLR4, NF-κB and NLRP3 in the cells as well as reducing the MH7A-positive cells. The expression levels of TLR4, IκB kinase β, NF-κB and NLRP3 were significantly reduced after treatment with each administration group, resulting in a decrease in the phosphorylation levels of TLR4 and NF-κB, indicating that the combination potently inhibited their phosphorylation. The combination of strychnine and atractylenolide II was also revealed to be the main active ingredient in the treatment of RA.

Rheuminations

I’ll be honest…it has been 35+ years since I started Medical School [MBBS]. And in the realm of Medicine at large, and Immunology/Rheumatology in specific, we are still struggling to find a ‘cure’ for chronic systemic inflammatory immune-mediated diseases also known as ‘autoimmune rheumatic diseases (ARD)’. Rheumatology is still in its cradle having gotten the recognition as a subspecialty of Medicine only in 1972. I have seen the field evolve in terms of understanding the orchestrated ‘play’ of the immune cells along with cytokines etc. over the past 3 decades, all of which has led to the concept and birth of ‘biologic’ disease modifying anti-rheumatic drugs [b-DMARDs]. The first b-DMARD to get approved by the Food and Drugs Administration [FDA] was etanercept, a TNF-alpha receptor fusion protein in 1998. Infliximab, a chimeric monoclonal antibody against TNF soon followed in 1999. Ever since then, there has been a flurry of b-DMARDs including 3 more in the same family of TNF-antagonists, 2 in the Interleukin [IL]-6 antagonist class, 1 blocker of the second co-stimulatory T-cell signaling: CTLA-4Ig, 3 IL-1 antagonists, B-cell depleting chimeric monoclonal antibody directed against CD-20 etc. Also, 3 oral Janus-kinase inhibitors have joined the ‘gang’ and are called targeted synthetic DMARDs. I still remember the pre-b-DMARD era when rip roaring rheumatoid arthritis was still around, and with my Ustaad Saheb (Mentor), all what we had to offer pharmaceutically were the conventional synthetic [cs] DMARDs including methotrexate, hydroxychloroquine, sulfasalazine, leflunomide and [the younger generation can hold their breath] cyclosporine, d-penicillamine, chlorambucil…GOLD injections and even cyclophosphamide! Corticosteroids have been around since 1950! The 1st and “so far” […well, I/You might be next one!] the only Nobel Prize winning revelation in the realm of Rheumatology......................................

The prevalence of hypertension among patients with psoriasis in clinical practice

Background. Psoriasis is a systemic chronic immune-mediated inflammatory skin disease of a multifactorial nature that affects about 2 to 3% of the population worldwide. Given the systemic nature of the disease, the level of comorbid diseases is high, especially those associated with damage to the cardiovascular system. According to the results of various meta-analyzes, it has been proven that among patients with psoriasis, the risk of developing hypertension is high.
 Aim. To evaluate the prevalence of arterial hypertension (AH) among patients with psoriasis.
 Materials and methods. We present an open, prospective, observational clinical trial, which includes 60 patients diagnosed with psoriasis vulgaris of varying severity and psoriatic arthritis. All patients underwent clinical and laboratory tests, including the level of total cholesterol, glucose, creatinine, C-reactive protein, calculation of glomerular filtration rate. Body mass index, blood pressure level according to the Korotkov method, severity of the disease by determining psoriasis area and severity Index (PASI), dermatological quality of life index (DLQI), levels of hospital anxiety and depression according to the HADS scale were also assessed. The SCORE2 scale was used to assess cardiovascular risk in patients aged 40 to 69 years, the SCORE 2OP scale for patients aged 70 to 89 years, respectively. Cardiovascular risk was defined as low for patients under 40 years of age. All study participants were examined for the presence of AH.
 Results. The prevalence of hypertension was 25%, with prevalence among men (15%). The prevalence of hypertension is directly proportional to the severity of psoriasis (13% with hypertension in patients with severe psoriasis, 12% with hypertension with moderate psoriasis, 2% with hypertension with mild psoriasis).
 Conclusion. Given the high prevalence of AH among patients with psoriasis, it is necessary to form a multidisciplinary approach to the treatment of patients, including a thorough assessment of cardiovascular risk in clinical practice.

Co-design and Development of EndoSMS, a Supportive Text Message Intervention for Individuals Living With Endometriosis: Mixed Methods Study.

Endometriosis, which affects 1 in 10 people assigned female at birth, is a chronic systemic inflammatory disease with a high symptom burden and adverse socioemotional impacts. There is a need for an accessible, cost-effective, and low-burden intervention to support individuals in managing their endometriosis condition. This study aimed to co-design and evaluate the acceptability, readability, and quality of a bank of supportive SMS text messages (EndoSMS) for individuals with endometriosis. In phase 1 of this mixed method design, 17 consumer representatives (individuals with endometriosis) participated across three 3-hour web-based (Zoom, Zoom Video Communications, Inc) focus groups. The transcripts were encoded and analyzed thematically. In phase 2, consumer representatives (n=14) and health care professionals (n=9) quantitatively rated the acceptability, readability, and appropriateness of the developed text messages in a web-based survey. All the participants initially completed a background survey assessing sociodemographic and medical factors. Consumer representatives demonstrated diverse sociodemographic characteristics (Mage=33.29), varying in location (metropolitan vs rural or regional), employment, and relationship and educational statuses. Participants reached a consensus regarding the delivery of 4 SMS text messages per week, delivered randomly throughout the week and in one direction (ie, no reply), with customization for the time of day and use of personal names. Seven main areas of unmet need for which participants required assistance were identified, which subsequently became the topic areas for the developed SMS text messages: emotional health, social support, looking after and caring for your body, patient empowerment, interpersonal issues, general endometriosis information, and physical health. Through a web-based survey, 371 co-designed SMS text messages were highly rated by consumers and health care professionals as clear, useful, and appropriate for individuals with endometriosis. Readability indices (Flesch-Kincaid scale) indicated that the SMS text messages were accessible to individuals with a minimum of 7th grade high school education. On the basis of the needs and preferences of a diverse consumer representative group, we co-designed EndoSMS, a supportive SMS text message program for individuals with endometriosis. The initial evaluation of the SMS text messages by consumer representatives and health professionals suggested the high acceptability and suitability of the developed SMS text messages. Future studies should further evaluate the acceptability and effectiveness of EndoSMS in a broader population of individuals with endometriosis.

Advances in imaging and treatment of atherosclerosis based on organic nanoparticles.

Atherosclerosis, a systemic chronic inflammatory disease, can lead to thrombosis and vascular occlusion, thereby inducing a series of serious vascular diseases. Currently, distinguishing unstable plaques early and achieving more effective treatment are the two main clinical concerns in atherosclerosis. Organic nanoparticles have great potential in atherosclerotic imaging and treatment, showing superior biocompatibility, drug-loading capacity, and synthesis. This article illustrates the process of atherosclerosis onset and the key targeted cells, then systematically summarizes recent progress made in organic nanoparticle-based imaging of different types of targeted cells and therapeutic methods for atherosclerosis, including optical and acoustic-induced therapy, drug delivery, gene therapy, and immunotherapy. Finally, we discuss the major impediments that need to be addressed in future clinical practice. We believe this article will help readers to develop a comprehensive and in-depth understanding of organic nanoparticle-based atherosclerotic imaging and treatment, thus advancing further development of anti-atherosclerosis therapies.

Brain structure and connectivity in psoriasis and associations with depression and inflammation; findings from the UK biobank

BackgroundPsoriasis is a chronic systemic inflammatory skin disease, coexisting with depression in up to 25% of patients. Little is known about the drivers of comorbidity, including shared neurobiology and depression brain imaging patterns in patients. An immune-mediated crosstalk between the brain and skin has been hypothesized in psoriasis. With the aim of investigating brain structure and connectivity in psoriasis in relation to depression comorbidity, we conducted a brain imaging study including the largest psoriasis patient sample to date (to our knowledge) and the first to investigate the role of depression and systemic inflammation in brain measures. Effects of coexisting psoriatic arthritis (PsA), which represents joint involvement in psoriasis and a higher putative inflammatory state, were further explored. MethodsBrain magnetic resonance imaging (MRI) data of 1,048 UK Biobank participants were used (131 comorbid patients with psoriasis and depression, age-and sex-matched to: 131 non-depressed psoriasis patients; 393 depressed controls; and 393 non-depressed controls). Interaction effects of psoriasis and depression on volume, thickness and surface of a-priori defined regions of interest (ROIs), white matter tracts and 55x55 partial correlation resting-state connectivity matrices were investigated using general linear models. Linear regression was employed to test associations of brain measures with C-reactive protein (CRP) and neutrophil counts. ResultsNo differences in regional or global brain volumes or white matter integrity were found in patients with psoriasis compared to controls without psoriasis or PsA. Thickness in right precuneus was increased in psoriasis patients compared to controls, only when depression was present (β = 0.26, 95% CI [Confidence Intervals] 0.08, 0.44; p = 0.02). In further analysis, psoriasis patients who had PsA exhibited fronto-occipital decoupling in resting-state connectivity compared to patients without joint involvement (β = 0.39, 95% CI 0.13, 0.64; p = 0.005) and controls (β = 0.49, 95% CI 0.25, 0.74; p < 0.001), which was unrelated to depression comorbidity. Precuneus thickness and fronto-occipital connectivity were not predicted by CRP or neutrophil counts. Precuneus thickening among depressed psoriasis patients showed a marginal correlation with recurrent lifetime suicidality. ConclusionsOur findings provide evidence for a combined effect of psoriasis and depression on the precuneus, which is not directly linked to systemic inflammation, and may relate to suicidality or altered somatosensory processing. The use of the UK Biobank may limit generalizability of results in populations with severe disease.

538 Bath-PUVA therapy changes inflammatory profiles for systemic effects beyond the skin

Psoriasis is a cutaneous disease as well as a systemic chronic inflammatory disease that is closely associated with multiple comorbidities, such as cardiovascular diseases, diabetes, and metabolic syndrome. Recently developed treatment modalities are highly effective for psoriasis skin lesions. The greater the extent of the body surface area affected, the more prone the patient is to psoriatic arthritis and systemic inflammation. Therefore, tight control of psoriatic skin lesions may reduce the incidence of future comorbidities.

Single-Cell RNA Sequencing Reveals the Immune Cell Profiling in IMQ Induced Psoriasis-Like Model.

Psoriasis is a chronic systemic inflammatory skin disease with a high recurrence rate. The immune response plays an important role in psoriasis. However, the subsets of immune cells involved in inflammation in psoriatic mice have not been fully studied. This study showed the immune environment characteristics of psoriasis in mice. We used single-cell RNA sequencing (10× Genomics) as an unbiased analytical strategy to investigate the heterogeneity of skin immune cells in imiquimod-induced psoriasis mice systematically. We identified 10 major clusters and their marker genes among 14,439 cells. The proportions of macrophages, NK/T cells, conventional dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs) were increased in psoriatic mice. Macrophages were the largest group and were further divided into 7 subgroups, and all macrophage clusters were increased in psoriatic mice. Differentially expressed genes in control versus psoriatic mice skin lesions showed that Fcgr4, Saa3 and Acp5 in macrophages, Acp5, Fcgr4 and Ms4a6d in NK/T cells, Saa3 in cDCs, and Ifitm1 in pDCs were upregulated in psoriasis mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis emphasized the role of oxidative phosphorylation signals and antigen processing and presentation signals in murine psoriasis-like models. Our study reveals the immune environment characteristics of the commonly used IMQ induced psoriasis-like models and provides a systematic insight into the immune response of mice with psoriasis, which is conducive to comparing the similarities and differences between the mouse model and human psoriasis.

Association between Periodontitis and Inflammatory Bowel Disease- Review of Current Literature on the Biologic Plausibility

Periodontitis, a chronic inflammatory disease of the supporting tissues of teeth, is etiologically associated with a subset of pathogenic organisms that thrive in the anoxic niche provided by the diseased periodontal pockets. These anaerobic gram-negative organisms resident in plaque biofilm and causing an overwhelming chronic inflammatory response in periodontal tissues have also been associated with other systemic chronic inflammatory diseases like cardiovascular, renal, and adverse pregnancy outcomes as per literature being published for the past twenty years or more. This paper aims to provide an overview on the biological plausibility of a strong association between systemic seeding of pathogenic oral bacteria and chronic bowel diseases like Inflammatory Bowel Diseases by reviewing recent literature from open-source journals on the same topic. Knowledge of the association between oral bacteria and gut inflammatory diseases will help in broadening the preventive and therapeutic options available currently by suggesting measures to suppress the systemic hyper-immune response.

Clinical practice guidelines for endometriosis in Japan (The 3rd edition).

Clinical practice guidelines for endometriosis in Japan (The 3rd edition).

Decreased fecal calprotectin levels in Spondyloarthritis patients colonized by Blastocystis spp.

Spondyloarthritis (SpA) is a group of chronic inflammatory systemic diseases mainly characterized by inflammation in the spine and/or peripheral joints. Although a link between SpA-pathogenesis, intestinal inflammation and gut dysbiosis has been proposed, studies have been focused on bacteria-host interactions and very little has been reported regarding intestinal parasites. Here, intestinal parasitic infection of 51 SpA-patients were evaluated and compared to healthy control individuals. No significant differences in the frequency of any parasite between SpA-patients and control individuals were found. Significantly higher levels of fecal calprotectin (FCP) were found in the SpA-patients compared to the control individuals. However, FCP levels were the same when comparing SpA-patients and control individuals, both colonized by Blastocystis spp. On the other hand, when comparing Blastocystis spp. colonized and Blastocystis spp. free SpA-patients, FCP levels were significantly higher in those Blastocystis spp. free. Without ignoring the small sample size as a study limitation, the results showed that in the SpA-patients colonized by Blastocystis spp., the FCP levels were significantly lower than those in the Blastocystis spp. free group and comparable to those in the control group. These findings seem to suggest a relationship between Blastocystis spp. and intestinal inflammation in SpA-patients, but studies intended to explore that interaction specifically should be designed.

Biological Treatments for Pediatric Psoriasis: State of the Art and Future Perspectives.

Psoriasis is a chronic systemic inflammatory disease that primarily affects the skin and is associated with multiple comorbidities with a considerable reduction in quality of life of affected patients. One-third of psoriasis cases begin in childhood and are associated with significant medical comorbidities such as obesity, metabolic syndrome, arthritis, and psychiatric disorders. In addition, because of its chronic nature and frequent relapses, psoriasis tends to require long-term treatment. Treatment of pediatric psoriasis usually involves the same methods used for adults. However, most treatments for pediatric psoriasis are used off-label, and research in this regard is still lacking. Targeted therapies involving the use of newly developed biologic drugs are also increasingly being applied to childhood psoriasis. This review summarizes the clinical features of pediatric psoriasis and focuses mainly on the updated concepts of pathogenesis and biological treatments of pediatric psoriasis.

Peripheral arthritis in psoriatic arthritis: from immunopathogenesis to therapy with Janus kinase inhibitors.

Psoriatic arthritis (PsA) is a chronic systemic inflammatory disease characterised by high phenotypic heterogeneity. Peripheral polyarticular, pauciarticular, axial, enthesitic, and dactylitic forms have been classically described, although it is not clear whether they all have the same pathophysiological mechanisms. Use of cytokine-targeted therapies in the last 20 years has significantly impacted the quality of life of patients with PsA even though a significant proportion of patients, regardless of the mechanism of action considered, remain non-responders, suggesting the need for better understanding of the pathophysiological basis of the disease to appropriately stratify patients and identify new therapeutic targets. The pre-clinical demonstration of the pathophysiological relevance of the JAK/STAT pathway in the pathogenesis of PsA and the emerging efficacy data from randomised controlled trials of JAK inhibitors in PsA patients have set the stage for a new pharmacological era in patients with PsA. In this review, we discuss the rationale for using approved JAK inhibitors for treatment of peripheral PsA and their positioning in the context of EULAR/GRAPPA guidelines.

Looking beyond the Skin: Pathophysiology of Cardiovascular Comorbidity in Psoriasis and the Protective Role of Biologics.

Psoriasis is a chronic systemic inflammatory disease associated with a higher incidence of cardiovascular disease, especially in patients with moderate to severe psoriasis. It has been estimated that severe psoriasis confers a 25% increase in relative risk of cardiovascular disease, regardless of traditional risk factors. Although the underlying pathogenic mechanisms relating psoriasis to increased cardiovascular risk are not clear, atherosclerosis is emerging as a possible link between skin and vascular affection. The hypothesis that the inflammatory cascade activated in psoriasis contributes to the atherosclerotic process provides the underlying basis to suggest that an anti-inflammatory therapy that improved atherosclerosis would also reduce the risk of MACEs. In this sense, the introduction of biological drugs which specifically target cytokines implicated in the inflammatory cascade have increased the expectations of control over the cardiovascular comorbidity present in psoriasis patients, however, their role in vascular damage processes remains controversial. The aim of this paper is to review the mechanistic link between psoriasis and cardiovascular disease development, as well as analyzing which of the biological treatments could also reduce the cardiovascular risk in these patients, fueling a growing debate on the modification of the general algorithm of treatment.

Anhedonia in endometriosis: An unexplored symptom.

Anhedonia is the diminished motivation and sensitivity to pleasurable stimuli. It has been reported to be more prevalent in patients with chronic pain as compared to healthy controls. Endometriosis is a chronic inflammatory systemic disease with a significant psychosocial impact that compromises wellbeing and the day-to-day life of patients. Women with endometriosis show significant psychological distress, even more pervasive when chronic pelvic pain is present. In the current review we will discuss the role of anhedonia in endometriotic chronic pelvic pain. We will also present new lines of research that could lead to more fully clarifying the psychological impact of endometriosis and its detrimental repercussions to quality of life and mental health.

34358 Long-term efficacy of dupilumab in adults with moderate-to-severe atopic dermatitis (AD): Results from an open-label extension (OLE) trial up to 4 years

Background: AD is a chronic systemic inflammatory disease often requiring long-term management. Here, we present long-term efficacy of dupilumab up to 4 years in adult patients with moderate-to-severe AD. Methods: The OLE (NCT01949311), with an initial duration of 3 years, enrolled adults with moderate-to-severe AD who participated in a dupilumab parent study. Protocol amendments extended the maximum treatment duration to 5 years. Following protocol amendments in 2017 and 2018, 114 and 272 patients re-entered the trial; 103 and 207 patients had a treatment interruption of >8 weeks between Weeks 148 and 164. Patients were treated with 300 mg dupilumab weekly. In 2019, patients transitioned to 300 mg every 2 weeks to align with approved dosage. Concomitant topical anti-inflammatory treatments were permitted. Data shown are for the overall study population (N = 2677). Results: 2207/1065/557/362/352 patients completed up to 52/100/148/172/204 weeks of treatment. 240 patients had treatment duration >204 weeks. Most withdrawals (59.5%) were due to dupilumab approval; 8.4%/4.3% withdrew due to adverse events/lack of efficacy. At Week 204, 95%/91%/76% of patients achieved 50%/75%/90% reductions in Eczema Area and Severity Index from parent study baseline (PSBL). 78.7%/70.8% of patients achieved ≥3/≥4-point reduction in the Peak Pruritus Numerical Rating Scale score from PSBL at Week 204. Treatment-emergent adverse events were reported in 2273 (84.9%) patients, with 99 (3.7%) permanently discontinuing treatment. Conclusions: Long-term dupilumab treatment showed sustained efficacy substantiated by improvement of AD signs and symptoms in patients with moderate-to-severe AD up to 204 weeks. Safety data were consistent with prior studies.

34385 Sustained long-term dupilumab efficacy in adult patients with moderate-to-severe atopic dermatitis transitioning from weekly dosing to every other week: Results from an open-label extension trial

Background: Atopic dermatitis (AD) is a chronic systemic inflammatory disease often requiring long-term management. Here, we evaluate long-term maintenance of the efficacy of dupilumab in adult patients with moderate-to-severe AD who changed dosing from once weekly (qw) to once every two weeks (q2w) in an open-label extension trial (NCT01949311).

34367 Safety of long-term dupilumab treatment in adults with moderate-to-severe atopic dermatitis: Results from an open-label extension (OLE) trial up to 4 years

Background: Atopic dermatitis (AD) is a chronic systemic inflammatory disease requiring long-term management. We extend the dupilumab safety profile in patients with moderate-to-severe AD to 204 weeks. Methods: The OLE (NCT01949311), with an initial duration of 3 years, enrolled adults with moderate-to-severe AD who participated in any dupilumab parent study. Protocol amendments allowed for patient re-entry and treatment extension for up to 5 years. Patients were treated with 300 mg dupilumab weekly. In 2019, patients transitioned to 300 mg every 2 weeks to align with approved dosage. Concomitant topical treatments were permitted. Data shown are for the overall study population (N = 2,677). Results: 2207/1065/557/362/352 patients completed up to 52/100/148/172/204 weeks of treatment. 240 patients had treatment duration of >204 weeks. Most withdrawals (59.5%) were due to dupilumab approval/commercialization; 8.4%/4.3% withdrew due to adverse events (AEs)/lack of efficacy. Exposure-adjusted incidence rates of treatment-emergent AEs (TEAEs) were lower in this OLE vs the 300c mg weekly+topical corticosteroid arm of the 1-year CHRONOS trial (167.5 vs 322.4 number of patients/100 patient-years). 10.4% of patients had serious TEAEs; 9.8%, severe TEAEs; 1.2%, ≥1 serious TEAE related to study drug; and 3.7%, TEAEs resulting in permanent drug discontinuation. The most common TEAEs were nasopharyngitis (28.9%) and conjunctivitis (20.0%, including allergic/bacterial/viral/atopic keratoconjunctivitis). The most common severe TEAEs by MedDRA Preferred Term were dermatitis atopic (0.9%) and conjunctivitis (0.7%). 95% patients with conjunctivitis TEAEs were reported as mild/moderate; 87% of conjunctivitis events were recovered/resolved. Conclusions: This analysis extends to 4 years the previous findings demonstrating dupilumab’s acceptable long-term safety profile.