Manifestations Of Inflammatory Disease Research Articles

Rheumatic aspects of arthralgias associated with aromatase inhibitor therapy (analysis of a clinical case series)

Objective: to describe the rheumatic aspects of arthralgia associated with aromatase inhibitor therapy in a clinical case series.Material and methods. The article presents a series of clinical cases – 16 patients (mean age 61±14 years) with histologically verified breast cancer (BC) and the onset of musculoskeletal pathology during hormone therapy with aromatase inhibitors (letrozole, anastrozole, exemestane). The laboratory and instrumental examination data, including ultrasound, joint X-rays, general and immunological blood tests with the determination of rheumatoid factor (RF), antibodies to cyclic citrullinated peptide (ACCP), CRP and antinuclear factor (ANF) are presented. The detected musculoskeletal pathology was compared with valid classification and/or diagnostic criteria for rheumatic diseases.Results and discussion. In 10 (63%) cases, musculoskeletal pathology debuted in the first 3 months of therapy with aromatase inhibitors and in all patients it was represented by inflammatory manifestations, including clinically significant synovitis (n=13), tenosynovitis (n=12), enthesitis (n=5), morning stiffness in the joints >30 min (n=6) and inflammatory rhythm lower back pain (n=1). In 15 (94%) patients, ultrasound showed signs of synovitis (with increased vascularization in 5 cases), tenosynovitis in 15 (94%), and erosions in 1 (6%). X-rays showed osteoarthritis in 12 patients, and chronic erosive arthritis in 2. Increased ESR >30 mm/h and CRP level >5 mg/l were present in 6 (38%) and 7 (44%) patients, respectively; ANF (Hеp2) titer 1/160 was found in 8 (53%) out 15 examined patients. RF and ACCP were not detected in any case. During rheumatological examination, the following were diagnosed: polymyalgia rheumatica (n=1), undifferentiated arthritis (n=6), psoriatic arthritis (n=1), rheumatoid arthritis (n=1), recurrent proliferative synovitis of the knee joints with a pronounced exudative component (n=3), inflammatory lesions of periarticular tissues (n=4).Conclusion. Based on the obtained data, it can be assumed that arthralgias induced by breast cancer hormone therapy may be a manifestation of inflammatory diseases of the musculoskeletal system. Given the heterogeneity of manifestations of musculoskeletal pathology in such patients, a complete rheumatological examination is necessary to establish the diagnosis and conduct adequate therapy.

Thrombotic Manifestations in Patients with Vexas Syndrome

Introduction: VEXAS syndrome, caused by somatic mutations in ubiquitin-like modifier activating enzyme 1 (UBA1) gene, is a late-onset and progressive autoinflammatory disease. Main hematologic manifestations include macrocytic anemia, thrombocytopenia, and dyspoiesis. Concomitant diagnoses of myelodysplastic syndrome (MDS) and plasma cell dyscrasia (PCD) are common. Venous thromboembolism (VTE) and arterial thrombosis (AT) have been reported. We describe the incidence and characteristics of thrombosis in a large cohort of 86 patients with VEXAS syndrome, along with detailed coagulation profiles in a subgroup of patients. We also explore potential predictors of thrombosis, and effect on overall survival (OS). Methods: Two cohorts of patients with confirmed VEXAS were included. Thirty patients were evaluated at the National Institutes of Health (NIH) Clinical Center and 56 patient records reviewed from referring institutions. Logistic regression models were used to determine predictors of thrombosis. Cox proportional hazards models and Kaplan Meier curves were used for survival analysis. Results: The total population consisted of 86 patients. Eighty-five patients (99%) were male with a median age of 64 years (range, 40-84 years) at disease onset. Hematologic manifestations included macrocytic anemia in 63 (73%), MDS in 25 (29%) and PCD in 17 (20%) patients. Thrombosis occurred in 45 patients (52%); 41 (48%) had VTE and 11 (12%) had AT, with a median time to event from disease onset of 18 and 34 months, respectively; five patients (5%) had both VTE and AT. Among VTE, there were 26 (30%) deep venous thrombosis (DVT), 12 (14%) pulmonary embolism (PE), and 7 (8%) superficial thrombophlebitis. Twenty-two (54%) of VTE cases were unprovoked. Recurrent VTE was seen in 15 (17%) of patients, among which 9 (53%) occurred while receiving anticoagulation. Arterial events included myocardial infarction in 7 (8%) patients, stroke in 2 (2%) patients, and peripheral arterial occlusion in 2 (2%) patients. Recurrent AT was seen in 2 (2%) patients. Patients from the NIH cohort underwent extensive coagulation testing. Fourteen patients (46%) had a positive lupus anticoagulant (LA), which was persistently positive 12 weeks apart in 8 of 9 patients re-tested. Of these 8 patients, 6 had a VTE, 1 had a stroke and 1 did not have thrombotic manifestations. Thirteen patients (43%) with thrombotic events were negative for LA. Median levels of fibrinogen, D-dimer, Factor (F) VII, FIX, and especially von Willebrand factor (VWF) and FVIII, were high in 15 tested VEXAS patients, but there was no significant difference between those with and without thrombosis (Table 1). Of 10 patients with high VWF and 17 with high FVIII activity, 6 (60%) and 9 (53%) had a thrombotic event, respectively; these correlated with high levels of CRP and ESR. No patients were found to have abnormal antithrombin III activity, Factor V Leiden, or prothrombin gene mutations. No difference in age, UBA1 gene mutation, median levels of CRP and ESR, presence of MDS or PCD was found between patients with or without thrombosis; MDS, PCD and UBA1 gene mutation were also not predictive of thrombosis. Among inflammatory disease manifestations, cardiac involvement (myocarditis, pericarditis, or pericardial effusion) correlated with the presence of any thrombosis (p = 0.03). When considering VTE alone, cardiac manifestations strongly predicted PE and DVT (p = 0.004 and p = 0.005 respectively), while the presence of chondritis correlated with PE (p = 0.02). Presence of thrombosis did not impact OS (Figure 1). Conclusions: Patients with VEXAS syndrome are at high risk of thrombosis, mainly venous, which can be recurrent despite anticoagulation therapy. The underlying etiology remains unclear, but many VEXAS patients have positive LA, high VWF and FVIII levels, suggesting inflammation, endothelial activation and/or an immune process as pathophysiologic. Cardiac manifestations, including myocarditis, pericarditis, and pericardial effusion, significantly correlated with thrombosis in general, while chondritis correlated with presence of PE. Presence of thrombosis did not impact OS. Given the high incidence of thrombosis, VEXAS patients should be carefully risk assessed for VTE and considered for prophylactic anticoagulation, and indefinite treatment if thrombosis has occurred. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Eustachian tube dysfunction and Allergic rhinitis in young adult population of Saudi Arabia

Introduction: Eustachian tube dysfunction (ETD) is a well-known co-morbid manifestation of inflammatory diseases of the nasal cavity. Allergic rhinitis (AR) is a common chronic condition that causes a significant amount of disease burden in the population. However, studies on ETD in patients with AR are still very limited. Materials and methods: A total of 60 healthy and 60 AR patients participated in the prospective comparative study. All of the subjects were subjected to a skin prick test. According to ARIA criteria, the severity of AR was classified as "mild" or "moderate-severe" and "persistent" or "intermittent." Eustachian Tube Dysfunction Questionnaire (ETDQ-7) subjective scores were obtained for both groups. For objective examinations, nasal cytology, Tympanometry, and Tubomanometry were used, and the data were statistically analyzed. Results: The mean eosinophil and neutrophil counts in nasal smears demonstrated a significant difference between the two groups. In the AR and control groups, the overall ETDQ-7 score was 21.6 and 9.7 respectively (p<0.001). Tympanometry reports that ETD was significantly higher in the AR group (83.3%) than in the control group (p<0.001). TMM also established that 84.2% of AR subjects had ETD, which was statistically significant.

Evaluation of some trace elements and antioxidants in sera of patients with rheumatoid arthritis: a case-control study.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that destroys joints. The concentrations of elements (Zn, Cu, Mg, Mn, Fe, Ni, Cr, K, Na, Ca, Pb, and Cd), as well as antioxidant glutathione GSH and lipid peroxidation marker malondialdehyde MDA, will be determined in this study. The study involves 120 female RA patients and 60 healthy females in the control group, all of whom are between the ages of 20 and 60. Patients having diabetes, hypertension, hyperthyroidism, or psoriasis, in addition to RA, were excluded. When RA patients were compared to healthy individuals, the levels of Cu, Ni, Na, Pb, and Cd were significantly higher (p < 0.01), whereas the levels of Zn, Mg, Mn, Cr, Ca, K, and Fe were significantly lower (p < 0.01). The Cu/Zn (2.21 and 1.16) and Na/k (38.67 and 34.87) ratios were also found to be significantly higher in RA patients compared to controls. Furthermore, the data indicated that GSH concentrations in RA patients were significantly lower (p < 0.01) than those in controls (655.90 and 1345.17mol/l, respectively). MDA levels in RA patients were significantly higher (p < 0.01) than those in controls (2.739 and 1.673mol/l, respectively). The data indicate that Cu/Zn and Na/k ratios can be of great value in the diagnosis and evaluation of RA patients. On this basis, we conclude that these elements can be relied upon to provide indications of RA risk and the measurement of oxidative stress can serve as a biomarker to monitor disease activity and severity in RA patients. Key Points • Trace elements may be of value and may have an expected significance in the early diagnosis, prognosis, and treatment evaluation of rheumatoid arthritis. • The distortion in the levels of trace elements may reflect their possible role in the pathogenesis of rheumatoid arthritis. • Oxidative stress can act as a biomarker to monitor disease activity and severity in patients with rheumatoid arthritis. • The trace elements can contribute to the manifestation of inflammatory diseases due to their role in the synthesis of some antioxidants or due to their effect on the immune system.

Clinical and ultrasound characteristics of the health status of fertile aged women, who smoke and have metabolic syndrome

Objectives: to identify clinical and ultrasound indicators that can determine the need for further examination of fertile aged women who smoke and have metabolic syndrome (MS) regarding the risk of developing somatic pathology or diseases of the reproductive system.Materials and methods. 2 groups of women of fertile age were examined: the first group consisted of 20 women who smoked with MS, the second group included 20 women who smoked without MS. All women were interviewed using a specially designed general and reproductive health questionnaire. Ultrasound examination of the abdominal cavity and pelvic organs was performed using convex and transvaginal sensors according to existing examination protocols.Results. Women of the first group had a higher body mass index and other obesity parameters, which is typical for MS. Women of the second group smoked more cigarettes per day. The identified early onset of menstrual function in women with MS may be a manifestation of hormonal homeostasis disorders at the end of puberty with a predominance of estradiol secretion and insufficient progesterone synthesis in the second phase of the menstrual cycle. A significant amount of blood loss during menstruation and painful menstruation in women of the first group may be a manifestation of adenomyosis, which confirms by echo-positive and echo-negative inclusions in the myometrium and thickening of the uterine walls. In most patients with MS ultrasound showed multifollicular ovaries, which may point at polycystic ovary syndrome, given changes in body mass index and ovarian structure as a response on hyperestrogenemia. Prolonged manifestation of MS also negatively affected the abdominal organs, as evidenced by echo-positive inclusions in the liver and pancreas parenchyma, which is a manifestation of inflammatory diseases of these organs.Conclusions. The combination of prolonged smoking and metabolic syndrome leads to more pronounced changes in the reproductive system and abdominal organs, which in turn expands the range of recommended methods of instrumental examination for such women.

The emergence of rheumatic immune-mediated inflammatory disease manifestations following SARS-CoV-2 vaccination

The emergence of rheumatic immune-mediated inflammatory disease manifestations following SARS-CoV-2 vaccination

Exercise as a multi-modal disease-modifying medicine in systemic sclerosis: An introduction by The Global Fellowship on Rehabilitation and Exercise in Systemic Sclerosis (G-FoRSS).

Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease whereby its main pathological drivers of disability and damage are vascular injury, inflammatory cell infiltration, and fibrosis. These mechanisms result in diffuse and diverse impairments arising from ischemic circulatory dysfunction leading to painful skin ulceration and calcinosis, neurovascular aberrations hindering gastrointestinal (GI) motility, progressive painful, incapacitating or immobilizing effects of inflammatory and fibrotic effects on the lungs, skin, articular and periarticular structures, and muscle. SSc-related impairments impede routine activities of daily living (ADLs) and disrupt three critical life areas: work, family, social/leisure, and also impact on psychological well-being. Physical activity and exercise are globally recommended; however, for connective tissue diseases, this guidance carries greater impact on inflammatory disease manifestations, recovery, and cardiovascular health. Exercise, through myogenic and vascular phenomena, naturally targets key pathogenic drivers by downregulating multiple inflammatory and fibrotic pathways in serum and tissue, while increasing circulation and vascular repair. G-FoRSS, The Global Fellowship on Rehabilitation and Exercise in Systemic Sclerosis recognizes the scientific basis of and advocates for education and research of exercise as a systemic and targeted SSc disease-modifying treatment. An overview of biophysiological mechanisms of physical activity and exercise are herein imparted for patients, clinicians, and researchers, and applied to SSc disease mechanisms, manifestations, and impairment. A preliminary guidance on exercise in SSc, a research agenda, and the current state of research and outcome measures are set forth.

Evolution of Our Understanding of XIAP Deficiency.

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.

Association of Dupilumab with Intraocular Inflammation

ABSTRACT Purpose To report four cases of uveitis after treatment with dupilumab for atopic dermatitis. Methods Retrospective case series. Results Data was collected from four patients with inflammation that developed after treatment with dupilumab. The first patient was thought to have developed posterior scleritis or Harada’s-type disease related to her treatment with dupilumab, with recurrence of intraocular inflammation upon restarting treatment. The second patient developed anterior and intermediate uveitis as well as cystoid macular edema in her right eye about two years after starting dupilumab treatment. The third patient developed a distinct relentless placoid chorioretinitis while on therapy with dupilumab. The fourth patient developed bilateral cystoid macular edema while on treatment with dupilumab. Conclusion We report a case series of patients treated with dupilumab who developed intraocular manifestations of inflammatory disease.

ORAL CARE AND CHOICE OF MEDICINES FOR TREATING GINGIVITIS AND PERIODONTITIS IN CHILDREN WITH TYPE 1 DIABETES MELLITUS

The anatomical and physiological characteristics of a growing organism require a specific approach to the prevention and treatment of periodontal diseases. Not enough attention is paid toward improving the oral health of children suffering from diabetes mellitus, as well as therapeutic and prophylactic measures aimed at preserving teeth and preventing exacerbations of the inflammatory process in periodontal tissues. The results of clinical studies indicate a high prevalence of dental diseases in patients with type I diabetes mellitus; there are not enough reliable results of such indicators depending on the age and duration of this endocrine pathology, diabetic complications, hypoglycemic therapy taking into account metabolic control. Diagnosis of periodontal diseases is complicated by the peculiarities of the child’s psychological perception, caused by age-specific characteristics and the influence of common manifestations of inflammatory diseases. Children of primary school age often demonstrate increased motor activity, a hyperergic reaction even to minor negative feelings, the difficulty of adequate behaviour in an unfamiliar environment and a correct assessment of what is happening, being stressed due to the presence of many phobias associated with doctors and medical manipulations, communicative difficulties caused by staying in the spotlight, meeting new people, talking with adults. Teaching children must necessarily be accompanied by educating parents, since within limited time interval of dental appointment a doctor does not have the opportunity to fully monitor and consolidate the knowledge and skills the child has received, and this responsibility falls on parents. In this case, some attention should be paid to issues of skills, motivation as well as on the importance dental care aspects for the development of the dentofacial system, since in the vast majority of cases, parents are not enough aware on these issues. In addition to educating and fostering the motivation, it is necessary to control the level of knowledge, the frequency and quality of tooth brushing. For young children, it is necessary to do complete cleaning up the chewing group of teeth due to the low level of children’s manual skills.

Comprehensive assessment of knee joint synovitis at 7\u2009T MRI using contrast-enhanced and non-enhanced sequences

BackgroundSeven T ultra-high field MRI systems have recently been approved for clinical use by the U.S. and European regulatory agencies. These systems are now being used clinically and will likely be more widely available in the near future. One of the applications of 7 T systems is musculoskeletal disease and particularly peripheral arthritis imaging. Since the introduction of potent anti-rheumatic therapies over the last two decades MRI has gained increasing importance particularly for assessment of disease activity in early stages of several rheumatic disorders. Commonly gadolinium-based contrast agents are used for assessment of synovitis. Due to potential side-effects of gadolinium non-enhanced techniques are desirable that enable visualization of inflammatory disease manifestations. The feasibility of 7 T MRI for evaluation of peripheral arthritis has not been shown up to now. Aim of our study was to evaluate the feasibility of contrast-enhanced (CE) and non-enhanced MRI at 7 T for the assessment of knee joint synovitis.MethodSeven T MRI was acquired for 10 patients with an established diagnosis of psoriatic or rheumatoid arthritis. The study pulse sequence protocol was comprised of a sagittal intermediate-weighted fat-suppressed (FS), axial fluid-attenuated inversion recovery (FLAIR) FS, sagittal 3D T1-weighted dynamic contrast enhanced (DCE) and an axial static 2D T1-weighted FS contrast-enhanced sequence (T1-FS CE). Ordinal scoring on non-enhanced (Hoffa- and effusion-synovitis) and enhanced MRI (11-point synovitis score), and comparison of FLAIR-FS with static T1-FS CE MRI using semiquantitative (SQ) grading and volume assessment was performed. For inter- and intra-reader reliability assessment weighted kappa statistics for ordinal scores and intraclass correlation coefficients (ICC) for continuous variables were used.ResultsThe total length of study protocol was 15 min 38 s. Different amounts of synovitis were observed in all patients (mild: n = 3; moderate: n = 5; severe: n = 2). Consistently, SQ assessment yielded significantly lower peripatellar summed synovitis scores for the FLAIR-FS sequence compared to the CE T1-FS sequence (p < 0.01). FLAIR-FS showed significantly lower peripatellar synovial volumes (p < 0.01) compared to CE T1-FS imaging with an average percentage difference of 18.6 ± 9.5%. Inter- and intra-reader reliability for ordinal SQ scoring ranged from 0.21 (inter-reader Hoffa-synovitis) to 1.00 (inter-reader effusion-synovitis). Inter- and intra-observer reliability of SQ 3D-DCE parameters ranged from 0.86 to 0.99.ConclusionsSeven T FLAIR-FS ultra-high field MRI is a potential non-enhanced imaging method able to visualize synovial inflammation with high conspicuity and holds promise for further application in research endeavors and clinical routine by trained readers.

Pharmacological Treatment of Bone Loss.

Bone loss is common in clinical practice, such as health assessment of postmenopausal women, treatment of tumor metastasis, side-effects of glucocorticoids, and skeletal manifestations of inflammatory diseases. The imbalance of remodeling between bone resorption and bone formation, the pathophysiological basis of bone loss, increases bone fragility. The treatment of bone loss is mainly carried out from the treatment of osteoporosis. There are various pharmacological therapies for bone loss, which will be introduced in 3 aspects, including antiresorptive agents, anabolic agents and new medications. Each kind of medication has its advantages, shortcomings and side-effects. Antiresorptive agents are widely applied in the treatment of bone loss, but can lead to overall decrease of bone turnover rate. Anabolic agents, mainly PTH, are usually combined with other anti-resorptive drugs, and PTHrP might be a promising pure anabolic agent for osteoporosis. In recent years, some novel therapies have been raised and tested in clinical trials which can be promising choices available for osteoporosis treatment. Future drug targets will mainly come from RANK-RANKL-OPG system and Wnt/β-catenin signaling pathway., and the pre-existing drugs could be explored in new patterns.

Mucocutaneous manifestations among persons receiving highly active anti-retroviral therapy

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;Mucocutaneous manifestations in patients positive for HIV are helpful in the diagnosis as well as treatment of the disease. Consequent to the introduction of Highly Active Anti-Retroviral Therapy (HAART), there seems to be an increase in the presentation of non-infective diseases. It was aimed to analyse the mucocutaneous manifestations in HIV infected patients taking HAART and correlate with age and CD4 lymphocyte count.&lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; A retrospective analysis of 125 People Living With HIV (PLWH) having mucocutaneous manifestations receiving HAART who attended a tertiary care city hospital over a period of ten months from January 2016 to October 2016 was carried out. The findings were correlated with CD4 count and age. The data were collected from the patient follow up cards maintained by qualified Dermatovenereologist.&lt;strong&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;There was no major gender difference in our study. The trans genders presented with only non-infectious skin diseases. Younger patients had a higher CD4 count (p=0.01%) which was statistically significant. Candidiasis and pruritic papular eruption were the commonest infective and non-infective diseases observed respectively. The mean CD4 count comparison was statistically significant (p=0.04). The count was highest for insect bite allergy and lowest for oral hairy leukoplakia. The mean age of disease manifestation was highest for Herpes zoster and lowest for aphthous ulcers 45 and 29 years respectively. All the adverse reactions observed were to efavirenz. &lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; &lt;span lang="EN-IN"&gt;With the improvement of CD4 count in PLWH receiving HAART, the proportion of non-infectious inflammatory disease manifestations are on the rise. Awareness about this fact is very important for effective management.&lt;/span&gt;&lt;/p&gt;

Multiple benefits of targeting inflammation in the treatment of type 2 diabetes.

The association between the metabolic syndrome and a pathological activation of the innate immune system is now well established. Thus, defective insulin secretion and action are due, at least in part, to islet, liver and fat inflammation in type 2 diabetes. Furthermore, an inflammatory process also seems to be involved in the development of cardiovascular, renal and ophthalmological complications of this disease. Interestingly, several other inflammatory diseases are associated with the metabolic syndrome, such as psoriasis, gout and rheumatic arthritis. The aim of this review is to discuss the clinical progress of anti-inflammatory drugs in the treatment of type 2 diabetes and then speculate on the possible further development of these drugs, with the aim of using the drugs in combination in order to combat the multiple manifestations of inflammatory diseases. This review summarises a presentation given at the 'Islet inflammation in type 2 diabetes' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Simone Baltrusch, DOI: 10.1007/s00125-016-3891-x , and Jerry Nadler and colleagues, DOI: 10.1007/s00125-016-3890-y ) and a commentary by the Session Chair, Piero Marchetti (DOI: 10.1007/s00125-016-3875-x ).

Newly recognized Mendelian disorders with rheumatic manifestations.

We review newly discovered monogenic immune-dysregulatory disorders that were reported in Pubmed over the last year. Fourteen novel monogenic immune-dysregulatory disorders that present with innate and acquired/adaptive immune dysregulation and inflammatory clinical phenotypes were identified. These include autosomal-dominant gain-of function mutations in viral innate immune sensors or their adaptors, TMEM173/STING IFIH1/MDA5 and DDX58/RIG-I that cause complex clinical syndromes distinct from IL-1-mediated diseases and present with a chronic type I interferon (IFN Type I) signature in peripheral blood. Gain-of-function mutations in NLRC4 add a novel inflammasome disorder associated with predisposition to macrophage-activation syndrome and highly elevated IL-18 levels. Mutations in ADA2, TRNT1 and COPA, AP1S3, and TNFRSF11A cause complex syndromes; loss-of-function mutations in enzymes and molecules are linked to the generation of 'cellular stress' and the release of inflammatory mediators that likely cause the inflammatory disease manifestations. A monogenic form of systemic-onset juvenile idiopathic arthritis is caused by homozygous mutations in LACC1. Lastly, mutations in PRKDC (recessive), STAT3, CTLA4, and PIK3R1 (all dominant) lead to impaired central and peripheral T-cell tolerance and present with variable disease manifestations of immunodeficiency and immune dysregulation/autoimmunity. A number of novel monogenic diseases that present with innate and/or acquired immune dysregulation reveal novel immune pathways that cause human inflammatory diseases and suggest potential novel targets for treatment.

Histologic and Immunohistochemical Features of the Skin Lesions in CANDLE Syndrome.

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a newly characterized autoinflammatory disorder, caused by mutations in PSMB8. It is characterized by early-onset fevers, accompanied by a widespread, violaceous, and often annular cutaneous eruption. Although the exact pathogenesis of this syndrome is still obscure, it is postulated that the inflammatory disease manifestations stem from excess secretion of interferons. Based on preliminary blood cytokine and gene expression studies, the signature seems to come mostly from type I interferons, which are proposed to lead to the recruitment of immature myeloid cells into the dermis and subcutis. In this study, we systematically analyzed skin biopsies from 6 patients with CANDLE syndrome by routine histopathology and immunohistochemistry methods. Skin lesions showed the presence of extensive mixed dermal and subcutaneous inflammatory infiltrate, composed of mononuclear cells, atypical myeloid cells, neutrophils, eosinophils, and some mature lymphocytes. Positive LEDER and myeloperoxidase staining supported the presence of myeloid cells. Positive CD68/PMG1 and CD163 staining confirmed the existence of histiocytes and monocytic macrophages in the inflammatory infiltrate. CD123 staining was positive, demonstrating the presence of plasmacytoid dendritic cells. Uncovering the unique histopathological and immunohistochemical features of CANDLE syndrome provides tools for rapid and specific diagnosis of this disorder and further insight into the pathogenesis of this severe life-threatening condition.

Genetic variability of genital mycoplasmas and its clinical value

The article presents data on genetic variability of genital mycoplasmas. The author presents the results of genetic variability studies for M. hominis, gene vaa, U. parvum, gene mba, and M. genitalium, gene mg192, sampled from women with different clinical manifestations of inflammatory diseases of the urogenital system. Based on the molecular typing results for 138 samples of genital mycoplasmas, the author revealed a relationship between clinical manifestations of inflammatory diseases of the urogenital system caused by U. parvum and different U. parvum serovars as well as different genetic variations of M. hominis.Infection with 6 U. parvum serovar results in the development of inflammatory diseases of the urogenital tract accompanied by subjective manifestations (р &lt; 0.05). Genetic variant II of М. hominis was revealed more often in patients with clinical manifestations of inflammatory diseases while variant I was revealed more often in patients infected with М. hominis without any signs of inflammation (р &lt; 0.05). Genetic variants of M. genitalium were determined; no significant differences in terms of their prevalence in the examined patients were revealed.

Genetic variants of genital mycoplasmas and their relation to the clinical course of inflammatory diseases of the urogenital system in women

Goal of the study. To study genetic variability of M. hominis (based on the vaa gene) and M. genitalium (based on the mg192 gene) derived from biological material samples taken from women with different clinical manifestations of inflammatory diseases of the urogenital system and clinically healthy women (for M. hominis). Materials and methods. Genetic variability of twenty M. hominis samples taken from patients with inflammatory diseases of the urogenital system and twenty M. hominis samples taken from patients without clinical and laboratory signs of inflammatory processes of the urogenital system was studied by the sequence analysis method. Genetic variability of eight M. genitalium samples taken from patients with different clinical signs of inflammatory diseases of the urogenital system was also examined by the sequence analysis method. Results. Three genetic variants of M. hominis based on the vaa gene were found; variant I was revealed more often in patients with clinical manifestations of inflammatory diseases (65.0%), and variant II - in clinically healthy women (60.0%). Three phylogenetic M. gentium groups based on the mg192 gene were revealed; two samples were referred to Groups I and II, and four samples were referred to Group III. Samples from each phylogenetic groups were taken from patients with clinical and laboratory manifestations of cervicitis and urethritis. Conclusion. The study data demonstrate a potential effect of the VAA surface protein on the virulence of opportunistic M. hominis pathogens.

Genetic variants of U. parvum and their role in the development of inflammatory diseases of the urogenital system

The article discusses the results of a study aimed at determining the frequency of different genetic variants of U. parvum in women with inflammatory diseases of the urogenital system and clinically healthy subjects. Molecular typing of 40 samples of U. parvum taken from women with different forms of inflammatory diseases of the urogenital system was performed for the mba gene. The authors revealed a relationship between clinical manifestations of inflammatory diseases of the urogenital system caused by U. parvum and different U. parvum serovars. An infection with 6 U. parvum serovar results in the development of inflammatory processes in the form of cervicitis or vaginitis accompanied by subjective manifestations more frequently than an infection with other serovars under examination (1 and 3) (p &lt; 0.05).

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the most severe clinical phenotype in the spectrum of cryopyrin- (NLRP3/NALP3) associated periodic syndromes (CAPS). The study of patients with NOMID/CINCA has been instrumental in characterizing the extent of organ-specific inflammatory manifestations and damage that can occur with chronic interleukin (IL)-1β overproduction. Mutations in CIAS1/NLRP3 lead to constitutive activation of the "NLRP3 inflammasome," an intracellular platform that processes and secretes increased amounts of IL-1β. The pivotal role of IL-1β in NOMID/CINCA has been demonstrated in several clinical studies using IL-1--blocking agents that lead to rapid resolution of the inflammatory disease manifestations. NOMID/CINCA is a monogenic autoinflammatory syndrome; and the discovery of the role of IL-1 in NOMID has led to the exploration in the role of IL-1 in other disorders including gout and Type II diabetes. The inflammation in NOMID/CINCA is continuous with intermittent flares, and organ manifestations encompus the central nervous system, eye, inner ear, and bones. This review discusses updates on the pathogenesis of NOMID/CAPS, emerging long term-outcome data regarding IL-1--blocking agents that have influenced our considerations for optimal treatment, and a monitoring approach tailored to the patient's disease severity and organ manifestations.