More than any other cytokine family, the 11 members of the IL-1 family are associated with innate immune responses, which occur in acute inflammation and chronic inflammatory conditions such as rheumatic diseases. In many rheumatic diseases, the severity of the condition can result from the balance between the pro-inflammatory and anti-inflammatory members of the IL-1 family. Pro-inflammatory family members (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β and IL-36γ) are found in the articular environment during arthritis and often correlate with the degree of inflammation present. IL-1β has emerged as pivotal for promoting inflammation, particularly in autoinflammatory diseases, whereas IL-1α and the IL-36 subfamily are associated with skin diseases. IL-33 regulates T helper 2 (TH2) cell-mediated diseases, in sharp contrast to IL-18, which mainly regulates TH1 cell-mediated responses. The IL-1 family also contains four members that suppress inflammation: two specific receptor antagonists (IL-1 receptor antagonist (IL-1Ra) and IL-36 receptor antagonist (IL-36Ra)), and two members that broadly suppress innate inflammation by non-specifically reducing several cytokines and chemokines (IL-37 and IL-38). In this Review, each of the eleven IL-1 family cytokines and their receptors are discussed, along with their putative roles in rheumatic disease and therapeutic options for targeting or promoting these cytokines. Cytokines from the IL-1 family perform important functions in innate immune reactions, but can also be involved in chronic inflammatory diseases. This Review highlights the roles of IL-1 family members in rheumatic diseases and potential therapeutic approaches to targeting them.

The IL-1 family of cytokines and receptors in rheumatic diseases.

Obesity is associated with greater areal BMD (aBMD) and is considered protective against hip and vertebral fracture. Despite this, there is a higher prevalence of lower leg and proximal humerus fracture in obesity. We aimed to determine if there are site‐specific differences in BMD, bone structure, or bone strength between obese and normal‐weight adults. We studied 100 individually‐matched pairs of normal (body mass index [BMI] 18.5 to 24.9 kg/m2) and obese (BMI >30 kg/m2) men and women, aged 25 to 40 years or 55 to 75 years. We assessed aBMD at the whole body (WB), hip (TH), and lumbar spine (LS) with dual‐energy X‐ray absorptiometry (DXA), LS trabecular volumetric BMD (Tb.vBMD) by quantitative computed tomography (QCT), and vBMD and microarchitecture and strength at the distal radius and tibia with high‐resolution peripheral QCT (HR‐pQCT) and micro–finite element analysis. Serum type 1 procollagen N‐terminal peptide (P1NP) and collagen type 1 C‐telopeptide (CTX) were measured by automated electrochemiluminescent immunoassay (ECLIA). Obese adults had greater WB, LS, and TH aBMD than normal adults. The effect of obesity on LS and WB aBMD was greater in older than younger adults (p < 0.01). Obese adults had greater vBMD than normal adults at the tibia (p < 0.001 both ages) and radius (p < 0.001 older group), thicker cortices, higher cortical BMD and tissue mineral density, lower cortical porosity, higher trabecular BMD, and higher trabecular number than normal adults. There was no difference in bone size between obese and normal adults. Obese adults had greater estimated failure load at the radius (p < 0.05) and tibia (p < 0.01). Differences in HR‐pQCT measurements between obese and normal adults were seen more consistently in the older than the younger group. Bone turnover markers were lower in obese than in normal adults. Greater BMD in obesity is not an artifact of DXA measurement. Obese adults have higher BMD, thicker and denser cortices, and higher trabecular number than normal adults. Greater differences between obese and normal adults in the older group suggest that obesity may protect against age‐related bone loss and may increase peak bone mass.

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Bone Density, Microstructure and Strength in Obese and Normal Weight Men and Women in Younger and Older Adulthood

Cachexia is the involuntary loss of muscle and adipose tissue that strongly affects mortality and treatment efficacy in patients with cancer or chronic inflammatory disease. Currently, no specific treatments or interventions are available for patients developing this disorder. Given the well-documented involvement of pro-inflammatory cytokines in muscle and fat metabolism in physiological responses and in the pathophysiology of chronic inflammatory disease and cancer, considerable interest has revolved around their role in mediating cachexia. This has been supported by association studies that report increased levels of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in some, but not all, cancers and in chronic inflammatory diseases such as chronic obstructive pulmonary disease (COPD) and rheumatoid arthritis (RA). In addition, preclinical studies including animal disease models have provided a substantial body of evidence implicating a causal contribution of systemic inflammation to cachexia. The presence of inflammatory cytokines can affect skeletal muscle through several direct mechanisms, relying on activation of the corresponding receptor expressed by muscle, and resulting in inhibition of muscle protein synthesis (MPS), elevation of catabolic activity through the ubiquitin-proteasomal system (UPS) and autophagy, and impairment of myogenesis. Additionally, systemic inflammatory mediators indirectly contribute to muscle wasting through dysregulation of tissue and organ systems, including GCs via the hypothalamus-pituitary-adrenal (HPA) axis, the digestive system leading to anorexia-cachexia, and alterations in liver and adipocyte behavior, which subsequently impact on muscle. Finally, myokines secreted by skeletal muscle itself in response to inflammation have been implicated as autocrine and endocrine mediators of cachexia, as well as potential modulators of this debilitating condition. While inflammation has been shown to play a pivotal role in cachexia development, further understanding how these cytokines contribute to disease progression is required to reveal biomarkers or diagnostic tools to help identify at risk patients, or enable the design of targeted therapies to prevent or delay the progression of cachexia.

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Inflammation and Skeletal Muscle Wasting During Cachexia.

Desmoid-type fibromatosis (DF) is a locally aggressive fibroblastic neoplasm that has variable clinical and biologic behaviors ranging from indolent tumors that can undergo spontaneous regression to aggressive tumors with a tendency toward local invasion and recurrence. The management of DF has evolved considerably in the last decade from aggressive first-line surgery and radiation therapy to systemic treatment (chemotherapy, hormonal therapy, and targeted therapy) and symptomatic local control (surgery and radiation therapy). Imaging plays an important role in each of these treatment settings. In surgical candidates, computed tomography (CT) and magnetic resonance (MR) imaging are the modalities of choice for assessing resectability and surgical planning. For evaluating recurrence, MR imaging is the modality of choice for extra-abdominal recurrence, whereas CT is the preferred modality for intra-abdominal recurrence. Signal intensity changes at MR imaging can be used to monitor the biologic behavior of certain DFs chosen for expectant management. Response to systemic treatment with anti-inflammatory agents, hormonal therapy (eg, tamoxifen), cytotoxic chemotherapy (eg, doxorubicin, vinblastine, methotrexate), and targeted therapy (eg, sorafenib), as well as to radiation therapy, can be assessed at CT by monitoring size and attenuation changes or at MR imaging by monitoring size, T2 signal intensity, and degree of enhancement. Several patterns of response can be seen at imaging. Imaging also helps in detecting complications associated with systemic therapy and radiation therapy. (©)RSNA, 2016.

Role of Imaging in Management of Desmoid-type Fibromatosis: A Primer for Radiologists.

Background Unilateral cerebral palsy (CP) is a condition that affects muscle control and function on one side of the body. Children with unilateral CP experience difficulties using their hands together secondary to disturbances that occur in the developing fetal or infant brain. Often, the more affected limb is disregarded. Constraint-induced movement therapy (CIMT) aims to increase use of the more affected upper limb and improve bimanual performance. CIMT is based on two principles: restraining the use of the less affected limb (for example, using a splint, mitt or sling) and intensive therapeutic practice of the more affected limb. Objectives To evaluate the effect of constraint-induced movement therapy (CIMT) in the treatment of the more affected upper limb in children with unilateral CP. Search methods In March 2018 we searched CENTRAL, MEDLINE, Embase, CINAHL, PEDro, OTseeker, five other databases and three trials registers. We also ran citation searches, checked reference lists, contacted experts, handsearched key journals and searched using Google Scholar. Selection criteria Randomised controlled trials (RCTs), cluster-RCTs or clinically controlled trials implemented with children with unilateral CP, aged between 0 and 19 years, where CIMT was compared with a different form of CIMT, or a low dose, high-dose or dose-matched alternative form of upper-limb intervention such as bimanual intervention. Primarily, outcomes were bimanual performance, unimanual capacity and manual ability. Secondary outcomes included measures of self-care, body function, participation and quality of life. Data collection and analysis Two review authors independently screened titles and abstracts to eliminate ineligible studies. Five review authors were paired to extract data and assess risk of bias in each included study. GRADE assessments were undertaken by two review authors. Main results We included 36 trials (1264 participants), published between 2004 and 2018. Sample sizes ranged from 11 to 105 (mean 35). Mean age was 5.96 years (standard deviation (SD) 1.82), range three months to 19.8 years; 53% male and 47% participants had left hemiplegia. Fifty-seven outcome measures were used across studies. Average length of CIMT programs was four weeks (range one to 10 weeks). Frequency of sessions ranged from twice weekly to seven days per week. Duration of intervention sessions ranged from 0.5 to eight hours per day. The mean total number of hours of CIMT provided was 137 hours (range 20 to 504 hours). The most common constraint devices were a mitt/glove or a sling (11 studies each).We judged the risk of bias as moderate to high across the studies. Key results Primary outcomes at primary endpoint (immediately after intervention)CIMT versus low-dose comparison (e.g. occupational therapy)We found low-quality evidence that CIMT was more effective than a low-dose comparison for improving bimanual performance (mean difference (MD) 5.44 Assisting Hand Assessment (AHA) units, 95% confidence interval (CI) 2.37 to 8.51).CIMT was more effective than a low-dose comparison for improving unimanual capacity (Quality of upper extremity skills test (QUEST) - Dissociated movement MD 5.95, 95% CI 2.02 to 9.87; Grasps; MD 7.57, 95% CI 2.10 to 13.05; Weight bearing MD 5.92, 95% CI 2.21 to 9.6; Protective extension MD 12.54, 95% CI 8.60 to 16.47). Three studies reported adverse events, including frustration, constraint refusal and reversible skin irritations from casting.CIMT versus high-dose comparison (e.g. individualised occupational therapy, bimanual therapy)When compared with a high-dose comparison, CIMT was not more effective for improving bimanual performance (MD -0.39 AHA Units, 95% CI -3.14 to 2.36). There was no evidence that CIMT was more effective than a high-dose comparison for improving unimanual capacity in a single study using QUEST (Dissociated movement MD 0.49, 95% CI -10.71 to 11.69; Grasp MD -0.20, 95% CI -11.84 to 11.44). Two studies reported that some children experienced frustration participating in CIMT.CIMT versus dose-matched comparison (e.g. Hand Arm Bimanual Intensive Therapy, bimanual therapy, occupational therapy)There was no evidence of differences in bimanual performance between groups receiving CIMT or a dose-matched comparison (MD 0.80 AHA units, 95% CI -0.78 to 2.38).There was no evidence that CIMT was more effective than a dose-matched comparison for improving unimanual capacity (Box and Blocks Test MD 1.11, 95% CI -0.06 to 2.28; Melbourne Assessment MD 1.48, 95% CI -0.49 to 3.44; QUEST Dissociated movement MD 6.51, 95% CI -0.74 to 13.76; Grasp, MD 6.63, 95% CI -2.38 to 15.65; Weightbearing MD -2.31, 95% CI -8.02 to 3.40) except for the Protective extension domain (MD 6.86, 95% CI 0.14 to 13.58).There was no evidence of differences in manual ability between groups receiving CIMT or a dose-matched comparison (ABILHAND-Kids MD 0.74, 95% CI 0.31 to 1.18). From 15 studies, two children did not tolerate CIMT and three experienced difficulty. Authors' conclusions The quality of evidence for all conclusions was low to very low. For children with unilateral CP, there was some evidence that CIMT resulted in improved bimanual performance and unimanual capacity when compared to a low-dose comparison, but not when compared to a high-dose or dose-matched comparison. Based on the evidence available, CIMT appears to be safe for children with CP.

Constraint‐induced movement therapy in children with unilateral cerebral palsy

It was aimed to evaluate KL-6 glycoprotein levels to determine if it may be a diagnostic marker for the connective tissue diseases (CTDs) predicting CTD-related interstitial lung diseases (ILDs) (CTD-ILD) development and to examine if there was a difference between patients and healthy controls. The study included 113 patients with CTD (45 CTD without lung involvement, 68 CTD-ILD) and 45 healthy control subjects. KL-6 glycoprotein levels were analyzed with ELISA in patients and the control group. The relationship between KL-6 glycoprotein levels and CTD-ILD was assessed. In the comparison of all the groups in the study, significantly higher levels of KL-6 were determined in the CTD-ILD group than in either the CTD without pulmonary involvement group or the healthy control group (p < 0.008 and p < 0.001, respectively). There was no statistically significant difference between the KL-6 levels in the healthy control group and the CTD without pulmonary involvement group (p = 0.289). The KL-6 levels did not differ significantly according to the connective tissue diseases in the diagnostic groups (systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, mixed connective tissue disease, scleroderma, polymyositis/ dermatomyositis). In the healthy control group, there was a statistically significant difference between KL-6 levels in smokers and non-smokers. Smokers had significantly higher serum KL-6 levels compared with non-smokers (p < 0.05). There was no statistically significant difference between smoking status (pack-year) and serum KL-6 levels. There was no statistically significant correlation between serum KL-6 levels and time since diagnosis of CTD and CTD-ILD. The level of KL-6 as a predictive factor could be used to identify the clinical development of ILD before it is detected on imaging modality. Further prospective clinical studies are needed to define whether levels of KL-6 might have prognostic value or might predict progressive ILD.

Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study

Is age or the body mass index (BMI) more determinant of the bone mineral density (BMD) in geriatric women and men

Objective: To investigate the effect of anti-interleukin-1 (anti-IL-1) treatment on the frequency and severity of attacks and other disease-related clinical parameters and to evaluate the adverse effects associated with anti-IL-1 treatment in 26 patients with refractory familial mediterranean fever (FMF).Methods: The study included 26 FMF patients followed up in our centre using colchicine for 4 months to 30 years. The treatment was switched to anti-IL-1 treatment for various reasons; 20 cases were resistant to colchicine, 8 were intolerant to colchicine, and 3 had prolonged arthritis under colchicine. Clinical response was monitored through the number of attacks, and laboratory inflammation was monitored through erythrocyte sedimentation rate, C-reactive protein, and serum amyloid A concentrations. Colchicine resistance was defined as at least two attacks/month together with C-reactive protein and serum amyloid A levels above the normal range between attacks. The colchicine dose was increased to ...

Anti-interleukin-1 treatment in 26 patients with refractory familial mediterranean fever.

https://www.pedneur.com/article/S0887-8994(14)00285-9/pdf

Effects of Neuromuscular Electrical Stimulation on the Wrist and Finger Flexor Spasticity and Hand Functions in Cerebral Palsy

Objectives This study aims to evaluate the efficacy of kinesiology taping (KT) on pain, movement restriction, walking speed, daily living activities, and isokinetic muscle performance in female patients with knee osteoarthritis. Patients and methods The study included 61 female patients (mean age 53.5±3.5 years; range 50 to 60 years) who were admitted to Physical Medicine and Rehabilitation Outpatient Clinic with complaints of mechanical knee pain. Knee osteoarthritis was diagnosed according to the clinical/ radiological criteria of the American College of Rheumatology and patients with Kellgren-Lawrence grade 2 and 3 were included. Patients were randomly divided into two groups. Both groups received transcutaneous electrical nerve stimulation for 30 minutes, hot pack for 30 minutes, and therapeutic ultrasound for 10 minutes in a day for three weeks (five days in a week). Also, one group was treated with KT (KT group, n=31) while the other group was treated with sham-KT (sham-KT group, n=30) one time a week for three weeks. A home program of around the knee strengthening exercises was recommended for all patients. All patients were evaluated with visual analog scale, Western Ontario and McMaster Osteoarthritis Index (WOMAC) values, goniometric measurement of active knee range of motion, 50-meter walking distance, and isokinetic knee extensor muscle peak torque measurements before treatment, at the end of treatment, and at one month and three months after treatment. Results There was a significant improvement in after treatment and first month visual analog scale values in the KT group compared to the sham-KT group (p<0.05). In the KT group, the WOMAC pain and WOMAC total scores decreased significantly after treatment compared to the sham-KT group (p<0.05). Visual analog scale values were significantly decreased after treatment in both groups (p<0.05). In both groups; WOMAC pain, stiffness, physical function, and total values decreased significantly after treatment (p<0.05). In both groups, isokinetic quadriceps peak torque measurements were increased after treatment (p<0.05). Conclusion The application of KT to females with knee osteoarthritis appears to be a method that may be effective on pain and functional capacity.

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Mustafa Turgut Yildizgoren

Papers

Association of serum KL-6 levels with interstitial lung disease in patients with connective tissue disease: a cross-sectional study

Is age or the body mass index (BMI) more determinant of the bone mineral density (BMD) in geriatric women and men

Anti-interleukin-1 treatment in 26 patients with refractory familial mediterranean fever.

Effects of Neuromuscular Electrical Stimulation on the Wrist and Finger Flexor Spasticity and Hand Functions in Cerebral Palsy

Does Kinesiology Taping Improve Muscle Strength and Function in Knee Osteoarthritis? A Single-Blind, Randomized and Controlled Study.