Time-Dependent Effect of Eggshell Membrane on Monosodium-Iodoacetate-Induced Osteoarthritis: Early-Stage Inflammation Control and Late-Stage Cartilage Protection.

Osteoarthritis (OA) is a chronic degenerative joint disease that causes chronic pain, swelling, stiffness, disability, and significantly reduces the quality of life. Typically, OA is treated using painkillers and non-steroidal anti-inflammatory drugs (NSAIDs). While current pharmacologic treatments are common, their potential side effects have prompted exploration into functional dietary supplements. Recently, eggshell membrane (ESM) has emerged as a potential functional ingredient for joint and connective tissue disorders due to its clinical efficacy in relieving joint pain and stiffness. Despite promising clinical evidence, the effects of ESM on OA progression and its mechanism of action remain poorly understood. This study evaluated the efficacy of Ovomet®, a powdered natural ESM, against joint pain and disease progression in a monosodium iodoacetate (MIA)-induced rodent model of OA in mice and rats. The results demonstrate that ESM significantly alleviates joint pain and attenuates articular cartilage destruction in both mice and rats that received oral supplementation for 5 days prior to OA induction and for 28 days thereafter. Interestingly, ESM significantly inhibited mRNA expression levels of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), as well as inflammatory mediators, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase in the knee joint cartilage at the early stage of OA, within 7 days after OA induction. However, this effect was not observed in the late stage at 28 days after OA induction. ESM further attenuates the induction of protein expression for cartilage-degrading enzymes like matrix metalloproteinase (MMPs) 3 and 13, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), in the late-stage. In addition, MIA-induced reduction of the protein expression levels of cartilage components, cartilage oligomeric matrix protein (COMP), aggrecan (ACAN) and collagen type II α-1 chain (COL2α1), and cartilage extracellular matrix (ECM) synthesis promoting transcriptional factor SRY-Box 9 (SOX-9) were increased via ESM treatment in the cartilage tissue. Our findings suggest that Ovomet®, a natural ESM powder, is a promising dietary functional ingredient that can alleviate pain, inflammatory response, and cartilage degradation associated with the progression of OA.

Does psychological distress predict risk of orthopaedic surgery and postoperative opioid prescribing in patients with hip pain? A retrospective study.

BACKGROUND: Clinicians and public health professionals have allocated resources to curb opioid over-prescription and address psychological needs among patients with musculoskeletal pain. However, associations between psychological distress, risk of surgery, and opioid prescribing among those with hip pathologies remain unclear. METHODS: Using a retrospective cohort study design, we identified patients that were evaluated for hip pain from January 13, 2020 to October 27, 2021. Patients' surgical histories and postoperative opioid prescriptions were extracted via chart review. Risk of hip surgery within one year of evaluation was analyzed using multivariable logistic regression. Multivariable linear regression was employed to predict average morphine milligram equivalents (MME) per day of opioid prescriptions within the first 30 days after surgery. Candidate predictors included age, gender, race, ethnicity, employment, insurance type, hip function and quality of life on the International Hip Outcome Tool (iHOT-12), and psychological distress phenotype using the OSPRO Yellow Flag (OSPRO-YF) Assessment Tool. RESULTS: Of the 672 patients, n = 350 (52.1%) underwent orthopaedic surgery for hip pain. In multivariable analysis, younger patients, those with TRICARE/other government insurance, and those with a high psychological distress phenotype had higher odds of surgery. After adding iHOT-12 scores, younger patients and lower iHOT-12 scores were associated with higher odds of surgery, while Black/African American patients had lower odds of surgery. In multivariable analysis of average MME, patients with periacetabular osteotomy (PAO) received opioid prescriptions with significantly higher average MME than those with other procedures, and surgery type was the only significant predictor. Post-hoc analysis excluding PAO found higher average MME for patients undergoing hip arthroscopy (compared to arthroplasty or other non-PAO procedures) and significantly lower average MME for patients with public insurance (Medicare/Medicaid) compared to those with private insurance. Among those only undergoing arthroscopy, older age and having public insurance were associated with opioid prescriptions with lower average MME. Neither iHOT-12 scores nor OSPRO-YF phenotype assignment were significant predictors of postoperative mean MME. CONCLUSIONS: Psychological distress characteristics are modifiable targets for rehabilitation programs, but their use as prognostic factors for risk of orthopaedic surgery and opioid prescribing in patients with hip pain appears limited when considered alongside other commonly collected clinical information such as age, insurance, type of surgery pursued, and iHOT-12 scores.

Rapid onset pembrolizumab-induced inflammatory arthritis diagnosed using musculoskeletal ultrasound.

Immune checkpoint inhibitors have revolutionised the treatment of cancer. While very effective, they commonly cause a wide spectrum of immune-related adverse events. These immune-related adverse events can be fatal and often have significant effects on quality of life. They therefore require prompt recognition and management. We report the case of a woman presenting with widespread joint pain and stiffness 6 hours after her first pembrolizumab infusion. She had no joint swelling on physical examination but an ultrasound scan revealed widespread musculoskeletal inflammation, confirming the diagnosis of inflammatory arthritis. To the best of our knowledge, this is the fastest reported inflammatory arthritis onset following immune checkpoint inhibitor treatment. It highlights the importance of timely imaging in patients on immune checkpoint inhibitors who present with new non-specific musculoskeletal pain. Her symptoms improved dramatically with intramuscular triamcinolone injection.

Abatacept inhibits inflammation and onset of rheumatoid arthritis in individuals at high risk (ARIAA): a randomised, international, multicentre, double-blind, placebo-controlled trial.

BACKGROUND: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. METHODS: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). FINDINGS: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. INTERPRETATION: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. FUNDING: Innovative Medicine Initiative.

Single dose thermoresponsive dexamethasone prodrug completely mitigates joint pain for 15 weeks in a murine model of osteoarthritis.

In this study, we aimed to assess the analgesic efficacy of a thermoresponsive polymeric dexamethasone (Dex) prodrug (ProGel-Dex) in a mouse model of osteoarthritis (OA). At 12 weeks post model establishment, the OA mice received a single intra-articular (IA) injection of ProGel-Dex, dose-equivalent Dex, or Saline. Comparing to Saline and Dex controls, ProGel-Dex provided complete and sustained pain relief for >15 weeks according to incapacitance tests. In vivo optical imaging confirmed the continuous presence of ProGel-Dex in joints for 15 weeks post-injection. According to micro-CT analysis, ProGel-Dex treated mice had significantly lower subchondral bone thickness and medial meniscus bone volume than Dex and Saline controls. Except for a transient delay of body weight increase and slightly lower endpoint liver and spleen weights, no other adverse effect was observed after ProGel-Dex treatment. These findings support ProGel-Dex's potential as a potent and safe analgesic candidate for management of OA pain.

Randomized placebo-controlled, double-blind clinical trial of nanoemulsion curcumin in women with aromatase inhibitor-induced arthropathy: an Alliance/NCORP pilot trial.

PURPOSE: Aromatase inhibitor (AI) therapy reduces risk of recurrence and death for postmenopausal women with breast cancer (BC); however, AI-induced arthralgia (AIIA) can lead to discontinuation of treatment. Curcumin, a bioactive polyphenolic substance, may help ameliorate inflammation-related conditions including osteoarthritis and pain. METHODS: We conducted a multisite randomized placebo-controlled, double-blind pilot trial (Alliance A22_Pilot9) to evaluate the effects of nanoemulsion curcumin (NEC, 200 mg/day) in postmenopausal women experiencing AIIA for ≥ 3 months. The primary objective was to determine the feasibility of using Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) to detect changes from 0 (T0) to 3 months (T3) of NEC treatment in AI-induced symptoms and well-being; secondary objectives included evaluation of changes in Disabilities of the Shoulder, Arm, and Hand (DASH), Brief Pain Inventory-short form (BPI-SF), grip strength, and biomarkers at T0 and T3. RESULTS: Forty-two patients were randomized to NEC or placebo; 34 women completed the 3-month study. Patient-reported outcome measures (PROMs: FACT-ES, DASH, BPI-SF) and biospecimens were collected at T0-T3 in > 80% of participants. Adherence was ≥ 90% for both arms. PROMs and grip strength did not differ significantly by treatment arm. Plasma curcumin was detected only in NEC arm participants. Serum estradiol and estrone levels were below detection or low on study agent. Gastrointestinal adverse effects were commonly reported in both arms. CONCLUSION: NEC versus placebo in a multisite randomized trial is feasible and well-tolerated. Additional studies with larger sample size are needed to further evaluate the efficacy and safety of NEC in treatment of AIIA. CLINICALTRIALS: gov Identifier: NCT03865992, first posted March 7, 2019.

TET1-mediated epigenetic regulation of tumor necrosis factor-α in trigeminal ganglia contributes to chronic temporomandibular joint pain.

Chronic temporomandibular joint (TMJ) pain profoundly affects patients' quality of life. Trigeminal tumor necrosis factor-α (TNFα) plays a pivotal role in mediating TMJ pain in mice, yet the underlying epigenetic mechanisms remain enigmatic. To unravel these epigenetic intricacies, we employed a multifaceted approach. Hydroxymethylated DNA immunoprecipitation (hMeDIP) and chromatin immunoprecipitation (ChIP) followed by qPCR were employed to investigate the demethylation of TNFα gene (Tnfa) and its regulation by ten-eleven translocation methylcytosine dioxygenase 1 (TET1) in a chronic TMJ pain mouse model. The global levels of 5-hydroxymethylcytosine (5hmc) and percentage of 5hmc at the Tnfa promoter region were measured in the trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) following complete Freund's adjuvant (CFA) or saline treatment. TET1 knockdown and pain behavioral testing were conducted to ascertain the role of TET1-mediated epigenetic regulation of TNFα in the pathogenesis of chronic TMJ pain. Our finding revealed an increase in 5hmc at the Tnfa promoter region in both TG and Sp5C of CFA-treated mice. TET1 was upregulated in the mouse TG, and the ChIP result showed TET1 direct binding to the Tnfa promoter, with higher efficiency in the CFA-treated group. Immunofluorescence revealed the predominant expression of TET1 in trigeminal neurons. TET1 knockdown in the TG significantly reversed CFA-induced TNFα upregulation and alleviated chronic TMJ pain. In conclusion, our study implicates TET1 as a vital epigenetic regulator contributing to chronic inflammatory TMJ pain via trigeminal TNFα signaling. Targeting TET1 holds promise for epigenetic interventions in TMJ pain management.

Comparison of reporting rates of arthritis and arthralgia following AstraZeneca, Pfizer-BioNTech, Moderna, and Janssen vaccine administration against SARS-CoV-2 in 2021: analysis of European pharmacovigilance large-scale data.

This study aimed to investigate the reporting rates of arthritis and arthralgia following the administration of four vaccines against SARS-CoV-2: Pfizer-BioNTech (Tozinameran), Moderna (CX-024414), AstraZeneca (Chadox1 NCOV-19), and Janssen (AD26.COV2.S) in 2021. We used data from the EudraVigilance database, specifically analyzing spontaneous reports of suspected adverse reactions (ADRs) from the European Union (EU)/European Economic Area (EEA) region. Age-group-specific reporting rates were calculated by dividing the number of arthralgia and arthritis reports per 1,000,000 vaccine doses administered per age group. Reporting rates were compared using a rate ratio among the four vaccines, using the AstraZeneca vaccine as a comparator. The AstraZeneca vaccine was associated with the highest rate of arthralgia across all age groups. Arthritis reporting rates were significantly lower, with the AstraZeneca vaccine having the highest rates in most age groups, except the 60-69 and 80+ groups, where the Janssen and Pfizer-BioNTech vaccines demonstrated higher reporting rates, respectively. The distribution of arthritis rates did not follow the arthralgia pattern, being higher in the 50-79 age group. This study is the first spontaneous reporting system analysis of arthritis reporting rates post-SARS-CoV-2 vaccination at a European level, revealing a higher reporting of suspected musculoskeletal adverse reactions after AstraZeneca vaccination. The findings underscore the need to consider commonly reported events like arthralgia in risk-benefit assessments prior to vaccination against SARS-CoV-2. Given the high prevalence of rheumatic and musculoskeletal diseases and vaccine hesitancy in this population, our results could influence vaccine choice and acceptance.

Effect of whole-body cryotherapy versus placebo cryotherapy on joint pain induced by aromatase inhibitors in women with early stage breast cancer: a randomised clinical trial.

INTRODUCTION: Hormone therapy (HT) is a major adjuvant treatment for breast cancer. Despite their effectiveness, aromatase inhibitors can cause several side effects, including arthralgia in 35%-50% of patients. These side effects frequently lead to the premature discontinuation of HT. Whole-body cryotherapy (WBC) can be used for managing arthritic pain. The primary objective of this study will be to evaluate the effect of WBC on aromatase-induced joint pain, compared with placebo cryotherapy, in patients with hormone-dependent breast cancer receiving adjuvant aromatase inhibitors. The secondary objectives will be to evaluate WBC safety and its effect on analgesic consumption, HT adherence and quality of life. METHODS AND ANALYSIS: In this randomised, placebo-controlled, double-blinded clinical trial, 56 patients with aromatase inhibitor-induced joint pain and a Brief Pain Inventory-Short Form (BPI-SF) score ≥3 for the worst pain experienced in the previous week will be randomised into the WBC or placebo cryotherapy arm (10 sessions in each group). The primary outcome will be the BPI-SF score at week 6 post-treatment. The secondary outcomes will include the BPI-SF scores at months 3 and 6 post-treatment, the BPI-SF pain severity index and pain interference index, the Health Assessment Questionnaire score, the number of days of aromatase inhibitor treatment and analgesic consumption in the 15 days before the visits at week 6 and months 3 and 6 after cryotherapy. The incidence of adverse events will also be investigated. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee Est IV of Hospital Civil, Strasbourg, France. Protocol V.5 was approved in December 2022. The results will be disseminated in a peer-reviewed journal and presented at international congresses. TRIAL REGISTRATION NUMBER: NCT05315011.

The lived experience of patients with breast cancer on adjuvant endocrine therapy: side effects and coping strategies during the first year of medication initiation.

PURPOSE: Adjuvant endocrine therapy (AET) is pivotal for hormone receptor-positive breast cancer patients, significantly enhancing survival rates. Yet, adherence to AET remains challenging due to side effects. This study delves into the lived experience of breast cancer survivors concerning AET-induced side effects and examines differences in symptom profiles between Tamoxifen and aromatase inhibitors (AIs). METHODS: We interviewed 35 breast cancer survivors on AET, conducting qualitative iterative analysis using grounded theory. A codebook was developed to aid data coding and interpretation. NVIVO software facilitated comprehensive transcript analysis. RESULTS: Survivors reported a spectrum of side effects like hot flashes, sexual issues, joint pain, stiffness, mood swings, and fertility concerns. Symptom profiles differed based on AET type. Tamoxifen users experienced more frequent sexual side effects and mood swings, while AIs were linked to joint pain, stiffness, and bone health worries. Those on AET for over 6 months expressed heightened concerns about side effects. CONCLUSION: Tailored patient education, aligned with AET type, empowers survivors to manage side effects using self-regulatory strategies. Acknowledging distinct symptom profiles enables informed decisions, improving adherence and quality of life. IMPLICATIONS: This study underscores tailored survivorship support, equipping patients with tools to manage side effects, enhancing adherence, and long-term outcomes. The findings inform the integration of comprehensive survivorship programs, emphasizing individualized strategies for managing side effects and promoting better adherence and improved quality of life.

Regular walking exercise prior to knee osteoarthritis reduces joint pain in an animal model.

We investigated the effect of regular walking exercise prior to knee osteoarthritis (OA) on pain and synovitis in a rat monoiodoacetic acid (MIA)-induced knee OA model. Seventy-one male Wistar rats were divided into three groups: (i) Sedentary + OA, (ii) Exercise + OA, and (iii) Sedentary + Sham groups. The Exercise + OA group underwent a regular treadmill walking exercise at 10 m/min (60 min/day, 5 days/week) for 6 weeks, followed by a 2-mg MIA injection in the right knee. The right knee joint was removed from rats in this group at the end of the 6-week exercise period and at 1 and 6 weeks after the MIA injection. After the 6 weeks of treadmill exercise but before MIA injection, there were no significant differences among the three groups in the pressure pain threshold, whereas at 1 week post-injection, the Exercise + OA group's pressure pain threshold was significantly higher than that in the Sedentary + OA group, and this difference persisted until the end of the experimental period. The histological changes in articular cartilage and subchondral bone revealed by toluidine blue staining showed no difference between the Sedentary + OA and EX + OA groups. The expression levels of interleukin (IL)-4 and IL-10 mRNA in the infrapatellar fat pad and synovium were significantly increased by the treadmill exercise. Significant reductions in the number of CD68-, CD11c-positive cells and IL-1ß mRNA expression and an increase in the number of CD206-positive cells were observed at 1 week after the MIA injection in the Exercise + OA group compared to the Sedentary + OA group. These results suggest that regular walking exercise prior to the development of OA could alleviate joint pain through increases in the expressions of anti-inflammatory cytokines in the rat infrapatellar fat pad and synovium.

Impact of CDK4/6 Inhibitors on Aromatase Inhibitor-Associated Musculoskeletal Syndrome (AIMSS) in the Adjuvant Setting.

Background: Third-generation aromatase inhibitors (AIs) are the mainstay of treatment in hormone receptor (HR)-positive breast cancer. Even though it is considered to be a well-tolerated therapy, AI-induced musculoskeletal symptoms are common and may be accused for treatment discontinuation. Recently, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors changed the therapeutic setting, and currently, ribociclib, palbociclib, and abemaciclib are all approved in combination with nonsteroidal AIs in patients with ER-positive, HER2-negative advanced or metastatic breast cancer. This systematic review aims to identify the frequency of aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) in the adjuvant setting in patients under AI monotherapy compared to patients under combination therapy with AIs and CDK4/6 inhibitors and demonstrate the underlying mechanism of action. Methods: This study was performed in accordance with PRISMA guidelines. The literature search and data extraction from all randomized clinical trials (RCTs) were done by two independent investigators. Eligible articles were identified by a search of MEDLINE and ClinicalTrial.gov database concerning the period 2000/01/01-2021/05/01. Results: Arthralgia was reported in 13.2 to 68.7% of patients receiving AIs for early-stage breast cancer, while arthralgia induced by CDK4/6 inhibitors occurred in a much lower rate [20.5-41.2%]. Bone pain (5-28.7% vs. 2.2-17.2%), back pain (2-13.4% vs. 8-11.2%), and arthritis (3.6-33.6% vs. 0.32%) were reported less frequently in patients receiving the combination of CDK4/6 inhibitors with ET. Conclusions: CDK4/6 inhibitors might have a protective effect against joint inflammation and arthralgia occurrence. Further studies are warranted to investigate arthralgia incidence in this population.

Comparison of chemical-induced temporomandibular osteoarthritis rat models (monosodium iodoacetate versus collagenase type II) for the study of prolonged drug delivery systems.

OBJECTIVE: To compare two agents that can induce a rat model of temporomandibular joint osteoarthritis (TMJOA) by chemical induction: monosodium iodoacetate (MIA) and collagenase type 2 (Col-2). We wished to ascertain the best agent for assessing drug-delivery systems (DDSs). METHOD: Male Wistar rats underwent intra-articular injection with MIA or Col-2. They were manipulated for 30 days. The head withdrawal threshold (HWT), immunohistological assessment, and positron emission tomography (PET) were used to evaluate the relevance of our models. RESULTS: For both the MIA and Col-2 groups, pain persisted for 30 days after injection. Change in the HWT showed that Col-2 elicited a strong action initially that decreased progressively. MIA had a constant action upon pain behavior. Histology of TMJ tissue from both groups showed progressive degradation of TMJ components. CONCLUSIONS: MIA and Col-2 induced orofacial pain by their local chemical action on TMJs. However, based on a prolonged and greater sustained effect on the pain threshold, persistent histological changes, and imaging results, MIA appeared to be more suitable for creation of a rat model of TMJOA for the study of DDSs.

Disproportionate articular pain is a frequent phenomenon in rheumatoid arthritis and responds to treatment with sarilumab.

OBJECTIVES: In some patients with RA, joint pain is more severe than expected based on the amount of joint swelling [referred to as disproportionate articular pain (DP)]. We assessed DP prevalence and the effects of sarilumab, an IL-6 inhibitor, on DP. METHODS: Data from RA patients treated with placebo or 200 mg sarilumab in the phase 3 randomized controlled trials (RCTs) MOBILITY and TARGET, adalimumab 40 mg or sarilumab 200 mg in the phase 3 RCT MONARCH and sarilumab 200 mg in open-label extensions (OLEs) were used. DP was defined as an excess tender 28-joint count (TJC28) over swollen 28-joint count (SJC28) of ≥7 (TJC28 - SJC28 ≥ 7). Treatment response and disease activity were determined for patients with and without DP. RESULTS: Of 1531 sarilumab 200 mg patients from RCTs, 353 (23%) had baseline DP. On average, patients with DP had higher 28-joint DAS using CRP (DAS28-CRP) and pain scores than patients without DP, whereas CRP levels were similar. After 12 and 24 weeks, patients with baseline DP treated with sarilumab were more likely to be DP-free than those treated with placebo or adalimumab. In RCTs, more sarilumab-treated patients achieved low disease activity vs comparators, regardless of baseline DP status. In OLEs, patients were more likely to lose rather than gain DP status. CONCLUSION: About one-quarter of patients with RA experienced DP, which responded well to sarilumab. These data support the concept that other mechanisms (potentially mediated via IL-6) in addition to inflammation may contribute to DP in RA. TRIAL REGISTRATIONS: NCT01061736, NCT02332590, NCT01709578, NCT01146652.

Comparison of the clinical effectiveness of treatments for aromatase inhibitor-induced arthralgia in breast cancer patients: A systematic review with network meta-analysis.

Aromatase inhibitor-induced arthralgia (AIA) contributes to poor adherence of aromatase inhibitor therapies in patients with breast cancer. A systematic review using network meta-analysis (NMA) was conducted to examine the clinical effectiveness of multiple therapies and rank probabilities for the management of AIA. Randomized controlled trials (RCTs) assessing treatments for AIA in postmenopausal women with stage 0-III hormone receptor-positive breast cancer were searched from inception to October 2021. The main NMA involved 1516 participants from 17 RCTs. Acupuncture was the highest ranked intervention to improve pain intensity followed by sham acupuncture, multicomponent herbal medicine, exercise, duloxetine, vitamin D, omega-3 fatty acids, physical therapy, testosterone, and inactive controls. Single natural products were inferior to controls. The current review provides new insights into the management of AIA in breast cancer survivors for increased survival and can be utilized to make evidence-based decisions regarding treatment.

[Impact of adapted physical activity on joint pain induced under adjuvant hormone therapy for breast cancer: A review of the literature]. / Impact de l'activité physique adaptée sur les douleurs articulaires induites sous hormonothérapie adjuvante du cancer du sein : une revue de la littérature.

Hormone therapy provides an excellent survival rate after cancer but has many side effects, including joint pain in one out of two women. This leads about 13 % of women to stop their treatment within the first 6 months, impacting on its effectiveness, survival and the risk of recurrence. In order to better manage pain and quality of life, physical activity is highly recommended. In this context, the present review proposes a state of the art on the effects of adapted physical activity, based on the works referenced in PubMed. These studies show that physical activity has proved its worth in the primary prevention of cancer and is being evaluated in secondary prevention, particularly in the reduction of adverse effects. Overall, there is a reduction in joint pain, an improvement in quality of life and fatigue. Physical activity also plays a role in tertiary prevention. Paradoxically, oncologists and educators often note a reduction in the practice of physical activity due to fear of the onset of pain. It seems necessary to reinforce communication with patients and health professionals and to recommend the practice of physical activity in an appropriate setting.

Musculoskeletal immune-related adverse events in 927 patients treated with immune checkpoint inhibitors for solid cancer.

OBJECTIVE: The prevalence of the musculoskeletal immune-related adverse events (irAEs) is probably underestimated, as most studies report only severe side effects. Our aim was to describe and characterize all musculoskeletal irAEs in a large cohort of patients treated with immune checkpoint inhibitors (ICI). METHODS: We conducted a retrospective study among patients who received ICI from 07/27/2014 to 05/08/2020 at the medical oncology department of the Institut Paoli-Calmettes, Marseille, France. All medical files were systemically reviewed by a rheumatologist who collected clinical features, time of occurrence, treatment regimen, irAEs management, course and outcomes. We also assessed tumor response 3 months after introduction of ICI, according to severity and treatments used to manage musculoskeletal irAEs. RESULTS: Among 927 patients treated with ICI for a solid tumor, 118 patients (12.7%) presented a musculoskeletal irAE. Their median age was 66.5, 61% were male, and they mainly had a lung (57.6%) or urological cancer (27.1%). The most frequently involved ICI was an anti PD-1. Arthralgias and myalgias were the most frequent musculoskeletal irAEs (9.8%) and inflammatory rheumatic features were reported in 36 patients (3.9%) with elevated acute phase reactants and negative immunological markers. The median time of onset was 2 months (IC 95% 1.8; 2.7). Tumor response at 3 months did not differ according to musculoskeletal irAE severity, type of manifestation (arthralgias/myalgias versus inflammatory rheumatic features), pain patterns (mechanical versus inflammatory) or irAE treatments. CONCLUSION: Musculoskeletal irAEs in this large cohort of patients treated with ICI were frequent (12.7%), mostly mild and well tolerated.

Immune checkpoint inhibitor-induced arthralgia is tightly associated with improved overall survival in cancer patients.

OBJECTIVES: With the increased use of immune checkpoint inhibitors (ICIs) in cancer patients, arthralgia has been the most commonly reported musculoskeletal immune-related adverse event (irAE). We aimed to characterize arthralgia and its association with overall survival (OS). MATERIAL AND METHODS: Randomized controlled trials (RCTs) reporting on data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (ORs) with 95% CIs were calculated for arthralgia using a random-effects model meta-analysis. Individual patient data were reconstructed from RCTs assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry. RESULTS: We analysed 14 377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20, 1.56). Of the 369 patients in the YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs, which was noticeably more frequent than in those without arthralgia (OR 1.92, 95% CI 1.04, 3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80, 8.39). In the YCU registry, patients with (vs without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17, 0.65, P < 0.001). CONCLUSIONS: If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS, and the condition of patients with irAEs must be carefully evaluated to determine optimal management.

Clinical characteristics associated with falls in patients with non-metastatic castration-resistant prostate cancer treated with apalutamide.

BACKGROUND: The phase III SPARTAN study demonstrated that apalutamide significantly improves metastasis-free survival and overall survival vs. placebo in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). However, patients receiving apalutamide experienced falls more frequently vs. those receiving placebo (15.6% vs. 9.0%). METHODS: 806 patients with nmCRPC randomized to apalutamide in SPARTAN and treated with apalutamide in addition to ongoing androgen deprivation therapy (ADT) were included in this post-hoc analysis investigating clinical variables associated with a subsequent fall. Time to a fall was assessed with Cox proportional-hazards models adjusted for baseline characteristics and time-varying factors. Statistical inference was based on final multivariable models. RESULTS: Falls were reported for 125/803 (15.6%) patients treated with apalutamide and ADT. Most falls were grade 1 or 2 and did not require hospitalization. Median time from randomization to first fall was 9.2 months (range 0.1-25.3 months). In the final multivariable model of both baseline and after-baseline covariates, baseline patient characteristics (older age, poor Eastern Cooperative Oncology Group performance status, history of neuropathy, and α-blocker use before study treatment) remained significantly associated with fall; after-baseline clinical characteristics significantly associated with time to fall were development of neuropathy, arthralgia, and weight loss before fall. CONCLUSIONS: This analysis identified risk factors for fall among nmCRPC patients treated with apalutamide. Clinical management can minimize these identified risks while enhancing patient outcomes. Preventive interventions should be considered when the identified baseline conditions and post-treatment neuropathy, arthralgia, or weight decrease are present, to reduce risk of fall. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01946204.

Tamoxifen induced hands deformities.

INTRODUCTION: Tamoxifen is widely used for the treatment of hormone-responsive breast cancer. In this article, we report a case of a patient who developed hand deformities following long-term administration of tamoxifen. CASE REPORT: A 57-year-old woman, followed for invasive ductal carcinoma of the left breast under tamoxifen for 7 years, presenting joint pain with deformities in her fingers. MANAGEMENT & OUTCOME: Following the appearance of the adverse effect, tamoxifen was stopped. A series of biologic and radiologic analysis were performed in order to explain the appearance of this event. A substitution treatment was discussed and a rheumatologist's opinion was requested. DISCUSSION: Tamoxifen appears to be associated with the development of inflammatory osteoarthritis resembling rheumatoid arthritis. Possible mechanisms of such an effect are discussed.