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Idiopathic inflammatory myopathies (IIM) are marked by progressive muscle weakness and lasting disability. Therapies targeting patient well-being include the use of prescription drugs as well as exercise. Maintaining or increasing muscular strength and endurance as well as cardiorespiratory fitness (CRF) improves quality of life (QoL) as well as functional status in IIM patients. This narrative review highlights exercise interventions in patients of different IIM subtypes with the intent to provide a summary table with exercise recommendations that will safely and effectively improve QoL in myositis patients.
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Miosite , Qualidade de Vida , Humanos , Miosite/diagnóstico , Miosite/terapia , Exercício Físico/fisiologia , Terapia por Exercício/efeitos adversos , Força MuscularRESUMO
Metabolic myopathies are a set of rare inborn errors of metabolism leading to disruption in energy production. Relevant to skeletal muscle, glycogen storage disease and fatty acid oxidation defects can lead to exercise intolerance, rhabdomyolysis, and weakness in children and adults, distinct from the severe forms that involve multiple-organ systems. These nonspecific, dynamic symptoms along with conditions that mimic metabolic myopathies can make diagnosis challenging. Clinicians can shorten the time to diagnosis by recognizing the typical clinical phenotypes and performing next generation sequencing. With improved access and affordability of molecular testing, clinicians need to be well-versed in resolving variants of uncertain significance relevant to metabolic myopathies. Once identified, patients can improve quality of life, safely engage in exercise, and reduce episodes of rhabdomyolysis by modifying diet and lifestyle habits.
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Erros Inatos do Metabolismo , Miopatias Mitocondriais , Doenças Musculares , Rabdomiólise , Humanos , Qualidade de Vida , Doenças Musculares/diagnóstico , Doenças Musculares/genética , Doenças Musculares/terapia , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/metabolismo , Músculo Esquelético/metabolismo , Miopatias Mitocondriais/diagnósticoRESUMO
With rapid advances in immuno-oncology, immune checkpoint inhibitors (ICIs) are increasingly used for a broad array of malignancies. This has led to a novel spectrum of adverse effects including ICI-related myositis, a potentially life-threatening neuromuscular complication that must be diagnosed and treated promptly. Significant gaps exist in the current understanding of ICI-related myositis due to the rarity of the condition and the lack of evidence-based guidelines, prompting the need to synthesize the most relevant and recent published works in the field. This review provides a broad overview of ICI-related myositis with an emphasis on pathophysiology, epidemiology, clinical features, workup, management and future directions.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Miosite , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Miosite/tratamento farmacológicoRESUMO
OBJECTIVE: This systemic review assesses skin tone representation in images of DM rashes in medical education literature. METHODS: A review was performed of 59 dermatology, 11 neurology, 10 neuromuscular, 7 rheumatology and 6 internal medicine textbooks published between 2011 and 2021 and 3 online image databases (UpToDate, VisualDx and DermNet NZ) that were available through an online medical school library. After extracting images, images with poor lighting or unclear rashes were removed. Authors graded skin tone independently on the Massey and Martin Skin Colour Scale (MMSCS) from 1 (very light) to 10 (very dark). The median score was taken for a final score, grouped within MMSCS 1-2, 3-4, 5-7 or 8-10. Inter-rater reliability was assessed using Kendall's coefficient of concordance (W). RESULTS: Six hundred and twenty-one images were extracted after reviewing 93 textbooks and 3 online databases. Of the 561 images analysed, 73.1% of images represented MMSCS 1-2, followed by 3-4 (13.4%), 5-7 (11.8%) and 8-10 (1.8%). Inter-rater reliability was high (W = 0.835). Of the images in MMSCS 5-10, 59.2% were in online databases and 80.6% of textbook images were in dermatology books. CONCLUSIONS: Patients with lighter skin tones were represented in a higher number of DM-related educational materials compared with patients with darker skin tones. Our findings add to current research implicating that darker skin tones are under-represented in cutaneous educational materials, specifically for DM. This leads to the inability to properly characterize skin involvement in DM and may lead to inappropriate exclusion from clinical trials due to erroneous skin scoring.
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Dermatomiosite , Exantema , Humanos , Grupos Raciais , Reprodutibilidade dos Testes , Pele , Pigmentação da PeleRESUMO
OBJECTIVES: Pain is commonly reported in people living with myositis. This study assesses the presence of pain in the subtypes of myositis as well as the frequency of opioid and non-opioid pain medication use. METHODS: A survey was developed and distributed by Myositis Support and Understanding, a patient-led advocacy organization, to members of its group. Multivariate logistic regression analysis and chi-squared tests were performed. RESULTS: A total of 468 participants completed the survey. A total of 423 participants (DM n = 183, PM n = 109 and IBM n = 131) were included, based on reported diagnosis, for final analysis. Some 91.5% of myositis participants reported current or past pain, with 99% attributing their pain to myositis. There was a lower likelihood of pain in participants aged >60 years [odds ratio (OR) 0.2, 95% confidence interval (CI) 0.1, 0.6, P = 0.003]. The percentage of participants reporting pain was statistically different based on myositis type (DM 97.2%, IBM 80.9% and PM 94.5%, P < 0.001), with a higher likelihood of pain in DM compared with IBM (OR 3.7, 95% CI 1.3, 10.2, P = 0.011). There was a lower likelihood of pain in participants aged >60 years (OR 0.2, 95% CI 0.1, 0.6, P = 0.003). Of the 387 participants reporting pain, 335 reported using pain medications (69% prescribed opioids). Male sex, age >60 years and myositis subtype were not associated with likelihood of non-opioid use. CONCLUSION: Pain is a commonly reported symptom in myositis with variable treatment strategies, including opioid medications. This study highlights the importance of addressing pain as part of myositis treatment as well as the need for future studies understanding treatment effectiveness.
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Analgésicos Opioides , Miosite , Humanos , Masculino , Analgésicos Opioides/uso terapêutico , Miosite/complicações , Miosite/tratamento farmacológico , Miosite/diagnóstico , Dor/tratamento farmacológico , Dor/etiologiaRESUMO
INTRODUCTION/AIMS: Peripheral neuropathies commonly affect quality of life of patients due to pain, sleep disturbances, and fatigue, although trials have not adequately explored these domains of care. The aim of this study was to assess the impact of nortriptyline, duloxetine, pregabalin, and mexiletine on pain, sleep, and fatigue in patients diagnosed with cryptogenic sensory polyneuropathy (CSPN). METHODS: We implemented a Bayesian adaptive design to perform a 12-wk multisite, randomized, prospective, open-label comparative effectiveness study in 402 CSPN patients. Participants received either nortriptyline (n = 134), duloxetine (n = 126), pregabalin (n = 73), or mexiletine (n = 69). At prespecified analysis timepoints, secondary outcomes, Patient Reported Outcomes Measurement Information System (PROMIS) surveys including Short Form (SF)-12, pain interference, fatigue, and sleep disturbance, were collected. RESULTS: Mexiletine had the highest quit rate (58%) due to gastrointestinal side effects, while nortriptyline (38%) and duloxetine (38%) had the lowest quit rates. If tolerated for the full 12 wk of the study, mexiletine had the highest probability (>90%) of positive outcomes for improvements in pain interference and fatigue. There was no significant difference among the medications for sleep disturbance or SF-12 scores. Adverse events and lack of efficacy were the two most common reasons for cessation of therapy. DISCUSSION: Physicians caring for patients with CSPN should consider mexiletine to address pain and fatigue, although nortriptyline and duloxetine are better medications to trial first since they are better tolerated. Future research should compare other commonly used medications for CSPN to determine evidence-based treatment strategies.
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Atividades Cotidianas , Neuropatias Diabéticas , Teorema de Bayes , Neuropatias Diabéticas/tratamento farmacológico , Método Duplo-Cego , Cloridrato de Duloxetina/uso terapêutico , Fadiga/tratamento farmacológico , Fadiga/etiologia , Humanos , Mexiletina/uso terapêutico , Nortriptilina/uso terapêutico , Dor/tratamento farmacológico , Pregabalina/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Sono , Resultado do TratamentoRESUMO
Myelopathy is a clinical diagnosis with many causes. A focused history and neurologic exam can help identify a myelopathic syndrome that guides a targeted workup. Though an exact cause may not always be identified, a thoughtful clinical approach can narrow down the differential diagnosis enough to treat the patient.
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Doenças da Medula Espinal , Diagnóstico Diferencial , Humanos , Exame Neurológico , Doenças da Medula Espinal/diagnóstico , Doenças da Medula Espinal/terapiaRESUMO
INTRODUCTION: High altitude headache (HAH) and acute mountain sickness (AMS) are common pathologies at high altitudes. There are similarities between AMS and migraine headaches, with nausea being a common symptom. Several studies have shown ibuprofen can be effective for AMS prophylaxis, but few have addressed treatment. Metoclopramide is commonly administered for migraine headaches but has not been evaluated for HAH or AMS. We aimed to evaluate metoclopramide and ibuprofen for treatment of HAH and AMS. METHODS: We performed a prospective, double-blinded, randomized, field-based clinical trial of metoclopramide and ibuprofen for the treatment of HAH and AMS in 47 adult subjects in the Mount Everest region of Nepal. Subjects received either 400 mg ibuprofen or 10 mg metoclopramide in a 1-time dose. Lake Louise Score (LLS) and visual analog scale of symptoms were measured before and at 30, 60, and 120 min after treatment. RESULTS: Subjects in both the metoclopramide and ibuprofen arms reported reduced headache severity and nausea compared to pretreatment values at 120 min. The ibuprofen group reported 22 mm reduction in headache and 6 mm reduction in nausea on a 100 mm visual analog scale at 120 min. The metoclopramide group reported 23 mm reduction in headache and 14 mm reduction in nausea. The ibuprofen group reported an average 3.5-point decrease on LLS, whereas the metoclopramide group reported an average 2.0-point decrease on LLS at 120 min. CONCLUSIONS: Metoclopramide and ibuprofen may be effective alternative treatment options in HAH and AMS, especially for those patients who additionally report nausea.
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Doença da Altitude/prevenção & controle , Inibidores de Ciclo-Oxigenase/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Cefaleia/prevenção & controle , Ibuprofeno/uso terapêutico , Metoclopramida/uso terapêutico , Adulto , Doença da Altitude/tratamento farmacológico , Anti-Inflamatórios não Esteroides/uso terapêutico , Antieméticos/uso terapêutico , Método Duplo-Cego , Feminino , Cefaleia/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Montanhismo , Nepal , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Posttraumatic stress disorder (PTSD) is associated with an increased risk of developing cardiovascular disease, especially in women. Evidence indicates that men with PTSD exhibit lower maximal oxygen uptake (VÌo2max) relative to controls; however, whether VÌo2max is blunted in women with PTSD remains unknown. Furthermore, it is unclear what determinants (i.e., central and/or peripheral) of VÌo2max are impacted by PTSD. Therefore, we evaluated the central (i.e., cardiac output; QÌc) and peripheral (i.e., arteriovenous oxygen difference) determinants of VÌo2max in women with PTSD; hypothesizing that VÌo2max would be lower in women with PTSD compared with women without PTSD (controls), primarily due to smaller increases in stroke volume (SV), and therefore QÌc. Oxygen uptake (VÌo2), heart rate (HR), QÌc, SV, and arteriovenous oxygen difference were measured in women with PTSD (n = 14; mean [SD]: 43 [11] yr,) and controls (n = 17; 45 [11] yr) at rest, and during an incremental maximal treadmill exercise test, and the QÌc/VÌo2 slope was calculated. VÌo2max was not different between women with and without PTSD (24.3 [5.6] vs. 26.4 [5.0] mL/kg/min; P = 0.265). However, women with PTSD had higher QÌc [P = 0.002; primarily due to greater SV (P = 0.069), not HR (P = 0.285)], and lower arteriovenous oxygen difference (P = 0.002) throughout exercise compared with controls. Furthermore, the QÌc/VÌo2 slope was steeper in women with PTSD relative to controls (6.6 [1.4] vs. 5.7 [1.0] AU; P = 0.033). Following maximal exercise, women with PTSD exhibited slower HR recovery than controls (P = 0.046). Thus, despite attenuated peripheral oxygen extraction, VÌo2max is not reduced in women with PTSD, likely due to larger increases in QÌc.NEW & NOTEWORTHY The current study indicates that VÌo2max is not different between women with and without PTSD; however, women with PTSD exhibit blunted peripheral extraction of oxygen, thus requiring an increase in QÌc to meet metabolic demand during exercise. Furthermore, following exercise, women with PTSD demonstrate impaired autonomic cardiovascular control relative to sedentary controls. We interpret these data to indicate that women with PTSD demonstrate aberrant cardiovascular responses during and immediately following fatiguing exercise.
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Transtornos de Estresse Pós-Traumáticos , Masculino , Humanos , Feminino , Consumo de Oxigênio/fisiologia , Débito Cardíaco/fisiologia , Volume Sistólico/fisiologia , Frequência Cardíaca/fisiologia , Teste de Esforço , Oxigênio/metabolismoRESUMO
BACKGROUND: Glycogen storage disease type 5 (GSD) is an autosomal recessive inherited metabolic myopathy caused by a deficiency of the enzyme muscle glycogen phosphorylase. Individuals with GSD5 experience physical activity intolerance. OBJECTIVE: This patient-led study aimed to capture the daily life experiences of GSD5, with a focus on adapting to and coping with their physical activity intolerance. METHODS: An online survey was composed in close collaboration with patient organizations. It consisted of customized and validated questionnaires on demographics, general health and comorbidities, physical activity, psychosocial well-being and functioning, pain, fatigue and adapting to and coping with GSD5. RESULTS: One hundred sixty-two participants (16 countries) participated. The majority, nâ=â86 (69%) were from the Netherlands, USA or UK. We observed a high rate of misdiagnosis prior to GSD5 diagnosis (49%), surprisingly a relatively high proportion had not been diagnosed by DNA testing which is the gold standard. Being diagnosed had a strong impact on emotional status, daily life activities and important life choices. A large proportion had not received any rehabilitation (41%) nor medical treatment (57%) before diagnosis. Engagement in vigorous and moderate physical activity was reduced. Health related quality of life was low, most likely related to low physical health. The median Fatigue Severity Score was 4.3, indicating moderate to severe fatigue. Participants themselves had found various ways to adapt to and cope with their disability. The adaptations concerned all aspect of their life, including household chores, social and physical activities, and work. In addition to lack of support, participants reported limited availability of information sources. CONCLUSION: Participants have provided guidance for newly diagnosed people, including the advice to accept one's limited abilities and maintain an active lifestyle. We conclude that adequate counseling on ways of adapting and coping is expected to increase both health-related quality of life and physical activity.
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Doença de Depósito de Glicogênio Tipo V , Humanos , Qualidade de Vida/psicologia , Dor , Exercício Físico , Fadiga/etiologiaRESUMO
The economic burden of idiopathic inflammatory myopathies (IIMs) within the US is underexplored. We hypothesized that IIMs patients experience considerable personal financial burden due to risks of multi-specialist visits, chronic long-term care, costs associated with disability, medical treatment, and overall high spending costs within the US healthcare system. We surveyed members of Myositis Support and Understanding (MSU) (response rate 4.7 %), and of the 470 survey participants that self-reported with diagnoses of IIMs, we assessed financial burden using two validated measures: (1) Financial Worry Score, and (2) Financial Burden Composite Score (FBCS). We determined factors associated with increased FBCS using logistic and Poisson regression respectively. High financial worry was endorsed by 202 participants (43 %) and the average FBCS ± SD was 1.8 ± 1.9. The odds of financial worry among participants with Medicaid is 3.016 times the odds of financial worry among participants without Medicaid (p = 0.011), and the odds of financial worry among participants with private high-deductible insurance is 3.216 times the odds of financial worry among participants who do not have private high-deductible insurance (p =< 0.001). Given the link between personal financial burden and potential effects on patient outcomes, it is essential for physicians to consider patient financial health when determining management or treatment courses. Identifying specific risk factors that can further exacerbate personal financial burden can help physicians identify vulnerable patients to reduce financial hardship.
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Pessoas com Deficiência , Miosite , Estados Unidos , Humanos , Estresse Financeiro , Gastos em Saúde , Efeitos Psicossociais da DoençaRESUMO
Background: Sporadic inclusion body myositis (sIBM) is a rare and slowly progressive skeletal muscle disease that can cause hand dysfunction, which is a major source of disability. Tendon transfers have been reliably used to improve function in other neuromuscular settings. Given that sIBM patients often present with flexion impairments and mostly functioning extensors, we investigated the potential opportunity for tendon transfer surgery to improve hand dysfunction in sIBM patients. Methods: We conducted a scoping review for studies of sIBM and tendon transfers, extracted descriptions of hand function and surgical technique, and recorded results in terms of hand function. We also conducted an institutional review board-approved survey with 470 participants to determine baseline patient-reported function and to determine participant perceptions and expectations for tendon transfer surgery to improve hand function in sIBM. Results: We identified three published case reports on tendon transfers in sIBM patients with subjectively improved grip and pinch strength, but standardized measures of hand function or quality-of-life were not reported. Within the surveyed cohort, half of participants reported that they would consider surgery, yet only 8% had been referred to a hand surgeon. Fifty four percent of participants reported that they would consider surgery if there would be 1-2 years of benefit after surgery. All participants who would consider surgery also had significant upper extremity disability. Discussion: Tendon transfer surgery has the potential to improve quality-of-life for sIBM patients, and there is significant patient interest in this approach. To objectively assess its efficacy, we propose conducting a surgical trial.
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Purpose: Peripheral neuropathies after shoulder arthroscopy are rare, though likely under-reported. Many resolve spontaneously, but some patients are left with permanent neurological deficits. The purpose of this study was to review the literature to better characterize this patient population, diagnostic tests performed, the timing and type of surgical intervention, and report clinical outcomes. Methods: A systematic literature review was performed. Articles in English were identified from PubMed, EMBASE, and CINAHL in August 2021. Article titles and abstracts were screened for relevance by two authors and discordant abstracts were resolved by the senior author. Data were subsequently extracted from the included articles. Results: Seventeen articles were identified yielding a total of 91 patients. The average age was 53 ± 12 years, and most patients were male (72%). Rotator cuff repair (62%) was the most common procedure performed. A peripheral neuropathy was identified an average of 80 ± 81 days from the index procedure (range, 0-240 days). Most commonly, peripheral nerve injury presented as a mononeuropathy, with the median nerve (39%) and ulnar nerve (17%) affected predominantly. Seventeen percent of patients underwent a secondary surgery at an average of 232 ± 157 days after the index procedure. At the final follow-up, 55% of neuropathies had resolved, 14% partially improved, and 22% showed no clinical improvement. The most proposed etiologies were postoperative immobilization (29%) and intraoperative positioning (20%), but several possible etiologies have been suggested. Conclusions: Peripheral neuropathies after arthroscopic shoulder procedures are rare. While most spontaneously resolve, up to 1 in 5 patients may have persistent neuropathic symptoms. A high index of suspicion should be maintained throughout the postoperative period. When neurologic deficits are identified, patients should undergo a thorough diagnostic workup and be referred to a subspecialist in a timely manner.
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Idiopathic inflammatory myopathies are a heterogeneous set of systemic inflammatory disorders primarily affecting muscle. Signs and symptoms vary greatly between and within subtypes, requiring supportive laboratory and pathologic evidence to confirm the diagnosis. Several studies are typical assessments for patients with suspected inflammatory myopathy, including muscle enzymes, autoimmune markers, imaging, and muscle biopsy. Misdiagnoses of myositis are not only related to the overlap of clinical phenotype with non-inflammatory myopathies, but also due to the limitations of diagnostic tests employed. Since many of the investigative tests are non-specific, they share features with other disorders, including muscular dystrophies, endocrine, toxic, and metabolic myopathies, and other neuromuscular or rheumatologic conditions. Recognizing the limitations of tests and understanding the shared features between inflammatory and non-inflammatory myopathies can help prevent misdiagnosing myositis with one of its several mimics.
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Dermatomiosite , Miosite de Corpos de Inclusão , Miosite , Autoanticorpos , Biomarcadores , Biópsia , Dermatomiosite/diagnóstico , HumanosRESUMO
Sedentary lifestyle, chronic disease, or microgravity can cause muscle deconditioning that then has an impact on other physiological systems. An example is the nervous system, which is adversely affected by decreased physical activity resulting in increased incidence of neurological problems such as chronic pain. We sought to better understand how this might occur by conducting RNA sequencing experiments on muscle biopsies from human volunteers in a 5-week bed-rest study with an exercise intervention arm. We also used a computational method for examining ligand-receptor interactions between muscle and human dorsal root ganglion (DRG) neurons, the latter of which play a key role in nociception and are generators of signals responsible for chronic pain. We identified 1352 differentially expressed genes (DEGs) in bed rest subjects without an exercise intervention but only 132 DEGs in subjects with the intervention. Among 591 upregulated muscle genes in the no intervention arm, 26 of these were ligands that have receptors that are expressed by human DRG neurons. We detected a specific splice variant of one of these ligands, placental growth factor (PGF), in deconditioned muscle that binds to neuropilin 1, a receptor that is highly expressed in DRG neurons and known to promote neuropathic pain. We conclude that exercise intervention protects muscle from deconditioning transcriptomic changes, and prevents changes in the expression of ligands that might sensitize DRG neurons, or act on other cell types throughout the body. Our work creates a set of actionable hypotheses to better understand how deconditioned muscle may influence the function of sensory neurons that innervate the entire body.
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Repouso em Cama/efeitos adversos , Exercício Físico , Gânglios Espinais/fisiologia , Músculo Esquelético/metabolismo , Transcriptoma , Adulto , Feminino , Gânglios Espinais/citologia , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Células Receptoras Sensoriais/fisiologiaRESUMO
PURPOSE: The COVID-19 pandemic is correlated with decreased physical activity (PA). Transitioning to remote work may impact people's acceptability and preferences for remotely delivered behavioral interventions, including PA. The objective was to examine perceptions of COVID-19 impacts on PA engagement and motivation, and perspectives related to remotely delivered PA interventions. DESIGN: Cross-sectional small-group interview. SETTING: Harris County, Texas. Participants: Insufficiently active, overweight/obese adults (16 healthy adults [aged 25-52 years], and 7 cancer survivors [aged 50-74 years]). METHOD: Group discussion was guided by semi-structured questions. Audio-transcribed data (278 pages) was analyzed using Braun and Clarke's process centering identification, analysis, organization, description, and reports. RESULTS: Overall, participants expressed a decreased level of PA due to the pandemic. Difficulties (e.g., care-taking activities, working from home, and safety concerns) negatively affected motivation. Participants indicated high acceptability of remotely delivered PA interventions, with advantages of virtual technology features (e.g., did not have to maintain a gym membership) and even accountability in maintaining a PA routine (e.g., using virtual groups to engage in community support). CONCLUSION: Participants described COVID-19 negatively affects access to PA opportunities yet also expressed willingness to engage in remotely delivered PA interventions instead of in-person programs because of their COVID-19 experiences. Remote interventions can greatly increase accessibility and offer opportunities to provide personalized motivation and accountability that people need to be more physically active.
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COVID-19 , Pandemias , Adulto , Idoso , Estudos Transversais , Exercício Físico , Humanos , Pessoa de Meia-Idade , SARS-CoV-2RESUMO
Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a chronic pain syndrome identified by the presence of noninfectious pelvic or perineal pain lasting longer than 3 months. Current diagnoses and treatments for the syndrome solely depend on and target symptoms, respectively. Thus far, the mechanistic disturbances responsible for the pathogenesis of CP/CPPS have remained largely elusive and treatments, and therefore, continue to be ineffective. To move toward successful management and treatment of CP/CPPS, it is necessary to elicit the underlying biological mechanisms responsible for the syndrome. Therefore, a phenotyping system that is able to bridge the gap between current symptom-based diagnosis and future mechanistic approaches to diagnosis and treatment is needed. In this article, we examine current CP/CPPS phenotyping systems, analyze their utility, and make suggestions for changes in clinical approaches to the syndrome that would both promulgate a mechanistic understanding and advance treatment approaches.
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Dor Crônica/genética , Dor Pélvica/genética , Prostatite/genética , Dor Crônica/diagnóstico , Dor Crônica/etiologia , Técnicas Genéticas , Humanos , Masculino , Dor Pélvica/diagnóstico , Dor Pélvica/etiologia , Fenótipo , Prostatite/complicações , Prostatite/diagnóstico , SíndromeRESUMO
Immune-related adverse events (irAE) may affect almost any organ system and occur at any point during treatment with immune checkpoint inhibitors (ICI). We present a patient with advanced lung cancer receiving antiprogrammed death 1 checkpoint inhibitor who developed a delayed-onset visual irAE treated with corticosteroids. Through assessment of longitudinal biospecimens, we analyzed serial autoantibodies, cytokines, and cellular populations. Months after ICI initiation and preceding clinical toxicity, the patient developed broad increases in cytokines (most notably interleukin-6 (IL-6), interferon-γ (IFNγ), C-X-C motif chemokine ligand 2 (CXCL2), and C-C motif chemokine ligand 17 (CCL17)), autoantibodies (including anti-angiotensin receptor, α-actin, and amyloid), CD8 T cells, and plasmablasts. Such changes were not observed in healthy controls and ICI-treated patients without irAE. Administration of corticosteroids resulted in immediate and profound decreases in cytokines, autoantibodies, and inflammatory cells. This case highlights the potential for late-onset changes in humoral and cellular immunity in patients receiving ICI. It also demonstrates the biologic effects of corticosteroids on these parameters. Application of humoral and cellular immune biomarkers across ICI populations may inform toxicity monitoring and management.
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Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Encefálicas/secundário , Carcinoma de Células Escamosas/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Neoplasias Pulmonares/patologia , Pessoa de Meia-IdadeRESUMO
Elucidating the cross-talk between inflammatory and cell proliferation pathways might provide important insights into the pathogenesis of inflammation-induced cancer. Here, we show that the receptor-interacting protein 1 (RIP1)-an essential mediator of inflammation-induced nuclear factor-kappaB (NF-kappaB) activation-regulates p27(Kip1) levels and cell-cycle progression. RIP1 regulates p27(Kip1) levels by an NF-kappaB-independent signal that involves activation of the phosphatidylinositol 3-kinase (PI3K)-Akt-forkhead pathway. Mouse embryonic fibroblasts (MEFs) from RIP1-knockout mice express high levels of p27(Kip1). Reconstitution of MEFs with RIP1 downregulates p27(Kip1) levels in a PI3K-dependent manner. RIP1 regulates p27(Kip1) at the messenger RNA level by regulating the p27(Kip1) promoter through the forkhead transcription factors. RIP1 expression blocks accumulation of cells in G(1) in response to serum starvation and favours cell-cycle progression. Finally, we show that overexpression of p27(Kip1) blocks the effects of RIP1 on the cell cycle. Thus, our study provides a new insight into how components of inflammatory and immune signalling pathways regulate cell-cycle progression.