Pharmacotherapeutic advances in fibromyalgia: what's new on the horizon?

INTRODUCTION: This review delves into Fibromyalgia Syndrome (FMS), a chronic pain condition demanding thorough understanding for precise diagnosis and treatment. Yet, a definitive pharmacological solution for FMS remains elusive. AREAS COVERED: In this article, we systematically analyze various pharmacotherapeutic prospects for FMS treatment, organized into sections based on the stage of drug development and approval. We begin with an overview of FDA-approved drugs, discussing their efficacy in FMS treatment. Next, we delve into other medications currently used for FMS but still undergoing further study, including opioids and muscle relaxants. Further, we evaluate the evidence behind medications that are currently under study, such as cannabinoids and naltrexone. Lastly, we explore new drugs that are in phase II trials. Our research involved a thorough search on PUBMED, Google Scholar, and clinicaltrials.gov. We also discuss the action mechanisms of these drugs and their potential use in specific patient groups. EXPERT OPINION: A focus on symptom-driven, combination therapy is crucial in managing FMS. There is also a need for ongoing research into drugs that target neuroinflammation, immunomodulation, and the endocannabinoid system. Bridging the gap between benchside research and clinical application is challenging, but it holds potential for more targeted and effective treatment strategies.

Environmental factors and fibromyalgia syndrome: a narrative review.

This in-depth review of fibromyalgia (FM), which is a complex condition characterised by chronic pain, fatigue, sleep disturbances, and a spectrum of diagnostically and therapeutically challenging symptoms, underlines the need for a comprehensive and integrated approach that also takes into account the psychological factors affecting patient responses. We focus on the substantial impact that environmental factors (climatic variations, air pollution, electromagnetic field exposure, physical and emotional traumas, dietary patterns, and infections) have on the manifestation and intensity of symptoms, and advocate personalised, holistic treatment of patients' psychological and environmental sensitivities by suggesting the benefits of tailored dietary and stress management. We also call for further research into the complex interplay of environmental, biological and psychological factors influencing FM in order to develop more effective individualised treatments that are capable of enhancing patient care and outcomes.

Treatment of developmental hip dysplasia with manual therapy following Pavlik harness failure: a case report with long-term follow-up.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common musculoskeletal disorder in newborns, ranging from mild dysplasia to complete dislocation. Early detection and intervention are crucial for managing DDH. However, in some cases, standard orthopedic treatments such as the Pavlik harness fail, and alternative approaches are needed. Our study explores the possibility that manual therapy, specifically the Mézières-Bertelè Method (MBM), could be beneficial in cases of DDH that are resistant to conventional treatments. CASE DESCRIPTION: We present a case of a 20-month-old female who had been suffering from persistent DDH (Graf's type IIIC on the left), pain and limping, despite previous conventional treatments, including the Pavlik harness. The patient received daily MBM sessions for six months, followed by maintenance sessions every two months. OUTCOMES: After undergoing the MBM treatment, the patient showed clinical improvements, such as normal neuromotor development and restored hip joint parameters. We observed normal walking and running abilities, and X-ray parameters returned to normal levels. The patient sustained positive outcomes during long-term follow-up until the age of 7. CONCLUSION: The MBM manual therapy was used to treat a challenging case of DDH resistant to conventional treatment. This case report suggests a possible correlation between manual therapy and improved outcomes in resistant DDH and highlights the potential relevance of addressing the inherent musculoskeletal components of the condition.

Treating Dystonia in a Soccer Player Through an Integrated Rehabilitative Approach: A Case Report.

CONTEXT: Sport-related dystonia is a rare form of activity-specific dystonia that can severely impair an athlete's ability to perform. Due to a lack of data on the condition, it is difficult to diagnose and often overlooked, and no gold standard treatment has yet been defined. CASE PRESENTATION: We present a rare and challenging case of sport-related dystonia that affected a 24-year-old male professional soccer player. The patient presented with severe rigidity and dystonia of the right lower-extremity, particularly the ankle and foot. The symptoms set on >1 year prior to the presentation to our outpatient clinic. He began to complain of stiffness and difficulty moving his lower limbs, especially his right leg, initially when playing soccer, but then also when walking normally. On presentation, he was unable to run and walked with difficulty, supporting his body weight only on the outside of his right foot. He also reported a motor trick and reverse motor trick involving the oral musculature in order to move his lower limb more freely. MANAGEMENT AND OUTCOMES: An integrated rehabilitation approach based on postural rehabilitation, neuromuscular rehabilitation, and dental intervention was used to successfully treat this condition. The approach included: (1) postural rehabilitation with the Mézières-Bertelè method to reduce muscular stiffness, (2) neuromuscular re-education with Tai Chi exercises and electromyography-guided biofeedback, and (3) dental intervention and swallowing rehabilitation to limit impaired oral habits (due to the relationship between his impaired lower limb movements and motor tricks of the oral musculature). After 7 months of integrated rehabilitation, the patient returned to professional soccer. CONCLUSIONS: This case report highlights the potential efficacy of an integrative rehabilitation approach for sports dystonia, particularly in cases where traditional treatments may not be effective. Such an approach could be considered a valuable option in the management of this rare, but debilitating, condition in athletes. Further research is needed to assess the effectiveness of this approach in larger populations.

Consideration for alpha-gal syndrome in two critically ill persons with group O blood who received group B plasma.

BACKGROUND: The U.S. Centers for Disease Control and Prevention (CDC) has reported increasing rates of alpha-gal syndrome, an allergic response after meat ingestion (AGS). AGS has been associated with prior exposure to tick bites or other biologics characterized by a life-threatening immunoglobulin E (IgE)-mediated hypersensitivity to galactose-alpha-1,3-galactose (alpha-gal) an oligosaccharide structurally similar to the group B antigen on red blood cells (RBC) found in most non-primate mammalian meat and products derived from these mammals. In 2023, Transfusion reported 3 group O recipients of group B plasma in the Washington, D.C. metropolitan area with no history of meat allergy who had anaphylactic transfusion reactions compatible with AGS. AIMS: We investigated allergic reactions in 2 additional patients who received ABO minor-incompatible blood products at 2 hospitals in the D.C. area during fall 2023. METHODS: For both patients, a medical chart review was performed and IgE levels to alpha-gal were measured. RESULTS: The first patient, a 64-year-old, O-positive patient status post heart transplant with no known allergies, was admitted with acute COVID-19 induced antibody-mediated transplant rejection and placed on extracorporeal membrane oxygenation (ECMO). While undergoing plasma exchange (PLEX) (50% albumin/50% fresh frozen plasma (FFP)), the patient tolerated 2 units of group O FFP and 1 unit of group A FFP before becoming hemodynamically unstable during transfusion of 1 unit of B-positive FFP. PLEX was stopped. The patient later died of sepsis from underlying causes. The second patient, a 57-year-old O-positive man with a history of melanoma and neuro fibromatosis type 1, was undergoing an abdominal resection including transfusion of 3 units of O-positive RBC when he suffered hypotension and ventricular tachycardia requiring intraoperative code after receiving 2 units of group B FFP. Hiveswere noted after resuscitation. The patient had a history of tick bites but no known allergies. He is alive 5 months after the possible allergic event. Both patients had full transfusion reaction evaluations and immunology testing results above the positive cutoff for anti-alpha-gal IgE. DISCUSSION AND CONCLUSION: Two patients with O-positive blood and no known allergies experience danaphyl axis after transfusion with group B FFP. The symptoms cannot definitively be imputed to an allergic transfusion reaction, but the presence of IgE against alpha-gal supports an association. Medicating patients with antihistamines and IV steroids pre-transfusion may prevent allergic reactions. Restricting group B plasma-containing products (plasma, platelets, cryoprecipitate) for patients who experience AGS-like symptoms may be considered.

Fibromyalgia: one year in review 2024.

Fibromyalgia (FM) remains a condition with a pathogenesis that is not completely understood, affecting a significant portion of the global population. This article summarises the main advances in FM during the last year. Even in 2023, research on FM was notably active. From a clinimetric perspective, studies have been conducted to evaluate the possibilities of interchanging the primary indices of disease severity, primarily for studies with substantial case numbers. Regarding FM pathogenesis, ongoing research focuses on small fiber neuropathy: some studies have documented its association with central sensitisation, while others have revealed distinct sensory profiles in patients with FM and small fiber neuropathy compared to those solely with small fiber neuropathy. Dorsal root ganglia seem to play a crucial role in the pathogenesis of FM as they host satellite glial cells, which are targeted by pain-driving immunoglobulin G. These antibodies have been identified in a subset of patients exhibiting high symptom severity. An important study conducted on animal models confirmed the role of neuroinflammation at the level of dorsal root ganglia, in this case mediated by polymorphonuclear neutrophils. Mounting evidence underscores the link between COVID-19 and the persistence of FM symptoms after recovery. In identifying potential biomarkers aiding FM diagnosis, research has also concentrated on studying the expression of specific circulating microRNAs. Recent discoveries have unveiled novel therapeutic strategies for FM, especially focused in non-pharmacological interventions. This includes a focus on non-invasive brain stimulation and exercise programs, all directed towards relieving symptoms and improving functionality in individuals affected by the condition.

Relationship between inflammatory laboratory parameters and severity of adolescent idiopathic scoliosis: A pilot study.

BACKGROUND: Adolescent idiopathic scoliosis is a complex condition whose pathogenesis may include inflammation and signs of joint and bone degeneration. OBJECTIVE: The main objective of this study is to evaluate the relationship between the severity of adolescent idiopathic scoliosis and inflammatory blood parameters. METHODS: The study recruited patients with adolescent idiopathic scoliosis who attended the Rehabilitation Center of the Apostolo Foundation in Merate (LC). The scoliosis curve (Cobb's angle) was used as a severity index to compare with inflammatory blood parameters (white blood cells subpopulations, immunoglobulins, protein electrophoresis). In addition, the study used an overall severity grading called "Scoliosis Score" which includes all spine angles and Risser's score (bone development index). RESULTS: Thirty-four subjects were recruited (mean age 14 years, 2 months), 30 females and 2 males. A significant correlation was found between Cobb's angle and the percentage values of beta-2 globulins in a directly proportional manner (r= 0.42, p= 0.01), and gamma globulins in an inversely proportional manner (r=-0.366, p= 0.04). However, no significant correlation between Cobb's angle and the absolute values of white blood cells and percentage subpopulations was found (r= 0.0821 p= 0.655). A moderate, inverse correlation was found between the Scoliosis Score and the percentage of neutrophils (r=-0.385, p= 0.02), a direct correlation was found between the Scoliosis Score and the percentage of lymphocytes (r= 0.404, p= 0.02). In addition, there was a strong correlation of the Scoliosis Score with alpha-2 globulin (r= 0.564, p= 0.0012), beta-1 globulin (r= 0.478, p= 0.0074), and beta-2 globulin (r= 0.370, p= 0.044) and an inverse relationship with gamma globulin (r=-0.625, p= 0.0002). The main correlations were confirmed by regression analysis. CONCLUSION: The correlation between beta-2 globulins and gamma globulins with Cobb's angle and the Scoliosis Score suggests a link between spinal curvature and inflammation in scoliosis patients, This link may indicate the significance of these parameters for diagnosing, staging the disease, and monitoring therapies.

Reprint of "Residual pain in rheumatoid arthritis: Is it a real problem?"

Pain is a significant issue in rheumatoid arthritis (RA) and can have a negative impact on patients' quality of life. Despite optimal control of inflammatory disease, residual chronic pain remains a major unmet medical need in RA. Pain in RA can be secondary to inflammation but can also generate neuroendocrine responses that initiate neurogenic inflammation and enhance cytokine release, leading to persistent hyperalgesia. In addition to well-known cytokines such as TNFα and IL-6, other cytokines and the JAK-STAT pathway play a role in pain modulation and inflammation. The development of chronic pain in RA involves processes beyond inflammation or structural damage. Residual pain is often observed in patients even after achieving remission or low disease activity, suggesting the involvement of non-inflammatory and central sensitization mechanisms. Moreover, fibromyalgia syndrome (FMS) is prevalent in RA patients and may contribute to persistent pain. Factors such as depression, sleep disturbance, and pro-inflammatory cytokines may contribute to the development of fibromyalgia in RA. It is essential to identify and diagnose concomitant FMS in RA patients to better manage their symptoms. Further research is needed to unravel the complexities of pain in RA. Finally, recent studies have shown that JAK inhibitors effectively reduce residual pain in RA patients, suggesting pain-reducing effects independent of their anti-inflammatory properties.

Feldenkrais awareness though movement intervention for fibromyalgia syndrome: A proof-of-concept study.

INTRODUCTION: The Feldenkrais Method® is a form of awareness through movement (ATM) aimed at improving spatial and kinesthetic awareness through verbally guided movements, in order to learn more effective actions. METHOD: The present study, a proof-of-concept, observational, non-controlled prospective study, aims at exploring the effectiveness of ATM for fibromyalgia syndrome (FM), measuring the effect by means of multi-dimensional questionnaires, administered at baseline and after 4 months of ATM activity. RESULTS: One hundred twenty-eight FM patients (mean age 54 years old, 2% males) participated in the study. A statistically significant improvement was found in FM-specific measures (Polysymptomatic Distress Scale, PDS) (p = 0.003) and the Pain Catastrophization Scale (PCS) (p = 0.020); coherently, the Revised Fibromyalgia Impact Questionnaire (FIQR) showed a trend in improvement after the intervention, although this improvement was not statistically significant. The logistic regression analysis found a correlation between PDS, fatigue and anxiety measures; PCS, years from diagnosis and anxiety. CONCLUSION: ATM could improve FM-specific measures and pain-related catastrophizing. Further studies are needed to identify FM subgroups in order to find personalized targets that can be used to guide treatments.

Inflammatory signaling in NASH driven by hepatocyte mitochondrial dysfunctions.

Liver steatosis, inflammation, and variable degrees of fibrosis are the pathological manifestations of nonalcoholic steatohepatitis (NASH), an aggressive presentation of the most prevalent chronic liver disease in the Western world known as nonalcoholic fatty liver (NAFL). Mitochondrial hepatocyte dysfunction is a primary event that triggers inflammation, affecting Kupffer and hepatic stellate cell behaviour. Here, we consider the role of impaired mitochondrial function caused by lipotoxicity during oxidative stress in hepatocytes. Dysfunction in oxidative phosphorylation and mitochondrial ROS production cause the release of damage-associated molecular patterns from dying hepatocytes, leading to activation of innate immunity and trans-differentiation of hepatic stellate cells, thereby driving fibrosis in NASH.

The prospect of universal coronavirus immunity: characterization of reciprocal and non-reciprocal T cell responses against SARS-CoV2 and common human coronaviruses.

T cell immunity plays a central role in clinical outcomes of Coronavirus Infectious Disease 2019 (COVID-19) and T cell-focused vaccination or cellular immunotherapy might provide enhanced protection for some immunocompromised patients. Pre-existing T cell memory recognizing SARS-CoV-2 antigens antedating COVID-19 infection or vaccination, may have developed as an imprint of prior infections with endemic non-SARS human coronaviruses (hCoVs) OC43, HKU1, 229E, NL63, pathogens of "common cold". In turn, SARS-CoV-2-primed T cells may recognize emerging variants or other hCoV viruses and modulate the course of subsequent hCoV infections. Cross-immunity between hCoVs and SARS-CoV-2 has not been well characterized. Here, we systematically investigated T cell responses against the immunodominant SARS-CoV-2 spike, nucleocapsid and membrane proteins and corresponding antigens from α- and ß-hCoVs among vaccinated, convalescent, and unexposed subjects. Broad T cell immunity against all tested SARS-CoV-2 antigens emerged in COVID-19 survivors. In convalescent and in vaccinated individuals, SARS-CoV-2 spike-specific T cells reliably recognized most SARS-CoV-2 variants, however cross-reactivity against the omicron variant was reduced by approximately 47%. Responses against spike, nucleocapsid and membrane antigens from endemic hCoVs were significantly more extensive in COVID-19 survivors than in unexposed subjects and displayed cross-reactivity between α- and ß-hCoVs. In some, non-SARS hCoV-specific T cells demonstrated a prominent non-reciprocal cross-reactivity with SARS-CoV-2 antigens, whereas a distinct anti-SARS-CoV-2 immunological repertoire emerged post-COVID-19, with relatively limited cross-recognition of non-SARS hCoVs. Based on this cross-reactivity pattern, we established a strategy for in-vitro expansion of universal anti-hCoV T cells for adoptive immunotherapy. Overall, these results have implications for the future design of universal vaccines and cell-based immune therapies against SARS- and non-SARS-CoVs.

Residual pain in rheumatoid arthritis: Is it a real problem?

Pain is a significant issue in rheumatoid arthritis (RA) and can have a negative impact on patients' quality of life. Despite optimal control of inflammatory disease, residual chronic pain remains a major unmet medical need in RA. Pain in RA can be secondary to inflammation but can also generate neuroendocrine responses that initiate neurogenic inflammation and enhance cytokine release, leading to persistent hyperalgesia. In addition to well-known cytokines such as TNFα and IL-6, other cytokines and the JAK-STAT pathway play a role in pain modulation and inflammation. The development of chronic pain in RA involves processes beyond inflammation or structural damage. Residual pain is often observed in patients even after achieving remission or low disease activity, suggesting the involvement of non-inflammatory and central sensitization mechanisms. Moreover, fibromyalgia syndrome (FMS) is prevalent in RA patients and may contribute to persistent pain. Factors such as depression, sleep disturbance, and pro-inflammatory cytokines may contribute to the development of fibromyalgia in RA. It is essential to identify and diagnose concomitant FMS in RA patients to better manage their symptoms. Further research is needed to unravel the complexities of pain in RA. Finally, recent studies have shown that JAK inhibitors effectively reduce residual pain in RA patients, suggesting pain-reducing effects independent of their anti-inflammatory properties.

Case Report: Kinetics and durability of humoral and cellular response of SARS-CoV-2 messenger RNA vaccine in a lung and kidney transplant recipient.

We present a case report of a 63-year-old female health care worker who is 15 years status post double lung transplant and six years status post living related donor kidney transplant who is healthy on a chronic immunosuppression regimen including prednisone, mycophenolate, and tacrolimus who received the SARS-CoV-2 mRNA vaccine (Pfizer-BioNTech BNT162b2) primary series and had poor initial humoral response to the COVID-19 mRNA vaccine, then demonstrated a robust, sustained immune response against S1 and S2 antigens for over seven months after receiving the recommended vaccine doses, including booster dose, without developing COVID-19 or other serious adverse events. Her immune response to vaccination indicates effective formation of anti-spike T cell memory despite chronic immunosuppression. This case report provides a comprehensive characterization of her immune response to this SARS-CoV-2 vaccination series. As vaccine effectiveness data is updated, and as better understanding of immune response including hybrid immunity emerges, these findings may reassure that recipients of SOTs may be capable of durable immune responses to emerging variants of SARS-CoV-2.

Is psyche-soma dichotomy still clinically appropriate?

This article proposes a historical recontextualisation of the mind-body relationship and offers some evidence-based reflections on the current clinical appropriateness of psyche-soma dichotomy and psychosomatics. The debate concerning the mind-body relationship has a long medical, philosophical, and religious history, with psyche-soma dichotomy and psychosomatics alternating as the dominant clinical approach, depending on the prevalence of cultural orientations at different times. However, both models simultaneously benefit and limit the clinical practice.The neurosciences have reduced the gap between psyche and soma diseases, which can now be seen as overlapping and sharing a common pathogenesis. Diseases should also be considered as illnesses by considering all of their biopsychosocial aspects to avoid therapeutic failures due to only partially effective or ineffective interventions. Patient-centred care integrated with guideline recommendations may be the best means of uniting the psyche and the soma.

Fibromyalgia: one year in review 2023.

Fibromyalgia (FM) is a chronic syndrome characterised by widespread pain that affects millions of people worldwide. This article discusses various aspects of FM described in scientific papers published in 2022 and indexed in the PubMed database, including the most recent diagnostic acquisitions (especially in relation to the juvenile form of FM), risk factors, co-morbidities and objective measures. Emphasis is placed on the importance of identifying FM early and improving diagnostic methods (e.g. physical measurements, including walking test performance, hand grip force, and autonomic tests). The article also considers hypotheses concerning the pathophysiology of FM, including the role of inflammation, gut dysbiosis, and neuroinflammation, and possible treatment options, including medications such as antioxidants and kinin antagonists, neurostimulation, and mind-body interventions. Although ketamine, vitamin D, and hormone therapy have shown promise in reducing FM symptoms, further research is needed to optimise their use. Neurostimulation techniques, such as transcutaneous electrical nerve stimulation, transcranial direct-current stimulation and transcranial magnetic stimulation, have been investigated in terms of their efficacy in reducing pain and improving the quality of life. Finally, the role of nutrition is discussed as study findings suggest that weight control, modified high-antioxidant diets, and nutritional supplementation can help to alleviate the symptoms of FM.

Peripheral B cells from patients with hepatitis C virus-associated lymphoma exhibit clonal expansion and an anergic-like transcriptional profile.

Chronic HCV infection remains a global health concern due to its involvement in hepatic and extrahepatic diseases, including B cell non-Hodgkin lymphoma (BNHL). Clinical and epidemiological evidence support a causal role for HCV in BNHL development, although mechanistic insight is lacking. We performed RNA-sequencing on peripheral B cells from patients with HCV alone, BNHL alone, and HCV-associated BNHL to identify unique and shared transcriptional profiles associated with transformation. In patients with HCV-associated BNHL, we observed the enrichment of an anergic-like gene signature and evidence of clonal expansion that was correlated with the expression of epigenetic regulatory genes. Our data support a role for viral-mediated clonal expansion of anergic-like B cells in HCV-associated BNHL development and suggest epigenetic dysregulation as a potential mechanism driving expansion. We propose epigenetic mechanisms may be involved in both HCV-associated lymphoma and regulation of B cell anergy, representing an attractive target for clinical interventions.

The prospect of universal coronavirus immunity: a characterization of reciprocal and non-reciprocal T cell responses against SARS-CoV2 and common human coronaviruses.

T cell immunity plays a central role in clinical outcomes of Coronavirus Infectious Disease 2019 (COVID-19). Therefore, T cell-focused vaccination or cellular immunotherapy might provide enhanced protection for immunocompromised patients. Pre-existing T cell memory recognizing SARS-CoV2 antigens antedating COVID-19 infection or vaccination, may have developed as an imprint of prior infections with endemic non-SARS human coronaviruses (hCoVs) OC43, HKU1, 229E, NL63, pathogens of "common cold". In turn, SARS-CoV2-primed T cells may recognize emerging variants or other hCoV viruses and modulate the course of subsequent hCoV infections. Cross-immunity between hCoVs and SARS-CoV2 has not been well characterized. Here, we systematically investigated T cell responses against the immunodominant SARS-CoV2 spike, nucleocapsid and membrane proteins and corresponding antigens from α- and ß-hCoVs among vaccinated, convalescent, and unexposed subjects. Broad T cell immunity against all tested SARS-CoV2 antigens emerged in COVID-19 survivors. In convalescent and in vaccinated individuals, SARS-CoV2 spike-specific T cells reliably recognized most SARS-CoV2 variants, however cross-reactivity against the omicron variant was reduced by approximately 50%. Responses against spike, nucleocapsid and membrane antigens from endemic hCoVs were more extensive in COVID-19 survivors than in unexposed subjects and displayed cross-reactivity between α- and ß-hCoVs. In some, non-SARS hCoVspecific T cells demonstrated a prominent non-reciprocal cross-reactivity with SARS-CoV2 antigens, whereas a distinct anti-SARS-CoV2 immunological repertoire emerged post-COVID-19, with relatively limited cross-recognition of non-SARS hCoVs. Based on this cross-reactivity pattern, we established a strategy for in-vitro expansion of universal anti-hCoV T cells for adoptive immunotherapy. Overall, these results have implications for the future design of universal vaccines and cell-based immune therapies against SARS- and non-SARS-CoVs.