Behçet disease: From pathogenesis to novel therapeutic options.

Behçet disease (BD) is a complex, multi-systemic inflammatory condition mainly hallmarked by oral and genital ulcers which can also affect the vessels, gastrointestinal tract, central nervous system and even the axial skeleton. Without a clear classification among autoimmune or autoinflammatory conditions, BD has been recently classified as a MHC-I-opathy. BD aetiology is still obscure, but it is thought that certain microorganisms can elicit an aberrant adaptive immune response in the presence of a permissive genetic background. Altered T-cell homeostasis, mostly Th1/Th17 expansion and Treg impairment, could lead to an overactivation of the innate immunity, which underlies tissue damage and thus, signs and symptoms. Immunosuppression and/or immunomodulation are central to the BD management. A complex armamentarium ranging from classical synthetic disease-modifying antirrheumatic drugs to new-era biologic agents or small molecules is available in BD, with different therapeutic outcomes depending on disease manifestations. However, the precise disease mechanisms that underlie BD symptoms are not fully deciphered, which may limit their therapeutic potential and add a significant layer of complexity to the treatment decision-making process. The aim of the present review is to provide an exhaustive overview of the latest breakthroughs in BD pathogenesis and therapeutic options.

One year in review 2021: fibromyalgia.

Fibromyalgia (FM) is a syndrome of unknown aetiology characterised by chronic pain, fatigue, and disturbed sleep. This review presents and summarises the 2020 literature on FM by retrieving all articles indexed in PubMed between 1 January 2020 and 31 December 2020. The attention of the scientific community towards FM is constantly growing, and this year's review is focused on the diagnostic, pathogenetic and therapeutic aspects of this syndrome. In particular, the treatment options for FM, both pharmacological and non-pharmacological, have been extensively studied.

Hyperbaric oxygen therapy in fibromyalgia and the diseases involving the central nervous system.

OBJECTIVES: This paper briefly describes the therapeutic mechanisms underlying hyperbaric oxygen therapy (HBOT), and reviews data concerning its effects and efficacy in Parkinson's disease (PD) and fibromyalgia (FM). METHODS: The studies included in this review all evaluated the effect of HBOT in patients with diseases involving CNS. The PubMed databases were searched from 1980 to September 2019 using the keywords: 'hyperbaric oxygen therapy', 'fibromyalgia' and 'Parkinson's disease'. RESULTS: HBOT is already indicated in various diseases and is the subject of continuous research and development. Data from models of PD show that it may play a neuroprotective role because of its ability to reduce oxidative stress and neurodegeneration, and protect against neuronal apoptosis. It is effective in improving the symptoms and quality of life of fibromyalgia patients, and rectifies abnormal brain activity in pain-related areas. Evidence from animal studies supports its use as an alternative treatment for other rheumatic diseases as it alleviates pain and reduces inflammation. CONCLUSIONS: Data mainly from animal studies support the use of HBOT in the treatment of PD and rheumatic diseases, but further work is necessary to clarify its therapeutic role in patients with these chronic disorders.

Psoriatic arthritis: From pathogenesis to pharmacologic management.

The pathogenesis of psoriatic arthritis (PSA) is still a matter of debate. A favourable genetic background is interwoven with environmental triggering factors in a complex network. Shared antigens and the recirculation of immune cells may account for the clinical manifestations, involving both cutaneous and articular sites. A favourable genetic background has been demonstrated in many genomic and proteomic studies, being associated to polymorphic variants of the genes coding for Major Histocompatibility Complex I and cytokine pathways. In genetic-predisposed individuals, triggering factors, like infections, dysbiosis or mechanic stress may promote the development of the disease. The subsequent activation of the innate and adaptive immune system, following the stimulation of Toll-like Receptors, culminates in the expansion of dendritic cells, macrophages, CD4+ and CD8+ T cells, neutrophils, monocytes, Natural Killer lymphocytes and other cells with the final inflammation and damage of skin, joint and enthesis. Particularly, the activation of CD4+ T helper 17 lymphocytes represents a crucial point in the pathogenesis of the disease. The participation of the visceral adipose tissue may amplify the inflammatory process by means of the synthesis of pro-inflammatory adipokines. Current therapeutic algorithms address the variety of clinical manifestations with a tailored strategy aiming to achieve the best control of the symptoms with minimal side effects. Conventional immunosuppressive drugs, biologic agents and synthetic small molecules offer different attack routes and may be chosen individually or in combination according to the phenotype of the disease.

Il-6 Involvement in pain, fatigue and mood disorders in rheumatoid arthritis and the effects of Il-6 inhibitor sarilumab.

Interleukin 6 (IL-6) is a pleiotropic cytokine that plays a role in the neuroendocrine system, insulin resistance, lipid metabolism, vascular disease, mitochondrial activities, neuropsychological behaviour, and also mediates communications between the immune and central nervous system (CNS). Treatment with anti-IL-6 or anti-IL-6R agents seems to alleviate allodynia and hyperalgesia, so it may be a valid option when treating the many conditions involving pathological pain as rheumatoid arthritis.

Hyperbaric oxygen treatment of fibromyalgia: a prospective observational clinical study.

OBJECTIVES: Fibromyalgia (FM) is a syndrome of unknown aetiology that is characterised by widespread musculoskeletal pain, fatigue and disordered sleep, and often associated with neuropsychiatric and cognitive symptoms. Current treatment options are only partially effective, but hyperbaric oxygen therapy (HBOT) seems to be capable of relieving some of the symptoms. The aim of this study was to evaluate the efficacy and safety of HBOT after fewer sessions than generally used, chosen on the basis of pre-clinical and clinical data showing its rapid and sustained antinociceptive effect. METHODS: Patients with FM underwent HBOT (100% oxygen at 2.5 ata with air breaks) administered on three days per week for a total of twenty 90-minute sessions. Pain, fatigue, the quality of sleep, symptoms of anxiety and depression, and the patients' health-related quality of life were prospectively assessed before and after ten and twenty sessions. RESULTS: Twenty-eight of the 32 study patients completed the 20 HBOT sessions. Pain scores and the symptoms of anxiety (but not those of depression) significantly improved after both 10 and 20 sessions, whereas fatigue and FM symptom severity scores significantly improved only after 20 sessions. There was no significant change in the quality of sleep. The adverse effects were limited. CONCLUSIONS: These findings support the view that HBOT is an effective, rapid and safe means of treating various symptoms of FM.

One year in review 2019: fibromyalgia.

Fibromyalgia is characterised by chronic pain, fatigue and functional symptoms. Its aetiopathogenesis is still a matter of debate, but various pharmacological and non-pharmacological therapies are currently available for its treatment. We review the literature concerning the most recent findings related to the aetiopathogenesis, diagnosis, clinical aspects and treatment of FM published between January 2018 and January 2019.

Infections in rheumatoid arthritis.

PURPOSE OF REVIEW: The purpose of this review is to provide an update concerning recent advances in the evidence- based study of serious infections in patients with rheumatoid arthritis (RA) treated with biological drugs or conventional disease-modifying antirheumatic drugs (DMARDs), concentrating on studies published in the last 18 months. RECENT FINDINGS: New studies have further strengthened existing evidence relating the use of biological drugs to serious infections. The risk does not seem to be any different with short-term or long-term use. There is still a lack of conclusive studies identifying biomarkers, but it is plausible that the drugs have direct effects on cytokines and cell activity and then serious infections. SUMMARY: The frequent infections of patients with RA may be due to the disease itself (altered immunological function, disability, immobility, joint surgery), extra-articular manifestations or DMARDs, immunosuppressants and steroids. The use of biological drugs lead to the development of serious infections including tuberculosis. Patients should be informed of their increased risk, and physicians need to be aware of these complications and how to treat them.

An update on emerging drugs for fibromyalgia treatment.

INTRODUCTION: Fibromyalgia (FM) is a chronic disorder whose symptoms of pain, fatigue, sleep disturbances and depression have a devastating effect on patients' lives as it limits their ability to engage in everyday working and social activities, and make it difficult to maintain normal relationships with family, friends and employers. None of the currently available drugs are fully effective against the whole spectrum of symptoms. The aim of this narrative review is to summarise the data relating to the new therapeutic options that have become available over the last few years. Areas covered: Increasing efforts by the pharmaceutical industry have led to the introduction of new investigational drugs and new formulations of older drugs, and studies have been carried out in order to investigate the possibility of using drugs that are currently used for other diseases. Expert opinion: Slight improvements in the health of FM patients treated with drugs targeting a range of molecular mechanisms have been observed, but there is still no single drug that is capable of offering substantial efficacy against all of the characteristic symptoms of FM. The identification of new and improved therapies for FM requires consideration of the heterogeneity of the condition, which suggests the existence of different patient subgroups, a relationship between central and peripheral aspects of the pathophysiology, and the need for combined treatment with drugs targeting multiple molecular mechanisms.

Acute and chronic pain in orthopaedic and rheumatologic diseases: mechanisms and characteristics.

Pain is one of the most frequent clinical symptoms encountered by orthopaedic surgeons and rheumatologists as it is one of the main reasons for patients seeking medical help. Traumas and/or inflammatory rheumatologic diseases give rise to two different types of acute pain, but their chronic evolution is so similar that they both need to be treated as early as possible. It is now widely accepted that chronic pain is a disease per se, and that its location may be less important than the way in which it is perceived by people suffering from it. Consequently, its pharmacological and non-pharmacological treatment should be based on its specific characteristics, other disease-related factors, the ability of patients to cope with it, and the way in which they live their lives.

Influence of autonomic nervous system dysfunction in the genesis of sleep disorders in fibromyalgia patients.

OBJECTIVES: Fibromyalgia (FM) is characterised by chronic musculoskeletal pain, autonomic nervous system (ANS) dysfunction, and disturbed sleep. The aim of this study was to evaluate the influence of ANS dysfunction on the genesis of sleep disorders. METHODS: Fifty female FM patients and 45 healthy subjects matched for age, gender and body mass index underwent a clinical, polysomnographic and autonomic profile evaluation at rest and during a tilt test in order to determine muscle sympathetic nerve activity (MSNA), plasma catecholamine levels, and the spectral indices of cardiac sympathetic (LFRR) and vagal (HFRR) modulation computed by means of the spectrum analysis of RR during sleep. RESULTS: The FM patients had a higher heart rate (HR), more MSNA and a higher LF/HF ratio, and lower HFRR values at rest (p<0.05), and showed no increase in MSNA, a smaller decrease in HFRR, and an excessive rate of syncope (46%) during the tilt test. Their sleep was less efficient (p<0.01), and they had a higher proportion of stage 1 non-REM sleep (p<0.001), experienced many arousals and periodic limb movements (PLMs) per hour of sleep (p<0.001) and a high proportion of periodic breathing (PB%) (p<0.0001). Their cyclic alternating pattern (CAP) rate was significantly increased (p<0.001). During sleep, they had a higher HR and LF/HF ratio, and a lower HFRR (p<0.001). The number of tender points, CAP rate, PB% and PLMI correlated positively with HR and the LF/HF ratio, and negatively with HFRR during sleep. CONCLUSIONS: Our findings seem to show that sleep causes the same effects as a stressful test in FM patients. A vicious circle is created during sleep: pain increases sympathetic cardiovascular activation and reduces sleep efficiency, thus causing lighter sleep, a higher CAP rate, more arousals, a higher PLMI, and increasing the occurrence of PB, which gives rise to abnormal cardiovascular neural control and exaggerated pain sensitivity.

Impaired lung transfer factor in fibromyalgia syndrome.

OBJECTIVES: The aim of this study was to evaluate whether pulmonary diffusing capacity is impaired in patients with fibromyalgia (FM) as it is in those with other diseases characterised by autonomic nerve system (ANS) dysfunction such as type 1 diabetes. METHODS: Forty-five consecutive anti-nuclear antibody (ANA)-negative female Caucasian patients aged 50.1± 5.6 years with FM and compared with 45 healthy female control volunteers matched in terms of age and body mass index (BMI). The autonomic function has been evaluated by means of standard electrocardiography (ECG), finger blood pressure respiration, and muscle sympathetic nerve activity (MSNA) at rest and during a stepwise tilt test up to 75°. Their autonomic profiles were drawn up on the basis of MSNA, plasma catecholamine levels, and spectral indices of cardiac sympathetic and vagal modulation, and sympathetic vasomotor control computed by means of the spectrum analysis of RR and systolic arterial pressure (SAP) variability. Lung volumes and dynamic spirometry parameters were assessed by means of plethysmography. All of the patients were clinically evaluated and completed the FQI and COMPASS questionnaire. RESULTS: There was no difference in lung volumes between the FM patients and healthy controls, but DLCO (83±4 vs. 96±5; p<0.001), Kco (84±5 vs 98±5; p<0.001), DM (12.7±2.4 vs 13.6±1.8; p<0.05) and Vc (48±3.9 vs 65±7; p<0.001) were significantly reduced in the patients. The COMPASS-31, RCS and pain VAS scores significantly correlated with DLCO, Kco and Vc with the correlation being particularly close in the case of Vc. Furthermore, univariate Cox proportional hazard analysis showed that the three scores were all significantly associated with an increased risk of impaired DLCO (respectively, χ(2) 16.21, p<0.0005; χ(2) 7.09, p<0.005; χ(2) 6.37, p<0.01). CONCLUSIONS: FM impairs DLCO mainly as a result of a reduction in Vc, and that this defect is inversely proportional to the severity of the dysfunction suggesting a relationship between impaired DLCO and autonomic nerve dysfunction.

Frequency of Renal Function Parameter Abnormalities in Patients with Psoriatic Arthritis and Rheumatoid Arthritis: Real-World Evidence from Clinical Practice.

OBJECTIVE: Patients with psoriatic arthritis (PsA) or rheumatoid arthritis (RA) commonly develop renal dysfunction due to either systemic inflammation or drug-related nephrotoxicity. This study compared renal function parameters in patients with PsA versus those with RA and examined the impact of clinical remission or disease relapse on renal function. METHODS: This single-center retrospective study was conducted at the University Hospital of Messina, Italy. Adult patients (aged ≥18 years) with PsA or RA who attended the rheumatology clinic within the past 6 months were identified from electronic medical records. RESULTS: In total, 45 patients with PsA (n = 23) or RA (n = 22) were included. The mean (standard deviation) age was 55.6 (15.9) years, and 78% of participants were female. Patient age, renal function, and medical history were generally similar between the two disease groups, although significantly more RA patients were smokers, and more PsA patients had comorbid hypertension. The prevalence of estimated glomerular filtration rate [eGFR] ≤90 mL/min/1.73 m2 at 1, 6, and 12 months of treatment ranged from 38.5% to 58.3% in the PsA group and from 45.5% to 54.5% in the RA group and did not significantly differ between disease groups. Clinical remission did not appear to affect renal function parameters in either disease group; however, relapse was associated with significantly higher serum creatinine levels in PsA patients at the same timepoint. CONCLUSION: In this study, patients with PsA and RA had a similar prevalence of renal function parameter abnormalities over 12 months of treatment. Disease relapse may impact renal function in patients with PsA.

IL-23 in axial spondyloarthritis and psoriatic arthritis: a good fit for biological treatment?

INTRODUCTION: Interleukin 23 (IL-23) is a pro-inflammatory cytokine that plays a protective role against bacterial and fungal infections. However, the dysregulation of the IL-23/IL-17 axis provides a solid substrate for the development of various inflammatory diseases, such as psoriatic arthritis (PsA) and ankylosing spondylitis (AS). AREAS COVERED: In different clinical trials, several drugs against IL-23 have shown efficacy and safety toward PsA, with excellent results on skin and joint scores. However, the same drugs did not show the same efficacy in AS, suggesting that IL-23 may not be a relevant driver of the pathobiology and clinical symptoms of active axial spondyloarthritis (axSpA). EXPERT OPINION: These drugs have shown an excellent efficacy and a good safety profile toward PsA, while in AS the efficacy of the IL-23 blockade is lacking for reasons not yet known. Several hypotheses have been reported, but further studies will be needed for a greater understanding. This suggests the involvement of pathways or mechanisms for the development of SpA that remain unknown. In order to allow a wide use of IL-23 inhibitors, further clinical trials and long-term prospective studies are necessary.

Effect of biological DMARDs and JAK inhibitors in pain of chronic inflammatory arthritis.

INTRODUCTION: The advent of biological disease-modifying anti-rheumatic drugs (bDMARDs) and, more recently, of Janus kinase inhibitors (JAKi) has had a major impact on the long-term outcomes of chronic inflammatory arthritis (IA). However, the persistence of pain, even in patients with a complete pharmacological control of peripheral inflammation, represents an important clinical challenge in the treatment of IA. AREAS COVERED: In this review, we provide an overview of possible mechanisms underlying pain in IA and its assessment, as well as the effects of bDMARDs and JAKi on pain management. EXPERT OPINION: The overall data showed a good effect of bDMARDs and JAKi on pain, which is more pronounced for JAKi. However, it is challenging to distinguish the effect on the different types of pain (nociceptive, neuropathic, and nociplastic).

Differences in depression, anxiety and stress disorders between fibromyalgia associated with rheumatoid arthritis and primary fibromyalgia.

Fibromyalgia (FM) was frequently observed in patients with rheumatoid arthritis (RA). We aimed to evaluate the differences in psychiatric comorbidities and life adversities between patients with Rheumatoid arthritis + FM (secondary fibromyalgia [SFM]) and people with primary FM (PFM). In a cross-sectional, observational study, patients with PFM and SFM underwent a structured interview for the lifetime diagnosis of major depression (MDD), panic disorder (PD) and post-traumatic stress disorder (PTSD) and were assessed for childhood/adulthood adversities and FM-related symptoms severity. Thirty patients with PFM and 40 with SFM were recruited. The univariate analysis showed that the lifetime rates of MDD were significantly higher in PFM versus SFM (76.7 % and 40%, respectively, p < 0.003), as well as the rates of PD (50 % and 15%, respectively, p < 0.003), whereas there was no difference in PTSD rates. The rates of sexual abuse and physical neglect were significantly higher in PFM patients versus SFM patients (p < 0.005 and p < 0.023). Life events occurring before FM onset were different in PFM and SFM groups. In the logistic regression model, lifetime PD and physical neglect remain independent risk factors for PFM. PFM and SFM differ in psychiatric comorbidities and environmental adversities, suggesting that common pathogenesis may develop through different pathways.

The effect of drugs used in rheumatology for treating SARS-CoV2 infection.

INTRODUCTION: SARS-CoV-2 is a novel coronavirus that was first isolated from a group of patients hospitalized with pneumonia in China at the end of 2019, and, in February 2020, the syndrome it caused was named coronavirus disease 2019 (COVID-19) by the World Health Organization. In the absence of specific antiviral treatments capable of neutralizing the etiological agent, one therapeutic approach is to control the cytokine storm responsible for the most severe forms of the disease. The characteristic cytokine profile of severely affected patients is increased levels of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor alpha (TNF-α). AREAS COVERED: This article discusses the pathogenesis of COVID-19 as a rationale for using the biological and targeted synthetic drugs used in rheumatology (anti-TNF, anti-IL-1 and anti-IL-6 agents and baricitinib) to treat the disease, and provides key information concerning their potential benefits and adverse effects. EXPERT OPINION: Interleukin inhibition seems to be a promising means of treating COVID-19 patients when respiratory function declines (or even earlier) if there are laboratory data indicating the presence of a cytokine storm because the interleukins are key drivers of inflammation. However, it is important to consider the risks and benefits of biological agents carefully, and critically analyze the evidence concerning their use in COVID-19 patients.

The Rheumatology Drugs for COVID-19 Management: Which and When?

INTRODUCTION: While waiting for the development of specific antiviral therapies and vaccines to effectively neutralize the SARS-CoV2, a relevant therapeutic strategy is to counteract the hyperinflammatory status, characterized by an increase mainly of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, and tumor necrosis factor (TNF)-α, which hallmarks the most severe clinical cases. 'Repurposing' immunomodulatory drugs and applying clinical management approved for rheumatic diseases represents a game-changer option. In this article, we will review the drugs that have indication in patients with COVID-19, including corticosteroids, antimalarials, anti-TNF, anti-IL-1, anti-IL-6, baricitinib, intravenous immunoglobulins, and colchicine. The PubMed, Medline, and Cochrane Library databases were searched for English-language papers concerning COVID-19 treatment published between January 2020 and October 2020. Results were summarized as a narrative review due to large heterogeneity among studies. In the absence of specific treatments, the use of immunomodulatory drugs could be advisable in severe COVID-19 patients, but clinical outcomes are still suboptimal. An early detection and treatment of the complications combined with a multidisciplinary approach could allow a better recovery of these patients.

Differences between diffuse idiopathic skeletal hyperostosis and spondyloarthritis.

Diffuse idiopathic skeletal hyperostosis (DISH) is a skeletal syndrome that has been known for more than 70 years. Yet, its pathogenesis and treatment options are still under investigation. DISH and spondyloarthritidies may manifest itself clinically as very similar disorders causing impaired axial flexibility, axial pain and peripheral tendinopathies. On the other hand, these two processes are different in many ways, from different genetic and metabolic predispositions, to different clinical and imaging manifestations, and at last, a different attitude toward treatment. The knowledge of the similarities and differences between DISH and spondyloarthritidies can guide the clinician toward a better diagnostic and treatment approach. This review tries to emphasize these details.