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).

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.

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.

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.

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.

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.

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.

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.

Toxicological considerations in the treatment of axial spondylo-arthritis.

INTRODUCTION: The first-line treatment of axial spondyloarthritis (SpA) is with non-steroidal anti-inflammatory drugs (NSAIDs) and is followed by tumor necrosis factor (TNF) inhibitors (the main treatment for patients not responding to NSAIDs) or drugs targetting the IL-23/IL-17 pathway. The efficacy of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and sulfasalazine (SSZ) has not been demonstrated, although SSZ can be considered in patients with concomitant peripheral arthritis. AREAS COVERED: This review describes the beneficial and toxicological effects of the drugs used to treat axial SpA. EXPERT COMMENTARY: Growing concerns about the safety of anti-TNF drugs underline the need to ensure that all clinicians are capable of taking appropriate preventive action and adequately treating affected 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.

Concerns about the safety of anti-TNF agents when treating rheumatic diseases.

INTRODUCTION: More than 15 years after its introduction, there is still no agreement as to whether anti-TNF treatment increases the risk of developing infections, cardiovascular or neurological diseases, or auto-antibodies. Anti-TNF drugs reduce inflammation and sub-clinical atherosclerosis in rheumatoid arthritis (RA) patients, but they also alter their lipid profiles and can lead to the development of severe infections. Furthermore, as they increase the risk of developing demyelinating diseases, are not recommended in patients with multiple sclerosis or related disorders. The authors searched the Medline database for English language articles concerning the adverse events of anti-TNF drugs published between 1998 and December 2019, and have summarized their contents relating to infections, malignancies, cardiovascular diseases, autoimmunity and neurological diseases. Patients should be fully informed of the increased risks associated with anti-TNF drugs, and physicians should know how to treat them. AREAS COVERED: This review considers these safety concerns, their possible underlying causes, and other aspects that are important in clinical practice. EXPERT OPINION: Growing concern about the safety of anti-TNF drugs underlines the need to ensure that all clinicians are capable of taking appropriate preventive and therapeutic action.

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.

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.

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.

Controlled-release pregabalin in the treatment of fibromyalgia.

INTRODUCTION: Fibromyalgia (FM) is a chronic disorder whose symptoms of musculo-skeletal pain, fatigue, sleep disturbances, and cognitive impairment pervade the personal, occupational, and social aspects of a patient's life. Together with the antidepressants duloxetine and milnacipran, the anticonvulsant pregabalin (PGB) is one of the three drugs approved by the Food and Drug Administration for the treatment of FM. The aim of this narrative review is to summarize the data relating to the efficacy and safety of the controlled-release formulation of PGB (PGB-CR) in patients with FM. Areas covered: Efforts by the pharmaceutical industry have led to the introduction of new formulations of already approved drugs to enhance treatment convenience and adherence. Expert opinion: Although there are no published studies specifically comparing PGB-CR and PGB-IR formulations in FM patients, the efficacy and safety profiles of PGB-CR seem to be similar to those of the IR formulation, and the convenience of once-daily dosing potentially enhances patient compliance. However, the amount of evidence is not sufficient to draw any definite conclusions, and further studies of larger patient samples are needed.

Adverse events, clinical considerations and management recommendations in rheumatoid arthritis patients treated with JAK inhibitors.

BACKGROUND: A new class of oral synthetic drugs has been developed for the treatment of rheumatoid arthritis (RA) with the aim of blocking the Janus kinase/signal transducer and activator of transcription (JAK-STAT) system. Tofacitinib and baricitinib have been approved for the treatment RA patients who inadequately respond to methotrexate or anti-tumor necrosis factor drugs. The aim of this narrative review is to summarize the data concerning the drugs' basic mechanisms and clinical trial results in order to inform clinicians about the serious and non-serious adverse events associated with JAK inhibitors. Areas covered: The mechanisms, adverse events, and clinical trial data associated with the use of JAK inhibitors in RA patients were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1999 and April 2018 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: Management of the adverse events of JAK inhibitors is challenging because of the lack of robust treatment data used and the heterogeneity of the events themselves. Treatment decisions are often made clinically on the basis of age and the burden of comorbidities, and require the multidisciplinary collaboration of rheumatologists and other specialists.

From autoinflammation to autoimmunity: old and recent findings.

Autoimmune diseases and autoinflammatory diseases have a number of similar etiopathogenetic and clinical characteristics, including genetic predisposition and recurrent systemic inflammatory flares. The first phase of ADs involves innate immunity: by means of TLRs, autoantigen presentation, B and T cell recruitment and autoantibody synthesis. The second phase involves adaptive immunity, a self-sustaining process in which immune complexes containing nucleic acids and autoantibodies activate self-directed inflammation. The link between autoimmunity and autoinflammation is IL-1ß, which is crucial in connecting the innate immune response due to NLR activation and the adaptive immune responses of T and B cells. In conclusion, although ADs are still considered adaptive immunity-mediated disorders, there is increasing evidence that innate immunity and inflammasomes are also involved. The aim of this review is to highlight the link between the innate and adaptive immune mechanisms involved in autoimmune diseases.