Optimizing withdrawal strategies for anti-TNF-α therapies in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disease that significantly impacts patients' quality of life. While treatment options have expanded over the years, including the introduction of tumor necrosis factor-alpha (TNFα) inhibitors (TNFi), optimizing withdrawal strategies for these agents remains a challenge. AREAS COVERED: This review examines the current evidence on TNFi withdrawal strategies in RA, focusing on factors influencing withdrawal decisions such as disease activity monitoring, treatment response, patient characteristics, and biomarkers. A comprehensive literature search was conducted, including randomized controlled trials, observational studies, and expert guidelines. The pathophysiology of RA, current pharmacological agents, and the treat-to-target strategy are discussed to provide a holistic understanding of RA management. EXPERT OPINION: Withdrawal strategies could be suitable for certain patients, keeping in mind that several factors influence withdrawal decisions, including treatment response, disease activity and monitoring, and patient characteristics. The decision to withdraw TNFi must balance the benefits against the potential risks of disease flare and long-term treatment-related adverse effects. Combining DMARDs and TNFi early improves outcomes, supporting tapering strategies for cost-effectiveness and flare prevention. Future directions, including precision medicine approaches, patient-centered care models, and health economics analyses, are proposed to further optimize RA management and improve patient outcomes.

Development of Morphea Following Treatment with an ADA Biosimilar: A Case Report.

BACKGROUND: Tumor necrosis factor alpha (TNFα) is a pivotal cytokine involved in the pathogenesis of certain inflammatory diseases, such as rheumatoid arthritis (RA), spondyloarthropathies, and inflammatory bowel diseases. In the last two decades, TNFα inhibitors (TNFi) have revolutionized the treatment and outcome of the above disorders. However, the use of TNFi has been associated with the development of many autoimmune phenomena and paradoxical skin manifestations that may present as the same type of clinical indications for which the TNFi effectively used. Thus, they may display as arthritis, uveitis, colitis, psoriasis, and several other cutaneous clinical manifestations, among them the development of morphea, a localized scleroderma skin lesion. CASE PRESENTATION: We describe a 58-year-old woman with seronegative RA, refractory to methotrexate, who was treated with ABP-501 (Hefiya), an adalimumab (ADA) biosimilar and developed an oval-shaped, deep skin lesion of approximately 3.5cm in size, affecting the left part of her back compatible with morphea 3 months after the initiation of therapy. ADA biosimilar was discontinued and two months later, she had substantial skin improvement. CONCLUSION: This is the first report of morphea manifestation during TNFi biosimilar since the patient had no other trigger factors for morphea development like trauma and infections. Physicians dealing with patients treated with TNFi biosimilars should be aware of paradoxical skin reactions, among them morphea; thus, close monitoring, a minute and careful clinical examination, and a follow- up check are required.

Cutaneous immune-related phenomena in patients with inflammatory arthritides treated with biological therapies: Clinical and pathophysiological considerations.

In recent years, identifying the pathophysiologic mechanisms underlying autoimmune arthritides and systematic diseases has led to the use of biological drugs. The primary targets of those biological therapies are cytokines, B cells, and co-stimulation molecules. So far, these targeted therapies have shown good clinical improvement and an acceptable toxicity profile. However, by blocking components of an intact immune system, autoimmune phenomena and paradoxical inflammation have emerged, and among them many cutaneous immune-related adverse events (irAEs). In this article, we review the current state of knowledge on the clinical features and mechanisms of specific cutaneous irAEs observed during treatment with biological therapies. Among those, psoriatic skin lesions are the most commonly observed. Herein, we also report new cases of cutaneous irAEs recently seen in our clinic to help physicians treating inflammatory arthritides recognize cutaneous irAEs early and better manage patients receiving biologic therapies.

Axial Spondyloarthritis: Evolving concepts regarding the disease's diagnosis and treatment.

Spondyloarthritis (SpA) is a chronic inflammatory disease that affects the axial skeleton (axSpA) and/or the peripheral joints (p-SpA) and entheses. The natural history of SpA in the decades of the 80 and 90 s involved a progressive disease with pain, spinal stiffness, ankylosis of the axial skeleton, structural damage of peripheral joints, and a poor prognosis. In the last 20 years, enormous advances in understanding and managing SpA have occurred. With the introduction of the ASAS classification criteria and MRI, early disease recognition is now possible. The ASAS criteria widened the spectrum of SpA to include all the disease phenotypes, such as radiographic (r-axSpA), non-radiographic (nr-axSpA), and p-SpA and extraskeletal manifestations. Nowadays, the treatment of SpA is based on a shared decision between patients and rheumatologists and includes non-pharmacological and pharmacological therapies. Moreover, the discovery of TNFα, IL-17, which play a pivotal role in disease pathophysiology, has revolutionized disease management. Thus, new targeted therapies and many biological agents are now available and used in SpA patients. TNFα inhibitors (TNFi), IL-17, and JAK inhibitors were proven to be efficacious, with an acceptable toxicity profile. Overall, their efficacy and safety are comparable with some differences. Sustained clinical disease remission, low disease activity, improvement of patient's quality of life, and prevention of progression of structural damage, are the results of the above interventions. The concept of SpA has changed in the last 20 years. The disease burden can be ameliorated by early and accurate diagnosis and targeting therapies.

TNFα inhibitor biosimilar associated with polychondritis. A case-based review.

Relapsing polychondritis (RP) is a rare autoimmune disease characterized by inflammation of the cartilage structures of the body with typical features of auricular chondritis, nasal and ocular inflammation, audio-vestibular damage, as well as respiratory tract manifestations. It is associated with several autoimmune diseases and many other disorders. Tumor necrosis factor alpha (TNFα) inhibitors treat many chronic inflammatory disorders. They have proven effective and relatively safe in many clinical trials and observational studies. However, several autoimmune phenomena and paradoxical inflammation have been described with TNFα inhibitors, among them RP. This report presents a 43-year-old man with psoriatic arthritis treated with ABP-501 (Amgevita), an adalimumab (ADA) biosimilar and who developed RP, 8 months after the initiation of the treatment. This, is the first report of RP development during TNFα inhibitors biosimilar. We concluded that rheumatologists dealing with patients treated with TNFα inhibitors (originators or biosimilars), should be aware of several paradoxical reactions which may emerge and RP, is one of them.

Epidemiology of rheumatoid arthritis: genetic and environmental influences.

INTRODUCTION: Rheumatoid arthritis (RA) is a chronic systemic disease characterized by articular involvement and extra-articular manifestations. The incidence and prevalence of the disease vary across populations, and there is an ongoing debate on whether a change of RA occurrence over time exists or is due to methodological issues and other biases. Moreover, the disease's onset is related to an interaction of genetic and environmental factors that influence its expression. AREAS COVERED: This review explores the latest knowledge on RA epidemiology and the possible risk factors associated with its presentation to identify potential warning signs that may in the future help disease management. EXPERT OPINION: Current epidemiological evidence suggests a significant impact of smoking, sex hormones, and lifestyle status in RA occurrence. However, the association between these variables has not yet been thoroughly studied. Still, their effect must be interpreted as they may present subsequently integral indicators for a more rational approach of the disease.

Janus kinase versus TNF inhibitors: where we stand today in rheumatoid arthritis.

INTRODUCTION: In recent decades, Rheumatoid arthritis (RA) treatment landscape has evolved with the induction of new biological and targeted therapies that provide significant therapeutic benefits in patients with sustained disease. AREAS COVERED: Tumor necrosis factor inhibitors (TNFi) were the first biologics used in the treatment of RA. Although they present a significant efficacy, an insufficient response of some patients led to further research and discovery of targeted therapies, such as Janus kinase inhibitors (JAKi), which act at a molecular level, regulating many cytokines. Clinical benefits have been seen with both TNFi and JAKi as monotherapy and combined with conventional synthetic disease-modifying antirheumatic drugs. Still, some significant side effects have been reported with JAKi, and several questions remain about their safety and selectivity in action. This review summarizes the current knowledge on the mechanism of action, the clinical efficacy, and safety of TNFi vs. JAKi. EXPERT OPINION: TNFi and JAKi are particularly useful in treating inflammatory arthropathies. Both drug categories are recommended by ACR and EULAR institutions in RA patients suffering from moderate to severe disease. Safety data in long-term studies are required to determine the optimal benefit to the risk profile of JAKi use.

Treatment strategies of COVID-19: A rheumatology perspective.

The clinical progression of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to critical illness is associated with a systemic and uncontrolled inflammatory response of the innate and adaptive immunity with the release of a plethora of proinflammatory cytokines termed "cytokine storm". In the absence of an effective treatment, many off-label agents from the armamentarium of rheumatology are used. Here, from the perspective of a rheumatologist, we will discuss the current therapeutic strategies in critically ill patients with SARS-CoV-2 pneumonia. Thus, we will discuss the agents that aim to target viral entry and its replication into the host cell and those focusing and targeting the inflammatory response. In this setting, many agents have been used with promising results but, not all have been approved by the International Authorities and Institutions. In the first step (viral entry), SARS-CoV-2 monoclonal antibodies and remdesivir have been approved to be used and, in the second step, corticosteroids along with interleukin-6 inhibitors, or Janus Kinase inhibitors are currently used.

Anti-Rheumatic Drugs May Ameliorate the Clinical Course and Outcome of COVID-19 In Rheumatoid Arthritis Patients.

Current data demonstrated that in patients with coronavirus disease-19 (COVID-19), there is a dysregulation of the immune system during the severe form of the disease. This dysregulation is expressed with an uncontrolled release of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6, IL-17, tumour necrosis factor alpha (TNFa) and chemokines, associated with increased serum ferritin levels and other acute phase reactants. On the other side, these cytokines play a pivotal role in autoimmune rheumatic diseases (ARD), mostly in rheumatoid arthritis (RA) and the spondyloarthropathies. Patients affected with ARD represent a particular vulnerable group, considering that they may be in an immunocompromised status due to their ailment and its treatment on one side, but on the other side, they may be protected from their immunosuppressive therapy. To this end, we present five patients with RA treated with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) and biologic (b) DMARDs who were affected from COVID-19 and we will try to give answers to the above hypothesis.

Patterns and factors associated with pneumococcal vaccination in a prospective cohort of 1,697 patients with rheumatoid arthritis.

Introduction: Patients with rheumatoid arthritis (RA) are at increased risk for serious infections. Pneumococcal vaccination is among the most important preventive measures, however, vaccine uptake is suboptimal. We explored the rate and factors associated with pneumococcal vaccination in a contemporary RA cohort. Materials and methods: Multi-center, prospective, RA cohort study in Greece. Patient and disease characteristics and influenza and pneumococcal vaccinations were documented at baseline and 3 years later. Results: One thousand six hundred and ninety-seven patients were included and 34.5% had already received at least one pneumococcal vaccine at baseline. Among 1,111 non-vaccinated patients, 40.1% received pneumococcal vaccination during follow-up, increasing the vaccine coverage to 60.8%. By multivariate analysis, positive predictors for pneumococcal vaccination included prescription of influenza vaccine (OR = 33.35, 95% CI: 18.58-59.85), history of cancer (OR = 2.35, 95% CI: 1.09-5.06), bDMARD use (OR = 1.85, 95% CI: 1.29-2.65), seropositivity (OR = 1.47, 95% CI: 1.05-2.05), and high disease activity (DAS28-ESR, OR = 1.33, 95% CI: 1.17-1.51). Male sex (OR = 0.65, 95% CI: 0.43-0.99) was a negative predictor for pneumococcal vaccination during follow-up. Discussion: Despite increasing rates of pneumococcal vaccine coverage, 40% of RA patients remain unvaccinated. Severe disease, bDMARD use, comorbidities, and more importantly flu vaccination were the most significant factors associated with pneumococcal vaccination, emphasizing the currently unmet need for cultivating a "vaccination culture" in RA patients.

TNF-induced Lupus. A Case-Based Review.

Nowadays, tumor necrosis factor-alpha (TNFα) inhibitors have revolutionised the treatment of inflammatory arthritides by demonstrating efficacy with an acceptable toxicity profile. However, autoimmune phenomena and clinical entities have been reported ranging from an isolated presence of autoantibodies to full-blown autoimmune diseases, including drug-induced lupus (DIL). Case Presentation: A 62-year-old woman with rheumatoid arthritis (RA) refractory to methotrexate and prednisone was treated with adalimumab (ADA). 4 months later, she presented acute cutaneous eruptions after sun exposure, positive ANA (1/640 fine speckled pattern), Ro (SSA) and anti- Smith (Sm) antibodies with no other clinical or laboratory abnormalities. The diagnosis of DIL was made, ADA was discontinued, and she was treated successfully with prednisone plus local calcineurin inhibitors. Conclusion: Thus, we review the literature for cases of DIL development in patients treated with TNFα inhibitors. Rheumatologists should be aware of the possible adverse events and the requirement of careful clinical evaluation and monitoring.

Pleural effusion in psoriatic arthritis patients: a case series and review of the literature.

Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Pulmonary involvement is a rare extra-articular manifestation of the disease characterized by rigidity of the chest wall and apical pulmonary fibrosis. Pleural effusion is uncommon in PsA. We present four cases of patients with PsA who developed pleural effusions. We report for the first time a PsA patient who was drug-naïve and developed unilateral pleuritis. We also describe one PsA case with pleuritis while he was on methotrexate (MTX) and two PsA cases on tumor necrosis factor (TNF) inhibitors. The literature review revealed six cases with pleural effusion, which were drug-induced. These patients presented pleural effusions while they were treated with MTX (2 patients) and TNF inhibitors (4 patients). In PsA patients with pleuritis, a detailed investigation to rule out infections is necessary. In addition, increased pharmacovigilance will detect cases of drug-induced serositis.

Use of conventional synthetic and biologic disease-modifying anti-rheumatic drugs in patients with rheumatic diseases contracting COVID-19: a single-center experience.

To examine whether patients with inflammatory arthritis (IA) treated with conventional synthetic (cs) disease-modifying anti-rheumatic drugs (DMARDs) and/or biologic (b) DMARDs, could be affected from SARS-CoV-2 infection and to explore the COVID-19 disease course and outcome in this population. This is a prospective observational study. During the period February-December 2020, 443 patients with IA who were followed-up in the outpatient arthritis clinic were investigated. All patients were receiving cs and/or bDMARDs. During follow-up, the clinical, laboratory findings, comorbidities and drug side effects were all recorded and the treatment was adjusted or changed according to clinical manifestations and patient's needs. There were 251 patients with rheumatoid arthritis (RA), 101 with psoriatic arthritis (PsA) and 91 with ankylosing spondylitis (AS). We identified 32 patients who contracted COVID-19 (17 RA, 8 PsA, 7 AS). All were in remission and all drugs were discontinued. They presented mild COVID-19 symptoms, expressed mainly with systemic manifestations and sore throat, while six presented olfactory dysfunction and gastrointestinal disturbances, and all of them had a favorable disease course. However, three patients were admitted to the hospital, two of them with respiratory symptoms and pneumonia and were treated appropriately with excellent clinical response and outcome. Patients with IA treated with cs and/or bDMARDs have almost the same disease course with the general population when contract COVID-19.

Comparable or higher prevalence of comorbidities in antiphospholipid syndrome vs rheumatoid arthritis: a multicenter, case-control study.

OBJECTIVES: Evidence on comorbidity prevalence in antiphospholipid syndrome (APS) and its difference from high comorbidity burden rheumatic diseases is limited. Herein, we compare multiple comorbidities between APS and RA. METHODS: A total of 326 patients from the Greek APS registry [237 women, mean age 48.7 (13.4) years, 161 primary APS (PAPS), 165 SLE-APS] were age/sex matched (1:2 ratio) with 652 patients from a Greek multicentre RA cohort of 3115 patients. Prevalence of cardiovascular (CV) risk factors, stroke, coronary artery disease (CAD), osteoporosis, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), depression and neoplasms were compared between APS and RA patients using multivariate regression analysis. RESULTS: Ηyperlipidemia and obesity (ΒΜΙ ≥ 30 kg/m2) were comparable while hypertension, smoking, stroke and CAD were more prevalent in APS compared with RA patients. Osteoporosis and depression were more frequent in APS, while DM, COPD and neoplasms did not differ between the two groups. Comparison of APS subgroups to 1:2 matched RA patients revealed that smoking and stroke were more prevalent in both PAPS and SLE-APS vs RA. Hypertension, CAD and osteoporosis were more frequent only in SLE-APS vs RA, whereas DM was less prevalent in PAPS vs RA. Hyperlipidaemia was independently associated with CV events (combined stroke and CAD) in PAPS and SLE-APS, while CS duration was associated with osteoporosis in SLE-APS. CONCLUSION: Comorbidity burden in APS (PAPS and SLE-APS) is comparable or higher than that in RA, entailing a high level of diligence for CV risk prevention, awareness for depression and CS exposure minimization.

Preclinical discovery and development of adalimumab for the treatment of rheumatoid arthritis.

Introduction: Rheumatoid arthritis (RA) is an autoimmune disease that is characterized by progressive joint disorders with significant pain and stiffness. In the past, RA was a difficult -to-treat ailment, but nowadays with the advent of biologics and better treatment strategies, disease remission is an achievable goal. Tumor necrosis factor α (TNFα) inhibitors were the first category of biologics to emerge with adalimumab being the first fully human TNFα.Areas covered: the authors provide an overview of the historical events that led to the discovery of TNFα inhibitors and more specifically the drug adalimumab. Several key trials are presented regarding the safety of the drug as well as its successful journey, but there is also a narrative description of the drug's future after patent expiration.Expert opinion: Adalimumab is a fully human TNFα inhibitor with a fairly rapid onset of action. It has a generally good safety and efficacy profile. Clinicians must be aware of the possible side effects and treat them in a timely manner or discontinue the drug where appropriate. Due to the success of the bio-originator adalimumab, a multitude of biosimilars have emerged but not, thus far, for all of the indications of the bio-originator.

Cutaneous Autoimmune Phenomena of the Anti-TNFa Biosimilars. Casebased Review.

BACKGROUND: Psoriasis (Pso) is a common chronic inflammatory disease affecting the skin, both sexes, and all ages. It can be associated with other chronic inflammatory musculoskeletal disorders and certain drugs, including tumor necrosis factor α (TNFα) antagonists. CASE PRESENTATION: A 64-year-old man with seronegative rheumatoid arthritis (RA) refractory to leflunomide and prednisone was treated with SB-4 (Benepali), an etanercept biosimilar 50mg/week subcutaneously. He responded well to the treatment, but a year later, he developed erythematous skin eruptions affecting mainly in the palms of both hands. Skin biopsy showed a picture compatible with Pso. SB-4 was discontinued, and the skin lesions disappeared with the addition of topical steroid therapy. This is the only case of psoriatic skin lesions associated with SB-4 treatment. CONCLUSION: Thus, we review and discuss the relevant literature of Pso cases related to SB-4 and other anti-TNFα biosimilars. Rheumatologists dealing with patients on anti-TNFα biosimilars should be aware of and recognize these complications.

Recent advances in the opioid mu receptor based pharmacotherapy for rheumatoid arthritis.

INTRODUCTION: Opioids are used for severe forms of acute and cancer pain. Over the last years, their potential use in patients with noncancer pain such as those with rheumatoid arthritis (RA) has been postulated. A recent population-based comparative study showed that chronic opioid use was 12% vs. 4% among RA and non-RA patients, respectively. Another study showed an increase from 7.4% to 16.9% (2002 to 2015). In general, there has been an increasing tendency to use opioids in recent years. AREAS COVERED: The authors have performed an extensive literature search using PubMed for articles including noncancer pain and the use of the mu opioid receptor (MOR) agonists in patients with RA. EXPERT OPINION: Data is not sufficient to support opioid use for the treatment of chronic pain in patients with RA. Data is scarce and inconclusive. Rheumatologists should think and ponder the question: Why is this patient in pain? Differential diagnosis should include a disease flare, degenerative changes of the musculoskeletal system, and fibromyalgia. And while there are new strategies for opioid administration currently being researched, unfortunately, they are far from being applied to human subjects in the everyday clinical setting, and are still being evaluated at an experimental level. CNS: Central nervous system; DORs: delta opioid receptor agonists; GI: Gastrointestinal; GPCRs: G protein-coupled receptors; IL: Interleukin; JAK: Janus kinase; KORs: kappa opioid receptor agonists; MCPs: Metacarpophalangeal joints; MORs: Mu opioid receptor agonists; MTPs: Metatarsophalangeal joints; NSAIDs: Non-steroidal anti-inflammatory drugsOA: Osteoarthritis; ORs: Opioid receptors; PD: Pharmacodynamic; PIPs: Proximal interphalangeal joints; PK: Pharmacokinetic; PNS: Peripheral nervous system; RA: Rheumatoid arthritis; RGS: Regulator of G protein signaling; SSRIs: Selective serotonin reuptake inhibitors; TNF: Tumor necrosis factor.

Clinical, Serological and Immunological Characteristics in Greek Patients with Psoriatic Arthritis: The Role of IL-17, IL-23, and Sclerostin.

Psoriatic arthritis (PsA) is an inflammatory form of arthritis that belongs to the family of spondyloarthritis (SpA) and is related to skin psoriasis. The incidence and prevalence of the disease vary considerably between countries. PsA is classified into axial PsA and peripheral PsA, with a wide range of other extra-articular manifestations. Although the aetiology of the disease is unknown, genetic, environmental, and immunologic factors appear to affect its appearance. In recent years, the role of the immune system in the pathogenesis of PsA has been increasingly investigated. Specific cytokines such as tumour necrosis factor (TNF), interleukin (IL-) 17 and IL-23, play an essential role affecting joint structures. This observation led to the emergence of tumour necrosis factor inhibitors (TNFi) that offer considerable therapeutic benefit to PsA patients. However, chronic inflammation causes bone loss, while new bone formation may also occur in both peripheral and axial skeleton. The molecular mechanisms underlying these processes have not yet been fully understood. So far, the role of the Wnt/ß-catenin pathway and its inhibitors (Dickkopf and sclerostin) has been evaluated in ankylosing spondylitis (AS), but in PsA has not been studied sufficiently. The present study aims to investigate the epidemiological characteristics and clinical features (articular and extra-articular manifestations) as well as the treatment of PsA patients in the region of northwestern (NW) Greece. It also aims to evaluate the role of specific cytokines and sclerostin in patients with PsA, giving evidence to possible future biomarkers or even therapeutic targets for the disease.