Cytokines as Therapeutic Targets in Rheumatoid Arthritis and Other Inflammatory Diseases

The human immune system involves highly complex and coordinated processes in which small proteins named cytokines play a key role. Cytokines have been implicated in the pathogenesis of a number of inflammatory and autoimmune diseases. Cytokines are therefore attractive therapeutic targets in these conditions. Anticytokine therapy for inflammatory diseases became a clinical reality with the introduction of tumor necrosis factor (TNF) inhibitors for the treatment of severe rheumatoid arthritis. Although these therapies have transformed the treatment of patients with severe inflammatory arthritis, there remain significant limiting factors: treatment failure is commonly seen in the clinic; safety concerns remain; there is uncertainty regarding the relevance of immunogenicity; the absence of biomarkers to direct therapy decisions and high drug costs limit availability in some healthcare systems. In this article, we provide an overview of the key efficacy and safety trials for currently approved treatments in rheumatoid arthritis and review the major lessons learned from a decade of use in clinical practice, focusing mainly on anti-TNF and anti–interleukin (IL)-6 agents. We also describe the clinical application of anticytokine therapies for other inflammatory diseases, particularly within the spondyloarthritis spectrum, and highlight differential responses across diseases. Finally, we report on the current state of trials for newer therapeutic targets, focusing mainly on the IL-17 and IL-23 pathways

Tumor Necrosis Factor-Alpha Inhibitory Therapy for Non-Infectious Autoimmune Uveitis

Biologic agents represent a mainstay in the treatment of refractory non-infectious, immune-mediated uveitis. Tumor necrosis factor (TNF)-α inhibitors have demonstrated efficacy in inducing and sustaining disease remission in numerous systemic inflammatory disorders and their associated uveitic entities. In particular, studies have shown that infliximab and adalimumab can induce steroid-free disease remission in patients with Behçet’s disease and juvenile arthritis as treatments that are superior to conventional disease-modifying immunosuppressive agents. Patients receiving anti-TNF-α therapy may experience adverse events and should be closely monitored for the development of opportunistic infections, reactivation of tuberculosis and hepatitis, demyelinating disease and neuropathies, as well as malignancies

Long-term safety and efficacy of etanercept in the treatment of ankylosing spondylitis

[EN] To date, anti-tumor necrosis factor alfa (anti-TNF-α) therapy is the only alternative to nonsteroidal anti-inflammatory drugs for the treatment of ankylosing spondylitis. Etanercept is a soluble TNF receptor, with a mode of action and pharmacokinetics different to those of antibodies and distinctive efficacy and safety. Etanercept has demonstrated efficacy in the treatment of ankylosing spondylitis, with or without radiographic sacroiliitis, and other manifestations of the disease, including peripheral arthritis, enthesitis, and psoriasis. Etanercept is not efficacious in inflammatory bowel disease, and its efficacy in the treatment of uveitis appears to be lower than that of other anti-TNF drugs. Studies of etanercept confirmed regression of bone edema on magnetic resonance imaging of the spine and sacroiliac joint, but failed to reduce radiographic progression, as do the other anti-TNF drugs. It seems that a proportion of patients remain in disease remission when the etanercept dose is reduced or administration intervals are extended. Etanercept is generally well tolerated with an acceptable safety profile in the treatment of ankylosing spondylitis. The most common adverse effect of etanercept treatment is injection site reactions, which are generally self-limiting. Reactivation of tuberculosis, reactivation of hepatitis B virus infection, congestive heart failure, demyelinating neurologic disorders, hematologic disorders like aplastic anemia and pancytopenia, vasculitis, immunogenicity, and exacerbation or induction of psoriasis are class effects of all the anti-TNF drugs, and have been seen in patients with ankylosing spondylitis. However, etanercept is less likely to induce reactivation of tuberculosis than the other anti-TNF drugs and it has been suggested that etanercept might be less immunogenic, especially in ankylosing spondylitis. Acute uveitis, Crohn’s disease, and sarcoidosis are other adverse events that have been rarely associated with etanercept therapy in patients with ankylosing spondylitis.Senabre-Gallego, JM.; Santos-Ramírez, C.; Santos-Soler, G.; Salas-Heredia, E.; Sánchez Barrioluengo, M.; Barber, X.; Rosas, J. (2013). Long-term safety and efficacy of etanercept in the treatment of ankylosing spondylitis. Patient Preference and Adherence. 7:961-972. doi:10.2147/PPA.S33109S961972

Update on bioagent therapy in sarcoidosis

Corticosteroids are still the cornerstone of treatment for patients with sarcoidosis requiring systemic therapy. However, alternative agents and especially methotrexate may be considered for patients with refractory disease or requiring prolonged treatment with intolerable side effects. Although bioagent therapies have hitherto not clearly demonstrated superior efficacy and safety over corticosteroids in pulmonary sarcoidosis, infliximab may modestly improve lung function in patients with active disease resistant to steroids. Further studies will be needed to assess both safety and efficacy of infliximab in pulmonary sarcoidosis. Infliximab may be considered in a limited number of patients with severe extrapulmonary systemic manifestations of sarcoidosis, with careful individual evaluation of the risk-benefit ratio

Are Patients at Risk for Recurrent Disease Activity After Switching From Remicade® to Remsima®? An Observational Study

Background: Since the late ‘90s, infliximab (Remicade®) is being used successfully to treat patients with several non-infectious immune mediated inflammatory diseases (IMIDs). In recent years, infliximab biosimilars, including Remsima® were introduced in clinical practice. Aim: To investigate the interchangeability of Remicade® (originator infliximab) and its biosimilar Remsima® in patients with rare immune-mediated inflammatory diseases (IMIDs). Methods: This two-phased prospective open label observational study was designed to monitor the transition from Remicade® to Remsima® in patients with rare IMIDs. All included patients were followed during the first 2 years. The primary endpoint was the demonstration of non-difference in quality of life and therapeutic efficacy, as measured by parameters including a safety monitoring program, physicians perception of disease activity (PPDA) and patient self-reported outcomes (PSROs). Secondary outcomes included routine blood analysis, pre-infusion serum drug concentration values and anti-drug antibody formation. Results: Forty eight patients treated with Remicade® were switched to Remsima® in June-July 2016 and subsequently monitored during the first 2 years. The group consisted of patients with sarcoidosis (n = 17), Behçet's disease (n = 12), non-infectious uveitis (n = 11), and other diagnoses (n = 8). There were no significant differences in PPDA, PSROs, clinical and laboratory assessments and pre-infusion serum drug concentrations between the groups. De novo anti-drug antibodies were observed in two patients. Seven patients with sarcoidosis and five with another diagnosis developed a significant disease relapse (n = 7) or adverse events (n = 5) within 2 years; 10 of these patients discontinued Remsima® treatment, one withdrew from the study and one received additional corticosteroid therapy. Conclusions: We observed no significant differences in PSROs, PPDA and laboratory parameters after treatment was switched from Remicade® to Remsima®. However, disease relapse or serious events were observed in 12 out of 48 patients when treatment was switched from Remicade® to Remsima®. The choice to switch anti-TNF alpha biologics in patients with rare IMIDs, particularly in sarcoidosis, requires well-considered decision-making and accurate monitoring due to a possibly higher incidence of disease worsening

Μακροχρόνια χορήγηση βιολογικών παραγόντων και αναπνευστική λειτουργία στην αγκυλοποιητική σπονδυλοαρθρίτιδα

Στόχος της μελέτης είναι η μέτρηση της κινητικότητας του θωρακικού και του κοιλιακού τοιχώματος στην ήρεμη αναπνοή και η συσχέτιση με τους κλινικούς δείκτες βαρύτητας της νόσου. Επίσης η εκτίμηση της βελτίωσης της κινητικότητας μετά τη χορήγηση των ανταγωνιστών του TNF. Δευτερεύοντες στόχοι είναι η εκτίμηση της κινητικότητας του θωρακικού και του κοιλιακού τοιχώματος κατά την ομιλία, η μέτρηση της αναπνευστικής λειτουργίας και ο έλεγχος της χρησιμότητας της δοκιμασίας SNIP στην εκτίμηση των εισπνευστικών δυνάμεων. 60 ασθενείς με αγκυλοποιητική σπονδυλοαρθρίτιδα και διάφορους βαθμούς προσβολής. Μετρήσεις: προ της έναρξης αγωγής με anti-TNF , 3, 6 και 12 μήνες μετά. Καταγραφή: ιστορικό, σωματομετρικά χαρακτηριστικά, δείκτες ενεργότητας νόσου, αναπνευστικές μετρήσεις(πληθυσμογραφία, δυνάμεις μυών, σπειρομέτρηση). Η χορήγηση των antiTNF στην ΑΣ βελτιώνει την κινητικότητα του θώρακα από τους 3 πρώτους ως και τους 12 μήνες χορήγησης. Το πρότυπο συμμετοχής του θωρακικού κλωβού και του κοιλιακού τοιχώματος σχετίζεται αρνητικά με το δείκτη BASFI. Ο τρόπος κίνησης των δύο διαμερισμάτων κατά τη διάρκεια της ήρεμης αναπνοής, σχετίζεται με την κινητικότητά τους κατά την ομιλία. Η δοκιμασία SNIP μπορεί να χρησιμοποιηθεί συμπληρωματικά στους ασθενείς με χαμηλή τιμή MIP.The main objective of the study was the assessment of the relationship between thoracoabdominal motion during quiet breathing and standardized indices of disease severity in patients with ankylosing spondylitis and the evaluation whether thoracoabdominal motion improves after institution of biologic agents. Secondary objectives was the evaluation of the pattern of chest wall configuration during speech production,PFTs evaluation in these patients and to test if SNIP can be used alternatively to inspiratory muscle evaluation in these patients. 60 A.S. patients were included in this study and impedance plethysmography was performed. 21 healthy was the control group. 4 visists were performed: before the initiation of treatment, at 3,at 6 and at 12 months. The pattern of thoracoabdominal motion during quiet braething correlates with BASFI and its response to anti-TNFa treatment is significant from the first 3 months lasting for at least 1 year. The relative contribution of the ribcage and abdomen to lung volume displacement during speech production correlates with the relative contribution during quiet breathing. SNIP can be used complementary to A.S. patients having low MIP

Sarcoidosis and spondyloarthritis: A coincidence or common etiopathogenesis?

Background: Sarcoidosis is a multisystem granulomatous disease. Co-existence with spondyloarthritis (SA) has been more described as an adverse effect of anti-TNF α therapy than an association. We report herein a case of a typical sarcoidosis confirmed by histological proofs and an advanced SA with a bamboo column. Case Presentation: A 48-years-old woman presented with inflammatory back pain for 5 years and ankle swelling for 1 year. On physical examination, she had an exaggerated dorsal kyphosis and disappearance of lumbar lordosis with limitation in motion of the cervical and lumbar spine. Laboratory tests did not show an inflammatory syndrome or hypercalcemia. Plain radiographies of the spine and pelvic revealed a triple ray appearance with sacroiliitis grade 4. Chest radiography and CT confirmed the presence of bilateral hilar lymph nodes and parenchymal nodes. Bronchoscopy and biopsies were performed showing non-calcified granulomatous reaction without cell necrosis. The diagnosis of SA was performed based on 9 points of Amor criteria associated with pulmonary sarcoidosis. She was treated with 15 mg per week of methotrexate and 1mg/kg/day of prednisone for pulmonary disease with good outcomes. Conclusions: Sarcoidosis may be associated to SA besides paradoxical drug effect. The same physio pathological pathways mediate by TNF α are arguments for association than hazardous coincidence

Pulmonary Sarcoidosis in Behçet's Disease Treated with Adalimumab

TNF-α antagonists are used to treat various rheumatic diseases including sarcoidosis. However, there have been increasing reports of sarcoidosis in relation to treatment using these drugs. The pathogenesis of this reaction remains unknown. This is a report of a clinical case of sarcoidosis in Behçet's disease (DB) with mucocutaneous and intestinal involvement in treatment using adalimumab, with improvement after anti-TNF suspension and corticosteroid therapy

Immune-Mediated Skin Reactions Induced by Recombinant Antibodies and Other TNF-Alpha Inhibitors

Biologic agents that act by inhibiting tumour necrosis factor alpha (TNF-alpha) have become a breakthrough treatment for chronic inflammatory diseases. This highly effective treatment has surprisingly brought us new adverse effects that we had not encountered before the age of biologics. Immune-mediated reactions are a group of adverse effects with not clearly understood etiopathogenesis. It turns out that TNF-alpha inhibitors are able to disrupt the cytokine cascade in genetically predisposed individuals. Some of the theories assume a cross reaction and overproduction of interferon (INF) alpha, while others put an emphasis on dysregulation of cytokines, in particular interleukin (IL)-17. Similarly, debatable is the role of the reactions mentioned in the etiopathogenesis, the production of antibodies against biologics and the production of antinuclear antibodies. The most common immune-mediated skin reactions are psoriasis and psoriasiform reactions, lupus-like syndrome, sarcoidosis, alopecia areata, vasculitis and lichenoid reactions. Less common reactions described in our paper include pyoderma gangrenosum and morphea. Most of these reactions belong to the so-called paradoxical reactions. Paradoxical psoriasis is an adverse effect, represented by occurrence of a disease caused by the therapeutic class of drugs normally used to cure or improve symptoms of such disease