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.

PDGF enhances orbital fibroblast responses to TSHR stimulating autoantibodies in Graves' ophthalmopathy patients.

PURPOSE: Thyroid-stimulating hormone receptor (TSHR) stimulating autoantibodies are associated with Graves' ophthalmopathy (GO), the orbital manifestation of Graves' disease (GD). TSHR autoantibody levels and orbital TSHR expression levels correlate positively with GO disease activity. Platelet-derived growth factors (PDGF) are increased in GO and potently activate orbital fibroblast effector functions. We investigated the possible relationship between PDGF and TSHR expression on orbital fibroblasts and how that influences the immunopathological effects of TSHR autoantibodies on orbital fibroblast activity. METHODS: Orbital fibroblasts were stimulated with PDGF-AA, PDGF-AB, and PDGF-BB, and TSHR expression was determined by flow cytometry. Stimulatory effects of bovine TSH and GD immunoglobulins on orbital fibroblasts (with or without PDGF-BB preincubation) were determined by IL-6, IL-8, chemokine (C-C motif) ligand (CCL)-2, CCL5, CCL7, and hyaluronan ELISA. The TSHR blocking antibody K1-70 and the cAMP inhibitor H89 were used to determine involvement of TSHR signaling. RESULTS: PDGF-AB and PDGF-BB stimulation increased TSHR expression on orbital fibroblasts, whereas PDGF-AA did not. Furthermore, stimulation with bovine TSH and immunoglobulins from GD patients induced IL-6, IL-8, CCL2, and hyaluronan production by orbital fibroblasts, and PDGF-BB preincubation enhanced this response of orbital fibroblasts. Blocking studies with a TSHR blocking antibody and a cAMP inhibitor inhibited these effects, indicating the involvement of TSHR signaling and thus of TSHR stimulating autoantibodies herein. CONCLUSIONS: These findings indicate that PDGF-B containing PDGF isoforms amplify the immunopathological effects of TSHR-stimulating autoantibodies in GO patients by stimulating TSHR expression on orbital fibroblasts.

Orbit-infiltrating mast cells, monocytes, and macrophages produce PDGF isoforms that orchestrate orbital fibroblast activation in Graves' ophthalmopathy.

PURPOSE: Platelet-derived growth factors (PDGF) are regulators of fibroblast activity that may be involved in the pathophysiology of Graves' ophthalmopathy (GO). We unraveled the expression and origin of PDGF family members in GO orbital tissue and investigated the effect of PDGF isoforms on IL-6 and hyaluronan production and proliferation by orbital fibroblasts. METHODS: PDGF-A, PDGF-B, PDGF-C, PDGF-D, PDGF-Rα, and PDGF-Rß expression was determined by real-time quantitative PCR and PDGF-A and PDGF-B protein expression was determined by Western blot in orbital tissues. Orbital tissues were immunohistochemically stained for PDGF-A and PDGF-B expression, together with stainings for T cells, monocytes, B cells, macrophages, and mast cells. Effects of PDGF-AA, PDGF-AB, and PDGF-BB on orbital fibroblast proliferation and IL-6 and hyaluronan production were examined. Finally, effects of PDGF-BB- and PDGF-AA-neutralizing antibodies on IL-6 and hyaluronan production in GO whole orbital tissue cultures were tested. RESULTS: GO orbital tissue showed increased PDGF-A and PDGF-B mRNA and protein levels. Increased numbers of PDGF-A- and PDGF-B-positive monocytes, macrophages, and mast cells were present in GO orbital tissue. PDGF-BB stimulated proliferation and hyaluronan and IL-6 production by orbital fibroblasts the most, followed by PDGF-AB and PDGF-AA. Finally, in particular imatinib mesylate and PDGF-BB-neutralizing antibodies reduced IL-6 and hyaluronan production by whole orbital tissue cultures from GO patients. CONCLUSIONS: In GO, mast cells, monocytes, and macrophages may activate orbital fibroblasts via secretion of especially PDGF-AB and PDGF-BB. Preclinical studies with whole orbital tissue cultures show that blocking PDGF-B chain containing isoforms can be a promising treatment for GO.

Anti-TNF-alpha therapy for sight threatening uveitis.

AIM: To describe the effect of additional treatment with anti-TNF-alpha therapy in a case series of 13 patients with serious sight threatening uveitis. METHODS: 13 patients with serious sight threatening uveitis were included, of whom six had Behçet's disease, five had idiopathic posterior uveitis, one had sarcoidosis, and one birdshot retinochoroiditis. Onset and course of ocular inflammation, inflammatory signs, and visual acuity were assessed. Patients were treated with 200 mg (approximately 3 mg/kg) infliximab infusion. Repeat infusions were given based on clinical response. RESULTS: Infliximab treatment resulted in an effective suppression of ocular inflammation in all patients. In patients with non-Behcet's disease uveitis visual acuity in six out of eight improved or was stable. In patients with Behcet's disease visual acuity in five out of six improved or was stable. CONCLUSION: Anti-TNF-alpha treatment may be of value in the treatment of uveitis, and in patients with Behçet's disease, leading to suppression of ocular inflammation, vasculitis, and improvement of vision in the majority. Based on these results a controlled masked study is warranted.

Somatostatin-related therapeutics in ophthalmology: a review.

Somatostatin and its derivatives have been predominantly studied and succesfully used in endocrinological diseases. This article reviews the rationale of the use of somatostatin and its derivatives in ophthalmology based on current understanding of its action in the eye and summarizes previously published controlled studies and case series. The article points out future possible applications. Larger randomised controlled studies are necessary to confirm its current and future use. New ways of application could facilitate its broader use in ophthalmology.

Experience with cyclosporine in endogenous uveitis posterior.

Treatment with cyclosporine (CsA) has considerably improved the visual prognosis of patients suffering from endogenous posterior uveitis (EPU). However, the therapeutic benefits of CsA are partially outweighed by its many side effects, most notably nephrotoxicity and hypertension. Low-dose CsA regimens have reduced toxicity but have not been able to completely eliminate this problem. New therapeutic approaches, such as anti-tumor necrosis factor alpha treatment or immunosuppression with drugs including tacrolimus, sirolimus, and interleukin-2 receptor antibodies, are currently under evaluation. Hopefully such strategies will further reduce the morbidity of EPU and minimize the adverse effects associated with conventional therapies.

Somatostatin in diabetic retinopathy.

Diabetic retinopathy is a leading cause of legal blindness in the adult population (30-70 year olds). The anatomical changes that occur in the retina during the course of disease are well defined in the literature but the causes are not yet fully understood. Laser photocoagulation of the retina and vitrectomy are currently used to treat diabetic retinopathy but the procedures are invasive and provide only temporary protection. The use of long-acting analogues of the naturally occurring peptide, somatostatin, has been considered by some a promising therapeutic option for retinopathy over the last decade. Experimental evidence supports its use in diabetic retinopathy but further clinical evidence, from larger treatment groups of longer trial duration, is required. Improved analogues with increased selectivity and modified bi-specific analogues are currently emerging and may help to make the use of somatostatin analogues a more realistic option in the treatment of diabetic retinopathy.

Autoantibodies to photoreceptor membrane proteins and outer plexiform layer in patients with cancer-associated retinopathy.

Cancer-associated retinopathy (CAR) is a paraneoplastic syndrome that is characterized by degeneration of the retina as a remote effect of cancer outside the eye. The detection of autoantibodies associated with the retinopathy may precede the diagnosis of the underlying cancer. We have examined the sera of two patients with CAR by Western blot analysis. Autoantibodies to a 40kD antigen doublet and a 35 kD antigen were detected. Tissue specificity of the autoantigens was determined by testing several different tissues. The 40 kD antigen doublet was most abundant in retinal extract but was also present in lung and spleen extracts. The 35 kD antigen showed little tissue specificity and was present in all tissues tested. Fractionation of retinal proteins into water-soluble and -insoluble proteins revealed that the 40 kD antigen doublet was highly insoluble and probably represented membrane-associated proteins. Immunohistochemical analysis of the retina showed that the 40 kD antigens locate to the photoreceptors while the 35 kD antigen is located in the outer plexiform layer.