Thyroid eye disease (TED) is a chronic inflammatory autoimmune disorder characterized by expansion and fibrosis of orbital tissues, leading to eyelid retraction, proptosis, periorbital edema, restricted ocular motility, corneal ulceration, and (rarely) compressive optic neuropathy. The relationship between TED pathogenesis and interleukin 6 (IL-6)-mediated signaling has created considerable interest in the therapeutic potential of monoclonal antibodies (mAbs) against interleukin 6 (IL-6) or its receptor (IL-6R). A randomized controlled trial (RCT) and several non-RCTs have reported clinical benefits from off-label use of the anti–IL-6R mAb, tocilizumab, in terms of disease activity, proptosis, thyroid-stimulating autoantibody titers (a key trigger for TED), quality of life, and possibly diplopia. Compared with recommended first-line treatment options for TED (high-dose glucocorticosteroids, and in some cases teprotumumab, a mAb against insulin-like growth factor 1 receptor), tocilizumab is associated with fewer adverse events and considerably lower risk of TED relapse following treatment discontinuation. Furthermore, most TED treatment options involve intravenous infusion, whereas tocilizumab can be administered by subcutaneous injection and thereby reduce treatment burden on patients and healthcare systems. Ongoing RCTs evaluating the efficacy and safety of long-acting anti–IL-6/IL-6R mAbs should provide evidence for additional potential reductions in treatment burden. This review aims to provide an overview of IL-6–mediated signaling in TED pathogenesis, evaluate the evidence supporting the use of anti–IL-6/IL-6R mAbs in individuals with TED, and compare the potential benefits and limitations associated with different anti–IL-6/IL-6R mAbs.
Background IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that affects the ocular adnexa. Although biologics targeting type 2 inflammation are widely used to treat severe asthma, IgG4-rich tarsal plate lesions following sequential biologic therapy have not been reported. Case Presentation: A 60-year-old woman with severe treatment-refractory asthma remained poorly controlled despite high-dose inhaled therapy and sequential biologic therapies—mepolizumab, benralizumab, dupilumab, and reintroduced mepolizumab at the referring hospital. After referral, dupilumab was reintroduced and subsequently switched to tezepelumab, after which systemic corticosteroid-requiring exacerbations ceased; however, three months later, painless bilateral upper tarsal conjunctival masses appeared and progressively enlarged. Pathological examination of the excised lesions revealed severe inflammatory thickening of the palpebral conjunctiva, with dense eosinophil- and plasma cell-rich infiltrates. Immunohistochemistry revealed numerous IgG4-positive plasma cells (170 cells/high-power field; IgG4/IgG ratio, 61%) and interleukin-4 receptor-positive cells. The serum IgG4 level measured at the time of eyelid mass development was markedly elevated at 375 mg/dL. Conclusions These findings strongly suggest IgG4-related ophthalmic disease or IgG4-rich inflammatory lesion that closely mimics IgG4-related disease involving the eyelids. This case highlights a rare IgG4-rich eyelid lesion emerging in severe asthma during sequential biologic therapy and raises the possibility that upstream cytokine blockade, particularly after prior IL-4 receptor inhibition, may unmask latent IgG4-related inflammation in susceptible individuals.
PURPOSE:To evaluate the primary efficacy and safety of satralizumab, an anti-interleukin-6 receptor antibody, in patients with thyroid eye disease (TED). DESIGN:SatraGO-1 (NCT05987423) and SatraGO-2 (NCT06106828) are identically designed, 72-week, double-masked, placebo-controlled, multicenter, 2-stage randomization phase 3 trials. PARTICIPANTS:Aged ≥18 years with active, moderate to severe TED (Clinical Activity Score [CAS] ≥3 for ≤12 months) or inactive TED (CAS <3 for ≥6 months). METHODS:Participants (SatraGO-1: N = 131; SatraGO-2: N = 127) were randomized 1:1 to receive loading doses of subcutaneous satralizumab or placebo at weeks 0, 2, and 4, followed by every-4-week dosing through week 20 (part I). MAIN OUTCOME MEASURES:The primary endpoint was the proportion of participants with active TED who achieved a proptosis response (≥2-mm reduction from baseline) at week 24. Secondary endpoints included the proportion of participants with a ≥2-point CAS reduction, disease inactivation (CAS of 0 or 1), and an ≥1-grade diplopia reduction at week 24. Efficacy outcomes were also reported for the combined active and inactive TED population. Safety was assessed in all participants exposed to study treatment. RESULTS:In participants with active TED, the satralizumab arm of both trials consistently showed an increased proportion achieving a proptosis response (SatraGO-1: 49.0% vs. 31.2%, P = 0.0715; SatraGO-2: 52.9% vs. 23.4%, P = 0.0011), CAS reduction (SatraGO-1: 78.0% vs. 54.9%, P = 0.0120; SatraGO-2: 89.6% vs. 63.3%, P = 0.0009), CAS of 0 or 1 (SatraGO-1: 68.0% vs. 45.1%, P = 0.0146; SatraGO-2: 68.8% vs. 40.8%, P = 0.0042), and diplopia reduction (SatraGO-1: 44.4% vs. 34.4%, P = 0.3371; SatraGO-2: 60.7% vs. 25.8%, P = 0.0044) vs. placebo, although not all comparisons reached statistical significance. Similar clinical benefits were observed in the combined active and inactive TED population. Satralizumab was well tolerated, with low rates of serious adverse events, treatment discontinuations, and infections, and no serious infections. CONCLUSIONS:Satralizumab demonstrated clinically meaningful improvements in proptosis, CAS, and diplopia, and had a favorable safety profile in participants with TED. Interleukin-6 pathway inhibition with subcutaneous satralizumab represents an efficacious and well-tolerated treatment option for patients with TED.
Purpose: The aim of this study was to investigate the influence of alignment and joint line correction on soft tissue balance after functionally aligned (FA) robotic arm-assisted cruciate-retaining (CR) total knee arthroplasty (TKA). Methods: This retrospective analysis included 59 patients who underwent unilateral FA CR-TKA. Knee phenotypes, including joint line obliquity (JLO) and arithmetic hip–knee–ankle angle (aHKA), and an intra-operative surgical plan using a robotic system were examined. The joint component gap balance at extension and flexion was measured using an offset-type tensor after insertion of the femoral trial components, and the correlations between gap balance and knee phenotypes were statistically evaluated. Correlations between gap balance and clinical outcomes were also evaluated. Result: The aHKA and its correction were positively correlated with extension gap balance, but not with flexion gap balance. The tibial JLO correction angles were positively correlated with extension gap balance. The tibial lateral bone resection thickness was positively correlated with the extension gap balance and the tibial JLO correction angle. Flexion gap balance was not correlated with tibial JLO correction angle or external rotational angle relative to the femoral posterior condylar axis, and the two factors were positively correlated with each other. No significant correlations were found between clinical outcomes and gap balance. Conclusions: Tibial JLO correction and tibial lateral bone resection thickness were associated with extension gap balance in FA CR-TKA. Knee phenotypes and tibial resection thickness should be considered when surgeons attempt to balance the extension gap in CR-TKA.
