Lilian Soto

Effect of interleukin‐6 receptor blockade on the balance between regulatory T cells and T helper type 17 cells in rheumatoid arthritis patients

A new paradigm has emerged relating the pathogenesis of rheumatoid arthritis (RA), focused on the balance between T helper type 17 cells and regulatory T cells (Tregs). In humans, both subpopulations depend on transforming growth factor (TGF)‐β for their induction, but in the presence of inflammatory cytokines, such as interleukin (IL)‐6, the generation of Th17 is favoured. Tocilizumab is a therapeutic antibody targeting the IL‐6 receptor (IL‐6R), which has demonstrated encouraging results in RA. The aim of this study was to evaluate the effect of tocilizumab on Th1 cells, Th17 cells, IL‐17 and interferon (IFN)‐γ double secretors Th17/Th1 cells, and Tregs in RA patients. Eight RA patients received tocilizumab monthly for 24 weeks and blood samples were obtained every 8 weeks to study T cell populations by flow cytometry. The frequency of Th17 cells, Th1 cells and Th17/Th1 cells was evaluated in peripheral blood mononuclear cells (PBMCs) activated in vitro with a polyclonal stimulus. Tregs were identified by their expression of forkhead box protein 3 (FoxP3) and CD25 by direct staining of PBMCs. Although no changes were detected in the frequency of Th1 or Th17 cells, the percentages of peripheral Tregs increased after therapy. In addition, the infrequent Th17/Th1 subpopulation showed a significant increment in tocilizumab‐treated patients. In conclusion, tocilizumab was able to skew the balance between Th17 cells and Tregs towards a more protective status, which may contribute to the clinical improvement observed in RA patients.

B cells from rheumatoid arthritis patients show important alterations in the expression of CD86 and FcγRIIb, which are modulated by anti-tumor necrosis factor therapy

IntroductionSeveral molecules help preserve peripheral B cell tolerance, but when altered, they may predispose to autoimmunity. This work studied the expression of the costimulatory molecule CD86 and the inhibitory receptor for IgG immune complexes FcγRIIb (CD32b), on B cells from rheumatoid arthritis (RA) patients, and the influence of anti-tumor necrosis factor (TNF) therapy.MethodsPeripheral B cells from 18 RA patients and 13 healthy donors were characterized using flow cytometry. Eleven patients who underwent a six-month adalimumab therapy were further assessed for phenotypic changes on their B cells.ResultsRA patients exhibited a high percentage of naïve and memory B cells expressing CD86. In contrast, expression of FcγRIIb was significantly reduced on RA memory B cells and plasmablasts as compared to healthy donors, probably due to downregulation of this receptor when differentiating from naïve to memory cells. These alterations on FcγRIIb were associated with high levels of anti-citrullinated vimentin autoantibodies. In addition, treatment with adalimumab normalized the expression of CD86 on memory B cells and reduced the expression of FcγRIIb, mainly on naïve B cells.ConclusionsOur findings show that peripheral B cells from RA patients have an altered expression of key molecules, such as CD86 and FcγRIIb. Because this latter receptor is required for feedback inhibition, a deficient expression might contribute to humoral autoimmune responses. Furthermore, these molecules are likely to be influenced by inflammatory factors, since they were modulated by TNF inhibition.

Discontinuation of tumour necrosis factor inhibitors in patients with rheumatoid arthritis in low-disease activity: persistent benefits. Data from the Corrona registry

BACKGROUND There is increasing interest in discontinuing biological therapies for patients with rheumatoid arthritis (RA) achieving good clinical responses, provided patients maintain clinical benefit. METHODS We assessed patients with RA from the Corrona registry who discontinued treatment with their first tumour necrosis factor inhibitor (TNFi) while in low-disease activity (LDA) or lower levels of disease activity. Patients were followed until they lost clinical benefit, defined as increased disease activity or change in RA medications. Duration of maintenance of clinical benefit was estimated using the Kaplan-Meier method. Cox proportional hazard models were assessed to identify factors related to maintenance of benefit. RESULTS We identified 717 eligible patients with RA from 35,656 in the Corrona registry. At discontinuation, patients had a median RA duration of 8 years, mean clinical disease activity score of 4.3±0.11; 41.8% were using TNFi as monotherapy. 73.4% of patients maintained benefit for >12 months after discontinuing therapy and 42.2% did so through 24 months. Factors predictive of maintaining clinical benefit in multivariate analysis included lower disease activity, less pain and better functional status at the time of TNFi discontinuation. Among 301 patients initiating their first TNFi within the registry, faster responders (ie, those who achieved LDA in 4 months or less) did better than slower responders (HR 1.54 (95% CI 1.17 to 2.04)). RA disease duration did not affect maintenance of clinical benefit. CONCLUSIONS Discontinuation of a first course of TNFi may be associated with persistent clinical benefit. Half of patients maintained response through 20 months. Several patient characteristics may help predict persistent benefit.

A short protocol using dexamethasone and monophosphoryl lipid A generates tolerogenic dendritic cells that display a potent migratory capacity to lymphoid chemokines

BackgroundGeneration of tolerogenic dendritic cells (TolDCs) for therapy is challenging due to its implications for the design of protocols suitable for clinical applications, which means not only using safe products, but also working at defining specific biomarkers for TolDCs identification, developing shorter DCs differentiation methods and obtaining TolDCs with a stable phenotype. We describe here, a short-term protocol for TolDCs generation, which are characterized in terms of phenotypic markers, cytokines secretion profile, CD4+ T cell-stimulatory ability and migratory capacity.MethodsTolDCs from healthy donors were generated by modulation with dexamethasone plus monophosphoryl lipid A (MPLA-tDCs). We performed an analysis of MPLA-tDCs in terms of yield, viability, morphology, phenotypic markers, cytokines secretion profile, stability, allogeneic and antigen-specific CD4+ T-cell stimulatory ability and migration capacity.ResultsAfter a 5-day culture, MPLA-tDCs displayed reduced expression of costimulatory and maturation molecules together to an anti-inflammatory cytokines secretion profile, being able to maintain these tolerogenic features even after the engagement of CD40 by its cognate ligand. In addition, MPLA-tDCs exhibited reduced capabilities to stimulate allogeneic and antigen-specific CD4+ T cell proliferation, and induced an anti-inflammatory cytokine secretion pattern. Among potential tolerogenic markers studied, only TLR-2 was highly expressed in MPLA-tDCs when compared to mature and immature DCs. Remarkable, like mature DCs, MPLA-tDCs displayed a high CCR7 and CXCR4 expression, both chemokine receptors involved in migration to secondary lymphoid organs, and even more, in an in vitro assay they exhibited a high migration response towards CCL19 and CXCL12.ConclusionWe describe a short-term protocol for TolDC generation, which confers them a stable phenotype and migratory capacity to lymphoid chemokines, essential features for TolDCs to be used as therapeutics for autoimmunity and prevention of graft rejection.

Infliximab can induce a prolonged clinical remission and a decrease in thyroid hormonal requirements in a patient with SAPHO syndrome and hypothyroidism

SAPHO syndrome is a rare entity that compromises the skeletal system (arthritis–osteitis) and is associated with various dermatological conditions such as palmoplantaris pustulosis (PPP) and acne. We present the case of a 39-year-old man with invalidating arthritis derived from a SAPHO syndrome and hypothyroidism (after radioiodine treatment for a Graves’ disease). Due to the severity and refractoriness of his disease, we decided to use infliximab. He showed a prompt and prolonged response of his joint and cutaneous manifestations after three doses of a tumor necrosis factor alpha (TNF-α) blocker. Interestingly, he also decreased his levothyroxine requirements after TNF-α blockade therapy.

Skewing dendritic cell differentiation towards a tolerogenic state for recovery of tolerance in rheumatoid arthritis.

To date, the available options to treat autoimmune diseases such as rheumatoid arthritis (RA) include traditional corticoids and biological drugs, which are not exempt of adverse effects. The development of cellular therapies based on dendritic cells with tolerogenic functions (TolDCs) has opened a new possibility to efficiently eradicate symptoms and control the immune response in the field of autoimmunity. TolDCs are an attractive tool for antigen-specific immunotherapy to restore self-tolerance in RA and other autoimmune disorders. A promising strategy is to inject autologous self-antigen-loaded TolDCs, which are able to delete or reprogram autoreactive T cells. Different protocols for the generation of stable human TolDCs have been established and the therapeutic effect of TolDCs has been investigated in multiple rodent models of arthritis. Pilot studies in humans confirmed that TolDC application is safe, encouraging clinical trials using self-antigen-loaded TolDCs in RA patients. Although an abundance of molecular regulators of DC functions has been discovered in the last decade, no master regulator of tolerogenicity has been identified yet. Further research is required to define biomarkers or key regulators of tolerogenicity that might facilitate the induction and monitoring of TolDCs.

Leflunomide decreases joint erosions and induces reparative changes in a patient with psoriatic arthritis

We read with great interest the article by Scott and colleagues,1 in which they report radiological improvement or halting of disease progression with leflunomide treatment in a group of patients with rheumatoid arthritis (RA). Leflunomide has also been reported to be effective in some studies including a small group of patients with psoriatic arthritis (PsA), but radiological evolution was not evaluated.2,3 We report the case of a patient with PsA who had clinical remission and radiological amelioration after a year with leflunomide treatment. To our knowledge, this is the first evidence that leflunomide may induce reparative changes such as filling of a bone cyst in a patient with PsA. A 37 year old white man presented in August 1997 with a history of pain in the left wrist, right ankle, and both feet during the previous three months. His past history and physical examination were unremarkable except for synovitis in the painful joints and a single well demarcated erythematous hyperkeratotic plaque on the trunk. A dermatologist was consulted and psoriasis vulgaris was confirmed …

The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis

Therapeutic blockage of cytokine signalling in autoimmune diseases has improved our understanding of the role of these cytokines in triggering, shaping and perpetuating autoimmune responses. In rheumatoid arthritis (RA), immunopathology is driven by a predominance of arthritogenic T helper cells secreting interferon‐γ [T helper type 1 (Th1)] and interleukin (IL)‐17 (Th17) over regulatory T cells (Treg). The pleiotropic cytokine IL‐6 is crucial to the differentiation of Th17 cells and the balance between pathogenic Th17 and protective Treg. Targeting the IL‐6 receptor (IL‐6R) by humanized antibodies improves signs and symptoms of RA, and has provided new insights into the mechanisms of inflammation and immune regulation. Here we review current evidence on the role of IL‐6 in the pathogenesis of RA and the molecular consequences of IL‐6R blockage in disease, with special focus on the Th17/Treg balance and plasticity.

Enfermedad de Behçet en Chile: Análisis clínico de 44 casos

12 years. According to BDCJ criteria, 13 patients had complete BD, 24 hadincomplete BD and 7 had a suspected BD. Thirty two patients fulfilled the ISG criteria. Forty twopatients (95%) had oral ulcers, 33 (75%) had genital ulcers and 29 (66%) hadophthalmological involvement. Eleven and three patients had symptoms of central andperipheral nervous system involvement, respectively. No gender differences were detected.

Systemic vasculitis associated with Fasciola hepatica infection

We report the case of a 50‐year‐old man who presented with systemic vasculitis associated with Fasciola hepatica infection. The patient presented with severe skin, kidney, spleen, ophthalmic, and neurological compromise. An immunological examination for primary vasculitis was negative and other infections were discounted by microbiological and serological analyses. The patient was treated with steroids without clinical response. The Fasciola hepatica infection was confirmed by the presence of specific immunoglobulin G (IgG) serum antibodies detected by a quantitative enzyme‐linked immunosorbent assay (ELISA) with an optical density (OD) of 0.483 OD units (normal value<0.170 OD units) and a high‐titre complement fixation (1/80 dilution). The patient received treatment with triclabendazole and all symptoms and systemic manifestations resolved within weeks. Hence, this previously unreported vasculitis‐associated infection, if identified opportunely, can be treated and cured.