CD28 negative T cells are enriched in granulomatous lesions of the respiratory tract in Wegener's granulomatosis

356

153

Objective. To report baseline data on 180 patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET), and to examine demographic and clinical differences between patients with limited disease and those with severe disease.Methods. Definitions of limited and severe disease were agreed upon by consensus of the investigators at a pretrial meeting and were incorporated into the protocol as a stratification criterion. These data were applied prospectively to the WGET patient cohort, based on clinical features and the intention to treat patients according to disease activity. Data related to disease onset, date of diagnosis, clinical features, antineutrophil cytoplasmic antibody assays, tissue biopsy findings, and other medical history were collected on a baseline medical history form. Physician-investigators from each center participated in the development of this form, and all were certified in its use prior to the start of the trial. Selected data on patients who were screened for the trial but were not enrolled were also collected.Results. Several significant differences between the limited and severe disease subsets were observed. Patients with limited disease were nearly a decade younger at disease onset compared with patients with severe disease. Thirty-three percent of patients with severe disease were women, compared with 58% of those with limited disease. Despite their younger age at symptom onset, patients with limited disease tended to have longer disease duration, a greater likelihood of experiencing exacerbation of previous disease following a period of remission, and a higher prevalence of destructive upper respiratory tract disorders at the time of enrollment (e.g., saddle-nose deformity). Patients with limited WG were less likely than those with severe disease to have antibodies to either proteinase 3 or myeloperoxidase. Patients with severe disease had a higher likelihood of previous thyroid disease, particularly either Graves' disease or Hashimoto thyroiditis, suggesting the possibility of different pathogenetic factors within these disease subsets. Other observed differences between these subsets, such as the greater frequency of alveolar hemorrhage in the severe disease group, were related to the a priori definitions of limited and severe disease.Conclusion. There are significant differences between patients with limited WG and those with severe WG with regard to sex, age, the likelihood of recurrent disease, the risk of damage in certain organ systems, and, possibly, etiologic factors. These differences (and perhaps other differences that are currently unrecognized) in patient subsets may have implications for mechanisms of pathogenesis, prognosis, response to treatment, and the design of future clinical investigations.

Section: Discussionmentioning

confidence: 60%

Limited versus severe Wegener's granulomatosis: Baseline data on patients in the Wegener's granulomatosis etanercept trial

Stone¹

2003

356

153

“…Indeed, rituximab treatment in rheumatoid arthritis has been shown to lead to depletion of other major cell populations, such as T cells and macrophages within synovial tissue (37). Granulomatous lesions in WG are made up of monocyte-derived tissue macrophages, giant cells, CD4ϩ T cells, and B cells (38,39). In addition, it has been reported that the orbital granulomas of WG reflect a variable histopathologic picture of inflammation, fibrinoid necrosis, and, in particular, excessive fibrosis, but only rarely vasculitis (40).…”

Section: Discussionmentioning

confidence: 99%

Rituximab is effective in the treatment of refractory ophthalmic Wegener's granulomatosis

Taylor¹,

Salama²,

Joshi³

et al. 2009

169

Objective. To investigate the efficacy of rituximab in patients with refractory ophthalmic Wegener's granulomatosis (WG).Methods. Data from 10 consecutive patients with refractory ophthalmic WG treated with rituximab were retrospectively reviewed. In all patients, the ophthalmic disease was driving treatment decisions, and disease activity had persisted despite standard immunosuppressive treatment. Patients had refractory scleritis (n ‫؍‬ 3), orbital granulomas causing optic nerve compromise (n ‫؍‬ 4), or a combination of both conditions (n ‫؍‬ 3). All patients had been treated with at least 3 different immunosuppressive agents, and 5 patients had previously been treated with tumor necrosis factor ␣ blockade. Rituximab was administered intravenously in 2 doses, 2 weeks apart, in combination with standard treatment. Disease activity was monitored clinically by an interdisciplinary approach, including disease activity scoring, immunodiagnostics, and magnetic resonance imaging, as well as by corresponding reductions in the required dose of conventional medication.

“…Several chronic diseases, such as RA (10), juvenile idiopathic arthritis (11), ankylosing spondylitis (12), Wegener's granulomatosis (13), and Crohn's disease (14), have also been found to be associated with unusually high frequencies of CD28 null T cells that are disproportionate with patient age. In RA and Wegener's granulomatosis, the frequency of CD4ϩ,CD28 null T cells is correlated with the severity of clinical disease manifestations (15,16).…”

Section: Conclusion Overproduction Of Tnf␣ In Ra Induces a Global Domentioning

confidence: 99%

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Bryl¹,

Vallejo²,

Matteson³

et al. 2005

122

Objective. The immune system of patients with rheumatoid arthritis (RA) is characterized by the accumulation of CD4؉ T cells deficient in CD28 expression and the up-regulation of tumor necrosis factor ␣ (TNF␣). Previous in vitro studies have shown that TNF␣ induces transcriptional silencing of the CD28 gene. Because reduced expression of CD28 in T cells compromises immunocompetence, we examined whether CD28 expression is reduced in patients with RA in vivo and whether the reduction is related to TNF␣.Methods. Patients with RA and age-matched individuals were recruited. Peripheral blood mononuclear cells were stained for CD3, CD4, CD8, CD28, TNF receptor I (TNFRI), and TNFRII, and analyzed by quantitative flow cytometry. The number of CD28 and TNFR molecules was monitored in a subgroup of patients with RA undergoing treatment with anti-TNF␣.Results. In addition to higher frequencies of CD28 null T cells, patients with RA had significantly reduced numbers of CD28 and TNFRI molecules on CD4؉,CD28؉ T cells. Normal expression could be restored in vitro by overnight culture, suggesting that CD28 in patients was modulated by exogenous factors. In contrast, treatment with TNF␣ in vitro resulted in further down-regulation. CD28 expression was normalized in patients undergoing TNF␣-neutralizing therapy.Conclusion. Overproduction of TNF␣ in RA induces a global down-regulation of CD28 in CD4؉ T cells and may cause reduced sensitivity to costimulatory signals in T cell responses.