32 research outputs found
Impact of rituximab trials on the treatment of ANCA-associated vasculitis
No full textANCA-associated vasculitis (AAV) is a subgrouping of autoimmune disorders characterized by a chronic relapsing course. Induction therapy is usually effective, but 70% of patients will relapse and 20% develop refractory disease. In the relapsing and refractory subgroups, treatment is complicated by the cumulative exposure to toxic drugs that contribute to poor long-term outcomes. The anti-CD20 monoclonal antibody rituximab (RTX) depletes B cells, and the success of this targeted therapy has contributed to the evidence supporting a central role for B cells in AAV pathogenesis. Initial proof of RTX effectiveness originated from small, prospective trials and retrospective surveys conducted in AAV patients with relapsing and refractory disease; high remission rates permitted the reduction of glucocorticoids (GCS) doses and withdrawal of immunosuppressives. There has been controversy over the effectiveness of RTX in patients with predominantly granulomatous manifestations, where response rates have varied between studies, in part due to different RTX dosing regimens. These studies were followed by comparison of RTX against cyclophosphamide (CYC) for remission induction of new or relapsing AAV in two randomized trials, which led to the licensing of RTX for this indication. Subsequent attention has been turned to the use of RTX as a relapse prevention agent, to the potential for GCS sparing and to RTX-associated toxicity. We will discuss the impact that the results of RTX clinical trials have had on the management of AAV patients
Immunoglobulin G replacement for the treatment of infective complications of rituximab-associated hypogammaglobulinemia in autoimmune disease : a case series
No full textThe anti-CD20 B cell depleting monoclonal antibody rituximab is being used increasingly for autoimmune diseases, including patients with refractory disease with extensive prior exposure to immunosuppressive treatments. Rituximab, in this context, may be associated with increased risk of adverse effects, in particular hypogammaglobulinemia which predisposes to recurrent infections necessitating Immunoglobulin G replacement. Outcome data following Immunoglobulin G replacement after rituximab in patients with autoimmune disease are limited. We conducted a retrospective study in a tertiary referral lupus and vasculitis clinic of 288 patients who received rituximab. Clinical details of patients prescribed IgG replacement therapy following rituximab treatment were reviewed. We identified 12 patients with autoimmune disease, 10/12 with systemic vasculitis, received IgG replacement for the treatment of recurrent infections in the context of persistent moderate or severe hypogammaglobulinemia following rituximab. We observed a range of ages (16-67 years), rituximab dosages (2-15.8 g), previous immunosuppression (median 3.5 non-glucocorticoid agents) and duration of disease (2-228 months). Six continued to receive rituximab alongside IgG replacement therapy to maintain disease control. IgG replacement appeared to decrease the incidence and severity of infections, and recovery of IgG concentrations allowed cessation of IgG replacement in two patients after 4 and 7.5 years of treatment. IgG monitoring is useful for patients receiving rituximab. IgG replacement for sustained hypogammaglobulinemia with recurrent infections appeared to be useful in this series. The IgG replacement course is prolonged in most patients, but IgG recovery is reported
Rituximab-associated hypogammaglobulinemia: incidence, predictors and outcomes in patients with multi-system autoimmune disease
No full textRituximab is a B cell depleting monoclonal antibody used to treat lymphoma and autoimmune disease. Hypogammaglobulinemia has occurred after rituximab for lymphoma and rheumatoid arthritis but dataare scarce for other autoimmune indications. This study describes the incidence and severity of hypogammaglobulinemia in patients receiving rituximab for small vessel vasculitis and other multi-system autoimmune diseases. Predictors for and clinical outcomes of hypogammaglobulinemia were explored. We conducted a retrospective study in a tertiary referral specialist clinic. The severity of hypogammaglobulinemia was categorized by the nadir serum IgG concentration measured during clinical care. We identified 288 patients who received rituximab; 243 were eligible for inclusion with median follow up of 42 months. 26% were IgG hypogammaglobulinemic at the time that rituximab was initiated and 56% had IgG hypogammaglobulinemia during follow-up (5-6.9g/L in 30%, 3-4.9g/L in 22% an
Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis
No full textObjective. ANCA-associated vasculitis (AAV) is characterized by a chronic relapsing course. Rituximab
(RTX) is an effective maintenance treatment; however, the long-term outcomes after its discontinuation are
unclear. The aim of this study was to explore the long-term outcomes of AAV patients treated with repeatdose
RTX maintenance therapy.
Methods. AAV patients receiving a RTX treatment protocol consisting of an induction and maintenance
phase were included. For initial remission induction, RTX was dosed at 1 g every 2 weeks or 375 mg/m2
weekly for 4 consecutive weeks and for remission maintenance at 1 g every 6 months for 24 months. At
the first RTX administration, ongoing immunosuppressives were withdrawn.
Results. Sixty-nine patients were identified, 67 of whom were failing other therapies. Nine relapsed during
the RTX treatment protocol; however, all 69 were in remission at the end of the maintenance phase on a
median prednisolone dose of 2.5 mg/day and 9% were receiving additional immunosuppression. During
subsequent observation, 28 patients relapsed a median of 34.4 months after the last RTX infusion. Risk
factors for relapse were PR3-associated disease (P = 0.039), B cell return within 12 months of the last RTX
infusion (P = 0.0038) and switch from ANCA negativity to positivity (P = 0.0046). Two patients died and two
developed severe hypogammaglobulinaemia.
Conclusion. This study supports the efficacy and safety of a fixed-interval RTX maintenance regimen in
relapsing/refractory AAV. Relapses after discontinuation of maintenance therapy did occur, but at a lower
rate than after a single RTX induction course. PR3-associated disease, the switch from ANCA negative to
positive and the return of B cells within 12 months of the last RTX administration were risk factors for
further relaps
Chronic nasal Staphylococcus aureus carriage identifies a subset of newly diagnosed granulomatosis with polyangiitis patients with high relapse rate
No full textObjective. The aim of this study was to evaluate whether chronic nasal carriage of Staphylococcus aureus (SA) is related to relapses in patients with newly diagnosed ANCA-associated vasculitis (AAV).Methods. In two clinical trials (n = 200), for early systemic (n = 83) and generalized (n = 117) AAV, nasal swabs were obtained monthly and at the time of a relapse. Chronic nasal SA carriage (CNSAC) was defined as575% of cultures being SA positive, with non-carriers being SA negative in all cultures and remaining patients being intermittent carriers. Fifty-five of 200 (27.5%) patients received prophylactic trimethoprim/sulfamethoxazole (T/S) against Pneumocystis jirovecii.Results. Of the total AAV patients, 24/200 (12%) were chronic, 102/200 (51%) intermittent and 74/200 (37%) non-carriers. Of 65 relapsing patients, 10/24 (41.7%) were chronic, 32/102 (31.4%) intermittent and 23/74 (31.1%) non-carriers (P = 0.59). For all AAV patients, CNSAC was not associated with an increased relapse risk [odds ratio (OR) = 1.57, 95% CI: 0.66, 3.76; P = 0.31]. However, 23/24 chronic carriers had granulomatosis with polyangiitis (GPA). In the 73 patients with generalized GPA (hazard ratio = 4.10, 95% CI: 1.37, 12.25; P = 0.01) and the 78 patients with early systemic GPA during immunosuppression (hazard ratio = 2.73, 95% CI: 0.95, 7.87; P = 0.06), relapse rates were higher for chronic SA carriers. Prophylactic T/S was not associated with a reduced relapse risk (OR = 0.71, 95% CI: 0.36, 1.41; P = 0.33). Nevertheless, prophylactic T/S reduced CNSAC (OR = 0.19, 95% CI: 0.04, 0.91; P = 0.04).Conclusion. The frequency of CNSAC in newly diagnosed GPA paralleled that in the general population. This subset of GPA patients (23/151, 15.2%) has a high relapse rate despite immunosuppression and prophylactic T/S treatment, requiring further investigations on pathogenesis and therapy
Analysis of anti-idiotypic antibodies against anti-microsomal antibodies in patients with thyroid autoimmunity
No full textELECTRONIC ABSORPTION SPECTRA OF DIMETHYLSELENIDE AND DIMETHYLTELLURIDE
No full textThis work was supported by the Robert A. Welch Foundation. A. J. Harrison and D.R.W. Price, J. Chem. Phys., 30, 357 (1959). G. J. Hernandez, J. Chem. Phys., 38, 1644 (1963). S. D. Thompson, D. G. Carroll, F. Watson, M. O'Donnell, and S. P. McGlynn, J. Chem. Phys., 45, 1367 (1966).Author Institution: Department of Chemistry, North Texas State University DentonThe electronic absorption spectra of dimethylselenide and dimethyltelluride have been measured in the vapor phase between 3000 and 1200 \AA. The absorptions assigned to the non-bonding electrons in each case will be given principal consideration. Discussion of these bands and the spectrally determined ionization potentials will be given in light of the reported spectra of and $dimethylsulfide.^{3}
A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis
No full textPrimary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25ml/min per 1.73m2, and a urine protein to creatinine ratio over 1.8mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85ml/min per 1.73m2). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2mg/mg with all three Black patients having a mean decline of 3.6mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary
A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis.
No full textOBJECTIVE: Assessment of disease activity in vasculitis can be achieved using the BVAS, a clinical checklist of relevant symptoms, signs and features of active disease. The aim of this study was to revalidate the BVAS version 3 (BVAS v. 3) in a cohort of patients with systemic vasculitis. METHODS: A total of 238 patients with vasculitis from seven countries in Europe were evaluated at a single time point. Spearman's correlation coefficients were calculated between BVAS v. 3 scores, vasculitis activity index (VAI), physician's global assessment (PGA), the physician's treatment decision, CRP and the vasculitis damage index (VDI) to demonstrate that the BVAS v. 3 measures disease activity. RESULTS: WG (63%), Churg-Strauss syndrome (9%) and microscopic polyangiitis (9%) were the most common diagnoses. The BVAS v. 3 showed convergent validity with the VAI [ρ = 0.82 (95% CI 0.77, 0.85)], PGA [ρ = 0.85 (95% CI 0.81, 0.88)] and the physician's treatment decision [ρ = 0.54 (95% CI 0.44, 0.62)]. There was little or no correlation between BVAS v. 3 and the CRP level [ρ = 0.18 (95% CI 0.05, 0.30)] or with the VDI [ρ = -0.10 (95% CI 0.22, 0.03)]. The inter-observer reliability was very high with an intra-class correlation coefficient (ICC) of 0.996 (95% CI 0.990, 0.998) for the total BVAS v. 3 score. CONCLUSION: The BVAS v. 3 has been evaluated in a large cohort of patients with vasculitis and the important properties of the tool revalidated. This study increases the utility of the BVAS v. 3 in different populations of patients with systemic vasculitis
The role of biologic therapies in the management of systemic vasculitis.
No full textThe recent development of biologic therapies capable of selectively targeting components of the immune system has revolutionised the treatment of inflammatory arthritides. The steady increase in use of biologic agents coupled with the expansion in the knowledge of the pathogenesis of vascular inflammation has led to their application in the treatment of primary systemic vasculitis. These agents may have a role in addition to or in place of conventional immunosuppression and also be effective when the latter fails to induce remission. The use of biologics as targeted therapies has also, in reverse, improved our understanding of the pathophysiology of vascular inflammation. While the advent of biologics heralds a new era in the management of the systemic vasculitis, evidence for their efficacy is still in its infancy and has yet to match that of conventional immunosuppressants. In this review, we examine the up-to-date evidence for the use of biologics in systemic vasculitis, including TNF-alpha inhibitors, and highlight the challenges facing their use. We examine the rationale for using biologics based on the pathophysiology of vasculitis. Issues of toxicity and pharmacovigilance with the use of biologics are also discussed. Finally, future directions and predictions are presented
