Vickie McDonald

Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura

Summary.  Background: Increasingly, patients with acute, idiopathic, antibody mediated thrombotic thrombocytopenic purpura (TTP) are being treated with rituximab to achieve a durable remission, however, there is the potential that it is removed by plasma exchange (PEX). Objectives: To look at the pharmacokinetics and pharmacodynamics of rituximab in patients with acute idiopathic TTP undergoing PEX. Patients and methods: Patients who received rituximab for acute idiopathic TTP (group 1, n = 30) and a control group (group 2, n = 3) of TTP patients in remission receiving rituximab electively as maintenance were included. Rituximab levels were measured before/after each infusion, before/after PEX and in follow‐up. ADAMTS‐13 activity, anti‐ADAMTS‐13 IgG and CD19% were measured to assess response. Results: The median number of PEX to remission after rituximab was 10 (range 4–25). In group 1 there was no significant incremental rise in the peak serum rituximab level until dose 4. Trough levels were lower in patients who had had PEX since their last rituximab infusion. In the control group, there was an incremental rise in the peak serum rituximab level and all patients had detectable trough levels. The median fall in rituximab per PEX was 65%. All patients achieved CD19 < 1%. In group 1, the median time to undetectable rituximab was 5 months (range 0–12 months) and to B cell return was 7 months (range 3–24 months). ADAMTS‐13 increased and anti‐ADAMTS‐13 fell after therapy. There were three deaths and two relapses in group 1. Relapse was not temporally related to B cell return.

Human leukocyte antigen association in idiopathic thrombotic thrombocytopenic purpura: evidence for an immunogenetic link

Summary.  Background: Thrombotic thrombocytopenic purpura (TTP) is a rare, acute, life‐threatening disorder, associated with a deficiency in ADAMTS 13. The majority of acute, idiopathic, adult TTP cases are associated with anti‐ADAMTS 13 IgG antibodies. However, the factor(s) precipitating an acute TTP episode are not always obvious; indeed, a multifactorial etiology is likely. Objectives and Methods: DNA was used for human leukocyte antigen (HLA) class II typing, using polymerase chain reaction (PCR)–sequence‐specific primer and PCR–sequence‐specific oligonucleotide probe to methodology to investigate 50 European acquired idiopathic TTP cases. Results: There was an increase in the frequency of HLA‐DQB1*0301 (HLA‐DQ7) in patients with TTP as compared with controls [58.0% vs. 34.5% (P = 0.048)]. The frequencies of HLA‐DRB1*11 and HLA‐DRB3* were also significantly increased in TTP patients as compared with controls [44.0% vs. 12.0% (P = 0.0024) and 84.0% vs. 58.0% (P = 0.024)], although it remains uncertain whether susceptibility is influenced by HLA‐DQ or HLA‐DR molecules or other genes in this haplotype. The frequencies of HLA‐DRB1*04 and HLA‐DRB4 (HLA‐DR53) were significantly decreased in the patient group as compared with controls [10.0% vs. 35.0% and 26.0% vs. 61.5% (P = 0.0096 and P = 0.0024, respectively)], and may have a protective effect against the development of TTP. Conclusion: Analysis identified HLA class II types associated with susceptibility to and a protective effect against the development of acute acquired TTP in European patients. This provides the first description of a genetic factor predicting the risk of developing acquired antibody‐mediated TTP.

Rituximab in non-haematological disorders of adults and its mode of action.

Rituximab is currently licenced for the treatment of CD20 positive lymphoma and rheumatoid arthritis (RA), however, it is increasingly being used off‐label in a wide variety of non‐haematological conditions. Although there are limited numbers of randomised controlled trials, there is a growing body of evidence for its efficacy in rheumatology, renal disease, solid organ transplantation, neuromuscular disorders, skin and endocrine disorders. The mechanism of action of rituximab in these conditions is not always clear and is likely to be via modification of both B and T cell function. Rituximab appears to be well tolerated in most groups of patients but certain side effects may be more prominent in particular conditions. This review examines the evidence base behind the use of rituximab in non‐haematological conditions in adults and any special considerations that need to be taken into account when treating particular disease groups.

Thrombotic thrombocytopenic purpura precipitated by acute pancreatitis: a report of seven cases from a regional UK TTP registry

Thrombotic thrombocytopenic purpura (TTP) may be idiopathic or secondary. We report seven TTP cases precipitated by pancreatitis. The patients were admitted with acute pancreatitis and at that time had no clinical or laboratory features of TTP. The median time to develop TTP after pancreatitis was 3 d. The patients had moderately reduced ADAMTS13 activity (mean activity 49%; normal range 66–126%) with no evidence of anti‐ADAMTS13 inhibitory autoantibodies. The median number of plasma exchanges to remission was 10 (range 7–14) and no additional treatment with immunosuppression was required to maintain remission. There have been no relapses to date.

Acquired, noncongenital thrombotic thrombocytopenic purpura in children and adolescents: clinical management and the use of ADAMTS 13 assays

Thrombotic thrombocytopenic purpura (TTP) in children is rare and is often thought to be due to congenital ADAMTS13 deficiency. We report seven new cases of noncongenital TTP in children and adolescents and perform a review of the literature where ADAMTS13 assays have been performed in paediatric acquired TTP. All new cases were female and the median age was 13 years. Presenting clinical features included bruising/petechiae or bleeding, fever, neurological, and renal impairment. Median Hb and platelet counts on admission were 66 g/l and 10 × 109/l respectively. Two cases had raised Troponin T levels and one had an abnormal ECG. All cases had ADAMTS13 activity less than 5% and an inhibitor to ADAMTS13. The median number of plasma exchange to remission was 22.5. Six cases received rituximab. Three achieved normal ADAMTS13 activity and remain in remission. Two had persistently low ADAMTS13 activity with high anti-ADAMTS13 IgG levels and one of these relapsed. One had moderately reduced levels of ADAMTS13 in remission with no inhibitor, however, a fall in ADAMTS13 activity and increase in anti-ADAMTS13 IgG heralded clinical relapse. The literature review identified 12 acquired cases showing low ADAMTS13 activity and inhibition of ADAMTS13 (in 95%). In children and adolescents TTP may be due to acquired deficiency of ADAMTS13, associated with an inhibitor/Anti-ADAMTS13 IgG antibodies. Treatment of acquired disease requires PEX and usually immunosuppressive treatment. Rituximab appears to be an effective adjunctive treatment modality.

Serum rituximab levels and efficiency of B cell depletion: differences between patients with rheumatoid arthritis and systemic lupus erythematosus

Serum rituximab levels and efficiency of B cell depletion: differences between patients with rheumatoid arthritis and systemic lupus erythematosus SIR, Variability in clinical response to rituximab-induced B cell depletion therapy (BCDT) is well described in both RA and SLE [1, 2]. Recent evidence suggests that an inadequate depletion is associated with poor clinical response in both RA and SLE [3, 4]. Importantly, it was shown that clinical response depended on the degree of depletion and not the dose of rituximab in RA [4]. In a study of patients with RA, the majority of inadequate responders (IRs) to the first cycle of rituximab treatment had a greater number of circulating plasmablasts at base-line, with 90% not achieving adequate depletion, defined as CD19 + B cells <0.0001 Â 10 9 /l [using highly sensitive flow-cytometry (HSFC)], when compared with 60% of re-sponders. Importantly, 72% of the first-cycle IRs subsequently showed a clinical improvement following a second cycle of rituximab given 6 months after the first cycle [5]. In SLE, an initial Phase II dose-escalation study of rituximab employing three dosing regimens found that serum rituximab levels and the degree of B cell depletion were highly variable between patients regardless of the dose used [6]. Vital et al. [3] reported that in SLE, poor clinical response (as measured by BILAG 2004 score) was associated with an inadequate degree of depletion (>0.0001 Â 10 9 CD19 + B cells/l determined using HSFC at 2 weeks after the second dose of 1 g rituximab), which occurred in all IRs. Thus, inadequate depletion appears to be clinically relevant, but the underlying causes remain elusive. It is worth noting that earlier studies of BCDT in RA and SLE defined complete depletion as a CD19 + B cell count ranging from <0.005 to 0.01 Â 10 9 /l. We hypothesized that the levels of rituximab reached in the serum might be lower in patients with SLE, in whom inadequate depletion is more frequent, than in patients with RA. To test our hypothesis, we undertook a retrospective study that investigated (i) the relationship between rituxi-mab levels and CD19 + B cell count and (ii) whether there were any differences in the levels of rituximab in patients with RA and SLE receiving their first cycle of rituximab (thereby, although not absolutely, minimizing the confounding effect of human anti-chimeric antibodies). This study had ethical approval from the local research ethics committee …