MabThera - Physicians Area of MabThera for Rheumatoid Arthritis

For over 20 years, RA has been considered to be a T cell-mediated disease. Recent evidence, however, has sparked a strong interest in B cells and their key role in the pathogenesis of RA.

Although the underlying causes of RA remain elusive, B cells have been shown to play at least three critical roles in the pathophysiology of RA:

B cells can function as antigen-presenting cells, leading to T cell activation.

B cells present in the RA synovial membrane may secrete a range of pro-inflammatory cytokines, some of which are components in the process leading to joint inflammation and damage.

B cells produce auto-antibodies such as rheumatoid factor (RF). In the synovium, RF immune complexes may mediate complement activation and the propagation of the inflammatory cascade.

References: Lund et al. 2005; Silverman and Carson 2003.

MabThera is the first and only selective B cell-targeted therapy for RA. It is a genetically engineered, chimeric monoclonal antibody that selectively targets the subset of B cells that express the CD20* protein, leaving stem cells, pro-B cells and plasma cells unaffected.

After MabThera binds to CD20, depletion of CD20-positive B cells by MabThera occurs by three possible mechanisms:

Initiation of complement-mediated B cell lysis. The complex of MabThera with CD20 initiates the complement cascade, activating the membrane attack complex, which results in the lysis of CD20-positive B cells.

Initiation of cell-mediated cytotoxicity. Natural killer cells, macrophages and monocytes are recruited through the human-derived portion of MabThera when it is bound to CD20, inducing CD20-positive B cell lysis.

Promotion of CD20-positive B cell apoptosis. Apoptosis (programmed cell death) may be induced by the binding of MabThera, leading to CD20-positive B cell lysis.

*CD = cluster of differentiation

References: Clynes et al. 2000; Golay et al. 2000

If a patient experienced an infusion reaction during the first infusion, the patient needs to be carefully monitored during subsequent infusions. In such a case, the initial rate of the second infusion should be the same as for the first infusion.

The initial rate of 50 mg/hour can be escalated in 50 mg increments every 30 minutes to a maximum rate of 400 mg/hour.

Infusion reactions with MabThera are mainly mild–moderate, easily managed and reduce with further infusions.

In most cases, the infusion can be temporarily interrupted and subsequently resumed at a slower (50%) rate when all symptoms have completely resolved.

In the event of a severe reaction, infusion of MabThera should be stopped immediately and patients should receive aggressive symptomatic treatment.

The efficacy and safety of the combination of MabThera with DMARDs other than methotrexate remain to be investigated.

The benefits of a single course of treatment with MabThera remain optimal for at least 6 months in the majority of patients, and then start to decline. Patients should be treated to achieve and maintain a state of low disease activity/remission, avoiding disease flare. Therefore, subsequent treatment with MabThera should be considered from 6 months onwards based upon disease activity (most patients receive a repeat course after 6–12 months).

In clinical trials, no patients received a further course of treatment sooner than 16 weeks after the previous course of MabThera.

MabThera as monotherapy has been shown to be more effective than methotrexate alone, although the efficacy of MabThera is more pronounced and better sustained when used in combination with methotrexate. MabThera is approved for use in combination with methotrexate.

The efficacy of MabThera monotherapy was investigated in the Phase IIa study in a limited number of patients (n=40). Of these patients, 65% achieved an ACR20 response compared with 38% of patients receiving methotrexate (p=0.025). At the ACR50 level (the primary endpoint of the trial), the proportion of patients responding was higher in the MabThera monotherapy group than in patients continuing on methotrexate (33% versus 13%); this difference approached, but did not achieve, statistical significance (p=0.059).

Reference: Edwards et al. 2004

No opportunistic infections have been reported to date in RA clinical studies.

Unlike TNF inhibitor therapies, MabThera acts by depleting B cells and has no effect on granuloma stabilisation.

No cases of TB reactivation have been reported during the entire MabThera RA clinical development programme.

MabThera has been used in the treatment of more than 730,000 oncology patients without major safety concerns. In these patients, there is no evidence to date of an increased risk of TB reactivation.

There is currently no experience with the use of MabThera in patients with RA and previous hepatitis C. In other indications, the effect of MabThera on patients with prior hepatitis C is unclear. Screening for hepatitis C might be considered before MabThera treatment initiation in high-risk patients based on the treating physician’s opinion.

In RA clinical trials, patients were screened for hepatitis C antibodies before study entry.

Hepatitis C has been reported to be associated with various autoimmune diseases. A number of case reports and small studies have been published that assess the efficacy and safety of MabThera in some of these disease areas. In patients with hepatitis C-related autoimmune disease, the impact of MabThera treatment on hepatitis C viral load produced conflicting results, with either a minimal change or decrease in fluctuation of viral load, or an increase in viral load.

References: Aksoy et al. 2006; Roccatello et al. 2004; Sansonno et al. 2003; Weitz 2005; Zaja et al. 2003

The first infusion of each course lasts 4 hours 15 minutes. The second infusion of each course lasts 3 hours 15 minutes.

MabThera Summary of Product Characteristics:

During the first infusion of each course, the initial infusion rate of 50 mg/hour can be escalated in 50 mg increments every 30 minutes to a maximum rate of 400 mg/hour.

During the second infusion of each course, the initial rate of 100 mg/hour can be escalated in 100 mg increments every 30 minutes to a maximum rate of 400 mg/hour.

References: MabThera Summary of Product Characteristics

Pre-medication with intravenous glucocorticoids (methylprednisolone 100 mg or its equivalent) has been shown to significantly reduce both the frequency and the severity of acute infusion reactions and is therefore recommended before each infusion of MabThera. Oral glucocorticoids provide no additional benefit.

Reference: van Vollenhoven et al. 2005

The same as the initial course: 2 infusions of MabThera 1000 mg administered 2 weeks apart.

This regimen has been shown to maintain or further improve clinical response in patients receiving further courses of MabThera.

References: De Vita et al. 2006; Emery et al. 2006; Fleischmann et al. 2005; Keystone et al. 2006; Tak et al. 2006; van Vollenhoven et al. 2006; van Vollenhoven et al. 2006

The first signs of response are usually seen 4–8 weeks following the first infusion of MabThera in clinical trials. Maximal response is generally achieved from 16 weeks.

References: Emery et al. 2006; Cohen et al. 2006

There is currently no experience with MabThera in patients with RA with previous hepatitis B.

Based on reported reactivation of hepatitis B in patients with NHL, the US package insert recommends the screening of patients with a high risk of hepatitis B infection before starting treatment. Of note, the American College of Rheumatology also recommends screening patients with RA for hepatitis prior to MabThera initiation.

In RA clinical trials, no case of hepatitis B reactivation has been observed, however patients were pre-screened for HBV. One patient with RA developed a de novo hepatitis B infection 4 months after administration of the first dose of MabThera. This resolved without complication following treatment with lamivudine.

In the oncology setting, while both the underlying disease and the concomitant chemotherapy are confounding factors, very rare cases of hepatitis B reactivation (including reports of fulminant hepatitis) have been reported in patients treated with MabThera; the majority of these patients were also receiving chemotherapy.

References: ACR hotline, May 2006; Rituxan Prescribing Information

The duration of response to just 2 infusions of MabThera given 2 weeks apart is unprecedented – the majority of patients have a response that lasts for at least 6 months. Although extended therapeutic efficacy is seen in a small subset of patients for up to 12 months or longer, most patients lose their response between 6 and 12 months following the initial course of MabThera and require a repeat course at this time.

There are no clinical or biological markers that have been identified to date that can be used to predict the precise duration of effect of MabThera in individual patients.

Pharmacokinetic and pharmacodynamic data support the consideration of 6 months as a time marker for repeat treatment with MabThera. At 6 months, MabThera blood levels are below the limit of detection and the start of peripheral B cell return (repletion) is also apparent, although this is not necessarily predictive of a return of symptoms.

References: Breedveld et al. 2005; Cohen et al. 2006; Edwards et al. 2004; Edwards et al. 2005; Emery et al. 2006; Magrini et al. 2005