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MEDICAL FRONTIERS - 74th Annual Meeting of the American College of Rheumatology

Atlanta, Georgia / November 7-11, 2010

Predictive Biomarker Responders in the Real World

Observational data from a real-life setting have confirmed the effect of rituximab in tumour necrosis factor (TNF) inhibitor non-responders shown in the REFLEX (Randomized Evaluation of Long-term Efficacy of Rituximab in RA) trial (Arthritis Rheum 2006;54:2793-806) in terms of clinically significant improvement measured by the disease activity score (DAS)28. An even stronger difference in clinical response was found in the patients seropositive for cyclic citrullinated peptide antibody (CCP), suggesting that it may be a useful predictive biomarker for response to rituximab in patients with TNF blocker treatment failure.

The real-world findings from a retrospective cohort study were presented by Dr. Hendrik Schulze-Koops, University of Munich, Germany. Data on 196 patients with active rheumatoid arthritis (RA) who had failed a first TNF inhibitor were contributed by outpatient clinics, academic centres and community hospitals in Germany. Ninety patients had been subsequently treated with rituximab and 106 with a second TNF inhibitor. Both cohorts were comparable with respect to age, duration of disease, DAS28 value and percentage of patients with DMARD therapy at the time of therapy switch.

After a mean of 6.6 months’ therapy with the second biologic, the reduction in mean DAS28 was significantly greater with rituximab vs. the TNF inhibitor (-1.64 vs. -1.19; P=0.01). This cohort difference was similar in a subgroup of rheumatoid factor (RF)-positive patients, but even greater in a subgroup of anti-CCP-positive patients (Figure 1).

Figure 1.

The anti-CCP-positive patients also showed a significantly greater reduction in tender joint counts (-5.28 vs. -3.06; P=0.02). More patients on rituximab than on the TNF inhibitor reached a moderate-good EULAR response (82.2% vs. 71.7%); this difference was significant in the anti-CCP-positive patients (85.3% vs. 67.2%; P=0.01). “Support is growing for anti-CCP positivity over RF positivity as easy guidance to help identify those individuals who might respond best to rituximab,” Dr. Schulze-Koops noted.

Dr. Abdul Khan, Maidstone General Hospital, UK, and colleagues have also examined real-world treatment with rituximab in RA patients. They retrospectively analyzed data from 139 patients who failed DMARDs and anti-TNF therapy and were given one course of rituximab (1000 mg i.v. on days 1 and 15). The investigators found that despite evidence that patients with seropositive RA respond better to rituximab than those with seronegative disease (Isaacs et al., Tak et al. EULAR 2009), the rheumatologists followed UK national guidelines and put all the patients on rituximab. In this cohort, however, seropositive RA patients responded more effectively to rituximab than seronegative RA patients, even when well matched for disease activity, disease duration and prior treatment. Before treatment with rituximab, the 85 patients with seropositive RA had a significantly higher DAS28 compared with the 54 patients with seronegative RA (6.1 vs. 5.8; P=0.02), but after rituximab, the seropositive RA patients had significantly lower DAS28 (3.9 vs. 5.1) and significantly greater reduction in DAS28 (2.2 vs. 0.6) (both P<0.001).

Only 22% of seronegative RA patients had a good EULAR response compared with 81% of seropositive RA patients (P<0.001); among seropositive RA patients, 67% reached low DAS (<3.2) and 15% achieved remission (DAS<2.6), compared with 4% and 0% of seronegative RA patients. “Seronegative RA never responds to rituximab as well as seropositive RA,” Dr. Khan confirmed. “We are trying to challenge the idea that anyone who fails a TNF inhibitor can go on to rituximab, but we need data from a larger number of patients.”

Long-term Treatment Safety

Dr. Ronald van Vollenhoven, Karolinska University Hospital, Stockholm, Sweden, reported the latest pooled safety data from RA patients treated with rituximab in combination with methotrexate in 8 randomized, controlled clinical trials and 2 long-term, open-label extension studies. As of September 2009, 3189 patients had received =1 course of rituximab for a total exposure of 9342 patient-years. The analysis included more than 9 years of follow-up with up to 15 courses of rituximab. “Rituximab has remained generally well tolerated over time and over multiple courses, with a safety profile similar to that of the pooled placebo population and consistent with published data on patients with moderate to severe RA,” he told ACR delegates.

In the rituximab group, the most frequent adverse event (AE) was infusion-related reactions; most were common terminology criteria grade 1 or 2 and occurred after the first infusion of the first course (23.0%), with 0.5% considered serious (over all courses). The overall serious infection event (SIE) rate was 4.35 events/100 patient-years, comparable to that observed in the placebo population (4.29 events/100 patient-years). Rates of serious AEs (SAEs) and infections generally remained stable over time and over multiple rituximab courses and in patients in long-term follow-up (>5 years). “This was similar to previous analyses and generally remained stable over time and over course,” Dr. van Vollenhoven commented. The most frequent serious infections were of the lower respiratory tract, predominantly pneumonia (2%). Serious opportunistic infections were rare, with the rate comparable to the placebo population. Rates of myocardial infarction and stroke were consistent with rates in the general RA population.

Data on Multiple Courses

Since RA is a chronic disease, long-term use of treatments that target TNF or B-cells will be required for continued disease control, so assessment of the safety and efficacy of repeated courses of therapy is critical. Analysis of repeated rituximab treatment is ongoing in patients who participated in randomized controlled trials in a global clinical development program.

The latest results were presented here at the ACR by Dr. Edward Keystone, Professor of Medicine, University of Toronto, Ontario, who reported that an initial response is sustained through multiple courses of treatment. The data came from 500 patients with a prior inadequate response to TNF inhibitors who participated in one of 7 double-blind phase II or III clinical trials. All these patients had been exposed to =1 and =5 courses of rituximab 2 × 1000 mg i.v. infusions given 2 weeks apart with concomitant methotrexate 10-25 mg/week. Efficacy data were available at week 24 following their first course.

The proportion of patients with ACR20, 50 and 70 and EULAR responses at 24 weeks after each course of rituximab was maintained between the first and fifth course. These responses were mirrored by the proportion of patients with DAS28-ESR, low disease activity and DAS28 remission. The proportion of patients in DAS28 remission almost doubled (from 8.4% to 16.1%) between the first and fifth rituximab course. Improvements in physical function were also maintained, as indicated by the mean change in Health Assessment Questionnaire-Disability Index (HAQ-DI) (0.55 after the first course vs. 0.63 after the fifth course) and the proportion of patients who achieved minimal clinically important differences: decreases of =0.22 or =0.5 (65.5% vs. 66.9% and 43.3% vs. 47.3%, respectively). There were no unexpected safety findings over repeat courses and rates of infection and SIEs remained consistent.

Safety of Subsequent Biologics

Some RA patients who do not respond to rituximab may require subsequent treatment with other currently approved biologic disease-modifying antirheumatic drugs (DMARDs). An important clinical concern is whether these patients would become peripherally B-cell-depleted when they began another biologic DMARD, due to the long-lasting pharmacodynamic effect of rituximab. Dr. Mark Genovese, Stanford University Medical Center, Palo Alto, California, reported that in patients with moderate-to-severe active RA treated with rituximab in 8 clinical trials and 2 open-label extension trials, use of another biologic was not associated with an increase in the rate of SIEs.

Through September 2009, 283 patients in the trial had discontinued rituximab and subsequently started another biologic DMARD. At this time, most patients (83%) had peripheral B-cell depletion below the lower limit of normal (=80 cells/µL). The rate of SIEs following the first dose of rituximab and before receiving a subsequent biologic DMARD was 6.01 events/100 patient-years. Following subsequent biologic DMARDs, the SIE rate was 4.97 events/100 patient-years. A subgroup analysis of 230 patients who received a TNF inhibitor following rituximab showed no increase in rate of SIEs (6.03 vs. 4.51/100 patient-years). “Over the years the rates seem to be coming closer together,” Dr. Genovese noted. “The initial study suggested that we might see a higher infection rate post an additional biologic after rituximab, but as we have gone out further and we have seen more patients, we have seen this number fall to less than the pre-dose. I do not believe that rituximab is protective, but I think the take-home message is that there does not seem to be a real risk in using other biologics after rituximab.”

Mechanism of Inhibition of Joint Destruction

Osteoclasts are essential for the resorption of mineralized cartilage and subchondral bone in chronic RA. As reported by Dr. Maria J.H. Boumans, Academic Medical Center/University of Amsterdam, The Netherlands, here at the ACR, selective B-cell depletion with rituximab leads to a decrease in the receptor activator of nuclear factor-kappa (RANK)B, RANK ligand and osteoprotegerin (RANK/RANKL/OPG) cascade system that regulates osteoclast differentiation and activation. This is one of the mechanisms by which it may reduce the progression of joint destruction in RA, even in the absence of a clinical response.

In an open-label study, 28 RA patients either IgM RF-positive (82%) and/or anti-citrullinated protein/peptide antibodies (ACPPA)-positive (89%) were treated with rituximab without methylprednisolone premedication. At 16 weeks after treatment, there were significant decreases in serum levels of OPG (20%, P=0.001) and RANKL (40%, P=0.0001), while the OPG:RANKL ratio increased (P=0.006). In the synovial tissue, there was a significant decrease of 99% in RANK-positive osteoclast precursors (P=0.018) and a non-significant 25% decrease in OPG expression. “These effects were very strong and very clear,” Dr. Boumans told delegates. “The decrease in synovial osteoclast precursors associated with the increased OPG:RANKL in the serum may explain in part the protective effect of rituximab treatment against progression of joint destruction,” she suggested. “We have shown for the first time that depleting B-cells has effects on the RANK/RANKL/OPG system both in the serum and in the synovial tissue.”

Vasculitis

In observational studies, B-cell depletion with rituximab and glucocorticoids has been used to induce sustained remission in patients with severe refractory antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). However, the need for repeated treatments and the efficacy and safety of repeated and prolonged B-cell depletion for long-term remission maintenance is less clear.

The results of an observational retrospective study involving 53 patients who had achieved remission (Birmingham Vasculitis Assessment Score=0) with glucocorticoids and rituximab and treated with =2 courses of rituximab for relapses or to maintain remission between January 2000 and May 2010 were presented by Dr. Rodrigo Cartin-Ceba, Mayo Clinic, Rochester, Minnesota. A total of 209 courses of 4 weekly infusions at 375 mg/m2 and 24 courses of 2 weekly infusions of 1000 mg (median 4 rituximab courses/patient) were administered. All but one patient were proteinase 3 (PR3)-ANCA-positive.

All patients treated with rituximab and steroids achieved remission. All relapses occurred after reconstitution of B-cells and were accompanied or preceded by a rise in ANCA levels from nadir (except in one PR3-ANCA-negative patient). All patients treated pre-emptively had documented reconstitution and a rise in ANCA levels from nadir. No rise in ANCA levels was seen when B-cells were absent. There were no differences between patients treated with the 2 different dosing regimens. Prolonged B-cell depletion appeared well tolerated and associated with a relatively low risk of infection. With a follow-up of 230.4 patient-years, there were only 16 infusion-related AEs and 30 documented infections. B-cell depletion was effective at maintaining remission in these patients, supporting a crucial pathogenic role for B-cells in the disease, Dr. Cartin-Ceba remarked.

Led by Dr. Salvatore De Vita, University of Udine, Italy, a phase III randomized, controlled trial of patients with mixed cryoglobulinemia (MC) compared rituximab monotherapy to best available immunosuppressive (conventional) treatment. Patients had active glomerulonephritis, skin ulcers or peripheral neuropathy. Best conventional treatment consisted of high-dose corticosteroids, azathioprine, cyclophosphamide or plasmapheresis, ± corticosteroids (Group A) (rescue with rituximab allowed after failure at any time). In Group B, rituximab 1000 mg i.v. was given on days 1 and 15. The cycle was repeated in previous responders who relapsed. Low-dose corticosteroids (<0.1 mg/kg/day) were the only concomitant therapy permitted.

Fifty-nine MC patients (46 women, median age 65.5 years, 93% hepatitis C virus-positive) were studied, 57 of whom were evaluable at 24 months. Average survival time was significantly longer with rituximab vs. conventional therapy (529.1 days vs. 76.9 days, P<0.0001). Survival at 6 months was 3% vs. 71% and 3% vs. 61% at study end in Groups A and B, respectively (P<0.0001). Twenty-three of 28 (82.1%) patients in Group A were rescued with rituximab, mainly due to lack of efficacy/worsening.

Significantly higher rates of response were observed with rituximab for renal, cutaneous and neurologic end points. It also provided a steroid-sparing effect from the start of treatment and maintained. No major safety issues were observed.

Findings confirmed the biologic as the best choice in patients with active clinical manifestations when antiviral therapy fails or is contraindicated, as it is “more effective than standard immunosuppressants for nephritis, skin ulcers and neuropathy in MC syndrome, both in the short term and long term,” Dr. De Vita concluded.