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Rheumatology Advance Access originally published online on April 4, 2008
Rheumatology 2008 47(6):865-867; doi:10.1093/rheumatology/ken103
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Rituximab use in everyday clinical practice as a first-line biologic therapy for the treatment of DMARD-resistant rheumatoid arthritis

D. McGonagle1,2, A. L. Tan2, J. Madden1, L. Taylor1 and P. Emery2

1Department of Rheumatology, Calderdale Royal Hospital, Salterhebble, Halifax and 2Academic Unit of Musculoskeletal Disease, University of Leeds and Chapel Allerton Hospital, Leeds, UK.

Correspondence to: D. McGonagle, Academic Unit of Musculoskeletal Disease, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK. E-mail: d.g.mcgonagle{at}leeds.ac.uk


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. This study assessed the utility of rituximab for the therapy of RA in a non-academic environment in a group of cases where anti-TNF was either not available or relatively contraindicated.

Methods. Thirty-nine patients with active RA who had failed at least one DMARD received two rituximab infusions 2 weeks apart. Seventeen patients received two 1000 mg doses, and 22 received the 500 mg regimen. The 28-joint disease activity index (DAS28) and European League against Rheumatism (EULAR) response criteria were recorded at baseline, 3, 6, 9 and 12 months. RF and ANA were recorded at baseline and at 6 and 12 months.

Results. There was a significant improvement in the DAS28 at all time points, and EULAR response was observed in 29 of 33 patients (87.9%) at 3 months, 25 of 33 patients (75.8%) at 6 months, 22 of 29 patients (75.9%) at 9 months and 23 of 30 patients (76.7) at 12 months. Improvement was also noted in CRP, and both RF and ANA were generally reduced after treatment. Patients who were on the higher regimen of two 1000 mg doses appeared to respond slightly better compared with the lower dose regimen.

Conclusions. Rituximab is well tolerated in everyday clinical practice and may represent a good short-term treatment option where anti-TNF therapy is either unavailable or relatively contraindicated.

KEY WORDS: Rituximab, Rheumatoid arthritis, Biologics, Anti-tumour necrosis factor, Disease-modifying anti-rheumatic drugs, DAS28, European League Against Rheumatism response


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
RA is the commonest inflammatory arthropathy and affects nearly half a million patients in the UK. The current first-line treatment utilizes DMARDs that often have suboptimal responses [1]. The introduction of TNF inhibitors offered a new option for patients with DMARD-resistant disease [2]. Upon the licensing of anti-TNF agents, the health care service structure of the UK meant that literally hundreds of thousands of patients were potentially suitable for therapy. Given the costs of therapy, the prescribing of anti-TNF agents for inflammatory arthritis has been patchy, which has restricted the availability of anti-TNF agents in some regions [3].

Rituximab in combination with MTX was licensed in the UK in 2006 for the treatment of adult patients with severe active RA who have had an inadequate response to, or been intolerant to conventional DMARDs and one or more TNF inhibitors. However, the early clinical studies that demonstrated the efficacy of rituximab in RA were carried out in patients who had not previously received TNF inhibitors [4–6]. Recognizing that rituximab was going to be licensed for RA and due to the inability to obtain anti-TNF therapy, we have used rituximab as a first-line biological agent between 2004 and early 2007. In this article, we report our experience for the treatment of RA in daily clinical practice in a non-academic centre.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Between 2004 and early 2007 we identified 39 RA patients, all of whom met the ACR criteria for resistant RA [7], who received rituximab therapy. Clinical outcomes were available for 37 patients and toxicity data for all 39 patients. Thirty-four patients failed three DMARDs and one each failed one, two and seven DMARDs (Table 1). Three of the cases had also failed anti-TNF agents—two at our hospital and one elsewhere. The local drug and therapeutics committee authorized the use of rituximab. The local ethics committee agreed that the findings in this report were based on normal clinical practice and therefore were suitable for dissemination.


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  		TABLE 1. Demographics of patients

 
Seventeen patients received two 1000 mg intravenous infusions of rituximab 2 weeks apart; the other 22 patients received two 500 mg infusions 2 weeks apart. The reduced dosing regimen was introduced following reports of efficacy of this lower dose in RA [8]. Pre-medication consisted of methylprednisolone 100 mg by intravenous infusion, and chlorpheniramine at either 4 mg oral or 10 mg intravenous dose. All except two patients continued on DMARDs (32 on MTX, 2 on LEF and 1 on AZA).

The 28-joint disease activity score (DAS28) [9] based on the ESR was performed 3 monthly, and data were available at baseline, 3 months, 6 months, 9 months and 12 months. Response was determined by the change in DAS28 and the European League against Rheumatism (EULAR) response criteria [10]. Immunoglobulins were measured at baseline to ensure that patients did not have hypogammaglobulinaemia since this is a recognized complication of repeated rituximab therapy [6]. CRP was also measured at all time points.

All except 4 of the patients had autoantibody-positive disease, with 30 being RF-positive and 13 of whom were also ANA-positive. The clinical pattern of disease with synovitis as dominant illness and fulfilling the ACR criteria for RA, and absence of other clinical or serological features of SLE, leads these cases to be diagnosed as RA. Three of the RF-negative patients were ANA-positive. All of the other RF- and ANA-positive cases had a disease pattern of RA over time. The RF and ANA were measured before therapy and at 6 months following therapy.

Three patients had contraindications for anti-TNF agents: two patients had autoimmune leucopenia as part of the Felty's spectrum of disease with reduced neutrophil counts, and one patient had a chronic leg ulcer. One of the ANA-positive cases had previously developed a lupus-like illness on SSZ that regressed following drug cessation.

Statistical analysis
Results were presented as medians and ranges. Wilcoxon's matched-pairs signed rank test was used to measure the significance of the change from baseline. P-values <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
The treatment was generally well tolerated. Almost all patients showed a response as assessed by the DAS28 (P < 0.0001 at all time points) (Table 2). Some patients did not attend some of their follow-up appointments, and therefore did not have their DAS28 calculated at the relevant time points.


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  		TABLE 2. DAS28, change in DAS28 and EULAR responses of the patients at 3-month intervals

 
A EULAR response was observed in 29 of 33 patients (87.9%) at 3 months, 25 of 33 patients (75.8%) at 6 months, 22 of 29 patients (75.9%) at 9 months and 23 of 30 patients (76.7) at 12 months. Thirteen of 33 patients (39.4%) achieved good EULAR response at 3 months, and 12 of 33 patients (36.4%) at 6 months, 10 of 29 patients (34.5%) at 9 months and 15 of 30 patients (50.0%) at 12 months.

Improvement of CRP was also evident at all time points: baseline median 22 mg/l (1–85 mg/l), 3 months 17.0 mg/l (1–116 mg/l, P = 0.017), 6 months 8.0 mg/l (1–81 mg/l, P = 0.024), 9 months 12.5 mg/l (2–106 mg/l, P = 0.077) and 12 months 8 mg/l (1–60 mg/l, P = 0.001).

At 6 months, 15 of the 16 ANA-positive patients and 25 of the 30 RF-positive patients had a repeat test. The ANA became negative in 6 (40%) of these patients, and 22 (88%) patients who were positive for RF [median 245 U (24–2780 U)] had a reduction in the level of RF [median reduction 121 U (21–2255 U)], including 4 who became seronegative at 6 months. The reduction was sustained at 12 months, with 7/15 (46.7%) patients who were ANA-positive at baseline becoming negative, and 23/26 (88.5%) patients who were RF-positive at baseline had a reduction in RF [median reduction 160 U (14–1815 U)]. Four of these patients became RF-negative.

None of the patients received further rituximab infusions within the 6-month period. Twenty-five patients were retreated subsequently [median 13 months post initial infusions (7–27 months)]. Seven patients have received a third treatment to date [median 11 months after second treatment (5–19 months)]. Two patients were switched to anti-TNF following ‘early treatment failure’ by 6 months; another patient was also switched to anti-TNF following an allergic infusion reaction with the second infusion of the second course of treatment.

One patient presented acutely with a subacute onset of respiratory failure 3 months following therapy and died. The clinical impression was of bilateral bronchopneumonia and a possible MTX pneumonitis. The patient, a 67-yr-old male, had pre-existing asymptomatic rheumatoid lung disease that was evident on CT. Another patient, a 61-yr-old male, died of a myocardial infarction. He was awaiting coronary angiography for angina pectoris, and was retreated with rituximab 2 yrs after his initial successful treatment. The myoardial infarction occurred a month post-rituximab and was thought not to be related to the therapy.

Patients who received two 500 mg infusions of rituximab appeared to respond slightly less than those who received two 1000 mg infusions. At 3 months, 14 of 17 (82.4%) who received the 500 mg regimen achieved either a good or moderate EULAR response, whilst this is observed in 15 of 16 (93.8%) in the 1000 mg regimen. This slight difference between the lower and higher doses was also observed at 6 months [EULAR response in 11 of 17 (64.7%) 500 mg regimen and 14 of 16 (87.5%) 1000 mg regimen], 9 months [EULAR response in 9 of 14 (64.3%) 500 mg regimen and 13 of 15 (86.7%) 1000 mg regimen] and 12 months [EULAR response in 10 of 14 (71.4%) 500 mg regimen and 13 of 16 (81.3%) 1000 mg regimen].

In total, there were seven patients who were negative for RF at baseline. Of the six patients with available data, all six had a EULAR response at 3 months (3 good response, 3 moderate response), but only three had an EULAR response at 6 months (all three were on the 1000 mg regimen). By 12 months, these three patients were continuing to respond to treatment. Anti-CCP antibodies were not measured in these cases.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
This study reports the use of rituximab for RA in a ‘real world’ non-academic environment in patients, the vast majority of whom had not previously received anti-TNF therapy. A recent report showed the efficacy of rituximab in RA in a similar situation [11], but the patients in question had failed anti-TNF therapy, whilst our report focused mainly on patients who failed DMARDs only. Almost half the cases had disease where some rheumatologists would have concerns about using anti-TNF agents including risks of infection and strong ANA positivity [12, 13]. We found that rituximab was extremely well tolerated.

Based on the experience in haematology and oncology it would appear that the short-term safety data of rituximab is at least as good as the anti-TNF agents [14]. For example, there is no apparent increased risk of serious infections including tuberculosis. Concerns have also been raised that the anti-TNF agents may be associated with an increased long-term risk of lymphoreticular malignancies including lymphomas, some of which rituximab is licensed to treat [15]. In the case of malignancy, rituximab has been predominantly used as a single course of therapy. However, it is clear that RA patients will need to be repeatedly retreated. This has led to concerns that patients could eventually experience hypogammaglobulinaemia and an inability to prospectively mount humoral immune responses. Indeed, evidence for hypogammaglobulinaemia is emerging following repeated therapy but this has not been linked to infectious complications thus far [6].

Based on the reported efficacy of rituximab 500 mg 2 weeks apart, this regimen was implemented in many patients in the cohort, and in keeping with the published literature, we found that patients responded [8]. However, our impression was that the degree of the responses was less compared with the 1000 mg regimen, which would be compatible with the lower ACR 70 scores generally reported in the trial [8]. Nevertheless, some patients on the low dose had good responses. Since rituximab is likely to be a long-term treatment option, it might be prudent to start on the lowest possible effective dosing regimen. In conclusion, this report suggests that rituximab is a very effective first-line biological drug in clinical practice and can be safely given to patients who have relative contraindications for anti-TNF agents.

Formula

Disclosure statement: P.E. has received consultant fees, honoraria and grants/research support from Roche. All other authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. van der Heijden JW, Dijkmans BA, Scheper RJ, Jansen G. Drug insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside. Nat Clin Pract Rheumatol (2007) 3:26–34.[CrossRef][Web of Science][Medline]
  2. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet (1999) 354:1932–9.[CrossRef][Web of Science][Medline]
  3. Chen YF, Jobanputra P, Barton P, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess (2006) 10. iii–iv, xi–xiii, 1–229.
  4. De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G. Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum (2002) 46:2029–33.[CrossRef][Web of Science][Medline]
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  6. Popa C, Leandro MJ, Cambridge G, Edwards JC. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs. Rheumatology (2007) 46:626–30.[Abstract/Free Full Text]
  7. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum (1988) 31:315–24.[Web of Science][Medline]
  8. Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum (2006) 54:1390–400.[CrossRef][Web of Science][Medline]
  9. Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum (1995) 38:44–8.[Web of Science][Medline]
  10. van Gestel AM, Prevoo ML, van't Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum (1996) 39:34–40.[Medline]
  11. Jois RN, Masding A, Somerville M, Gaffney K, Scott DG. Rituximab therapy in patients with resistant rheumatoid arthritis: real-life experience. Rheumatology (2007) 46:980–2.[Abstract/Free Full Text]
  12. De Rycke L, Baeten D, Kruithof E, Van den Bosch F, Veys EM, De Keyser F. The effect of TNFalpha blockade on the antinuclear antibody profile in patients with chronic arthritis: biological and clinical implications. Lupus (2005) 14:931–7.[Abstract/Free Full Text]
  13. Atzeni F, Turiel M, Capsoni F, Doria A, Meroni P, Sarzi-Puttini P. Autoimmunity and anti-TNF-alpha agents. Ann N Y Acad Sci (2005) 1051:559–69.[CrossRef][Web of Science][Medline]
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Submitted 27 November 2007; revised version accepted 8 February 2008.
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