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Failure on one TNF inhibitor agent in RA



Case summary

Female patient (47 years) with a family history of Rheumatoid Arthritis, had a disease duration of 8 years. She had received methotrexate plus folic acid, and more recently with etanercept, but her condition was deteriorating with recent flares. She had difficulty with sleeping, with caring for children and using a computer keyboard, along with high levels of fatigue and pain. She was switched to rituximab in combination with methotrexate, resulting in an improvement in her disease activity and functional state.

Click here to view Professor Tak, Professor of Medicine, Director, Division of Clinical Immunology and Rheumatology, EULAR & FOCIS Center of Excellence, Academic Medical Center, University of Amsterdam, The Netherlands commenting on the need for an alternative RA treatment for patients who had deteriorated on other therapies.

image with video link

Physician's comment

The treatment options for this patient were limited following deterioration on the TNF inhibitor agent, etanercept. The close family history (mother) of severe RA and intolerance to methotrexate at higher doses along with the likely short lived effects of other DMARDs meant that identifying a suitable treatment was challenging. Following discussion of the options the patient decided to try rituximab and the response was consistent with clinical trial data.

Case details

Age:
47 years
Gender:
Female
Background

History of Rheumatoid Arthritis

Duration: 8 (diagnosis August 1999)
Rheumatoid factor: Yes
Erosions: Yes
Nodules: Yes
Evidence of active disease (at diagnosis): Swollen joints with raised inflammatory markers
Any other relevant information Jogger, smoking history. The patient is well educated and informed with high treatment expectations



Relevant family history/concomitant conditions

Family history of Rheumatoid Arthritis: Mother severely disabled with RA; she developed early cataracts and experienced multiple fractures



Management

Previous medications

Summary:
From August 1999 - July 2005 we used various combinations of DMARDs (methotrexate, sulfasalazine and hydroxychloroquine). We found that tolerability issues outweighed any clinical benefit. Therefore, at a follow up visit (August 2005), we started the patient on etanercept 50 mg weekly. Following excellent control initially, our patient became symptomatic and her RA began flaring once again. A physical examination revealed swelling and tenderness in her wrist, knees and ankles; x-rays revealed erosions of the wrists and finger joints. Her DAS28 score (4.79) revealed persistent moderately active disease.


Previous medications

Drug Dose Dates administered Prescribed / discontinued Comment / reason for dis- continuation:
DMARD 1 Methotrexate 20 mg sc until 1999 then 20/25 mg sc 1999

DMARD 2 Hydroxychloroquine 400 mg qd 1999 2005 Raised LFT and multiple GI disorders
DMARD 3 Sulfasalazine 3 g/day 2002 2005 Raised LFT and multiple GI disorders
Specific biologic Etanercept 25 mg sc 2x week 01/08/2005 01/11/2006 Lack of efficacy
Comment:
Both DMARDs were discontinued due to adverse reactions. Excellent control was achieved initially with etanercept but after 15 months RA began flaring.



Evidence of active disease before initiation of rituximab

General description

General description: Patient had experienced secondary loss of efficacy with etanercept, with tender joints of wrists, knees and right ankle and nodules increasing at both elbows and appearing on right hand.
Swollen joint
count (28): 		7
Tender joint
count(28 ): 		12
Early morning stiffness > 120 minutes
ESR 24 mm/hour (0-20)
CRP 2.2 mg/dL (N<1.5)
Rheumatoid factor
1280 IU (<20)
Other Anti-CCP positive
Disease activity assessment: DAS28 4.79






Figure 1: Subluxation of right wrist with swelling of MCP



Functional assessment

Functional assessment
Patient VAS Patient Global Assessment: 8/10. The patient's RA, pre-rituximab, was adversely affecting both her home and professional life.



Quality of life

Quality of life
General description Difficulty with sleeping, caring for her children and using a computer keyboard.
HAQ 1.7
VAS of Fatigue 9/10
VAS of Pain 7/10



Radiographic findings

Description Wrist and hands






Figure 2: Erosions and joint space narrowing of the 1 st, 2 nd and 3 rd MCP



Rituximab treatment

Rituximab treatment

Comment:
Treatment options for this patient were quite limited following failure on the TNF inhibitor agent, etanercept. Increasing dose of DMARD or adding another DMARD would not be suitable because the patient had failed on hydroxychloroquine and sulfasalazine and was intolerant of higher doses of methotrexate. A combination of methotrexate and leflunomide was considered but the patient had previous liver enzyme elevations. The beneficial effect of the addition of a DMARD after a previous DMARD failure is usually suboptimal and short-lived1. Corticosteroids were not an option because the patient's mother had developed early cataracts and experienced multiple fractures. Failure on one TNF inhibitor agent can lead to a poor response with subsequent TNF inhibitor agents2. In patients who experience an inadequate response to a TNF inhibitor, switching to rituximab may result in a better disease activity response compared to using an alternative TNF inhibitor agent3. She had evidence of erosions on her radiographs and new nodules, both evidence of aggressive disease. She required biologic treatment that can control symptoms and inhibit joint damage. Therefore, the patient decided to receive rituximab in combination with methotrexate 20 mg/week.


Course 1: November 2006: rituximab 1000 mg x 2 (Day 1 and 15), methotrexate 20 mg/week. Premedication with methylprednisolone 100 mg iv before each infusion
Infusion reactions Mild chills during first infusion which were resolved by slowing the infusion, and the second infusion was uneventful.
Comment:
Infusion reactions, generally mild to moderate may occur with rituximab, but, as in this case they can usually be readily resolved by slowing or stopping the infusion. Premedication with iv glucocorticoids significantly reduces both the incidence and severity of acute infusion reactions4. In the rituximab clinical studies, the incidence of infusion reactions was reduced after the first infusion. The number of patients experiencing these symptoms following the second infusion of the treatment course was substantially lower in all groups, irrespective of glucocorticoid premedication. The addition of oral prednisone did not appear to provide any further reduction in acute infusion reactions compared to patients that did not use oral prednisolone.3






Figure 3: DAS28 response during treatment with rituximab



Summary:
This case illustrates lack of efficacy following treatment with a TNF inhibitor agent. Switching to another TNF inhibitor agent is an option. However, registry data shows that switching TNF inhibitors in non-responders may not be effective2. Therefore we decided to change therapy to a drug with a different mechanism of action: rituximab (MabThera), a B-cell targeting agent. Rituximab is the first and only biological agent that has demonstrated inhibition of joint damage in patients who failed to respond to, or are intolerant to, a TNF inhibitor agent7 8. After one rituximab course (total of two infusions given two weeks apart) plus methotrexate 20 mg/week over 6 months, clinical improvement in the signs and symptoms of active RA were observed in addition to improvements in quality of life parameters reported by the patient such as feeling less tired and sleeping better. These patient reported outcomes were in line with those reported in recent clinical studies9. The DAS28 score at the end of treatment was 3.13 indicating low disease activity. In the REFLEX study, the response to rituximab was optimal following failure on one TNF inhibitor agent5. In addition there were no adverse reactions after the second infusion.


Click here to view Dr Edward Keystone MD, FRCP,Professor of Medicine, University of Toronto, Director of the Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, Canada discussing the effect of rituximab on radiographic progression in RTA patients.

image with video link




Further courses of rituximab

In the rituximab treatment guidelines, patients who show a EULAR response are eligible for repeat treatment if 24 weeks has passed since their last course, and they either

•  have significant residual disease (with a DAS = 3.2, CDAI > 10, SDAI > 11) or

•  if they show a deterioration after an initial response5.

Studies are on-going to establish the optimum re-treatment schedule for patients who show an initial response to rituximab.


References

References

1. Kremer J, Genovese M, Cannon GW, et al. Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: open-label extension of a randomized, double-blind, placebo controlled trial. J Rheumatol 2004;8:1521-31.
2. Hyrich KL, Lunt M, Watson KD, et al. Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum. 2007;56(1):13-20.
3. Finckh A, Ciurea A, Brulhart L, et al. Which subgroup of rheumatoid arthritis patients benefit most from switching to rituximab versus alternative ant-TNF agents after previous failure to anti-TNF agent? Ann Rheum Dis 2008;67(Supp II):127, OP-0249
4. 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 double-blind, placebo-controlled, dose-ranging trial (DANCER). Arthritis Rheum 2006;54:1390-1400.
5. Kremer JM, Tony H, Tak PP, et al. Efficacy of rituximab in active RA patients with an inadequate response to one or more TNF inhibitors. Ann Rheum Dis 2006;65(Suppl II):326.
6. Smolen JS, Keystone EC, Emery P, et al, Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66(2):143-50.
7. Keystone E, Emery P, Peterfy CG, et al. Rituximab inhibits structural joint damage in rheumatoid arthritis patients with an inadequate response to tumour necrosis factor inhibitor therapies. Ann Rheum Dis 3 Apr 2008 (epub: 3 4 2008)
8. Cohen S, Keystone E, Genovese MC, et al. Continued inhibition of structural damage in rheumatoid arthritis patients treated with rituximab at 2 years: REFLEX study. Ann Rheum Dis 2008;67(Suppl II):189[THU0167]
9. Keystone E, Burmester G, Furie-R, Loveless J E, et al. Improvement in patient-reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Arthritis Care Res 2008;59(6):785-793.