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Rituximab in a case of RA with sero-positive RF and anti-CCP



Case summary

This patient (female, 45 years of age) had inflammatory RA with systemic disease for one year. She had raised inflammatory markers, hand and feet radiographs revealed soft tissue swelling of her MCPs and PIPs bilaterally but without erosive propensity. Methotrexate and TNF inhibitor agents had given an inadequate response. After a total of 2 rituximab courses over 6 months, clinical improvement in the signs and symptoms of active RA were observed.

Physician's comment

This is a case of RA with systemic diseases - very active anti-inflammatory process but without erosive propensity. Following inadequate responses to methotrexate, prednisolone, etanercept and adalimumab, an improvement in the patients RA symptoms was seen following rituximab infusions.

Case details

Age:
45 years
Gender:
Female
Background

History of Rheumatoid Arthritis

Duration: 1 year
Any other relevant information

This patient was originally referred with bilateral synovitis involving hands, wrists and knee, fever, weight loss (55 kg >20%), heart murmur 2/6, inguinal adenopathy 5mm. She had no cutaneous symptoms and no previous inflammatory disease. Laboratory tests indicated a CRP of 195 mg/L and an ESR of 98 mm/hr




Relevant family history/concomitant conditions

Family history of Rheumatoid Arthritis: No relevant family history
Concomitant conditions:

Obesity, hypertension, diabetes

Other relevant investigations performed
  • Haemocultures and synovial fluid: sterile
  • Viral tests: negative
  • Biochemistry: normal
  • Immunology: ANA 1/80, anti-DNA IgM positive 1/71, anti-phospholipid antibody negative, RF 300 units, anti-CCP not available
  • Echocardiography: normal
  • Whole body CT scan: normal
  • Medullary biopsy: normal
  • Synovial biopsy; non-specific





Figure 1: Major wrist synovitis, interosseuous muscular amyotrophy








Figure 2: Bilateral synovitis of knees








Figure 3: Radiograph of hands showing global demineralisation, no clear erosion or joint space narrowing.








Figure 4: Radiograph of feet showing lobal demineralisation, no clear erosion or joint space narrowing






Management

Previous medications

Summary:
With our patient, the standard DMARD combination therapy had already been used for 6 months without adequate effect. We therefore introduced TNF inhibitor agent treatment in conjunction with methotrexate 20 mg weekly. However, a marginal clinical response (reflecting persistently active disease) was seen even after switching from one TNF inhibitor agent to another (total duration of TNF inhibitor agent treatment: 18 months).



Previous medications

Drug Dose Dates administered Prescribed / discontinued Comment / reason for dis- continuation:
DMARD 1 Methotrexate SC 20 mg/week March 2004 February 2006 Lack of efficacy
Specific biologic 1 Etanercept 25 mg twice weekly September 2004 May 2005 Lack of efficacy
Specific biologic 2 Adalimumab 40 mg/2weeks, then 40 mg/week May 2005 February 2006 Lack of efficacy
Steroid Methyl-prednisolone 1g for 3 successive days followed by 15 mg/day January 2004 February 2006 Lack of efficacy



Comment:
Inadequate response with adalimumab was confirmed by monitoring CRP and DAS28.










Figure 5: DAS28 values during previous treatment with DMARDS and TNF inhibitor agents








Figure 6: CRP values during previous treatment with DMARDS and TNF inhibitor agents
Evidence of active disease before initiation of rituximab

General description

ESR 95 mm/hour (0-12) - 98 mm/hour at initial diagnosis
CRP: 95 mg/L (<10) - 195 mg/L at initial diagnosis
Disease activity assessment: DAS28 9



Rituximab treatment

Rituximab treatment

Comment:

This case represents a patient with an inadequate response to 2 TNF inhibitors. Newer biologic agents that work through unique mechanisms are also available for patients with moderate to severe RA. In this case, we administered the B-cell targeting agent, rituximab (MabThera) in combination with weekly methotrexate to our patient.



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 positive response achieved with rituximab in patients who had previously failed on other agents.

image with video link

After a total of 2 rituximab courses over 6 months, clinical improvement in the signs and symptoms of active RA were observed. In addition there were no infusion reactions with rituximab. Disease activity was monitored to determine when a subsequent course was required to maintain this low disease activity.



All regimens Rituximab 1000 mg infusion x2 (Day 1 and 15)
Pemedication with methylprednisolone 100 mg iv before each infusion
Course 1:

February 2006

Course 2:

August 2006

Comment:
Premedication with iv glucocorticoids significantly reduces both the incidence and severity of acute infusion reactions1. In this case, no infusion reactions were observed with the repeat course of rituximab.



Clinical response to rituximab:





Figure7: CRP following treatment with rituximab




Figure 8: DAS28 response following treatment with rituximab



Comment:
Disease activity was monitored to determine when subsequent courses of rituximab were needed aiming for low disease activity.
Summary:

This was a case of RA with systemic disease very active inflammatory process but without erosive propensity. After the first course of rituximab, clinical improvement in the signs and symptoms of active RA were observed. In clinical studies, at 24 weeks rituximab demonstrated superiority over placebo, both in patients who had previously been treated with one TNF inhibitor and those who had been treated with at least 2 TNF inhibitors2. The clinical response to rituximab was optimal after 1 TNF inhibitor2.

This case also demonstrates that a repeat course of rituximab in RA can provide continued improvement of symptoms. Importantly, with repeat courses of rituximab no safety concerns have been reported in this patient.




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 response.4

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



References

References

1. 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.
2. 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.
3. Smolen JS, Keystone EC, Emery P, et al. Consensus statement on the use of rituximab in patients with rheumatoid arthritis. Annals Rheum Dis 2007 Feb;66(2):143-50.