Rituximab fixed retreatment versus on-demand ...

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Letters Table 1 The cutoff value, sensitivity, specificity, negative and positive predictive values of procalcitonin, TNFa, CRP and IL-6 for detecting bacterial infection in febrile patients with adult-onset Still’s disease Cutoff value Procalcitonin (ng/ml) 1.4 0.5 TNFa (pg/ml) 14.0 CRP (mg/l) 101 IL-6 (pg/ml) 101

Sensitivity (%)

Specificity (%)

NPV (%)

PPV (%)

p Value

100.0 100.0

100.0 76.9

100.0 100.0

100.0 66.7

,0.001 ,0.001

83.3

76.9

90.9

62.5

0.002

73.1

83.3

58.1

90.5

0.004

50.0

80.8

77.8

54.6

0.068

CRP, C-reactive protein; NPV, negative predictive value; PPV, positive predictive value; TNF-a, tumour necrosis factor alpha.

D-Y Chen,1,2 Y-M Chen,1,2 W-L Ho,1,2 H-H Chen,1,2 G-H Shen,3 JL Lan1,2 1 Yang-Ming University and Chung-Hsing University, Taipei, Taiwan; 2 Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan; 3 Chung-Hsing University, Taiwan, and Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan

Correspondence to: Dr J-L Lan, Taichung Veterans General Hospital, No 160, Section 3, Taichung-Kang Road, Taichung City 40705, Taiwan; jllan@mail. vghtc.gov.tw

3.

4.

5. 6.

Competing interests: None. Ethics approval: Ethics approval was obtained.

7.

Accepted 22 August 2008 Ann Rheum Dis 2009;68:1074–1075. doi:10.1136/ard.2008.098335

REFERENCES 1. 2.

Ka´da´r J, Petrovicz E. Adult-onset Still’s disease. Best Pract Res Clin Rheumatol 2004;18:663–76. Shin KC, Lee YJ, Kang SW, Baek HJ, Lee EB, Kim HA, et al. Serum procalcitonin measurement for detection of intercurrent infection in febrile patients with SLE. Ann Rheum Dis 2001;60:988–9.

Rituximab fixed retreatment versus on-demand retreatment in refractory rheumatoid arthritis: comparison of two B cell depleting treatment strategies Rituximab, an anti-CD20 monoclonal antibody, has been approved for treatment in patients with rheumatoid arthritis (RA) who have failed treatment with tumour necrosis factor (TNF) blocking agents.1 Previous studies have demonstrated its safety, efficacy and prevention of radiographic progression;2 3 however few studies have yet addressed the timing of repeated courses of rituximab. A study in 22 patients with RA showed that treatment with repeated courses of rituximab over a 5-year follow-up period was safe and well tolerated4 and additionally an open-label extension study of 3 large randomised, doubleblind studies in patients with RA showed that clinical efficacy was maintained with subsequent courses of rituximab, comparable to the first rituximab course, without increased additional safety concerns.5 Interestingly, one study reported that Ann Rheum Dis June 2009 Vol 68 No 6

8. 9.

10.

Eberhard OK, Haubitz M, Brunkhorst FM. Usefulness of procalcitonin for differentiation between activity of systemic autoimmune disease (systemic lupus erythematosus/systemic antineutrophil cytoplasmic antibody-associated vasculitis) and invasive bacterial infection. Arthritis Rheum 1997;40:1250–6. de Werra I, Jaccard C, Corrandin SB. Cytokines, nitrite/nitrate, soluble tumor necrosis factor receptors, and procalcitonin concentrations: comparisons in patients with septic shock, cardiogenic shock, and bacterial pneumonia. Crit Care Med 1997;25:607–13. Dele`vaux I, Andre M, Colombier M, Albuisson E, Meylheuc F, Be`gue RJ, et al. Can procalcitonin measurement help in differentiating between bacterial infection and other kinds of inflammatory processes? Ann Rheum Dis 2003;62:337–40. Scire` CA, Cavagna L, Perotti C, Bruschi E, Caporali R, Montecucco C. Diagnostic value of procalcitonin measurement in febrile patients with systemic autoimmune diseases. Clin Exp Rheumatol 2006;24:123–8. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi S, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol 1992;19:424–30. Pouchot J, Sampalis JS, Beaudet F, Carette S, Decary F, Salusinsky-Sternbach M, et al. Adult Still’s disease: manifestations, disease course, and outcome in 62 patients. Medicine 1991;70:118–36. Kettelhack C, Hohenberger P, Schulze G, Kilpert B, Schlag PM. Induction of systemic serum procalcitonin and cardiocirculatory reactions after isolated limb perfusion with recombinant human tumor necrosis factor-alpha and melphalan. Crit Care Med 2000;28:1040–6. Hoshino T, Ohta A, Yang D, Kawamoto M, Kikuchi M, Inoue Y, et al. Elevated serum interleukin 6, interferon-c, and tumor necrosis factor-a levels in patients with adult Still’s disease. J Rheumatol 1998;25:396–8.

rituximab retreatment was more effective; however, this was in patients whose disease activity had not completely returned to baseline levels.6 Therefore, the preferred timing of repeated treatment courses of rituximab is still a matter of debate and thus far has not been prospectively investigated. The present study compared the efficacy and safety of 2 B cell depleting strategies in 48 patients with refractory RA failing disease-modifying antirheumatic drugs (DMARD) combination therapy and/or at least 1 TNF blocking agent. In a prospective, two-centre, non-randomised, open-label pilot study, after initial treatment with 261000 mg rituximab, one group (n = 28) in one centre received fixed retreatment (FR) at 24 weeks with 161000 mg rituximab, while the other group (n = 20) in the other centre received retreatment with the same dose at disease relapse as on-demand retreatment (ODR). Clinical efficacy, safety and immunological outcomes were evaluated every 12 weeks for a period of 1 year. Patients were allowed to continue their daily or weekly dosages of DMARDs and corticosteroids, however TNF blocking agents required an 8-week wash-out period. The study was approved by the local ethics committees of both centres. Patients in both treatment arms were comparable with respect to baseline characteristics, as shown in table 1. After 1 year of follow-up, no significant differences were observed 1075


Letters Table 1 Study overview Patient characteristics Baseline: Age (years) Female (%) Disease duration (years) Positive rheumatoid factor (%) Positive ACPA status (%) Previous DMARDs (no.) Previous ant-TNF agents (no.) Current DMARDs (no.) DAS28 HAQ disability Radiographic score* At 1 year: Change in DAS28{ Change in HAQ disability{ Radiographic progression* ACR response ACR20 (%) ACR50 (%) ACR70 (%) EULAR response No (%) Moderate (%) Good (%) Adverse events: Any adverse event Serious adverse event Infusion-related adverse event Adverse event leading to withdrawal Death

Fixed retreatment (n = 28)

On-demand retreatment (n = 20)

p Value

53.7 (32.5 to 81.5) 71 13.2 (1.3 to 53.2) 86 82 4 (2 to 8) 1 (0 to 3) 1 (1 to 2) 6.06 (3.01 to 7.67) 1.63 (0.13 to 2.88) 56.5 (8 to 245)

58.5 (25.8 to 83.8) 60 13.4 (3.1 to 50) 95 85 5 (2 to 11) 2 (1 to 3) 1 (0 to 3) 6.73 (5.17 to 8.51) 1.50 (0.50 to 2.38) 52.5 (3 to 271)

0.28 0.41 0.99 0.30 0.79 0.05 0.05 0.85 0.09 0.66 0.57

2.13 (0.03 to 4.10) 0.25 (20.50 to 1.88) 5 (211 to 30)

1.77 (0.20 to 5.78) 0.13 (20.63 to 1.50) 4 (213 to 23)

64 28 4.0

53 18 5.9

12 60 28

27 53 20

24 5 4 4 1

(86%) (18%) (14%) (14%) (4%)

19 3 6 1 0

(95%) (15%) (30%) (5%) (0%)

0.51 0.48 0.33 0.47 0.44 0.78 0.481

0.30 0.79 0.19 0.30 0.39

*As quantified by the Sharp-van der Heijde score; {positive scores indicate the points of improvement in DAS28-cores; {positive scores indicate the points of improvement in HAQ-scores; 1p value was calculated by x2 test in contrast to non-parametric Mann– Whitney U tests used for all other variables presented. ACPA, anti-citrullinated protein/peptide antibodies; ACR, American College of Rheumatology; DAS28, 28-joint Disease Activity Score; DMARD, disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism; HAQ, Health Assessment Questionnaire; TNF, tumour necrosis factor.

between both treatment arms regarding change in 28-joint Disease Activity Score (DAS28) results, change in Health Assessment Questionnaire (HAQ) scores and radiographic progression. Additionally, American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response rates were comparable (table 1). Additionally, we found that both treatments were equally safe: 86% of the patients in the FR group compared to 95% in the ODR group had reported an adverse event (p = 0.30). One patient died 8 weeks after initiation of rituximab treatment from respiratory insufficiency due to progression of pre-existent lung fibrosis. Infusion-related events were seen in 14% of patients in the FR group and 30% in the ODR group (p = 0.19), of which all reported symptoms were mild with a common toxicity criteria (CTC) grade of 1 or 2. We demonstrated that over a 1-year follow-up period fixed retreatment and on-demand retreatment with rituximab resulted in comparable efficacy as measured by ACR response, EULAR response, change in DAS28 results and HAQ scores and radiographic progression. With respect to the safety profile, both treatment strategies were comparable. The present study warrants further randomised studies with longer follow-up of repetitive retreatment courses with rituximab, which are needed to evaluate different B cell depleting strategies. 1076

Y K O Teng,1 J Tekstra,2 F C Breedveld,1 F Lafeber,2 J W J Bijlsma,2 J M van Laar1,3 1

Department of Rheumatology, Leiden University Medical Center, The Netherlands; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, The Netherlands; 3 Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, UK 2

Correspondence to: J M van Laar, Musculoskeletal Research Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK; [email protected] Acknowledgements: We are grateful to M Yuksel and S van der Kooij for assessing radiographic progression scores. Funding: The study was supported by an unrestricted grant of Hoffman-Roche Ltd. The work of YKOT was supported by an Agiko grant from The Netherlands Organization for Scientific Research. Competing interests: Hoffman-Roche provided free supplies of rituximab for the patients included in the study. Ethics approval: Ethics approval was obtained. Accepted 4 September 2008 Ann Rheum Dis 2009;68:1075–1077. doi:10.1136/ard.2008.100438

REFERENCES 1.

Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial

Ann Rheum Dis June 2009 Vol 68 No 6


Letters

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evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum 2006;54:2793–806. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572–81. Emery P, Fleischmann R, Filipowicz-Sosnowska A, Schechtman J, Szczepanski L, Kavanaugh 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.

Refractory severe connective tissue disease thrombocytopenia: is rituximab treatment effective and safe? Rituximab, a chimeric monoclonal antibody against B cellspecific surface marker CD20, has shown encouraging results in treating autoimmune diseases.1–4 In this study, six patients with refractory severe thrombocytopenia (platelets (PLT) 4 to 106109/litre) were treated with rituximab (weekly infusion of 375 mg/m2 for 3–4 consecutive weeks), including three cases of systemic lupus erythematosus, one case each of primary Sjo ¨gren syndrome, undifferentiated connective tissue disease (CTD) and antiphospholipid syndrome (APS). Previous corticosteroids and immunosuppressive agents in all patients were continued. Disease durations were 3 months to 13 years. Prior to rituximab therapy, all patients had failed at least two courses of methylprednisolone pulse (1 g per day for 3 consecutive days) in combination with intravenous immunoglobulin (20 g per day for 3 to 5 consecutive days) plus at least two immunosuppressants, including cyclophosphamide, vincristine, mycophenolate mofetil and/or

4. 5.

6.

Popa C, Leandro MJ, Cambridge G, Edwards JC. Repeated B lymphocyte depletion with rituximab in rheumatoid arthritis over 7 yrs. Rheumatology (Oxford) 2007;46:626–30. Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum 2007;56:3896–908. Mease P, Keystone E, Kaell A, Emery P, St Clair EW, Dougados M, et al. Predicting outcome of second course of rituximab for rheumatoid arthritis. Ann Rheum Dis 2007;66(Suppl 2):434.

ciclosporine A. Patients 2, 4 and 5 had also undergone splenectomy without improvement. Five patients had suffered from treatment-related adverse events, including femoral head necrosis, secondary hypertension, diabetes and liver function impairment, and patients 5 and 6 had histories of recurrent lung infections (table 1). After the first infusion of rituximab, platelet counts increased within 1 week in patient 2 and 2 to 4 weeks in the other five patients, and were all above 1006109/litre within 3 to 9 weeks. Along with the improvement of thrombocytopenia, cutaneous haemorrhage and/or gastrointestinal bleeding disappeared. In addition, autoimmune haemolytic anaemia in patient 4 and proteinuria in patient 6 improved as well at week 2 and 7, respectively. Rituximab treatment had no significant effect on serum levels of immunoglobulin, including IgG, IgA and IgM. B cell counts (cell/mm3) in patients 1, 3 and 5 at the time of treatment were 480, 127 and 12, respectively. Complete B cell depletion (defined as less than 5 cells/mm3) was obtained in all three patients within 2 weeks after the first rituximab infusion. The mechanism by which rituximab led to thrombocytopenia remission may be through elimination of B lymphocytes necessary for autoantibody production. However, patient 2 experienced an early response, raising the possibility that B cells opsonised by anti-CD20 may contribute to Fc receptor blockade.5–7

Table 1 Rituximab therapy in six cases of refractory severe connective tissue disease (CTD) thrombocytopenia

Patient Sex/age

Disease

Disease duration (months)

1

F, 21

SLE

3

2

F, 54

UCTD

156

3

F, 58

PSS

60

4

M, 24

SLE

41

5

F, 41

APS

58

6

F, 31

SLE

108

Adverse events

Concurrent therapy

Infection

Duration of follow-up (months)

Outcome

Clinical features

Previous therapy

Thrombocytopenia, leukopenia, hypocomplementaemia, ANA(+), anti-dsDNA(+) Thrombocytopenia, arthritis, myalgia, ANA(+)

MP pulse, Pred, CTX, VCR

None

Pred, CsA

None

13

CR

MP pulse, Pred, CsA, VCR, IVIG, splenectomy MP pulse, Pred, MMF, IVIG

FHN, HBP, liver damage

Pred, MMF

None

35

CR

FHN

Pred, CsA

Herpes zoster, lung infection

2

Death

FHN,HBP

Pred, CsA

Lung infection

6

CR

Recurrent lung infections, SID

Pred, CsA, VCR

None

Recurrent lung infections

Pred, CsA, CTX

Pneumocystis carinii pneumonia

Parotid swelling, thrombocytopenia, antiSSA(+), anti-SSB(+) Evans syndrome, hypocomplementaemia, ANA(+), anti-dsDNA(+) Thrombocytopenia, DVT, PE, lupus anticoagulant (+) Fever, arthritis, serositis, pancytopenia, class IV LN, gastrointestinal vasculitis, hypocomplementaemia, ANA(+),anti-dsDNA(+)

MP pulse, Pred, CTX, VCR, IVIG, splenectomy MP pulse, Pred, CsA, CTX, VCR, IVIG, splenectomy MP pulse, Pred, CTX, CsA, IVIG

47

5

Thrombocytopenia recurred after 13 months Death

APS, antiphospholipid syndrome; CR, complete remission; CsA, ciclosporin A; CTX, cyclophosphamide; DVT/PE, deep venous thrombosis/pulmonary embolism; FHN, femoral head necrosis; HBP, hypertension; ILD, interstitial lung disease; IVIG, intravenous immunoglobulin; LN, lupus nephritis; MMF, mycophenolate mofetil; MP, methylprednisolone; MTX, methotrexate; Pred, prednisone; PSS, primary Sjo¨gren syndrome; SID, steroid-induced diabetes; SLE, systemic lupus erythematosus; UCTD, undifferentiated connective tissue disease; VCR, vincristine.

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Rituximab fixed retreatment versus on-demand retreatment in refractory rheumatoid arthritis: comparison of two B cell depleting treatment strategies Y K O Teng, J Tekstra, F C Breedveld, F Lafeber, J W J Bijlsma and Jacob M van Laar Ann Rheum Dis 2009 68: 1075-1077

doi: 10.1136/ard.2008.100438 Updated information and services can be found at: http://ard.bmj.com/content/68/6/1075

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