DOI 10.1002/art.27557

Unanswered questions in evaluating rituximabefficacy: comment on the article by Merrill et al

To the Editor:Having had very good experience with rituximab in

several patients with refractory systemic lupus erythematosus(SLE), we read the article by Merrill et al (1), which summa-rizes results of the Exploratory Phase II/III SLE Evaluation ofRituximab (EXPLORER) trial, a randomized, double-blindstudy, with great interest. There is now a significant body ofevidence that rituximab is most effective in reducing renalabnormalities and musculoskeletal symptoms of SLE in pa-tients positive for anti–double-stranded DNA (anti-dsDNA)antibodies. To a lesser extent, rituximab may reduce neuro-logic symptoms, cutaneous lesions, and cytopenia in thesepatients (2–4). However, we believe that by defining theachievement of British Isles Lupus Assessment Group(BILAG) (5) C scores or better in all systems (BILAG globalscore) as end points in a very heterogeneous group of patients,the authors strive for the impossible.

It would be interesting for the reader to know whetherrituximab therapy had a beneficial effect on any of the BILAGscores for individual systems. It also remains unclear whypatient subgroups were based solely on race and not onpredominant clinical manifestation and presence of anti-dsDNA antibodies.

Merrill and colleagues indicate that the patients weregiven steroids, which were tapered to control immediatedisease activity. We would be interested to know what theaverage total dose of steroids received by patients was through-out the 52-week trial, and if there was any difference in thetotal steroid dose between patients who received rituximab andthe controls who received placebo. The magnitude of thesteroid-sparing effect is one of most significant measures whenevaluating the efficacy of immunosuppressive drugs (6); didrituximab display any such effect in this trial?

In the EXPLORER trial, background immunosup-pressive treatment included azathioprine (100–250 mg/day),mycophenolate mofetil (1–4 gm/day), or methotrexate (7.5–27.5 mg/week). Merrill and colleagues indicate that the differ-ent types of background treatment were evenly distributedbetween the 2 study groups. Were patients in the placebo groupmatched according to the dosage of the immunosuppressivetherapy, or only according to the type of therapy? Did thisdosage remain stable throughout the 52-week trial? If not, werethere any differences between the rituximab and placebo groups?

Merrill and colleagues indicate that further evaluationof patient subsets, biomarkers, and exploratory outcome mod-els may improve the design of future SLE clinical trials. Weencourage the authors to perform these missing analyses basedon the data available from the EXPLORER trial.

In our opinion, an agent such as rituximab, whichtargets a single well-defined molecule, cannot be evaluated inbasic terms in an extremely heterogeneous group of patients,who displayed diverse clinical manifestations of SLE, immuno-logic markers, and background therapy. We believe that in thearea of biologic drugs, “targeted therapy” should also mean“targeting the right patient with the right drug.” This requires

rethinking of clinical trial design in diseases that are asheterogeneous as SLE.

Lidia Rudnicka, MD, PhDCentral Clinical Hospital

and Warsaw Medical UniversityMalgorzata Olszewska, MD, PhDWarsaw Medical UniversityAgnieszka Kardynal, MDCSK MSWiAWarsaw, Poland

1. Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM,Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized,double-blind, phase II/III Systemic Lupus Erythematosus Evalua-tion of Rituximab trial. Arthritis Rheum 2010;62:222–33.

2. Garcia-Carrasco M, Mendoza-Pinto C, Sandoval-Cruz M, Soto-VegaE, Beltran-Castillo A, Jimenez-Hernandez M, et al. Anti-CD20 ther-apy in patients with refractory systemic lupus erythematosus: a longi-tudinal analysis of 52 Hispanic patients. Lupus 2010;19:213–9.

3. Tew GW, Rabbee N, Wolslegel K, Hsieh HJ, Monroe JG, BehrensTW, et al. Baseline autoantibody profiles predict normalization ofcomplement and anti-dsDNA autoantibody levels following Rituximabtreatment in systemic lupus erythematosus. Lupus 2010;19:146–57.

4. Ramos-Casals M, Diaz-Lagares C, Khamashta MA. Rituximab andlupus: good in real life, bad in controlled trials. Comment on thearticle by Lu et al. Arthritis Rheum 2009;61:1281–2.

5. Symmons DP, Coppock JS, Bacon PA, Bresnihan B, Isenberg DA,Maddison P, et al, and Members of the British Isles LupusAssessment Group (BILAG). Development and assessment of acomputerized index of clinical disease activity in systemic lupuserythematosus. QJM 1988;69:927–37.

6. Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J,Natorska U, et al. Efficacy and safety of cyclophosphamide, aza-thioprine, and cyclosporine (ciclosporin) as adjuvant drugs inpemphigus vulgaris. Am J Clin Dermatol 2007;8:85–92.

DOI 10.1002/art.27514

Estimating medical costs attributable to osteoarthritisin the US population: comment on the article byKotlarz et al

To the Editor:In the recent article by Kotlarz et al, the authors

reported insurer and out-of-pocket medical expendituresamong insured US adults with osteoarthritis (OA) (1). Esti-mating costs for this large, growing, and disabling healthcondition is important, but we are concerned that the authorsoverestimated both individual and aggregate expenditures.

Using 1996–2005 Medical Expenditure Panel Survey(MEPS) data on US adults with health insurance, the authorsestimated that annual aggregate OA-attributable medical ex-penditures were $185.5 billion, or 19% of the $994 billion in2005 MEPS aggregate medical expenditures for the US adultpopulation (all in 2007 dollars) (2). This estimate seems high inlight of our own MEPS study of the broader category ofarthritis and other rheumatic conditions (AORC), a definitionthat includes people with OA (3). We found that 2003 AORC-attributable medical expenditures among all US adults wereonly 10% of aggregate medical expenditures ($80.8 billiondivided by $805 billion) (4,5).

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