Abatacept improves juvenile arthritis in randomized withdrawal trial, but study questioned

July 14, 2008

Abatacept is a rational alternative treatment for juvenile idiopathic arthritis (JIA) in children who do not respond to other treatments, conclude authors of an Article published early Online and in an upcoming edition of The Lancet. However, an accompanying Comment says the design of the study makes it difficult to determine the true effect of abatacept.

Some children with JIA either do not respond to, or are intolerant to, treatment with antirheumatic drugs, such as non-steroidal anti-inflammatory drugs or methotrexate. Dr Nicolino Ruperto, IRCCS Istituto G Gaslini Pediatria II, Largo Gaslini, Genova, Italy, and colleagues aimed to assess abatacept, which modulates the T cells in the immune inflammation response in arthritis, in children with JIA who had failed previous treatments.

The double-blind, randomised, controlled withdrawal trial enrolled 190 patients aged 6-17 years from 45 centres in Europe and the USA with a history of JIA, at least five joints with active disease, and inadequate response or intolerance to at least one disease-modifying antirheumatic drug. Before entering the randomisation phase, all 190 patients were given 10 mg/kg of abatacept intravenously for four months -- in the so-called 'open-label' phase of the study. Of the 170 patients who completed this lead-in course, 47 did not respond and were excluded. Of the patients that did respond, 1 left the study; 60 were randomly assigned to receive 10 mg/kg abatacept at 28-day intervals for six months, or until a flare of arthritis; the other 62 received placebo at the same dose and timing. The primary endpoint was flare of arthritis, which was defined as worsening of 30% or more in at least three of six core variables*, with at least 30% improvement occurring in no more than one variable.

The researchers found flare occurred in 33 of 62 (53%) of patients given placebo and 12 of 60 (20%) given abatacept. Median time to flare was six months in the placebo group, but not enough flare events occurred in the abatacept group to establish this figure. The risk of flare in patients who continued abatacept was less than a third (31%) of that for placebo during the double-blind period. Rates of adverse events were similar but high in both groups - 62% in the abatacept group and 55% in the placebo group. The trial also showed that after four months of treatment in the lead-in course 95 patients (50%) reached a 50% level of response** that increased to 77% (46/60) in the group of patients subsequently randomised to abatacept in the double blind phase.

The authors conclude: "Our data showed that abatacept had clinical benefits for patients, irrespective of juvenile idiopathic arthritis subtype...The availability of abatacept will provide clinicians with another alternative for the treatment of methotrexate-resistant patients....In conclusion, abatacept treatment induced improvement and was well tolerated in patients with active juvenile idiopathic arthritis who responded to this treatment in the open-label phase. Further research will be needed to establish the proper role of abatacept in comparison with other biological agents, and to address functional outcomes, the prevention and healing of joint erosions, and other structural damage in juvenile idiopathic arthritis."

In the accompanying Comment, Dr Thomas Lehman, Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, USA, says: "This design preselects responders to the placebo effect who might retain their response throughout the entire study period whether or not they are randomly assigned to placebo in the second phase. Combined with carryover effects, these factors can overestimate any potential benefit in clinical practice and underestimate side-effects, obscuring our knowledge of the drug's true risks and benefits."

He also discusses the possible 'enhanced placebo effect' in children, who for example can be keen to please their parents with the news that a treatment is working, and that proof of efficacy in adults is not necessarily the same for children. He concludes: "Paediatric rheumatologists have a responsibility to independently evaluate the safety in children of drugs approved for use in adults with arthritis. Many clinicians argue that they also have a responsibility to separately evaluate efficacy, which is true in an ideal world. However, paediatric rheumatologists should consider the countervailing responsibility not to unnecessarily enter children into studies that subject them to placebo control with the possibility of flare and worsening of their condition, when the studies are inadequately designed or powered to provide convincing proof of efficacy and safety."
-end-
*Notes to editors: The six core variables used by the American College of Rheumatologists are the number of active joints; the number of joints with limited range of motion; physician global assessment of disease severity; parent global assessment of overall wellbeing; functional ability assessed with the Childhood Health Assessment Questionnaire; and the red blood cell sedimentation rate, which gives an indication as to the level of inflammation in the body.

**For registration purposes the FDA and the EMWA consider a child as a responder if he/she shows at a least a 30% level of response as measured by the American College of Rheumatology (ACR). Different response levels can be measured, eg ACR-30, ACR-50, ACR-70 etc.

Dr Nicolino Ruperto, IRCCS Istituto G Gaslini Pediatria II, Largo Gaslini, Genova, Italy T) +39-010-382854/ +39-010-393425 E) nicolaruperto@ospedale-gaslini.ge.it

Dr Thomas Lehman, Chief, Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, USA T) +1 212-606-1151 E) goldscout@aol.com / Lehmant@hss.edu

Lancet

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