Juvenile idiopathic arthritis (JIA), also called juvenile rheumatoid arthritis, is a collective term for several forms of arthritis, all of which involve chronic long-term joint inflammation. This inflammation begins in patients who have not yet reached the age of 16. Chronic symptoms last at least six weeks. JIA may affect one or more joints and may involve other complications such as fever, rash, and/or eye inflammation. At the ACR Congress in San Diego, the benefits of early aggressive combination therapy were discussed. In addition, adalimumab and tocilizumab were compared.
Exactly what drives the immune system to malfunction in juvenile idiopathic arthritis (JIA) is unclear. The disease is not considered hereditary, and multiple family members are rarely involved. However, researchers believe that certain individuals have a genetic predisposition to developing JIA, but that they only develop the condition if they have been exposed to infection or other previously unknown triggers. Dietary or emotional factors do not seem to play a role here. In principle, JIA can affect children at any age, but onset in the first six months of life is rare. “It affects an estimated 300,000 children in the United States,” said Prof. Carol Wallace, MD, Washington.
Early combination therapy useful?
Several children’s hospitals and research centers in the United States have now compiled data in a double-blind, randomized placebo-controlled trial, “The Trial of Early Aggressive Therapy in Polyarticular Juvenile Idiopathic Arthritis” (TREAT) [1], which was presented at the ACR Congress.
In it, they compared two aggressive therapeutic approaches in the treatment of JIA in 85 patients aged two to 17 years. The question was which regimen would allow the children to achieve clinical inactivity of the disease within six months. In addition, there was the option to switch to the more aggressive therapy under certain conditions.
“Consequently, we were interested in identifying predictors of achieving and maintaining clinical disease inactivity. This is the first study that used this outcome criterion and compared two aggressive treatment approaches,” Prof. Wallace said.
Study design and results
Participants had polyarticular JIA for less than twelve months. They were randomized into two treatment arms:
Group 1: 42 patients received more aggressive combination therapy with methotrexate 0.5 mg/kg bw as a weekly injection, the tumor necrosis-
Factor (TNF) inhibitor etanercept 0.8 mg/kg bw weekly and prednisolone 0.5 mg/kg bw daily phased out to 0 within 17 weeks.
Group 2: 43 patients received less aggressive (mono) therapy with methotrexate 0.5 mg/kg bw as a weekly injection and placebo for etanercept and placebo for prednisolone.
Patients were assessed for attainment of inactivity status according to Wallace criteria at 1, 2, 4, 5, 6, 7, 8, 10, 12-month intervals. Patients who did not achieve an ACR Pedi 70 at four months or clinical inactivity at six months were assigned to open-label therapy with methotrexate, etanercept, and prednisolone. This exploration phase ended one year after baseline.
Thirty of 42 participants who started in group 1 achieved clinical inactivity at least once, compared with 28 of 43 participants who started in the less aggressive group 2. However, 17 of these 28 achieved status only after moving to the open-label phase.
The median number of days on therapy until clinical inactivity was 168.5 for group 1 and 192 for group 2. Crucially, JIA remained inactive for 139.5 days (median) during follow-up in group 1 but only 79 days in the other (p=0.016).
“So we can conclude that aggressive early treatment can help a large number of patients in the first 12 months. Combining an anti-TNF agent with methotrexate and prednisolone seems to lead to better maintenance of clinical inactivity than methotrexate alone,” Prof. Wallace concluded.
Indirect comparison of biologics
Laura Sawyer, London, presented a meta-analysis [2] that indirectly compared the efficacy of the TNF inhibitor adalimumab and the IL6 antibody tocilizumab in polyarticular JIA. “The objective was to use statistical methods to assess the relative effectiveness of biologic treatments, alone and in combination with methotrexate (MTX). Thus, we compared five randomized controlled trials (RCTs) with each other [3–7].”
Efficacy was compared based on American College of Rheumatology response rates (JIA ACR 30/50/70/90) reported at the end of the randomized double-blind phases. In addition, the authors calculated probabilities of achieving specific response rates with each biologic and placebo.
The original aim of the study could not be evaluated because ACR response rates were calculated methodologically differently in the five RCTs. Only adalimumab and tocilizumab could be compared. After controlling for prior biologic use, the probability of ACR30 with tocilizumab monotherapy (with a placeborate of 31%) was 68%, for ACR50 65%, for ACR70 61%, and for ACR90 41% versus adalimumab monotherapy 52%, 49%, 44%, and 26%, respectively.
With MTX combination therapy and an ACR30 placebo response of 52%, tocilizumab had a probability of ACR30 response of 77%, of ACR50 of 76%, of ACR70 of 67%, and of ACR90 of 51% compared with adalimumab 76%, 75%, 66%, and 49%, respectively. Neither in monotherapy nor in combination therapy were the differences between the two agents statistically significant.
“Based on these interpretive data, the expected efficacy of adalimumab and tocilizumab in polyarticular JIA appears to be comparable. However, as monotherapy, tocilizumab may work better than adalimumab,” Sawyer concluded.
Source: ACR/ARHP Annual Meeting, October 26-30, 2013, San Diego.
Literature:
- Wallace CA, et al: Predictors and Sustainability Of Clinical Inactive Disease In Polyarticular Juvenile Idiopathic Arthritis Given Aggressive Therapy Very Early In The Disease Course. ACR Abstract #790.
- Sawyer L, et al: Efficacy Of Biologic Treatments In Juvenile Idiopathic Arthritis With a Polyarticular Course: An Indirect Comparison. ACR Abstract #283.
- Ruperto N, et al: Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet 2008; 372(9636): 383-391.
- Lovell DJ, et al: Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis. N Engl J Med 2008; 359: 810-820.
- Lovell DJ, et al: Etanercept in Children with Polyarticular Juvenile Rheumatoid Arthritis. N Engl J Med 2000; 342: 763-769.
- Ruperto N, et al: A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis Rheum 2007; 56(9): 3096-3106.
- Unpublished data from CHERISH.
CONGRESS SPECIAL 2013; 6(1): 4-5
