Treatment Does Not Explain Slightly Increased Opportunistic Infections in JIA



WASHINGTON – Opportunistic infections in children with juvenile idiopathic arthritis are rare, but they occur at a significantly higher rate in JIA patients than in unaffected children, according to findings from an analysis of national Medicaid claims data.

However, the association between these infections and the use of immunosuppressive treatments for JIA appears weak.

The findings, based on data from 2000 through 2005, show that 42 infections occurred in 8,503 children with JIA, and 584 infections occurred in 360,362 non-JIA comparators, for incidence rates of 300 and 125 per 100,000 person years, respectively, and an incident rate ratio (IRR) of 2.4, Dr. Timothy Beukelman reported at the annual meeting of the American College of Rheumatology.

After excluding herpes zoster, which was by far the most common infection among those with JIA, the rate of opportunistic infections was fourfold higher in the JIA cohort compared with the non-JIA cohort.

The infections that occurred at a higher rate in the JIA cohort were Coccidioides (3 infections, for an incidence rate of 21 per 100,000 and an IRR of 101.0), Salmonella (5 infections, for an incidence rate of 35 per 100,000 and an IRR of 3.8), and herpes zoster infections (32 infections for an incidence rate of 225 per 100,000 and an IRR of 2.1), said Dr. Beukelman of the University of Alabama at Birmingham.

One infection each with Nocardia, nontuberculosis mycobateria, Toxoplasma, and Pneumocystis occurred, for an incidence rate of 7 per 100,000 for each of these infections. Incidence rate ratios were not calculated.

No infections with Aspergillus, Blastomyces, Histoplasma, Cryptococcus, Legionella, Listeria, John Cunningham virus, or tuberculosis were identified in the JIA cohort.

These findings differ from those in adults with rheumatoid arthritis (RA).

"We know that adults with RA who are treated with certain biologics have an increased incidence of some opportunistic infections, in particular tuberculosis, endemic mycoses, Listeria, and Legionella," Dr. Beukelman said.

Among the children with JIA, 1,392 used tumor necrosis factor (TNF) inhibitors, and 3,491 used methotrexate during follow-up. An analysis of the association between these treatments and herpes zoster infection found only weak associations with respect to current use of methotrexate (IRR, 1.4 vs. no current methotrexate or TNF inhibitor use), TNF inhibitors (IRR, 2.2 vs. current methotrexate use without current TNF inhibitor use), or glucocorticoids (IRR, 1.8 vs. no current glucocorticoid use), Dr. Beukelman said.

With respect to the Coccidioides infections, the rate was unexpectedly high in the JIA cohort, but two of the patients had no current exposure to TNF inhibitors, methotrexate, or glucocorticoids, and one had exposure only to methotrexate at the time of the infection. None had been treated by TNF inhibitors at any time during the study.

The findings are the first from a controlled trial to address and characterize the incidence of opportunistic infections in JIA patients, Dr. Beukelman said, noting that very little is known about the incidence of opportunistic infections in children with JIA.

Prior studies have, however, demonstrated a twofold increase in the rate of hospitalized infections associated with JIA vs. without JIA in the absence of immunosuppressive infection, so it appears that the JIA disease process itself may predispose to serious bacterial infections.

"We wondered if there might be a similar situation with opportunistic infections," he said.

The findings of the current study suggest that is, indeed, the case.

JIA in this study was based on physician diagnosis codes and dispensed medication. The comparator cohort was composed of children diagnosed with attention deficit hyperactivity disorder. The cohorts had 14,370 and 490,939 person-years of follow-up, respectively.

All subjects had a 3-month baseline period prior to study follow-up during which they were assessed for prevalent opportunistic infections and medication exposures. Infections were identified using physician diagnosis or hospital discharge codes, with the exception of mycoses, tuberculosis, and herpes zoster, which also required evidence of treatment with specific antimicrobials.

"Future studies of the association between opportunistic infections and JIA medications must consider there’s likely an increased rate of opportunistic infections associated with JIA itself, and not just with the medications we use to treat it," Dr. Beukelman said.

This study was supported by the Agency for Healthcare Research and Quality. Dr. Beukelman disclosed that he has received a research grant from Pfizer, and consulting fees and/or other remuneration from Novartis Pharmaceutical Corporation, and Genentech and Biogen IDEC Inc.

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