Clinical Observations on In iximab Treatment of Infantile Onset Takayasu Arteritis

Min Kang The Children's Hospital A liated to Capital Institute of Pediatrics Jianming Lai (  laijm99@sina.com ) The Children's Hospital A liated to Capital Institute of Pediatrics Dan Zhang The Children's Hospital A liated to Capital Institute of Pediatrics Yingjie Xu The Children's Hospital A liated to Capital Institute of Pediatrics Jia Zhu The Children's Hospital A liated to Capital Institute of Pediatrics Ming Li The Children's Hospital A liated to Capital Institute of Pediatrics

In iximab, 5-6mg/kg, was given intravenously at 0, 2, 6, 14, 22 and 30 weeks and, depending on the apparent effect of the treatment, additional IFX injections were given at 8-week intervals. At the beginning of treatment, glucocorticoid (GC) and immunosuppressive therapy was continued in 5 patients; another 5 patients were treated with IFX alone and their GC dose was adjusted during treatment in accordance with the infant's condition.

Clinical indicators
We abstracted infants' medical records for data on age, gender, medical history, physical examination, laboratory tests, cardiac ultrasound, vascular ultrasound, chest and abdomen enhanced CT, and CT angiography(CTA). We recorded time-varying clinical data on temperature, blood pressure, routine blood tests, in ammatory indices, cytokines, and immunity. Vascular ultrasound and/or CTA was used to evaluate progression of vascular lesions. We recorded GC and immunosuppressive agent doses administered before and after IFX was started.

Safety evaluation and follow-up
The infants were followed up every 1 to 3 months for 8 to 64 months to record their symptoms, liver and kidney functioning, and signs of infection. We conducted follow-up assessments in the hospital, during outpatient visits, and by telephone. We obtained data on height, weight, clinical symptoms, and treatment. No cases were lost to follow-up.

Statistical analysis
Continuous data are presented as means with standard deviations or ranges. Means were compared by independent-sample t tests. A p value <0.05 was considered statistically signi cant.

Baseline characteristics
Ten infants quali ed for the study -two boys and eight girls. The ages of onset of their TA ranged from 1 month, 17 days to 5 months, 7 days. At the time of diagnosis, durations of illness were less than 1 month in seven cases and 1-3 months in the other three cases.

Clinical manifestation and Medication before IFX
The most common clinical manifestation was fever in 9 cases (90%). Six (60%) infants had hypertension; three (30%) had weak or no detectable pulse; two (20%) had vomiting, and one had transient low-grade fever twice during the illness; no infants had rashes or vascular bruits ( Table 1).
Five of the infants were treated with IFX alone. Five infants had been treated with GC (1-1.5mg/kg/day) prior to receiving IFX, which was started because their in ammation indexes did not decrease and/or vascular imaging showed extensive involvement or no improvement. Cases 6, 7, and 8 had been treated with GC (1mg/kg/day) prior to receiving IFX; their in ammation indexes decreased slightly. After combination therapy with IFX, the GC doses were decreasedquickly at rst, then gradually, discontinuing at 12 weeks into therapy in 2 cases and 16 weeks in the other case. The Case 9 infant had been treated with prednisone (1.5mg/kg/day). Temperature and in ammatory indexes quickly returned to normal. After oral administration of prednisone for 4 months, the dose was reduced to 5mg/day for 3 months and was combined with methotrexate (MTX) for 4 more months. However, CTA showed that the celiac trunk artery and the left iliac artery were thinner than before, suggesting that the vascular lesion was worsening. The infant had slow growth and development. IFX therapy was added, and the prednisone was reduced and then discontinued in 2 weeks. For the Case 10 infant, oral GC (1mg/kg/day) was used in combination with antiinterleukin 6 receptor antibody (tocilizumab) (12mg/kg, every two weeks) for 3 months. The coronary arteries showed signi cant improvement, but CTA showed no more improvement than as seen at the beginning of the disease; therapy was changed to IFX (Table 2).
Note: Y represents positive, N represents negative.  Growth and development of nine infants with TA was similar to age-matched healthy infants after 8-64 months of follow-up. In one infant treated with GC combined with MTX, height was less than the 3rd percentile for same-age healthy infants. At eight months, height was at the 5th percentile.

Laboratory tests
At onset of TA, leukocyte and platelet counts were high, hemoglobin was low, and in ammatory indexes were high, suggesting that all ten cases were in the active, acute stage. Leukocytes and platelet counts decreased, and hemoglobin increased after two weeks of IFX treatment. At six weeks, these laboratory values improved compared with values before treatment (p<0.05); Two weeks after IFX treatment started, the in ammatory indexes of C-reactive protein and erythrocyte sedimentation rate decreased signi cantly compared with before treatment (p<0.05) ( Table 3). Note: *-after 6 weeks, WBC-leukocyte, HGB-hemoglobin, PLT-platelet, CRP-C-reactive protein, ESR-erythrocyte sedimentation rate, IFX=in iximab, GC=glucocorticoids.
Safety evaluation and follow-up 40%) were also commonly involved. All 10 infants were in active disease states at the time of diagnosis, with widespread vascular involvement, suggesting that the infants' conditions were serious and had poor prognoses.
Tumor necrosis factor alpha (TNF-α) is implicated in TA in ammation. IFX is a TNF-α inhibitor that has direct cytotoxicity and induces apoptosis of immune cells. IFX is reported to have signi cant effectiveness in refractory TA that is resistant to glucocorticoids and immunosuppressants [8,9,[17][18][19][20]. Our observations showed that IFX is also effective for treatment of TA in infants. Five of our cases were treated with IFX alone and ve were treated with IFX combined with GC. We found that temperatures rapidly normalized, in ammatory indexes decreased, and vascular lesions gradually improved with IFX therapy. Additionally, IFX enabled a reduction in dose or discontinuation of GC. In cases 1-8, vascular lesions treated with IFX in the early stage began to resolve within 1.5-3 months. Most of the affected arteries recovered within 13 months, but some remained stenotic, with intimal thickening and uneven lumens that which did not resolve. In Case 9, some vascular lesions worsened during GC and MTX treatment, but the vascular lesions gradually recovered after initiating IFX. In Case 10, the coronary arteries and abdominal aorta improved, but other vascular lesions did not improve during three months of combination GC and tocilizumab therapy. Some vascular lesions gradually recovered after initiating IFX. In 6 infants with hypertension, blood pressure returned to normal after 3-8 months of IFX treatment, showing that treatment with IFX could lead to inactive disease status. IFX was effective, bene cial, and well-tolerated in all 10 TA infants. In Case 9, growth and development lagged behind normal growth and development, but after stopping glucocorticoids and starting IFX, growth and development improved.
Our study showed that IFX has a good safety pro le for use in infants. During IFX treatment, only 1 infant had an allergic reaction, which was during the eighth infusion; other infusions were not associated with adverse events. No severe infections were diagnosed during treatment, consistent with previous reports [10,13,20] [21]. Early application of IFX in cases 1-8 had no impact on growth and development.
Our study had limitations. Our case series had only 10 infants, and the follow-up time was relatively short. Therefore, studies of long-term effectiveness and safety of IFX for infantile TA need to include more infants and have longer follow-up times.

Conclusions
In infant-onset TA, early use of IFX can signi cantly and rapidly decrease in ammation and resolve clinical features of active disease, improve vascular lesions, and sustain remission for longer time than treatment with glucocorticoids and methotrexate. IFX enables dose reduction or discontinuation of GC, which promotes normal infant growth and development. IFX appears to cure some cases of infantile TA and induces a high rate of clinical remission.