Background
Methods
Participants and stratification method
Definition of low-intensity IS (LIIS) and high-intensity IS (HIIS)
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LIIS included: (1) methotrexate (MTX) ≤15mg/m2/week or max. 15mg/week, (2) prednisolone (PDN) ≤0.5mg/kg/day (max. 10 mg/day) or (3) azathioprine (AZA) ≤2mg/kg/day (max. 100mg/day).
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HIIS included: (1) MTX >15mg/m2/week or >15mg/week, (2) PDN >0.5 to <2mg/kg/day or >10 to <20mg/day, (3) AZA >2 to 3mg/kg/day, (4) leflunomide ≤0,5mg/kg/days or ≤20mg/day, (5) cyclosporine A ≤ 3mg/kg/day with trough level ≤100μg/l, (6) tacrolimus and mTOR inhibitors with trough level ≤4ng/ml, (7) mycophenolate mofetil (MMF) ≤1200mg/m2/day or up to 2g/day, (7) etanercept ≤0.8mg/kg/week or up to 50mg/week, (8) adalimumab ≤24mg/m2 or up to 40mg every 2 weeks, (9) infliximab ≤6mg/kg up to every 4 weeks, (10) tocilizumab ≤12mg/kg up to every 2 weeks (if body weight ≤30kg) or ≤8mg/kg up to every 2 weeks if body weight ≥30kg, (11) anakinra ≤3mg/kg/day up to 150mg/day, and (12) abatacept ≤10mg/kg every 4 weeks. Combination therapy was allowed except for combination of two biologic DMARDs.
Pre-vaccination checklist
Step 1: Rating of immunosuppressive therapy | Step 2: Prerequisites | Step 3: Testing protocol | Step 4: Decision about vaccination |
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Low-intensity immunosuppression (LIIS) □ Prednisone ≤ 0,5mg/kg (max. 10mg) daily □ Methotrexate ≤ 15mg/m2 (max. 15mg) weekly □ Azathioprine ≤ 2mg/kg (max. 100mg) daily High-intensity immunosuppression (HIIS)
Glucocorticoids and synthetic DMARDs
□ Prednisone > 0,5 to < 2mg/kg (> 10mg to < 20mg) daily □ Methotrexate > 15mg/m2 or > 15mg to 30mg weekly □ Azathioprine > 2 to 3mg/kg daily □ Leflunomide ≤ 0,5mg/kg (max. 20mg) daily □ Cyclosporine ≤ 3mg/kg daily (trough level ≤ 100μg/l) □ mTOR-inhibitors (sirolimus or everolimus) (trough level ≤ 4 μg/l) □ Mycophenolate ≤ 1200mg/m2 (max. 2g) daily
Biological DMARDs
□ Abatacept ≤ 10mg/kg per 4 weeks □ Adalimumab ≤ 24mg/m2 (max. 40mg) per 2 weeks □ Anakinra ≤ 3mg/kg (max. 150mg) daily □ Etanercept ≤ 0,8mg/kg (max. 50mg) weekly □ Infliximab ≤ 6mg/kg per 4 weeks □ Tocilizumab ≤ 12mg/kg biweekly if weight < 30kg □ Tocilizumab ≤ 8mg/kg biweekly if weight > 30kg Special situations: • If on canakinumab, consider switching to anakinra temporarily. | I. Medical history and physical exam □ No family history or clinical evidence of primary immunodeficiency □ No measles-mumps-rubella vaccination at the same time or within < 4 weeks before VV □ For 2nd VV: At least 3 months from first dose of VV for patients on HIIS II. Clinical assessment □ Inactive rheumatic disease □ Stable antirheumatic therapy for at least 3 months □ No active infection III. Medications □ Not more than 2 synthetic DMARDs □ Not more than 1 biological agent +/− 1 synthetic DMARD □ No IV methylprednisolone pulse therapy or oral prednisone ≥ 2mg/kg or ≥ 20mg daily for > 2 weeks within < 1 month before and after VV □ No IV cyclophosphamide in previous 6 months □ No rituximab in previous 6 months or lasting B-cell deficiency □ No IVIG in previous 6 months (high-dose IVIG [2g/kg] 11 months) □ No blood products in previous 3 months □ No therapy with aspirin planned in 6 weeks after vaccination | Basic laboratory testing for all patients: □ VZV-IgG < 200 mIU/ml (prior to1st VV) □ WBC ≥ 3,000/mm3 □ Lymphocytes ≥ 1,200/mm3 □ IgG ≥ 500 mg/dl □ IgM ≥ 20mg/dl □ Tetanus toxoid antibody ≥ 0.1 IU/ml Additional laboratory testing for patients on HIIS or LIIS with abnormal basic lab result: □ CD4 cell count > 200/mm3 if > 5 yrs old OR CD4 cell count > 500/mm3 if 1-5 yrs old □ T cell function testinga positive Special situations: • If WBC < 3000/mm3: • exclude neutropenia <1500/mm3 • If lymphocytes 700-1.200/mm3: • rule out low CD4+ T-cells • If Lymphocytes < 700/mm3: • absolute contraindication • If IgG < 500mg/dl or IgM < 20mg/dl: • rule out humoral and cellular immunodeficiency • If tetanus antibody-level < 0,10IU/ml: • give tetanus vaccination and control serologic response in 4 weeks | □ All prerequisites are met □ Basic laboratory testing normal □ Additional lab testing normal (if applicable), or additional testing not applicable IF ALL THREE ITEMS ABOVE ARE CHECKED, VV IS SUPPORTED WITHOUT SUSPENSION OF THE CURRENT IMMUNOSUPPRESSION.b,c |
Vaccination
Determination of safety
Determination of immunogenicity and efficacy
Statistical analysis
Results
Screening for lack of varicella immunity and recruitment
Participants and baseline laboratory and immunologic data
Characteristic | Overall | Low-intensity immunosuppression (LIIS) | High-intensity immunosuppression (HIIS) | p value |
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Number | 23 | 9 (39%) | 14 (61%) | |
Female | 17 (74%) | 8 (89%) | 10 (71%) | 0.32a |
Age, median (range) years | 9.6 (1.8-17.8) | 8.3 (1.8-17.8) | 9.7 (2.7-17.8) | 0.33b |
Disease type | 8 JIA | 11 JIA | ||
6 oligoarthritis | 3 oligoarthritis | |||
1 polyarthritis | 3 polyarthritis | |||
1 psoriatic arthritis | 4 systemic arthritis | |||
1 Sjögren syndrome | 1 psoriatic arthritis | |||
2 JDM | ||||
1 MPA | ||||
Immunosuppressive drug therapy | 9 MTX <15mg/m2/wk | 2 MTX ≥15mg/m2/wk | N/A | |
1 MTX+TCZ | ||||
1 MTX+ADA | ||||
1 MTX+ANK+PDN | ||||
1 LEF | ||||
1 LEF+ABA | ||||
1 LEF+ANK+PDN | ||||
1 LEF+ETN+PDN | ||||
1 LEF+TCZ | ||||
2 ETN | ||||
1 ETN+PDN | ||||
1 MMF | ||||
Varicella vaccine history | 0.31a | |||
0 previous doses | 15 | 7 | 8 | |
1 previous dose | 8 | 2 | 6 | |
Baseline white blood cell count, median (range) per mm3 | 5900 (4100-8311) | 5100 (4100-6900) | 6715 (4400-8311) | 0.12b |
Baseline absolute lymphocyte count, median (range) per mm3 | 2433 (1156-4647) | 2295 (1156-3200) | 2519 (1158-4647) | 0.63b |
Serum IgG, mean (SD) mg/dl | 793 (542-1803) | 793 (637-1803) | 787 (542-1403) | 0.61b |
Tetanus toxoid antibody, mean (SD) IU/ml | 1.4 (0.1-6.2) | 2.2 (0.16-6.2) | 0.6 (0.1-2.7) | 0.01b |
CD4+ T cell count, mean (SD) per mm3 | N/A | N/A | 1371 (546) | N/A |
Positive T cell function, n (%) | N/A | N/A | 14 (100) | N/A |
Administration of the varicella vaccine
VZV-IgG response following vaccination
Safety assessments
Adverse event | LIIS group | HIIS group |
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Local reaction at injection site – n (%) | 1 (11%) | 1 (7%) |
Systemic rash | 0 (0%) | 0 (0%) |
Elevated temperature | 0 (0%) | 1 (7%) |
Headache | 0 (0%) | 1 (7%) |
Vomiting/gastroenteritis | 0 (0%) | 1 (7%) |
Arthralgia/joint complaintsa | 3 (33%) | 1 (7%) |