Addendum: proposed guidelines for autologous stem cell transplantation in juvenile chronic arthritis
Series Editor: P. Woo
N. M. Wulffraat,
W. Kuis and
R. Petty1
Department of Paediatric Immunology and Rheumatology, University Hospital for Children `Het Wilhelmina Kinderziekenhuis', PO Box 85090, 3508 AB Utrecht, The Netherlands and
1 Division of Rheumatology, British Columbia Children's Hospital, Vancouver, Canada
Summary
In order to be eligible for autologous stem cell transplantation (ASCT), patients must fulfil the following criteria:
- The diagnosis must be certain according to ACR or EULAR criteria; disease course subtypes: systemic onset with polyarticular course or polyarticular onset.
- Duration of the disease at least 1 yr.
- There must be evidence of active inflammatory disease for at least the last 6 months.
- There must be evidence of unresponsiveness to, or toxicity from, standard therapy.
- The patient's general condition must be such that the procedure of ABMT itself and the attendant procedures will not pose an undue risk.
Diagnosis
- Age at onset<16 yr.
- Arthritis (swelling or effusion, or the presence of two or more of the following signs: limitation of range of motion, tenderness or pain on motion, and increased heat) in one or more joints.
- Duration of disease 6 weeks or longer (EULAR criteria: 3 months or longer).
- Onset type defined by type of disease in first 6 months:
- Polyarthritis:
5 inflamed joints.
- Oligoarthritis: <5 inflamed joints.
- Systemic: arthritis with characteristic fever.
- Exclusion of other forms of juvenile arthritis.
Evaluation for ABMT
- Assessment of disease activity. Patients showing ongoing disease activity despite adequate treatment, by the following criteria [1]:
- Global physician's assessment (VAS).
- Patient's self-assessment for pain and severity (CHAQ, VAS).
- Mobility (EPM ROM).
- Swelling (active joint count).
- Laboratory: ESR, CRP.
- Medication history. Patients considered for ABMT must have failed to respond to standard therapy, or have unacceptable toxicity secondary to treatment. Treatment failure includes:
- Patients dependent on high-dose steroids (>0.3 mg/kg) or
- High-dose MTX (1 mg/kg s.c. or i.m. with a maximum of 40 mg for at least 3 months) or combination therapy of MTX and another second-line drug such as cyclosporin A (CsA) to control disease activity. Recurrence of disease activity after tapering steroids, MTX or combination therapy of MTX and CsA.
- Patients with active disease under treatment with the `Seattle protocol' [2] for 6 months.
Unacceptable toxicity includes:
- Failure to grow (<10th percentile for length) related to corticosteroid use.
- Osteoporosis causing, for example, vertebral compression fractures.
- Avascular necrosis.
- Unacceptable elevation of serum creatinine (>30% increase over baseline) on at least two occasions related to cyclosporin use.
- Cataract related to corticosteroid use.
- Unacceptable elevation of liver enzymes (>3 times the upper limit of normal on at least two occasions) related to MTX use.
- Intractable hypertension related to corticosteroid use.
- Intractable gastrointestinal toxicity.
- CNS toxicity related to corticosteroid use.
- Drug-induced neutropenia: prolonged drug-induced cytopenia, without available alternatives to control disease activity.
- Assessment of possibility for improvement
- Presence of active disease.
- Current therapy causing unacceptable toxicity.
- Radiographs show no evidence of bony destruction so severe that functional improvement cannot be anticipated.
- Good potential for rehabilitation (physical therapy, psychology).
- Adequate social factors.
- Exclusion criteria
- Severe chronic infection.
- No potential for improvement of function (in the broadest sense, as assessed above).
- Inadequate social factors.
- Severe organ dysfunction (heart, lungs, liver, renal).
- Functional class IV (Steinbrocker).
Current disease status juvenile chronic arthritis/juvenile rheumatoid arthritis
- The extent of active systemic disease is assessed.
- Systemic features include spiking fever, typical rash, pericarditis and hepatosplenomegaly.
- A polyarticular course is mandatory. The number of active joints, the joints with major functional limitations (degree of severity expressed as a percentage of range of motion) and the radiographic changes must be noted.
- Presence of active uveitis. Any significant visual impairment?
- Functional class: What do you consider to be the potential for regaining significant function if inflammation is completely controlled?
- Core set variables for improvement of JCA (see [1]).
Transplantation
- Graft.
- Peripheral blood stem cells.
- Bone marrow (preferred).
- Graft manipulation.
- Positive (CD34-positive) selection.
- Negative (CD3-positive) selection.
- Graft composition, if applicable after manipulation:
- CD34 numbers: >1x106 /kg.
- T-cell numbers: <1x105 /kg.
Conditioning regimen
The present, but limited, experience favours a conditioning of antithymocyte globulin (5 mg/kg for 4 days), followed by high-dose cyclophosphamide (50 mg/kg for 4 days) and low-dose total body irradiation (TBI) (4 Gy, single fraction, see also [3, 4]). Patients entering this study will not be randomized. It remains a decision of the individual centre either to give intensive conventional treatment (arm 1 of the study; see [2]) or to perform autologous stem cell transplantation (ASCT) with or without TBI (arm 2a and 2b of the study). After failure of intensive conventional treatment for at least 6 months, a patient may be included in arm 2.
Follow-up
- Engraftment.
- Short-term and long-term toxicity.
- Infections.
- Disease activity, as measured by the core set variables [1].
The Registry for Juvenile Rheumatic Diseases and Bone Marrow Transplantation
A registry will be designed in addition to minimal essential data already being registered for other purposes (e.g. MED A for EBMT ). However, we feel that this questionnaire really only asks for a minimum dataset. We do appreciate your efforts to keep the registry complete. In due course, we will make the MED-B registry suitable for paediatric autoimmune disease. We will keep you informed about new developments regarding this registry.
References
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Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:12029.[ISI][Medline]
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Wulffraat NM, van Royen A, Bierings M, Vossen JM, Kuis W. Autologous hemopoietic stem cell transplantation in 4 cases with refractory juvenile chronic arthritis. Lancet; 1999;353:5503.[ISI][Medline]
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Vossen JM, Brinkman DMC, Bakker B, Hoogerbrugge PM, ten Cate R. Rationale for high dose cyclophosphamide and medium-dose total body irradiation in the conditioning of children with progressive systemic and polyarticular juvenile chronic arthritis before autologous stem cell transplantation. Rheumatology 1999;38:7623.[Free Full Text]
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Wallace CA, Sherry DD. Intravenous pulse cyclophosphamide and methylprednisolone in the treatment of severe systemic onset juvenile rheumatoid arthritis. Arthritis Rheum 1997;40:18525.[ISI][Medline]
Accepted 15 March 1999