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Rheumatology 1999; 38: 777-778
© 1999 British Society for Rheumatology

Paediatric Rheumatology: Autologous Stem Cell Transplantation in Rheumatic Diseases of Childhood

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:

  1. The diagnosis must be certain according to ACR or EULAR criteria; disease course subtypes: systemic onset with polyarticular course or polyarticular onset.
  2. Duration of the disease at least 1 yr.
  3. There must be evidence of active inflammatory disease for at least the last 6 months.
  4. There must be evidence of unresponsiveness to, or toxicity from, standard therapy.
  5. 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

  1. Age at onset<16 yr.
  2. 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.
  3. Duration of disease 6 weeks or longer (EULAR criteria: 3 months or longer).
  4. Onset type defined by type of disease in first 6 months:
    1. Polyarthritis: >=5 inflamed joints.
    2. Oligoarthritis: <5 inflamed joints.
    3. Systemic: arthritis with characteristic fever.
    4. Exclusion of other forms of juvenile arthritis.

Evaluation for ABMT

  1. Assessment of disease activity. Patients showing ongoing disease activity despite adequate treatment, by the following criteria [1]:
    1. Global physician's assessment (VAS).
    2. Patient's self-assessment for pain and severity (CHAQ, VAS).
    3. Mobility (EPM ROM).
    4. Swelling (active joint count).
    5. Laboratory: ESR, CRP.

  2. Medication history. Patients considered for ABMT must have failed to respond to standard therapy, or have unacceptable toxicity secondary to treatment. Treatment failure includes:
    1. Patients dependent on high-dose steroids (>0.3 mg/kg) or
    2. 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.
    3. Patients with active disease under treatment with the `Seattle protocol' [2] for 6 months.

Unacceptable toxicity includes:

  1. Failure to grow (<10th percentile for length) related to corticosteroid use.
  2. Osteoporosis causing, for example, vertebral compression fractures.
  3. Avascular necrosis.
  4. Unacceptable elevation of serum creatinine (>30% increase over baseline) on at least two occasions related to cyclosporin use.
  5. Cataract related to corticosteroid use.
  6. Unacceptable elevation of liver enzymes (>3 times the upper limit of normal on at least two occasions) related to MTX use.
  7. Intractable hypertension related to corticosteroid use.
  8. Intractable gastrointestinal toxicity.
  9. CNS toxicity related to corticosteroid use.
  10. Drug-induced neutropenia: prolonged drug-induced cytopenia, without available alternatives to control disease activity.
  11. Assessment of possibility for improvement
  12. Presence of active disease.
  13. Current therapy causing unacceptable toxicity.
  14. Radiographs show no evidence of bony destruction so severe that functional improvement cannot be anticipated.
  15. Good potential for rehabilitation (physical therapy, psychology).
  16. Adequate social factors.
  17. Exclusion criteria
  18. Severe chronic infection.
  19. No potential for improvement of function (in the broadest sense, as assessed above).
  20. Inadequate social factors.
  21. Severe organ dysfunction (heart, lungs, liver, renal).
  22. Functional class IV (Steinbrocker).

Current disease status juvenile chronic arthritis/juvenile rheumatoid arthritis

  1. The extent of active systemic disease is assessed.
  2. Systemic features include spiking fever, typical rash, pericarditis and hepatosplenomegaly.
  3. 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.
  4. Presence of active uveitis. Any significant visual impairment?
  5. Functional class: What do you consider to be the potential for regaining significant function if inflammation is completely controlled?
  6. Core set variables for improvement of JCA (see [1]).

Transplantation

  1. Graft.
  2. Peripheral blood stem cells.
  3. Bone marrow (preferred).
  4. Graft manipulation.
  5. Positive (CD34-positive) selection.
  6. Negative (CD3-positive) selection.
  7. Graft composition, if applicable after manipulation:
    1. CD34 numbers: >1x106 /kg.
    2. 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

  1. Engraftment.
  2. Short-term and long-term toxicity.
  3. Infections.
  4. 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

  1. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:1202–9.[Web of Science][Medline]
  2. 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;353:550–3.[Web of Science][Medline]
  3. 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;38:762–3.[Free Full Text]
  4. Wallace CA, Sherry DD. Intravenous pulse cyclophosphamide and methylprednisolone in the treatment of severe systemic onset juvenile rheumatoid arthritis. Arthritis Rheum 1997;40:1852–5.[Web of Science][Medline]
Accepted 15 March 1999


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