PEDIATRIC RHEUMATOLOGY EUROPEAN SOCIETY CLINICAL
GUIDELINES:
SYSTEMIC ARTHRITIS
Michael F Hofer1, Traudel Saurenmann2,
1 Children’s Hospital,
2 Children’s Hospital, University of
Zurich, Zurich, Switzerland
3 Dept. of Pediatrics,
4 Hospital de
5 University Children’s Hospital
Medical Center, Utrecht, The Netherlands
Contact:
Michael Hofer
CHUV, 1011
Genčve, SW
1211
michael.hofer@chuv.hospvd.ch
Key words:
Juvenile
idiopathic arthritis (JIA), systemic arthritis.
Synonym: systemic form of JCA/JRA
(Still’s Disease)
Editor’s Note: PROJ is pleased to publish the Pediatric Rheumatology
European Society guidelines for the management of pediatric rheumatic disease.
The views expressed are those of the authors and the PRES Council. If there are
any questions or concerns, please e-mail a PROJ editor.
(cspencer@larbida.org, lww@uchicago.edu)
Introduction
Systemic arthritis is a chronic inflammatory multisystem disease with
flares and clinical and laboratory signs of acute inflammation, which represents 10 to 20 % of JIA patients. This disease affects
equally boys and girls, and there is a slight predominance of cases occurring
between the first and the fourth year of life, but less marked than in other
forms of JIA, such as oligo- or poly-arthritis. It is characterised by daily
fever spikes, arthritis and/or polyarthralgias, an evanescent rash, lymphoid
organ hypertrophy, and/or serositis. There is a large differential diagnosis
including many infectious, malignant and inflammatory diseases. It is an
exclusion diagnosis, and typical or specific autoantibodies are not known. The
therapy is based on medical measures (antiinflammatory and immunosuppressive
drugs), physical therapies, education and if necessary surgical procedures.
Systemic arthritis is a potentially severe
disease, which requires highly specialised paediatric care for diagnostic and
therapeutic measures.
Definition (according to the ILAR classification of
1. Patient
younger than 16 years at disease onset with:
2. Arthritis of at least 6 weeks duration of one or more joints, at the
same time or after the onset of
3. daily fever spikes for at least two weeks and
4. associated with one or more of the followings:
- Evanescent, not fixed erythematous rash
- Generalised lymph node enlargement
- Hepatomegaly and/or splenomegaly
- Serositis.
Joint involvement can be oligoarticular or polyarticular and may be absent
during the first months of disease, but is obligatory in order to confirm the
diagnosis. When arthritis is not present initially, disease onset will be
determined as the onset of the systemic signs. Fever spikes and other systemic signs
may last for months or even years. A large differential
diagnosis needs to be considered because of the similarities between the
systemic symptoms and infectious or malignant diseases.
Classification and measurement of disease severity
Systemic
onset juvenile arthritis is a distinct entity and the term is used in all three
classification systems of juvenile arthritis (ACR, EULAR and ILAR). The
severity of the disease is characterised by the amount of generalised
inflammatory reaction and by the activity of joint inflammation. Very different
disease courses may be seen. At one end of the scale, there is a monophasic course
that resolves after a few months duration without sequelae, and on the other
end there are courses with persistent systemic features and/or severe
polyarticular destructive arthritis not responding to therapy, leading to
severe incapacity or even early death.
Serious complications of systemic onset JIA are the macrophage
activation syndrome (MAS), also known as hemophagocytic histiocytosis, and,
after long-standing active disease, amyloidosis.
Leading symptoms
Systemic
arthritis is characterised by:
·
Arthritis and polyarthralgias
(often with involvement of the neck). Only polyarthralgias may be present
during the first months of disease.
·
Fever spikes, higher than 39°C,
with a once daily, sometimes twice daily pattern, and subsequent returns to
normal or even subnormal levels. Fever occurs usually in the late afternoon or
in the evening, and patients may have chills during the rise of the
temperature.
·
Evanescent exanthema, which is
usually present on the trunk and proximal extremities, but may occur anywhere
on the body. The rash is pale pink (salmon) with a pale center, macular in 90%
of patients, and maculopapular in about 10%. It may be
pruritic or have an associated Koebner phenomenon or may resemble urticaria.
The rash is migratory and is found most often simultaneously to the fever
spikes.
·
Hepatomegaly, splenomegaly,
lymphadenopathy (2/3 of patients).
·
Polyserositis (about 25 %)
There is no single pathognomonic diagnostic symptom
or sign. Moreover, the diagnosis is often only established later, because the
diagnosis requires the presence of arthritis, which may appear during the
course of disease.
How to establish the diagnosis
There
is no diagnostic tool that can give the definite diagnosis. In the presence of
fever and rash the diagnosis is made by exclusion of other diseases such as
infections, malignancies, vasculitis, inflammatory bowel disease and connective
tissue disease. Very often making the diagnosis requires waiting for more
disease symptoms to emerge, especially arthritis which often evolves weeks (or
even months) after onset of fever.
For
definite diagnosis of systemic onset JIA (ILAR criteria), other diseases must
be excluded and the following symptoms must be present:
-
Characteristic high spiking remitting fever
of 2 weeks duration (documented on at least 3 consecutive days)
-
Arthritis
-
And at least one of the following: typical
rash, enlargement of liver or spleen, lymphadenopathy, serositis
The purpose of each diagnostic procedure, especially technical, imaging, and invasive and laboratory tests
-
Thorough clinical examination to find hints
for the diagnosis (for example the rash is often overlooked)
-
Rule out infections by taking cultures of all
available body fluids and searching for microorganisms by other techniques
(PCR, serologic tests)
-
Rule out leukemia by assessing blood smears
and eventually bone marrow aspiration (before treatment with steroids);
evaluate for signs of systemic inflammation such as anaemia, leucocytosis,
thrombocytosis; be aware of signs for early MAS
-
Perform chest X-ray to evaluate for
serositis or, rarely, interstitial lung disease, as well as to assess for the
presence of generalized infections (disseminated tuberculosis), Hodgkin’s
disease, sarcoidosis
-
Bone scintigraphy may be helpful to exclude
osteomyelitis or tumours
-
Abdominal ultrasound to detect or document
enlargement of liver and spleen, exclude tumours
-
ECG to exclude myocarditis and evaluate for
pericarditis; echocardiography to exclude endocarditis or aneurysms and find
pericarditis and, where appropriate, to assess myocardial function.
-
Laboratory tests to find signs of
generalised inflammatory reaction (high ESR and CRP), to exclude organ
involvement that might be a hint for septicaemia, connective tissue disease,
MAS
-
Autoantibodies are usually not found in
systemic arthritis but are performed to rule out other autoimmune diseases such
as connective tissue diseases, if required.
List of usual technical, imaging or laboratory procedures
The type of diagnostic procedures to be performed will depend on
clinical presentation and the subsequent list is neither mandatory nor
complete.
Tests to assess inflammatory activity:
Complete blood count (CBC), erythrocyte sedimentation rate (ESR),
C-reactive protein (CRP), fibrinogen, ferritin, and iron.
Tests and
procedures to assess organ involvement:
Blood chemistry, X-ray assessments,
joint sonography, CT, MRI, echocardiography, electrocardiography, lung function
test, diagnostic taps of pleural/pericardial fluid or joints if indicated, with
microbiologic and other examination of these fluids.
Tests
indicated for the differential diagnosis:
Immunoglobulins, urinalysis, blood culture,
serologic tests for infectious agents, autoantibody determination, complement
(C3, C4), bone marrow aspiration, abdominal sonography, bone scintigraphy, lung function assessment, biopsies,
radiological diagnostic methods if required.
Tests and
procedures used during the follow-up:
CBC, ESR, CRP, blood chemistry
controls as required for the treatment used, and urinalysis. In case of
diagnostic uncertainty, the tests for organ involvement or for other diseases
in the differential diagnosis may have to be repeated.
Evaluation of individual diagnostic procedures
All
diagnostic procedures may add to the correct evaluation of the patient, but do
not permit a diagnosis in the absence of astute assessment of the complete clinical
picture. The normal values for each test are set by the laboratory. Additional
tests may be required according to initial results and follow-up.
For
the control and evaluation of a child’s disease course and of any organ
changes, e.g., the possible development of amyloidosis, a close monitoring of clinical and laboratory data as well as imaging
is necessary. The early recognition or prevention of amyloidosis has an
important influence on the prognosis.
Which diseases have to be excluded?
A
large differential diagnosis has to be considered depending on the clinical
presentation, including in particular:
-Infectious diseases (severe bacterial infections,
viral infections including EBV and CMV.)
-Malignancies (leukaemia, lymphoma, generalized
neuroblastoma, histiocytosis)
-Chronic
inflammatory diseases (inflammatory bowel disease, sarcoidosis, Behçet’s
disease)
-Other rheumatic diseases (SLE, JDM,
-Periodic fever syndromes (FMF, TRAPS, HIDS, CINCA)
-Miscellaneous diseases and syndromes
(immune deficiency, Castleman’s disease)
Which procedures allow the diagnosis?
The diagnosis is a clinical one. Other diagnoses need to be excluded by
the history, physical examination and the necessary laboratory, imaging and
other procedures.
Which diagnostic procedures are not required?
Diagnostic and therapeutic strategies may need to be modified
individually and according to the
disease course of each child. As the
diagnosis of systemic juvenile idiopathic arthritis is made by exclusion,
extensive diagnostics may be necessary to exclude diseases with similar
clinical symptoms and systemic involvement. Therefore, it is not usually
justified to criticize a diagnostic procedure as not required or indicated in
retrospect. Arthroscopy or other surgical procedure are only needed in very
special cases.
Indication that should perform these diagnostic
procedures?
If systemic juvenile idiopathic arthritis is considered clinically,
further assessment and the final diagnosis should be made by or with the help
of a pediatric rheumatologist. Additional consultations may be needed by other
subspecialists including a pediatric hematologist, nephrologist, cardiologist,
infectious disease specialist, radiologist, and by the orthopedic surgeon when
deemed necessary.
Treatment
The treatment should be chosen depending of the type of presentation and
the course of the disease. The aim of the treatment is to control the systemic and
the joint inflammation and to limit the complications, as well as the damage to
the musculoskeletal apparatus. The treatment usually consists of
pharmacotherapy (NSAID, corticosteroids and other drugs), education and physical and occupational therapy. The
treatment has to be supervised by a pediatric rheumatologist. Interdisciplinary
management may be necessary for organ involvement.
Since the etiology of the disease is not known, no
specific treatment or cure is available.
Symptomatic
treatment
Fever: acetaminophen, NSAID (e.g., indomethacin),
physical measures
Drug treatment
NSAID:
naproxen (15 mg/kg/d), bid
ibuprofen (40 mg/kg/d), tid
diclofenac (2-3 mg/kg/d), bid
indomethacin (2-3
mg/kg/d), bid or tid
Steroids:
Prednisone: oral, initially 1-2 mg/kg, qd
to qid, with gradual reduction after response to treatment
(decrease to < 0.2 mg/kg/d as soon as possible).
Methylprednisolone: intravenous
pulses of 500 or 1000 mg/1.73 m2 (20-30 mg/kg) for 3 consecutive
days; may be repeated weekly to monthly.
Intraarticular
steroid injection
Remissive drugs:
(during phases of systemic involvement, these drugs may have an increased rate of side effects.)
Usual drugs Methotrexate: 10-25 mg/m2/week,
weekly dose
Oral or
parenteral),
Optional: folic acid (5 mg/week or 1 mg daily) (however, folic acid might reduce
the therapeutic effect of methotrexate)
CBC and transaminases to be assessed during treatment
Azathioprine: 2-3 mg/kg/d, daily dose
CBC and transaminases to be assessed during treatment
Cyclosporine
A: 3-5 mg/kg/d (trough level below 150 µg/ml),
CBC, transaminases, creatinine and urinalysis to be assessed during
treatment
Blood
pressure monitoring
Uric
acid and serum lipid control
Etanercept: 0.4 mg/kg s.c. twice weekly
For persisting arthritis, combination therapy of above mentioned drugs
may be tried
Special drugs: Intravenous
immunoglobulins (controversial)
Leflunomide
(under investigation for pediatric patients)
Infliximab,
adalimumab (under investigation for pediatric patients)
Thalidomide
(under investigation), anti IL-6 (under investigation)
Cyclophosphamide
pulse therapy (in conjunction with steroid
pulse therapy)
In case of treatment resistance or atypical disease course, re-evaluate patient to assess for infection, macrophage activation syndrome (MAS) and other inflammatory diseases such as vasculitides.
Interventional treatment
Autologous bone
marrow transplantation may be considered
as a treatment of last resort in persistently active disease and after failure
of several combinations of therapies including high dose methotrexate and
treatment with etanercept.
Surgical procedures
Patients with long-standing joint involvement should be assessed
together with a specialized pediatric orthopedic surgeon. Surgical procedures
will be considered as treatment for impending or detected damage to the
osteoarticular apparatus (soft tissue surgery correcting tendons and ligaments
in rare cases, joint prosthesis, if possible not before final growth is
reached). Particular attention should be given to the cervical spine and
radiological procedures performed if there is a risk of atlanto-dental subluxation
with consecutive spinal cord injury. In case of untreatable localized
arthritis, synovectomy may be considered. The anesthesist should be advised of
the risk related to temporomandibular and/or cervical arthritis (difficult
intubation, risk of quadraplegia).
Rehabilitation
Rehabilitation represents a key issue in case of long-standing joint
involvement: intensive physical therapy, occupational therapy, cryotherapy, use
of weight supporting aids, functional or supportive splinting. All these measures
should enhance optimal participation in daily life activities, school,
extracurricular activities, sports including physical education and active
leisure time. Rehabilitation will also include psychological support for the
patient and the family including early school and career advice to enable
adequate education and integration.
Prevention, education, treatment of secondary
diseases
Early referral to a center specialized in pediatric rheumatology is
essential, since these patients need experienced medical care with regular
clinical and laboratory assessments. Patient education programs are useful for
this chronic disease in order to improve patient’s and parents’ adherence to
treatment and the quality of life for the patient and his family.
Secondary disease may be due to systemic arthritis itself or due to the
treatment. Macrophage activation syndrome (MAS) may complicate systemic
arthritis, and should be treated early with methylprednisolone, prednisone and
cyclosporine. Long-standing chronic inflammation recalcitrant to treatment may
induce amyloidosis. Treatment of amyloidosis is with methotrexate and
anti-TNF-agents. Only if acute phase response cannot be controlled by these
measures should chlorambucil may be tried. Chlorambucil bears the risk of secondary
leukemia.
The main risk of immunosuppressive therapy is infection, which should always be
considered in the differential diagnosis of fever. For osteoporosis
(consequence of disease and/or steroid therapy), calcium and vitamin D supplementation
should be used, and bisphosphonates may be indicated (still under investigation
in children). Physical exercise is likely to favor bone mineralization and
should be proposed depending on joint involvement. Growth retardation
(consequence of disease and/or steroid therapy) may be treated with growth
hormone supplementation, but placebo controlled data about long-term benefit
are missing. Furthermore, there are
reports that growth hormone therapy may induce MAS.