Child DMARD PDF

18th Expert Committee on the Selection and Use of Essential Medicines
(21 to 25 March 2011)
Section 2 Analgesics, antipyretics, NSAIMs, DMARDs
2.4 Disease-modifying agents used in rheumatoid disorders

Review of Disease‐Modifying Anti Rheumatic
Drugs in Paediatric Rheumatic disease

September 2010

Prepared by:
Peter Gowdie
Rheumatology and Clinical Pharmacology Fellow 2009
Royal Children’s Hospital
Melbourne, Australia

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Contents
1. Intent of review
2. Identification of priority conditions
3. Review of priority rheumatic disease
1. Juvenile Idiopathic arthritis
1. Epidemiology
2. Disease burden and outcome
3. Clinical manifestations
4. Complications
• macrophage activation syndrome
• uveitis
• amyloidosis
2. Idiopathic Inflammatory Myopathies (Juvenile Dermatomyositis)
1. Epidemiology
2. Clinical Manifestations
3. Complications
4. Course and Outcome
5. Overview of management
3. Systemic Lupus Erythematosus
1. Epidemiology
2. Clinical Manifestations
3. Course and outcome
4. Overview of management

4. DMARDs
1. Methotrexate
1. Mechanism of action and Pharmacology
2. Efficacy in Juvenile Idiopathic Arthritis
3. Efficacy in Juvenile Dermatomyositis
4. Dose and administration
5. Drug interaction and folate supplementation
6. Safety
7. Monitoring and supervision
8. Formulary
9. Summary recommendations

2. Leflunomide
4. Safety
5. Drug interaction
7. Formulary

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3. Sulphasalazine
4. Safety
5. Drug interaction
7. Formulary

4. Cyclosporin
2. Efficacy in Juvenile Idiopathic Arthritis and Macrophage Activation
Syndrome
3. Efficacy in Juvenile Dermatomyositis
5. Safety
6. Drug interaction
8. Formulary

5. Azathioprine
2. Efficacy in SLE
3. Efficacy in JIA
5. Safety
6. Drug interaction
8. Formulary

6. Hydroxychloroquine
2. Efficacy in SLE
4. Safety
5. Drug interaction
7. Formulary

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1. Intent of review

• To identify priority rheumatological conditions in children
• To outline the treatment options for these conditions
• To outline the role of DMARDs in the treatment of priority rheumatological
conditions
• To review the literature and collate the evidence for the efficacy of DMARDs in
priority conditions
• To review the safety of DMARDs and outline monitoring and supervision required
• To give recommendations for the inclusion of DMARDs on the WHO Essential
Medicines List

2. Identification of priority conditions

Paediatric Rheumatology encompasses a broad range of inflammatory disorders involving
the joints and connective tissues in children. Juvenile idiopathic arthritis is perhaps the most
well recognised of the rheumatic diseases of childhood however the specialty’s scope
includes conditions such as acute rheumatic fever, post‐streptococcal reactive arthritis,
Kawasaki disease and Lyme disease as well as chronic systemic conditions including
Systemic Lupus Erythematosus (SLE), Juvenile Dermatomyositis (JDM), and the vasculitides.

The most common rheumatic disease affecting children is chronic arthritis. The functional
impact of this disease can be significant and the timely administration of appropriate
therapy, including DMARDs, can be effective in improving outcome. While less common,
SLE and JDM are also are potentially devastating conditions and DMARD therapy plays an
equally important role in their management.

3. Review of priority conditions

3.1 Juvenile Idiopathic Arthritis

Chronic arthritis is a complex group of disorders comprising a number of clinical entities
with the common feature of arthritis. Each type is characterised by a different mode of
presentation and different disease course and outcome.
The three main groups of chronic arthritis are: those affecting few joints (oligoarticular);
those affecting many joints (polyarticular); and those systemic in onset. The classification of
chronic arthritis has been problematic over the past few decades especially in terms of
universally agreed upon definitions. This, in part, largely reflects the complex and
heterogeneous nature of this group of conditions and the as yet not clearly defined
immunogenetic factors contributing to their onset. It is also important to remember the
population (mostly Caucasian) in which each of the major classification criteria have been
described. For the purposes of this paper, the International League of Association for
Rheumatology (ILAR) criteria for classification of juvenile idiopathic arthritis (JIA) has been
used.[1]

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3.1.1 Epidemiology

JIA remains an uncommon but by no means rare condition affecting children worldwide. [2]
Estimates of incidence and prevalence however have been difficult to ascertain for many
reasons including: variation in diagnostic criteria; differences in ascertainment (community
vs clinical based studies); differences in study design; low frequency of disease and small
study numbers. [3]

In 2002 Manners and Bower summarised the most recent epidemiological studies to that
point and found a reported prevalence of 0.07 to 4.01 per 1000 children and an annual
incidence of 0.008 to 0.226 per 1000 children. [3] The large difference in reported prevalence
is considered to be largely due to varying study characteristics. The highest prevalence was
reported in community based studies where children were examined in classrooms or
homes. In 1993, Meilants performed an epidemiological study using a questionnaire
followed by clinical examination and found a prevalence of definite JIA of 1.67 per 1000.[4]
In 1996 Manners et al found a significantly higher prevalence (4.01 per 1000) in an urban
Australian community.[5] Similarly, Tayel et al found a prevalence of JIA amongst 10‐15 year
old school children in Alexandria, Egypt, of 3.3 per 1000.[6] Clinic based studies on the other
hand appear to report lower prevalence rates ‐ perhaps reflecting that many clinicians fail to
recognise JIA and therefore these children do not make their way to medical care in large
study centres, therefore underestimating the true prevalence.[7]

There is very little comparable data outlining the prevalence of JIA in populations other than
those of European descent. In fact, in the most heavily populated areas of the world
epidemiological data is very scarce. Outside of the US, UK and Canada some studies reveal
very different data. Lower frequencies of JIA have been reported in children in Japan (annual
incidence 0.0083 per 1000) and Costa Rica (annual incidence 0.068 per 10000 Arguedes 1998
and 0.054 per 1000 Arguedes 1995). In 1983 Hochberg reported an annual incidence of 0.066
per 1000 children and a prevalence of 0.26 per 1000 in urban black children in the USA
however other studies suggest that this is an underestimate. [8] Many of these studies are
ultimately limited by the small sample size and selection bias. One retrospective study
undertaken by Kurahara et al in 2002 demonstrated lower frequency of JIA in Hawaiians of
Filipino, Japanese and Samoan descent compared with Caucasians.[9] In a similar population
Kurahara also found increased prevalence of JIA in rural areas compared with urban
areas.[10]

The extent of juvenile arthritis in the developing world and the epidemiological impact of
ethnicity and geography needs further consideration especially in considering the impact
and burden of disease of this group of conditions.

3.1.2 Burden of Disease and outcome

The disease outcome and prognosis in JIA is variable and to some degree predictable based
on the different disease subtypes. For example, sero‐positive polyarticular JIA has a
relatively poor outcome compared with oligoarticular JIA whose outcome is generally very
good. [11, 12] However, the latter group are also the most at risk of debilitating uveitis as a
complication of their disease. Many children with JIA have an excellent prognosis and for the
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most part remain free from significantly debilitating disease. However, 50‐70% of patients
with systemic and polyarticular disease and 40‐50% of oligoarticular arthritis continue into
adulthood with active disease [Laxer/Hashkes]. It has been estimated that up to 20% of
children transition to adulthood with moderate to severe functional disabilities [13] and an
even higher percentage (30‐40%) have significant long‐term disabilities including
unemployment.[14] Major surgery, including joint replacement is required in 25‐50%. [14]
Delay in referral and initiation of acceptable therapy is associated with poorer outcome. [2]

The prognosis in JIA is frequently assessed with three main outcome measures: frequency of
remission, functional impairment and structural damage. Similar to the outlining of
epidemiology, outcome studies are also difficult to draw conclusions especially given the
prevailing use of three different classification systems and the variable outcome measures
without agreed upon definitions. For example, there remains no international agreement on
validated remission criteria for JIA

Remission rates vary between subgroups however, despite differing approaches and
definitions across studies, there is consistent reporting of higher remission rates in
oligoarticular disease. In the oligoarticular disease this ranged from 36% to 84%. [15]
Remission rates for polyarticular disease ranged from 12.5% to 65% whilst systemic disease
was 0 to 76%. [15] The large range can be explained by the relative infrequency of these
subtypes compared with oligoarticular disease and therefore the small sample sizes
potentially more influenced by chance. Similarly, functional outcome was better in the
oligoarticular subtype and the frequency of severe disability was low. By contrast, systemic
and polyarticular disease both have been documented to have significantly worse functional
outcome. Systemic JIA in particular has a large proportion of patients with severe disability.
[16]

Whilst estimates of the burden of disease at an individual level has been documented to
some extent, there remains considerable difficulty in acquiring data relating to estimates of
the global burden of this group of diseases. The global impact of juvenile arthritis on
disability and handicap, the educational and vocational disadvantages, life expectancy and
quality of life as well as the cost of medical care remains to be defined.

3.1.3 Clinical Manifestations of JIA

The common feature of all the subtypes of JIA is arthritis. Systemic symptoms typically occur
in systemic and polyarticular subtypes and include: fatigue, loss of weight, anaemia,
anorexia and fever. Joint inflammation results in pain and discomfort and at times
considerable morning stiffness. Large joints are the most frequently affected, however any
joint can be involved including cervical spine, thoraco‐lumbar spine and temporo‐
mandibular joint. Growth abnormalities are not uncommon and can result in short stature or
localised growth disturbance such as bony overgrowth, prematurely fused epiphyses and
limb length discrepancies. Other extra‐articular manifestations include: osteopenia,
rheumatoid nodules and muscle atrophy. Cardiopulmonary disease is also not uncommon
particularly in systemic onset disease. Pericarditis occurs in up to 9% [17] however
tamponade is rare. Myocarditis and endocarditis have also been documented to have
occurred.
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3.1.4 Complications of JIA

Macrophage Activation Syndrome
Macrophage Activation Syndrome (MAS) is potentially the most devastating sequelae of JIA.
MAS is similar in many ways to reactive haemophagocytic lymphohistiocytosis (HLH) and
the term MAS has come to refer to HLH secondary to rheumatic disease. MAS is most often
associated with systemic onset JIA, however, has been recognised with other rheumatic
diseases such as: polyarticular JIA, SLE, JDM and chronic infantile neurologic cutaneous and
articular syndrome (CINCA).

MAS contributes to a significant amount of the morbidity and mortality associated with
SoJIA. Estimates of the incidence of MAS in SoJIA vary. Sawhney et al report an incidence of
6.7%.[18] However, it is believed by many that MAS is integral to the pathogenesis of SoJIA
and that in fact occult MAS is common in patients with SoJIA.[19]

MAS is often difficult to distinguish clinically from SoJIA. Its features include: fever (often
more sustained that SoJIA), hepatosplenomegaly, anaemia, LFT abnormalities, rash,
coagulopathy and central nervous system dysfunction. Laboratory markers suggestive of
diagnosis include: decreasing white cell count and platelets, elevated ferritin,
hypertriglyceridemia, hypofibrinogenemia and evidence of haemophaocytosis on bone
marrow aspirate. Preliminary guidelines for the diagnosis of MAS in association with SoJIA
have been suggested. [20]

MAS is potentially fatal especially in those patients with multisystem involvement or when
diagnosis is delayed. Early diagnosis and vigorous treatment is necessary. Corticosteroids
and supportive care are the first line therapies, however, agents such as cyclosporin,
etoposide and IVIG . The use of cyclosporin in MAS is discussed in section 4.4.2.
Uveitis

One of the most important complications of JIA is uveitis. This is a chronic non‐
granulomatous inflammation affecting the iris and ciliary body the end result of which can
be devastating. In particular, band keratopathy and cataracts occur in 42‐58% whilst
glaucoma occurs in 19‐22%.[21] Its activity does not correlate with the course of the arthritis
and its own course is usually insidious and often asymptomatic mandating frequent
ophthalmological surveillance. Rates of uveitis vary between subtypes of arthritis with the
most frequent at‐risk group being oligoarticular JIA. Uveitis has been described in most
racial groups.

JIA is the most frequent non‐infectious systemic disease associated with uveitis in children.
Other less common non‐infectious causes include: ulcerative colitis, tubulo‐interstitial
nephritis syndrome, Behcet’s disease and chronic infantile neurologic cutaneous and
articular syndrome (CINCA). A high proportion of paediatric patients with uveitis do not
have an underlying cause found. Kump et al found no associated systemic disease in 58% of
patients with uveitis.[22]

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The management of uveitis should be supervised by an ophthalmologist in conjucttion with
a paediatrician or pediatric rheumatologist. Uveitis is usually managed with topical
corticosteroids with a mydriatic agent. Systemic prednisolone administered orally or
intravenously may be required in an attempt to achieve short term relief of inflammation. In
children in whom uveitis is difficult to control by these measures, additional
immunosuppressive agents have been used including increasing use of biological agents.
The efficacy of methotrexate is discussed in section 4.1.4.

Amyloidosis
Amyloidosis is the tissue deposition of the protein amyloid and can occur as a complication
of JIA. It is a rare complication in North America but occurs more frequently in parts of
Europe. It manifests as proteinuria, nephritic syndrome, hepatosplenomegaly or anaemia
and can eventually lead to renal failure. Amyloidosis and resultant renal failure as a
complication of JIA was, in the past, the major cause of death. The other main cause is
infection. Death rates have improved over recent decades and now the disease associated
death rate in Europe is <1% and less than 0.3% in North America. [2]

3.2 Idiopathic inflammatory myopathies (Juvenile Dermatomyositis
and Juvenile Polymyositis)

Idiopathic inflammatory myopathies (IIM) of childhood are rare conditions often associated
with significant disability. Of the inflammatory myopathies, Juvenile dermatomyositis is by
far the most common in children making up 85% of cases of IIM in childhood. [23, 24]
Juvenile polymyositis accounts for approximately 2‐8% and overlap syndromes with features
of other autoimmune diseases accounts for approximately 3‐10%. [25] The other types of
IIMs are rare in children and mostly documented in case reports only.

Juvenile dermatomyositis is a systemic vasculopathy characterised histologically by
perivascular B‐cell predominant inflammation and capillary loss. The pathogenesis is not
completely understood but it is thought to be an autoimmune process occurring in a
genetically susceptible child in response to an environmental stimuli.

3.2.1 Epidemiology

Juvenile dermatomyositis is a rare autoimmune myositis of childhood. It has an estimated
incidence in the United States of 3.2 per million children. [26] Mendez et al captured data
over a 4 year period between 1995 and 1998 and found the annual incidence ranged between
2.5 and 4.1 per million children. Incidence rates varied slightly between racial groups ‐ 3.4 for
white Caucasian, 3.3 for African‐American and 2.7 for Hispanics. [26] Symmons et al
estimated an incidence in the UK and Ireland of 1.9 per million children (95% confidence
intervals 1.4‐2.6). [27] The ratio of girls to boys was reported in these two studies to be 2.3:1
by Mendez et al and 5:1 by Symmons et al. [26, 27] The age of peak incidence in boys and
girls is similar. Pachman et al demonstrated a bimodal peak incidence in both boys (6 and 11
years) and girls (6 and 12 years). [28]

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3.2.2 Clinical Manifestations

Juvenile dermatomyositis (JDM) is a multisystem inflammatory condition ‐ it can affect the
muscle, skin, gastrointestinal tract, heart, lungs, kidneys and eyes. JDM can manifest in a
heterogeneous fashion, however, the main characteristics of the disease include: symmetrical
proximal muscle weakness, pathognomic skin involvement (eg Gottron’s papules,
heliotropic rash), and raised muscle enzymes. The diagnosis of JDM is made through the
application of diagnostic criteria established by Bohan and Peter in 1975: 1) presence of
characteristic rash ‐ heliotropic rash with periorbital oedema and Gottron’s papules; 2)
symmetrical proximal muscle weakness; 3) raised serum muscle enzymes (at least one of
CK, LDH, AST); 4) myopathic EMG; 5) muscle biopsy demonstrating necrosis and
inflammation.[29] Patients with a rash and two other of the criteria are considered to have
possible JDM, while rash with three additional criteria are considered to have definite JDM.
In practice, muscle biopsy and EMG are used less frequently today than they once were.
They are both invasive investigations and MRI is now considered a sensitive test for
myositis.

The clinical course and progression of the disease is also varied. Most commonly JDM
presents with an insidious evolution over a period of 3 to 6 months, however it can present
acutely. Ramanan et al reviewed the clinical features and outcomes of a large case series of
patients treated at the Hospital for Sick Children in Canada. [23] Of 120 patients with IIM,
105 had JDM. The most common clinical features at presentation were: Gottronʹs rash (91%),
heliotrope rash (83%), malar/facial rash (42%), nailfold capillary change (80%),
myalgia/arthralgia (25%), dysphonia or dysphagia (24%), anorexia (18%), fever (16%).[23]
Muscle weakness is progressive and frequently results in the inability to ambulate, sit
upright or attend to activities of daily living. Weakness may be accompanied by significant
pain. The pharyngeal and palatal muscles may also be involved resulting in difficulty
swallowing and dysphonia. This occurred in up to 24% of patients in Ramanan’s series [23]
and puts the patient at risk of aspiration

3.2.3 Complications

Calcinosis occurs in up to 40% of patients[30] and can result in significant disability. Deposits
in the subcutaneous tissues can be painful and lead to ulceration. Early and aggressive
control of inflammation may minimise the degree of calcinosis.[31] Cutaneous ulcerative
disease is another skin complication which is not infrequently seen. It is thought to be
associated with more severe and prolonged JDM. [32] Lipodystrophy has also been
described with JDM.

Cardiopulmonary abnormalities are also described however clinically significant
involvement in children with dermatomyositis is unusual. The most frequent cardiac
problems include cardiomegaly and nonspecific murmurs. More serious cardiac involvement
is unusual but potentially life threatening. Restrictive pulmonary disease due to poor chest
wall compliance and respiratory muscle weakness is common and has been reported in up to
78% patients. [33] Gastrointestinal vasculitis is rare but is a severe complication which can
lead to death. It manifests as abdominal pain, haematemesis and melaena.

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3.2.4 Course and Outcome of JDM

JDM typically follows a uniphasic course although the duration is quite variable. Stringer et
al followed the course of 84 patients with JDM. They found that the majority (60%) of
patients had a chronic disease course defined as no remission within 3 years of diagnosis.
[34] They also found that a small percentage of patients had a relapse following remission.

The outlook for patients with JDM has significantly improved over the past decades with the
use of more aggressive immunosuppressant therapies. Before the use of corticosteroids, this
illness was devastating. Many patients died or suffered long‐term progressive and disabling
disease. Functional outcome today is usually excellent with 65‐80% of patients achieving a
good outcome [2] Optimal outcome seems to be achieved if diagnosis is made shortly after
onset and treatment is vigorous. [35] Huber et al found that of 65 children with JDM, a
favourable outcome was predominant. Eight percent were left with moderate to severe
disability and there was one death. [36] Contractures and mild atrophy occur in
approximately 25% of patients[2] however in one study cohort none of the patients were
thought to be educationally or vocationally impaired due to their illness. [23] Although
deaths are now less frequent, chronically active disease occurs in substantial number of
patients and, in addition, side effects such as growth failure from prolonged steroid use are
not infrequent.

3.2.5 Overview of Management

Corticosteroids and general supportive care in a multidisciplinary team setting are the
mainstays of treatment of JDM. The use of corticosteroids has dramatically improved to
outlook for patients with JDM. High suppressive doses are used early and then tapered
gradually over one to two years. The degree of supportive care is dependent upon the degree
of disability. In patients with bulbar dysfunction or significant respiratory muscle weakness,
care needs to be directed to prevention of aspiration and ventilatory support. Physiotherapy
and occupational therapy is advised to avoid loss of motion and contractures in the first
instance and then later to strengthen in order to regain normal function.

Other immunosuppressive agents have not been subjected to randomised controlled trials
however they are now accepted as an important part of the management of JDM. Four
agents have been described in the treatment of JDM and the evidence for their use will be
reviewed within this document. They are: methotrexate, cyclosporine, azathioprine and
cyclophosphamide.

3.3 Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterised by
inflammation of the blood vessels and connective tissues resulting in damage to numerous
organ systems and associated with antinuclear antibodies. The diagnosis of SLE is based on
well described clinical and laboratory features and is supported by the use of the American
College of Rheumatology (ACR) adult SLE classification criteria first developed in 1982 and
then revised in 1997. However, there are well described differences in the clinical features,
serology and outcome of paediatric patients with lupus compared with adult patients [37]
10
and therefore the applicability of these diagnostic criteria have been questioned. There have
been few large scale validation studies of these criteria in the paediatric population. Ferraz et
al applied the ACR criteria to 103 paediatric patients with lupus and demonstrated a
sensitivity and specificity of 96% and 100% respectively.[38]

The aetiology of SLE is unknown. Susceptibility to the development of SLE is considered
multifactorial perhaps contributed by the interaction of genetic, acquired and perhaps
environmental factors. The pathogenesis involves disordered immunity with autoreactive T
and B cells and antibody and immune complex deposition.[2] The clinical manifestations and
course of SLE are extremely varied but can be associated with significant morbidity and
mortality.

3.3.1 Epidemiology

Paediatric SLE is a rare disease and is reported to have an annual incidence estimated at
between 0.36 – 0.9 per 100,000 per year depending on the population in which it is
studied.[2] There is no accurate prevalence data. Data from Rheumatology clinic surveys
report that SLE accounts for between 1% and 4.5% of clinic population.[2] Approximately
15% of patients with SLE have there disease onset in childhood. Onset is rare before the age
of 5 and it is more common in girls than boys with a ratio of approximately 5:1.[39, 40]

There are limited population based studies reporting data on the distribution of SLE across
racial groups. SLE has been observed disproportionately in people of African‐American,
Hispanic and Asian background. [2]

3.3.2 Clinical and Serological Manifestations

SLE is a multisystem inflammatory condition and can present with insidious onset or as an
acute life‐threatening illness. The disease can manifest with renal, CNS, cardiac, pulmonary,
musculoskeletal, cutaneous, gastrointestinal, hepatic and haematological features. One large
cohort of 256 patients with paediatric SLE reported that the most common clinical
manifestations were: arthritis (67%), malar rash (66%), nephritis (55%) and CNS disease
(27%).[40] Constitutional symptoms such as fever, fatigue and weight loss are common in
paediatric onset SLE. [41] Clinical features such as ulcers, alopecia, Raynaud’s phenomenon
and photosensitivity less common in paediatric SLE.[41] One study reported more severe
disease onset in paediatric patients compared to adult patients and that renal and
haematological features were more common. [37] Silverman et al supported this finding in
their study comparing paediatric with adult SLE. They found that children had more active
disease at onset with higher frequency of renal disease and lower frequency of
cardiopulmonary disease. [42]

Typical serological findings include: positive antinuclear antigen (ANA), positive double
stranded DNA (dsDNA), antibodies positive to extranuclear antigens (ENA), low
complement levels and positive lupus anticoagulant and antiphospholipid antibodies.

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3.3.3 Course and Outcome

SLE is characterised by a chronic relapsing and remitting course. Flares can occur at any time
in the course of the illness and are frequently precipitated by infection. Although overall
outcome for morbidity and mortality has improved in recent times with current therapeutic
options, SLE remains a serious and life‐threatening illness with an unpredictable prognosis.
In 1968, Meislin and Rothfield reported a 5 year survival in patients with renal involvement
and without renal involvement of 42% and 72% respectively.[43] In contrast, in 1998, Yang et
al reported a 5 year survival of 91% in patients with nephritis. [44]

3.3.4 Overview of Management

SLE is a complex, multisystem, chronic disease with potential for significant morbidity and
mortality and is therefore best managed by a multidisciplinary team experienced in the
management paediatric SLE. General aspects to management include: avoidance of
excessive exposure to sunlight and protection against UVB with sunscreen and appropriate
skin cover with clothing and headwear; prevention of infection with immunisation.

Corticosteroids remain the first line therapy for the management of paediatric SLE. NSAIDs
are frequently used to manage musculoskeletal complaints and hydroxychloroquine is used
as an adjunct to corticosteroids in the treatment of fatigue, mucucutaneous features and
arthritis. Immunosuppressive therapy including cyclophosphamide, azathioprine and
mycophenolate are generally considered early in the course of the disease if there is
evidence of diffuse proliferative glomerulonephritis, CNS involvement or pulmonary
haemorrhage.[45] Other immunosuppressants considered include methotrexate and
cyclosporin. The choice of drug remains controversial. In other active forms of the disease
there is no agreement on the timing of initiating immunosuppressant therapy. Many of
these patients are at risk of developing irreversible organ damage and, in addition,
potentially face many years of high dose corticosteroid therapy with its associated toxic
effects and may therefore warrant the addition of immunosuppressant therapy.

Mycophenolate initially showed promising results in maintaining disease control in adult
patients with resistant or relapsing lupus nephritis. It has since then been subject to meta‐
analysis and found to have no difference over azathioprine in terms of response rates or
development of end stage renal disease.[46] It appears to have a safer profile than
azathioprine especially regards to haematological complications.

Whilst current therapies have dramatically improved survival, there is hope that newer
agents including cytotoxic and biologic therapies may provide superior management and
ultimately lead to curative treatment. [47]

4. Disease‐Modifying Anti‐Rheumatic Drugs (DMARDs)

DMARDs are not used for immediate analgesic or anti‐inflammatory effect but rather for
their long term beneficial effects in controlling disease activity. These medications also play
an important role in reducing the long term exposure to medications such as prednisolone
12
and Non‐Steroidal Anti‐Inflammatory Drugs (NSAIDs). Historically, DMARDs were used
late in the course of disease progression as there were initial questions regarding toxicity and
safety. Moreover, the illnesses treated were not often considered life threatening and
therefore DMARD therapy was considered not warranted. It is now recognised, however,
that not only are many of these medications safe and effective for use in children but also
that their use early in the course of the disease may prevent irreversible damage and
decrease the burden of disease.

There are a number of DMARDs used in the treatment of rheumatic illnesses in children.
These include: methotrexate, sulfasalazine, azathioprine, leflunomide, hydroxychloroquine
and cyclosporine. Methotrexate is often considered as the first choice and it is used as
treatment in many diseases such as: JIA, JDM, SLE, vasculitis, uveitis and localised
scleroderma.

4.1 Methotrexate

4.1.1 Mechanism of action and Pharmacology

Methotrexate is a folic acid analogue and an inhibitor of dihydrofolate reductase and thereby
interferes with DNA synthesis by reducing the purine and pyrimidine supply in rapidly
dividing cells. This anti‐proliferative effect is achieved with high‐dose regimens and is used
for the treatment of tumours. In low‐dose DMARD therapy, methotrexate also has an
immunomodulatory and anti‐inflammatory effect. Although the exact mechanism of this
action remains unknown, Methotrexate is thought to effect the cellular production of a
variety of cytokines and thereby acts to inhibit cell mediated immunity.

There is significant variability in the pharmacokinetics of methotrexate between individuals
and also specific pharmacokinetic qualities that impact on the dosing and route of
administration. Methotrexate is absorbed by the gastrointestinal tract by a saturable process.
The average oral bioavailability is 0.7 but this can range from 0.25 to 1.49.[48] A number of
factors are thought to impact on this including: age, sex, dose, creatinine clearance, and fed
vs. fasting state. [49] There is debate in the literature as to whether meals have an impact on
the absorption of oral methotrexate. Absorption of orally administered methotrexate has
been shown in adult studies to be reduced at doses beyond 15mg [50, 51] and some groups
advocate for the use of parenteral methotrexate for doses higher than this.

Once absorbed, peak serum levels are reached in approximately 1.5 hours with the
elimination half life being 7 hours. The majority of elimination is through renal excretion and
circulating levels fall rapidly as the drug is distributed and eliminated. [2]

4.1.2 Efficacy of Methotrexate in Juvenile Idiopathic Arthritis

Methotrexate is the most frequently used second line agent in Juvenile Idiopathic Arthritis
and there is good evidence of its efficacy. The evidence for its use has been demonstrated in
randomised placebo controlled trials as well as from a large number of retrospective and
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uncontrolled studies. Furthermore, these studies have shown that Methotrexate is safe.
Table 1 summarises studies addressing the efficacy of methotrexate in JIA.

Giannini et al published a meta‐analysis in 1993 comparing methotrexate with
hydroxychloroquine, penicillamine and auranofin in JIA. A total of 520 patients were
enrolled in all the three studies included in the analysis and outcome measures included
physician’s global scale and ESR. Only methotrexate at 10mg/m2 showed improvement in
these domains. [52] In 2004, Paediatric Rheumatology International Trials Organisation
(PRINTO) published the results of a trial which ultimately compared intermediate with
higher dose methotrexate in patients who had failed to respond initially to standard doses.
The initial screening phase describes a total of 633 patients with JIA of which 72% responded
to a standard dose of methotrexate (8‐12.5mg/m2/week) after 6 months of therapy.[53]
The efficacy of methotrexate in the treatment of JIA has been demonstrated in prospective
controlled trials. A systematic Cochrane review in 2001 set out to evaluate the effects of
methotrexate on a number of functional domains, including functional ability, range of
motion, quality of life, overall well being and pain. Only two studies [54, 55], with a total of
165 patients with JIA, fulfilled the inclusion criteria for the Cochrane review of placebo‐
controlled randomised clinical trials. Based on these studies Takken et al concluded that
methotrexate has a clinical effect on patient centred disability.[56] Since then there has not
been any other published RCTs addressing the efficacy of methotrexate vs. placebo.

Despite the evidence for the efficacy of methotrexate there are many questions relating to its
use that remain unanswered or without sufficient evidence to enable concrete
recommendations. For example, the response to methotrexate between the various subtypes
of JIA has not been compared in a rigorous fashion. Woo et al found no difference in
response to methotrexate between patients with extended oligoarticular and systemic JIA
although overall there was a significant improvement of both groups compared with
placebo.[54] In contrast, Ravelli et al found that when compared to systemic JIA and
polyarticular JIA, extended oligoarticular JIA was the most likely to respond to
methotrexate. [57]

The optimal timing of discontinuation of methotrexate therapy following remission is also
unclear. As documented in table 1, Gottleib et al found that after a mean of 8 months in
complete remission (SD= 4 months) before discontinuation of methotrexate, relapse occurred
in 52% at a mean of 11 months.[58] Most patients respond when methotrexate is
restarted.[58]

In summary, methotrexate is efficacious in JIA however further studies are required to
further outline the duration of therapy before discontinuation.

14
Table 1. Evidence for the efficacy of Methotrexate in JIA

Author, Pop’n Type of Number of Subjects Duration Intervention Primary outcomes measured Conclusion and comments
Year study patients of study
Giannini, US and Multicentre 38x 10mg/m2 JIA ≥3 6 months 5mg/m2 vs Joint ROM 63% patients improved on 10mg/m2
1992[55] Soviet randomised MTX joints 10mg/m2 vs Swollen joints 32% on 5mg/m2
Union placebo 37x 5mg/m2 placebo Pain on joint movement 36% on placebo
controlled MTX Physician global score
39x placebo
Woo, UK and RCT double 88 Extended 12 months 15mg/m2 (up to Joint ROM Significant improvement in 3 out of 5
2000 [54] France blind oligo JIA 30mg/m2) vs Number active joints outcomes: physician global and
crossover (EOA) and placebo Physician global score parent/child global and ESR.
SoJIA Parent/child global score
ESR Percent overall improved: EOA 48%
on MTX vs 18% on placebo; SoJIA
25% MTX vs 16% placebo
No difference in frequency of SE
Cespedes- Patients from 521 PolyJIA 12 months 50 item Child Health After 6 months of treatment,
Cruz, multi-centre Questionnaire (CHQ) significant improvement in HRQOL
2008[59] international
RCT
Silverman, Multicentre RCT 86 completed PolyJIA 16 week MTX vs ACR Pediatric 30 (30% Both MTX and Leflunomide resulted
2005[60] international Double blind 16 weeks, 3-17 yrs +/-32 week leflunomide improvement compared with in high rates clinical improvement
70 entered old extension baseline in ≥3 of 6 variables following 16 week phase.
extension included in ACR core set 89% MTX vs 68% Leflunomide ACR
study (swollen joints, active joint count, Pedi 30 response
parent global assessment, LFT abnormalities noted more
physician global assessment, frequently with MTX than
CHAQ, ESR) Leflunomide
Ruperto, Multicentre RCT 633 patients Poly JIA 6 months Standard vs ACR Pedi 30 definition of In screening phase, 72% patients
2004[53] international screened in higher parenteral improvement responded to standard dose MTX.
phase one. dose of MTX (15 62.5% of patients in intermediate dose
80 patients
vs 30 group vs 57.5% in higher dose group
deemed to be
nonresponders
mg/m2/week) achieved ACR Pedi 30 response.
were Plateau of efficacy of MTX at
randomised 15mg/m2.
No additional therapeutic benefit with
doses >15mg/m2/week
15
Table 1.

Evidence for the efficacy of Methotrexate in JIA

Ravelli, Italy Retrospective 80 SoJIA 37 6 months 6 month clinical response, oligo JIA sybtype was best predictor
1999[57] analysis polyJIA 20 complete disease control, disease for short term clinical response and
oligo JIA relapse, hepatotoxicity, GI more likely to have relapse after
23 toxicity discontinuation
Al- Saudi Retrospective 18 SoJIA Mean 18 MTX Range 2.5- Joint evaluation 89% improved active joint count and
Sewairy, Arabia analysis months 15 mg/week Fever, rash functional class
1998 [61] LAD and splenomegaly 61% significant improvement in ESR,
Serositis Hb and plts
ESR, Hb, WCC and plts No withdrawals due to toxicity
Gottleib, USA Retrospective 25 patients in Poly, pauci Mean MTX range 5.2 – Length of time to relapse or Relapse in 52% after a mean of 11
1997[58] analysis remission for a and SoJIA follow up 15.9 mg/m2/dose continued remission following months.
2 centres mean duration of patients discontinuation of MTX Of those relapsed patients most
of 8 months post (10/13) achieved remission again
discontinu- within 7 months.
ation was Optimal time for discontinuing MTX
15 months unknown
Huang, Taiwan Retrospective 26 JIA Mean Mean weekly 73% responded
1996[62] chart review follow up dose MTX 10-15 39% achieved remission
3 years mg/m2 Prednisolone weaned in 93%
6 patients experienced SE, 1 patient
ceased MTX due to LFT abn
Reiff, USA Retrospective 21 (13/21 Refractory Mean Mean weekly Disease activity score based on 33% improved
1995[63] chart review SoJIA) JIA duration dose MTX 27 mg changes in concomitant therapy, 5% complete remission
15.2 labs, physician global, MTX well tolerated but limited role in
months radiological refractory JIA
Ravelli, Italy Retrospective 19 SoJIA 6 months MTX dose range Response defined as ≥50% 63% responded
1994[64] chart review therapy 7.5-11 reduction in number of joints with 37% no response to therapy
mg/m2/week active arthritis
Harel, USA 23 (5 SoJIA) 17/23 Median 2.5 MTX 7.5- Assessed radiological progression 11/17 responders had improved carpal
1993[65] responders yrs 10mg/m2 on serial wrist XR length
6/23 non All 6 nonresponders had progressive
responders loss of carpal length
Conc: radiological improvement in
those responded to MTX
Wallace, USA 49 PolyJRA At least 1 MTX 15mg/m2 45% remission on MTX
1993[66] (16/49 year
SoJIA)
16
4.1.3 Efficacy of methotrexate in Juvenile Dermatomyositis

Methotrexate is the most frequently used of the immunosuppressive agents described in the
treatment of JDM. A recent survey of Paediatric Rheumatologists demonstrated considerable
variation in the management of JDM. [34] This variance reflects the lack of data available on
which to base treatment. More recently three consensus protocols were developed at a
consensus meeting in Toronto involving 12 Paediatric Rheumatologists. Each of these
protocols involved the use of corticosteroids and methotrexate. [67]

Methotrexate has not been subjected to a prospective randomised controlled trial and
therefore evidence for its use is derived from observational studies only. In 2005 Ramanan et
al demonstrated in an inception cohort study the effectiveness of methotrexate. Thirty one
patients with JDM were commenced methotrexate as first line therapy at a mean dose of
15mg/m2 and their steroids aggressively tapered. These patients were compared to 22
historical controls treated with prednisolone alone. Patients in the study group were found
to have a shorter time to discontinuation of corticosteroids and also reduced cumulative
dose. [68] However, this study failed to demonstrate whether aggressive taper of steroids
alone without the addition of methotrexate had a similar outcome. Improved outcome with
the early initiation of prednisolone and methotrexate was also demonstrated by Al‐Mayoub
et al in a small series of patients with JDM and associated cutaneous ulceration and/or
dysphagia. [69] In a retrospective chart review, initiation of methotrexate in patients who
had failed to respond to steroid therapy within 6 weeks was thought to be beneficial in
reducing the overall risk of long term complications including calcinosis. [31]

There is currently an international multi‐centre prospectively randomised trial co‐ordinated
by PRINTO (Paediatric Rheumatology International Trials Organisation) which is
comparing prednisolone alone with prednisolone/methotrexate combination and
prednisolone/ cyclosporine combination in patients newly diagnosed with JDM. The results
of this trial are eagerly awaited in order to guide the management of JDM.

17
Table 2. Evidence for the efficacy of Methotrexate in JDM
Author/ Pop’n Type of Number Subjects Duration of Groups/Intervention Outcomes measured Conclusion and

of
Year study study comments
patients
Ramanan, Single Prospective 53 31 patients Control 2 groups. Study group: Time to discontinuation of Use of MTX and
cohort prospectively patients MTX 10‐20mg/m2/week steroids, cumulative steroid aggressively tapered
2005[68] centre,
study studied with 22 followed for 4 (max 25mg/week) and dose and steroid SE. steroids may be as
Canad with
controls years; study prednisolone 2mg/kg/d Disease activity: CHAQ, effective traditional
a historical
patients (max 75mg) with pred muscle strength, rash, long‐term steroid and
controls
followed for aggressively tapered every calcinosis, time to flare. decreases the
average 34.6 2 weeks cumulative steroid dose
months
Al‐ Saudi Prospective 12 newly Patients with Mean duration 2 groups: early (<6 wks) Resolution of clinical Improved muscle
cohort diagnosed dysphagia, of therapy was and late (5‐72 months post indications for MTX, weakness and lack of
Mayouf, Arabia
study JDM. dysphonia, GI 23.5 months diagnosis) MTX therapy. 6 decreased disease activity development of
2000[69]
bleeding, cutaneous patients per group (graded muscle strength and calcinosis in group
ulceration or resp enzyme levels) and treated early.
muscle involvement discontinuation of steroids One patient ceased MTX
were started MTX due to abdominal pain
early
Fischer, US Case series 4 3 patients wih JDM, 9‐31 months Pred plus MTX 1mg/kg/wk Steroid dose reduction, Improvement in all
1979[31] 1 patient with JPM intravenously muscle strength, enzyme parameters in 3 patients.
levels, EMG changes 4th patient initially
improved then relapsed
and died of bowel
perforation and sepsis
Miller, US Retrospectiv 16 16 patients with 6 year follow up MTX plus prednisolone Muscle strength, muscle All patients treated for
e chart recalcitrant JDM enzymes, prednisolone >8 months had clinical
1992[70]
review dosage, medication toxicity remission and therefore
concluded that MTX is
useful adjunct to
prednisolone. 31%
patients discontinued
18 MTX due to SE.
4.1.4 Efficacy of methotrexate in Uveitis

Methotrexate has been used in children with uveitis for many years. Its use is supported by
evidence largely from retrospective cohort studies.

A retrospective chart review found methotrexate to be an effective agent in the treatment of
uveitis. [71] Twenty five patients with uveitis received methotrexate (mean dose of
15.6mg/m2) and remission was achieved after a mean of 4.25 months. Six patients had
methotrexate ceased after remission for 12 months and of these 4 patients were still in
remission after 7.5 months. Other case series have demonstrated the effectiveness of
methotrexate in uveitis resistant to topical corticosteroids.[72, 73]

4.1.4 Dose and administration in JIA and JDM

Methotrexate is administered weekly. Although, as previously mentioned, the serum
elimination half‐life of methotrexate is 6‐7 hours its metabolites can be measured
intracellularly over 1 week. Methotrexate can be administered orally or parenterally. The
standard guideline for methotrexate use is an initial dose of 10 mg/m2/week grading up to
15mg/m2/week.[2] Oral methotrexate should be given on an empty stomach as food
decreases its bioavailability. Ruperto et al demonstrated that there was no additional benefit
of parenteral doses above 15mg/m2. [53] Parenteral administration is recommended for
doses >15mg/m2/week because of better bioavailability and gastrointestinal tolerability.
Parenteral dosing should also be considered in those children who have a poor response to
oral methotrexate or where poor compliance impacts on disease control.[2] There is no
difference in the bioavailability of subcutaneous and intramuscular therapy. [74]

4.1.5 Drug interaction and folate supplementation

A number of medications increase the bioavailability of methotrexate. These include:
phenytoin, oral contraceptive pill, tetracycline, barbiturates and tranquilizers. Co‐
trimoxazole should be avoided with methotrexate as it can cause severe bone marrow
suppression and skin ulcerations. In addition a number of medications, including penicillins
and cyclosporine, can lower the elimination of methotrexate by decreasing renal clearance.
Methotrexate is contraindicated in renal failure.

There is good evidence to support the use of folic acid supplementation to alleviate the
common gastrointestinal and oral mucosal side effects associated with methotrexate without
impacting on the beneficial anti‐inflammatory effects. [75]

The use of methotrexate is safe in combination with NSAIDS and corticosteroids. There is
some experience of combined DMARDs however controlled systematic studies are lacking
to support this strategy in the treatment of JIA.

19
Table 3. Adverse Effects of Methotrexate
Author, Type of Duration Subjects Drug and Hepatotoxicity Haematological GI toxicity other Conclusion
Year study of study and monitoring abnormality
numbers
Ortiz‐ Pro‐ 89 JIA MTX 14% patient had significantly 26% patients had No diff noted Few significantly
Alvarez, spective elevated LFTs (>2x ULN) abnormal FBE (low in terms of abn blood tests
2004 [76] study Monthly 52% had mild elevated liver granulocyte or duration and beyond 2 months.
blood tests func tests lymphocyte count or cummulative Blood tests every 4‐
Hb) dose MTX and 8 weeks
95% of patients with concurrent unnecessarily
abn had viral infection meds frequent
at the time of blood
test.
Lahdenne, Retro‐ Patients 34 JIA MTX (20‐ All 24 pts treated with low Aggressive MTX
2002 [77] spective on MTX 30mg/m2) for dose MTX had grade I therapy with
review. at least duration >2.4 Roenigk changes. concomitant meds
Liver bx
2.4 yrs yrs Of 10 patients on >20mg/m2, may contribute to
correlated
4 pts grade II histology and 5 minor reversible
with lab
findings grade I. No fibrosis or liver abn
cirrhosis
Graham, Retro‐ 84 – 296 62 poly MTX (5‐ Transient liver function abn Macrocytic anaemia in Nausea No PFT abn Suggest that well
1992 [78] spective weeks JIA 10mg/m2), occurred in 9/62 (14%) one patient on co‐ occurred in No stomatitis tolerated
review 3 monthly trimoxazole 14/62 patients. or rash
blood tests, 12 patients had liver biopsy – Peptic ulcer in
PFTs on 46 no fibrosis or cirrhosis No cases on TP or 4/62 patients
pts neutropenia also on
concomitant
NSAID
Giannini, US/Soviet 6 months 89 JIA ≥3 MTX 5 or 10 One patient had LFT abn 8 patients had
1992 [55] Multi‐ joints mg/m2 GI upset
centre RCT
Woo, DBRCT 12 88 15mg/m2 (up Total 20 patients on MTX Bone marrow failure Nausea and GI No difference in SE
2000 [54] cross over months EOA JIA to 30) vs had AST abn vs 16 placebo did not occur upset occurred between MTX and
and SoJIA placebo patients in similar placebo
numbers of
patients
20
Table 3. Adverse Effects of Methotrexate
Author, Type of Duration Subjects Drug and Hepatotoxicity Haematological GI toxicity other Conclusion
Year study of study and monitoring abnormality
numbers
Hashkes, Liver 25 2 biopsies showed grade IIIa No significant
1999 [79] biopsies patients, Roenigk changes fibrosis.
compared 33 4 showed grade II changes Biochem abn
with RF for
biopsies and 27 grade I. correlated with
hepatotox
No significant fibrosis changes
Hashkes, Liver 14 JIA 13/14 grade I Roenigk No significant
1997 [80] biopsies changes clinical
compared 1/14 grade II changes consequences
with RF for
No bx with significant despite minor histo
hepatotox
fibrosis. changes
13/14 LFT abn but only 5 had
>3x ULN
Kugathasan, Liver >3 years 9 JIA 10mg/m2/wk No clinical or biochemical
1996 [81] biopsies of MTX evidence of liver injury
All biopsies were normal
21
4.1.6 Safety

Methotrexate is generally well tolerated in children, however, it has a number of potentially
serious adverse effects. The most common side effect is nausea and vomiting for which folic
acid has been reported to be beneficial. [75] Most of the other side effects are mild and
reversible. Oral ulceration, alopecia, mood changes, rash, peptic ulcer and headache have
been reported to occur. Table 3 summarises reported adverse effects of methotrexate.

Hepatic toxicity is one of the main potentially serious adverse reactions with methotrexate
use. The exact mechanism is not clearly understood. [82] Children are thought to have a
reduced risk of methotrexate associated hepatotoxicity compared with adults as they
generally have fewer co‐existing diseases and fewer environmental exposures such as
alcohol. Acute mild liver function abnormalities occur in approximately 9% of children on
low dose therapy. [83] These changes are usually transient and improve with a period of
cessation. It is difficult to assess the true effect of methotrexate as it is often used in
combination with NSAIDs which may contribute to a transaminase rise.

The potential for long term liver damage with fibrosis and cirrhosis has raised concerns in
the past however there are only a few reports of fibrosis in children and no reports of
cirrhosis secondary to methotrexate. Refer to table 2 for summary of series addressing liver
fibrosis and cirrhosis.

Haematological abnormalities are rare with the use of methotrexate. The main toxic effects
described include: macrocytic anaemia, leukopenia, thrombocytopenia and pancytopenia. [2]
Only case reports of children with haematological side effects of MTX exist, however, the
adult literature reports a frequency of 1‐3%. [84] In patients with mild bone marrow
suppression, spontaneous recovery is usual within 2 weeks.[2] Malignancy due to
methotrexate remains an area of controversy. There have been a few cases described in
children with JIA on methotrexate of Hodgkins and Non‐Hodgkins lymphoma. [85, 86]

Methotrexate has been reported to have caused foetal death and congenital abnormalities
and therefore its use is not recommended for use in pregnancy. It is suggested that
pregnancy is avoided for a minimum of 3 months after completion of therapy in male
patients and for at least one ovulatory cycle in female patients.

4.1.7 Monitoring and supervision

Children with JIA on long term methotrexate require regular clinical and laboratory
monitoring both for the response to the medication and for its potential toxicities.

Hashkes et al examined liver biopsies in children with JIA on methotrexate and found a
relationship between biochemical liver function changes and histopathological changes
consistent with mild fibrosis.[79] Whilst the degree of fibrosis in this series was not
considered significant, the potential hepatotoxic effects of methotrexate have prompted the
introduction of guidelines for the monitoring of liver toxicity in patients taking methotrexate.
These guidelines were developed in 1994 and represent an expert consensus on the
22
monitoring of liver toxicity with methotrexate use in adult Rheumatoid Arthritis. Although
developed based on adult data, these guidelines form the basis for monitoring of children
with JIA on methotrexate.[87]

It is generally recommended that liver function, renal function and full blood examination be
performed at baseline for all patients. Monitoring of LFTs 4‐8 weekly was recommended by
Kremer et al in the initial guidelines published in 1994.[87] Since then, Ortiz‐Alvarez et al
monitored 89 patients with JIA prospectively and found that LFT abnormalities were usually
mild and resolved spontaneously and that more severe abnormalities settled rapidly with
discontinuation of methotrexate. [76] When there are no other co‐existing risk factors, 3
monthly monitoring following initial bimonthly for a few months seems to be appropriate.

4.1.8 Formulary

Australian brand name: Methoblastin: Tablets: yellow and uncoated, 2.5mg (round), 10mg
(capsule shaped); Injection: 25mg/ml, 1000mg/10ml
UK brand name: Maxtrex: 2.5mg, 10mg tablets; Metoject: prefilled syringe 10mg/ml (7.5mg,
10mg, 15mg, 20mg, 25mg)
US brand names: Rheumatrex: 2.5mg; Trexall: tablets 2.5mg, 5mg, 7.5mg, 10mg, 15mg
Canadian brand names: Apo‐Methotrexate; Ratio‐Methotrexate

4.1.9 Summary recommendations

Methotrexate has been shown to be an effective and safe therapy in the treatment of JIA. It is
associated with a number of potentially serious adverse effects and therefore its use requires
monitoring with blood tests and with close clinical supervision from a medical specialist
familiar with the potential risks. It is not recommended for use if access to this supervision is
unavailable. It is recommended for inclusion on the WHO complementary list of essential
medicines.

4.2 Leflunomide


Leflunomide is an immunomodulatory medication that inhibits pyrimidine synthesis
through its inhibition of the enzyme dihydro‐orotate dehydrogensase. Lymphocyte
proliferation depends on pyrimidine synthesis for proliferation and leflunomide therefore
has both anti‐proliferative and anti‐inflammatory effects.

The active metabolite is A77‐1726 to which leflunomide is actively converted via hepatic
metabolism. A77‐1726 is highly protein bound and has a half‐life of up to 18 days reaching a
steady state after approximately 20 weeks. [88]

The pharmacokinetics of leflunomide and its active metabolites are not affected by food
intake or by gender. It is excreted almost equally in urine and faeces. The pharmacokinetics
23
of oral leflunomide was studied in 73 paediatric patients aged 3‐17 years with polyarticular
JIA. [89] This analysis demonstrated that paediatric patients with bodyweights <40kg have a
reduced clearance compared to adults and therefore require dose adjustment (see “Dose and
administration” below).

4.2.2 Efficacy of Leflunomide in JIA

Leflunomide has been shown to be effective in a number of studies in adults with
Rheumatoid Arthritis. (See table 4) There are fewer studies in children with JIA, however,
Sliverman et al demonstrated in an open label study in children with refractory polyarticular
disease a good response to leflunomide. [90] In a randomised controlled trial of 94 patients,
Silverman compared leflunomide with methotrexate in polyarticular disease. This trial
concluded that treatment with leflunomide does result in clinical improvement but that the
rate of improvement was not as high as that seen with methotrexate (89% Leflunomide vs
68% methotrexate met ACR Pedi 30 response).[60]

Gao et al [91] addressed the potential for combining leflunomide with methotrexate by
comparing combination therapy with methotrexate alone. They found a significantly higher
response rate in those patients on combined therapy.

Whilst there does appear to be some evidence for the use of leflunomide in the paediatric
population, the exact role is yet to be defined. There appears to be a role in patients who are
intolerant to methotrexate or have failed to respond to methotrexate.

4.2.3 Dose and administration

Adult studies suggest the benefit of loading doses of 100mg/day for 3 days to rapidly achieve
steady state. This is not required and may result in significant side effects[2]. In their study,
Silverman et al used 100mg loading dose for one day in children <20kg, for two days in
children between 20 and 40kg, and 100mg for three days in children >40kg. This was
followed by maintenance dose of 10mg/day if <40kg and 20mg/d if >40kg. A recent
population pharmacokinetic study recommended that leflunomide doses be adjusted for
paediatric patients as follows: 10 mg/d for 10‐20 kg, 15 mg/d for 20‐40 kg, and 20 mg/d for >
40 kg.[89] The use of a loading dose may increase toxicity in children. (MIMS 2009)

4.2.4 Safety

The most commonly reported adverse effect is gastrointestinal upset which is reported to
occur in 17% of patients. This includes: abdominal pain, dyspepsia, diarrhoea and gastritis.
Other common side effects include: headache, rash and alopecia.

Liver function abnormalities are less frequently reported than with the use of methotrexate.
[60] There appears to be a particular risk when used in combination with methotrexate. [92]
In studies of leflunomide in adults with Rheumatoid arthritis, liver function abnormalities
are reported in approximately 5% of patients. These changes are mild and reversible. More
24
serious liver dysfunction is uncommon and is associated with concomitant alcohol
consumption, viral hepatitis or other pre‐existing liver disease.

Leflunomide is teratogenic and therefore it is recommended that patients have a negative
pregnancy test before starting treatment and use reliable contraception during therapy.

4.2.5 Drug interactions
The enzymes involved in the metabolism of leflunomide are not entirely known. In vitro
studies indicate that leflunomide inhibits cytochrome p450 and therefore caution should be
taken when co‐administered with other drugs involved in cytochrome p450 metabolic
pathways.


Monitoring is recommended with baseline and monthly full blood count and liver function
for 6 months, which can be reduced to 6‐8 weekly if stable.

4.2.7 Formulary

Because safety and efficacy in children has not been clearly established with the existing
evidence, most manufacturers do not list leflunomide with paediatric advice.

Australian brand names: Arava® (tablets 10mg, 20mg, 100mg); Arabloc® (tablets: 10mg,
20mg)

US brand names:

Canadian brand names:


In summary, despite limited studies in the paediatric population, leflunomide has been
shown to be effective for the treatment of JIA both as a monotherapy[60] and in combination
with methotrexate [91]. Its use in the treatment of rheumatic disease requires monitoring
with blood tests and close clinical supervision to ensure that the potential side effects are
minimised. It is not recommended for use if access to this supervision is unavailable. It is
recommended for inclusion on the WHO complementary list of essential medicines.
25
Table 4. Evidence for the efficacy of leflunomide in JIA
Author, Pop’n Type of Duration Number of Subjects Study groups Primary outcomes Conclusion and comments

Year study of study patients measured
Silverman, Multicentre DBRCT 16 week 86 completed Polyarticular MTX vs leflunomide Percentage of patients with Both MTX and Leflunomide
2005[60] international +/‐32 16 weeks JIA ‘ACR Pedi 30’ (30% resulted in high rates clinical
week 70 entered 3‐17 yrs old improvement compared with improvement following 16 week
extension extension baseline in ≥3 of 6 variables phase.
study included in ACR core set 89% MTX vs 68% Leflunomide
(swollen joints, active joint ACR Pedi 30 response
count, parent global
assessment, physician global LFT abnormalities noted more
assessment, CHAQ, ESR) frequently with MTX than
Leflunomide
Silverman, Open‐ 26 weeks 27 patients Refractory Leflunomide loading dose ACR Pedi 30 52% met ACR Pedi 30 response
2005[90] label Only 63% polyarticular ~100mg followed by 44% met ACR Pedi 50 and 19%
study patients JIA (failed 10mg/day (+/‐ increase to met ACR pedi 70. 44% patients
completed response or 20mg/d at 8 wks) responded as early as 4 weeks.
study intolerant of AE reported in 30% of patients ,
Methotrexate) ceased in 2 patients
Gao, China 26 weeks 40 patients Polyarticular Leflunomide (loading dose Tender and swollen joints, Significant difference in
2003[91] JRA of 1mg/kg/day) D1‐3 then parent and physician improvement on combination
0.2‐0.4 mg/d) plus MTX evaluation score, general compared with MTX alone.
(0.3mg/kg iv every 2 wks function score, ESR, CRP No significant difference in rate of
until remission then SE.
0.2mg/kg weekly orally) vs SE documented Combination therapy safe and well
MTX alone tolerated
26
Table 5. Evidence for the efficacy of Sulfasalazine in JIA

Author Pop’n Type Duration Number Subjects Study groups Outcomes Conclusion and comments
, of of study of
Year study patients
Van multicent DBRCT 24 weeks 69 Oligo and SSZ 50mg/kg/d ACR Pediatric 30 44% improved in SSZ group compared with 21%
Rossum, re Polyarthriti (max 2g/d) (without functional placebo group.
1998[93] s measure)
Placebo More AEs with SSZ resulting in withdrawal of 10
patients in total from study (all from SSZ group). All
AEs were transient and reversible. LFT abn n=2,
AEs Leukopenia n=2, hypoimmunoglobinaemia n=3,
anorexia/diarrhoea/ haematoma n=1 each.
Burgos‐ DBRCT 26 weeks 33 ERA SSZ 30‐ Reduction in active joints 46% in SSZ group compared with 42% in placebo group.
Vargas, 60mg/kg/d (max Significant differences only seen in physician and
2002[94] 2g) patient assessments
Placebo
Ansell, multicent Pilot 52 weeks 51 JIA (oligo, SSZ 40mg/kg/d Active joint count, patient 24% good response, 16% some response, 45% no
1991[95] re study, poly and increased assessment, ESR response.
Un‐ SoJIA) incrementally 8 patients withdrew due to AEs
controlle
over 6 weeks. AEs
d

Huang, Single Retrospe Mean 36 ERA and SSZ 50mg/kg/d Active joint count, ESR 39% patients in remission further 25% improved
1998[96] clinic ctive duration JIA (max 2g) Remission or
chart therapy improvement (defined as 11% patients some AE. One patient ceased SSZ.
review
2.5 yrs 25% reduction in joint
number for two No difference between ERA and JIA
consecutive visits)
Van multicent Pro‐ Median 9 61 Patients initially ACR Pediatric 30 Effective suppression of disease activity early with SSZ
Rossum, re spective years managed with has beneficial effects that persist for many years
2007[97] cohort (range 7‐ SSZ (32) vs
10) those managed
with placebo
(29)
Hoza, DBRCT 26 weeks 39 Oligo and SSZ 20‐ Any improvement in 4 48% SSZ group improved compared with 28%
1991[98] polyarthriti 30mg/kg/d criteria: Chloroquine group
27
Table 5. Evidence for the efficacy of Sulfasalazine in JIA
Author Pop’n Type Duration Number Subjects Study groups Outcomes Conclusion and comments

, of of study of
Year study patients
s Active joints, pain,
Chloroquine 3‐ morning stiffness, ESR, More AEs with SSZ
4mg/kg/d functional capacity
Ozdoga 4‐14 18 All types ESR Significant improvement in ESR, joint tenderness and
n, months JIA Joint tenderness count
1985[99] Active joint count

28
4.3 Sulfasalazine


The exact mechanism of action of sulfasalazine is not clearly understood. Its role in the
treatment of JIA is possibly due to its immunoregulatory and anti‐inflammatory effect
including, amongst other things: the inhibition of prostaglandin synthesis; inhibition of
bacterial growth; inhibition of leukotriene formation; modulation of leucocyte function;
inhibition of DNA synthesis; impairment of folate metabolism and effects of lymphocyte
number and function.

Sulfasalazine is poorly absorbed in the small intestine. In the colon, sulfasalazine is reduced
to two major active metabolites (5‐aminosalicylic acid and sulfapyridine) by colonic flora.
Sulfapyridine is rapidly absorbed and metabolised by acetylation in the liver. The rate of this
process varies between individuals and is genetically determined.

Both 5‐aminosalicylic acid and sulfapyridine have an affinity for collagen rich tissue and
concentrate in the synovial fluid as well as pleural spaces, intestinal wall and peritoneum.

4.3.2 Efficacy of Sulfasalazine in JIA

The use of sulfasalazine in the treatment of JIA was first reported in 1986 [99], although it
had been used for many years prior to this for the treatment of adult Rheumatoid arthritis.
Table 4 summarises the studies addressing efficacy of sulfasalazine in JIA and as is
illustrated in the table, whilst there are few controlled studies, there is some evidence to
support its use in JIA.

In a randomised double blinded placebo controlled trial of 69 patients, Van Rossum et al
found that sulfasalazine reduced the overall articular severity score, global assessments and
laboratory parameters. [ref] Adverse events were more frequent however these were found
to be transient and reversible.

Ozdogans study in 1986 [99]was a small uncontrolled trial (n=18) which demonstrated
benefits of SSZ. Eleven patients had an excellent response with only 3 patients showing no
response. Similarly in another open label study by Joos et al [100], 21 of 41 patients achieved
remission and significant improvement was seen in 12. In this study, no change was seen in
one patient and the condition worsened in three. Imundo and Jacobs [100, 101] observed that
the best response rate was ANA positive young girls with oligoarticular JIA, and that the
worse response (indicated by a high failure rate) was in systemic JIA. Only 28% had
complete remission. Other open label studies have shown that sulfasalazine is most effective
in boys older than 9 and adolescents with oligoarticular JIA, raising the question of its use in
enthesitis related arthritis (ERA).

The other controlled studies include a placebo‐controlled randomised blinded study of
patients (n=33) with ERA. [94] Burgos demonstrated no significant difference in response
rate however some improvement in physician and patient global assessments. Hoza et al also
29
[98] demonstrated no significant difference when sulfasalazine was compared to chloroquine
in oligoarticular and polyarticular JIA.

Sulfasalazine does not have consistent efficacy across subtypes of JIA. There is a broad
experience in open, uncontrolled trials which suggest the benefit of sulfasalazine in JIA, and
this is supported by the aforementioned blinded controlled Van Rossum trial. Some open
label trials found an increase response in older HLAB27 positive children with oligoarticular
disease, however this finding was not convincingly supported in a small blinded control
study. [94] Based on best available evidence, sulfasalazine is most effective in poly and oligo
articular disease and there does not appear to be a difference in response rates between these
groups. On the current evidence, sulfasalazine is not effective in the management of SoJIA
and, in fact, its use is potentially complicated by an increased risk of toxicity.


Sulfasalazine is administered orally in children with JIA. Initiation of therapy should begin
with a small dose followed by a grading up at weekly intervals. The recommended starting
dose is 5mg/kg twice daily for one week, then 10mg/kg twice daily for one week, then
20mg/kg twice daily for one week, then a maintenance dose of 20‐25mg/kg twice daily. The
maximum recommended dose in children is 2g/day.

Sulfasalazine should be administered after meals or with food and should not be
concurrently taken with antacids.

4.3.4 Safety

Intolerance and adverse events are frequently associated with sulfasalazine administration.
Adverse reactions frequently reported include: rash, gastrointestinal symptoms and
haematological abnormalities. One study [93] reports a discontinuation rate of
approximately 30%. They found that 86% of patients on sulfasalazine reported at least one
adverse event and this resulted in 10 patients (28.5%) requiring withdrawal from the study.
One patient was considered as having a serious adverse event but the authors noted that all
of the adverse events were reversible with discontinuation of therapy. [93]

Gastrointestinal intolerance is the most frequently reported side effect. Symptoms include:
anorexia, nausea, abdominal discomfort and diarrhoea. Liver function abnormalities also
occur commonly estimated to occur in approx 4% patients. More severe (and potentially
fatal) hepatotoxicity has been reported in association with DRESS syndrome (Drug Reaction
with Eosinophilia and Systemic Symptoms) – a hypersensitivity reaction thought due to the
sulfapyridine metabolite. Features include: fever, rash, raised liver function tests,
eosinophilia and lymphadenopathy. Corticosteroid therapy is frequently required to treat
DRESS syndrome.

Haematological side effects such as leucopenia have an incidence across the literature of 3%
[102]. Whilst leucopenia is reversible with cessation of the drug, other more rare but severe
haematological side effects such as agranulocytosis have been reported. Agranulocytosis is
30
said to occur in 1% of patients and usually begins within 5‐12 weeks of onset of therapy [103]
and is potentially fatal.

Skin rash is also a common side effect and occurred in half of the patients in the Van Rossum
trial [93]. Sulfasalazine has also been associated with other rarer complications such as drug
induced lupus erythematosus. This may occur after several or even years of therapy and
resolves following withdrawal.

4.3.5 Drug interaction

Sulfasalazine is generally well tolerated with other medications. Sulfasalazine may decrease
the bioavailability of cyclosporin. There are also reports of possible additive hepatotoxicity
when used in combination with methotrexate. Care should be taken when prescribing
sulfasalazine as numerous other drug interactions have been reported.


Full blood count and Liver function tests should be performed frequently following initiation
of sulfasalazine. Product information suggests baseline tests then 2 weekly for 3 months,
monthly for 3 months and then monthly thereafter. It is recommended that patients be
followed up clinically at least 3 monthly to ensure ongoing tolerance of sulfasalazine.

4.3.7 Formulary

Sulfasalazine is FDA approved for use in children for JIA polyarticular course. It is not
licensed for use in the UK.

Australian brand names: Pyralin, enteric coated tablets: 500mg; Salazopyrin and Salazopyrin
EN‐tabs tablets: 500mg

UK brand name: Salazopyrin and Salazopyrin EN‐tabs 500mg; Salazopyrin suspension
250mg/5ml and suppositories 500mg.

US brand names: Azulfidine, Azulfidine EN‐tabs, Sulfazin and Sulfazin EC, 500mg
Canadian brand names: Alti‐Sulfasalazine and Salazopyrin


The current literature suggests that sulfasalazine has a role as disease modifying therapy in
the treatment of JIA and particularly oligoarticular and polyarticular disease. It is not the
first DMARD of choice especially given the evidence supporting methotrexate. The
consideration of sulfasalazine as an alternative DMARD in JIA should be under specialist
supervision. Sulfasalazine therapy also requires specialist supervision particularly with
respect to the frequent risk of adverse effects. In addition, regular monitoring with blood
tests is recommended. Sulfasalazine is recommended for inclusion on the complimentary
WHO essential medicine list provided these resources are available.
31
4.4 Cyclosporin A


Cyclosporin A (CyA) is a potent immunomodulatory agent used to inhibit the adaptive
immune response and therefore effective in diseases known to be of autoimmune origin. It is
used to prevent rejection in solid organ transplant. The effects on the immune system are
likely multifactoral. Calcineurin, an important protein in the process of T and B cell
activation, is bound and inhibited by CyA. This results in impaired production of a number
of cytokines important in the proliferation of T cells. The effects of CyA on the T cell appear
to be specific and reversible. Cyclosporin may have other effects including effects on antigen
presentation.

CyA is incompletely absorbed form the gastrointestinal tract. Microemulsion preparations
are thought to provide improved absorption and bioavailability. It has multiple hepatic
metabolic pathways and is metabolised to many metabolites before excreted in the bile. Only
a small percentage is excreted in the urine. The half‐life is approximately 18 hours.

4.4.2 Efficacy of Cyclosporin in JIA and MAS

The role of cyclosporin in the treatment of JIA has not been clearly defined. It may be
particularly important in the treatment of SoJIA especially in association with MAS. As
illustrated in Table 6, there is little strong evidence supporting its efficacy and there are no
controlled trials. Evidence includes observational studies and case series.

Gerloni et al described a group of 34 patients with SoJIA in a prospective open trial [104] in
whom there was benefit in control of fever and in reducing steroid exposure. Twenty six
percent of patients withdrew from CyA treatment though due to adverse events. In addition,
50% withdrew due to lack of efficacy or flare of disease. Stephan et al reported the
effectiveness of CyA in 12 patients with reactive haemophagocytic syndrome. In five patients
CyA was used as first line therapy and in seven patients it was used when steroids had
failed. [105] Reiff et al described 22 patients (17 with JIA of which 14/17 had SoJIA) and
concluded that CyA resulted in improvement in the majority of patients. [106] Joint count
improved in 70% patients and in patients with SoJIA, fever resolved in 91%, anaemia
improved in 33% and concomitant prednisolone therapy was reduced in 77% of patients,
[106] supporting the hypothesis that CyA is more beneficial in the treatment of systemic
symptoms (such as fever and anaemia) than the control of arthritis. Mouy et al looked at a
small group of patients with MAS treated with CyA and demonstrated rapid improvement
in all patients. [107]

4.4.3 Efficacy of Cyclosporin in JDM

There are a number of small retrospective studies and case series reporting the benefits of
CyA in patients with JDM. These studies are summarised in Table 7. Similar to JIA, there are
currently no controlled trials however there is currently an international multi‐centre
32
prospectively randomised trial co‐ordinated by PRINTO (Pediatric Rheumatology
International Trials Organisation) which is comparing prednisolone alone with
prednisolone/methotrexate combination and prednisolone/cyclosporine combination in
patients newly diagnosed with JDM. The results of this trial are eagerly awaited in order to
guide the management of JDM.

Heckmatt et al studied 14 patients with JDM who had not fully responded to corticosteroids
or other immunosuppressants (methotrexate, azathioprine or cyclophosphamide) and had a
chronically active course averaging three years. [108] Many of these patients had serious
complications of the disease or of their previous treatment. Most patients were treated with
2.5‐7.5mg/kg/d (divided twice daily) and all patients were found to have improved muscle
strength and steroid dose reductions.


The generally accepted dose for the management of paediatric rheumatic diseases is 3‐
5mg/kg/day [2] orally and is usually divided twice daily. This is similar to the recommended
dosing in adult patients with rheumatoid arthritis. In one study of children with JDM, a dose
ranging between 2.5 to 7.5mg/kg/day was sufficient. [108]

4.4.5 Safety

Cyclosporin is associated with potentially considerable toxicity and requires careful
monitoring and supervision. Most side effects are dose dependent and responsive to dose
adjustment. Cyclosporin doses are significantly higher in the treatment of solid organ
transplantation compared to rheumatological indications and therefore the rates of side
effects is comparatively higher.

Renal function abnormalities and hypertension are the most concerning side effects and
responsible for the majority of withdrawals of therapy. Rises in creatinine and urea due to a
reduced glomerular filtration rate have been demonstrated. The exact mechanism for this is
unclear but these changes are usually reversible. In one series of 22 patients with JIA and
JDM on CyA, [106] serum creatinine doubled in 6 patients and GFR was reduced in one of 14
patients. Ostensen studied 14 patients on CyA and found marked rise in serum creatinine in
5 patients necessitating withdrawal. [109] These findings necessitate close monitoring of
renal function. Interstitial fibrosis and tubular damage may also occur[110] and may be
irreversible. Cyclosporin induced hypertension is also frequently seen in children and in
adults has been estimated to cause hypertension in approximately 10% of adults treated. A
recent Cochrane review demonstrated statistically significant increases in blood pressure
with CyA in a dose‐related fashion. They concluded that prescribers should find the lowest
effective dose in those patients requiring long term use. [111]

Other encountered side effects include: hypertrichosis, gingival hyperplasia, gastrointestinal
disturbance, tremor and paresthesias, hepatic dysfunction and bone marrow suppression.
These adverse effects are mostly reversible with reduction or cessation of therapy. In one
series of 22 patients, doses less then 3.5mg/kg/d were unlikely to cause hepatotoxicity and
33
bone marrow effects and that hypertension, gum hyperplasia and hypertrichosis were not
observed, suggesting that in children these side effects may be less common. [106] Since CyA
is an immunosuppressive agent, children administered CyA are at increased risk of infection.


Cyclosporin should be used with caution when administered in combination with other
potentially nephrotoxic medications. In particular, NSAIDs are frequently used in paediatric
rheumatic disease and may exacerbate the toxic effects of CyA. In this situation close
monitoring of renal function is recommended. The bioavailability of CyA increases when the
drug is taken with grapefruit juice.


It is recommended that blood pressure be monitored at least weekly for the first month of
therapy and then monthly thereafter. [2] In addition, laboratory monitoring is required
monthly particularly screening for renal, bone marrow or hepatic effects. Dose adjustment is
recommended if serum creatinine increases by >30%.

The need for monitoring of CyA levels in non‐transplant patients is unclear. It is generally
recommended that whole blood trough levels be maintained between 125 and 175μg/ml. [2]
Monitoring may be particularly important in patients with unexpected toxicity.

4.4.8 Formulary

Australian Brand names: Neoral® (caps 10, 25, 50 and 100mg, solution 100mg/ml),
Sandimmun®; Cicloral®(caps 25, 50 and 100mg)

U.S. Brand Names: Gengraf® (caps 25 and 100mg, solution 100mg/ml); Neoral® caps 25 and
100mg, solution 100mg/ml); Sandimmune® caps 25 and 100mg, solution 100mg/ml)

Canadian Brand Names: Apo‐Cyclosporine; Neoral®; Rhoxal‐cyclosporine; Sandimmune®
I.V.; Sandoz‐Cyclosporine


Cyclosporin has a role in the management of paediatric rheumatic disease. Several
observational studies provide evidence for its efficacy in treating JIA and in particular SoJIA
and associated MAS and also in the treatment of JDM. Cyclosporin is a potent
immunosuppressive agent and is associated with a number of potentially serious adverse
effects. The administration of cyclosporin should be under specialist supervision with the
facility to frequently monitor with blood tests. It is recommended for the WHO essential
medicines complimentary list.

34

Table 6. Evidence for the efficacy of Cyclosporin in JIA
Author, Pop’n Type of Number Subjects Duration of Intervention Outcomes measured Conclusion and comments

of
Year study patients study
Gerloni, Italy Open 41 34 patients with Avg duration All patients received CyA Improved fever; improved CyA has benefits in control of fever and
2001[104] prospective SoJIA and 7 therapy 1.4yr 3‐5mg/kg/d arthritis (50% decrease in reducing steroid exposure in patients
trial patients with JIA (max 7.2yr) number of active joints); Hb; with SoJIA. CyA is less effective in
and chronic ESR; physician global control of arthritis.
anterior uveitis SE of CyA. SE freq but usually mild and reversible.
26% patients withdrew due to SE.
Stephan, Multi‐ Retrospectiv 24 18 SoJIA, 2 polyJIA, Patients various Clinical and biological CyA consistently and rapidly effective
2001[105] centre e with 2 lupus, 2 accumulated measures of RHS in patients when used as first line
French observationa RHS unclassified over 10 yrs therapy and when steroids had failed
l study inflammatory
disorders
Reiff, US Retrospectiv 22 17 JRA, 5 JDM Mean period All patients received CyA Lab variables; joint count; CyA may be effective in treatment of
1997[106] e 16 months (6‐ mean dose 3.2mg/kg/d. joint swelling; morning refractory JRA and JDM.
observationa 42 months) Most patients received stiffness in patients with JRA. Concomitant MTX appears safe
l
concomitant CS and Muscle weakness and
16/22 patients received enzyme levels in JDM.
concomitant MTX.
Pistoia, Italy Case series 12 9 patients with CyA given for All patients received CyA Clinical and laboratory CyA was satisfactory overall and
1993[112] JCA (7 SoJIA, 2 9‐48 months at mean dose 5mg/kg/day measures of disease activity thought to be a promising agent in
poly); 3 patients after failure of CS therapy treatment of JIA and JDM.
with JDM
Mouy, Case series 5 5 patients with 3 patients failing to Clinical and biological Rapid improvement in all patients .
1996[107] MAS (4 SoJIA and respond to CS therapy markers of MAS Apyrexia in all patients within 48
1 polyJIA) had CyA added and 2 hours.
patients with less severe Biological abnormalities improved
manifestations treated more slowly.
with CyA alone
35

Table 7. Evidence for the efficacy of Cyclosporin in JDM
Author/ Pop’n Type of Number Subjects Duration of Intervention Outcomes measured Conclusion and comments

of
Reiff, US Retrospectiv 22 17 JRA, 5 JDM Mean period All patients received CyA Lab variables; joint count; CyA may be effective in treatment of
e 16 months (6‐ mean dose 3.2mg/kg/d. joint swelling; morning refractory JRA and JDM.
1997[106]
observationa 42 months) Most patients received stiffness in patients with JRA. Concomitant MTX appears safe
l
concomitant CS and Muscle weakness and
16/22 patients received enzyme levels in JDM.
concomitant MTX.
Pistoia, Italy Case series 12 9 patients with CyA given for All patients received CyA Clinical and laboratory CyA was satisfactory overall and
1993[112] JCA (7 SoJIA, 2 9‐48 months at mean dose 5mg/kg/day measures of disease activity thought to be a promising agent in
poly); 3 patients after failure of CS therapy treatment of JIA and JDM.
with JDM
Heckmatt, UK Case series 14 14 patients with Average 12 CyA starting at 2.5 Muscle weakness, extent of All patients improved on CyA.
1989[108] JDM not months mg/kg/d divided bd and rash, serum CK, Recovery of muscle strength, resolution
responded fully therapy to increased according to Monitoring of SE icluding of complications and reduction or
to CS and other time of clinical response. Max BP, serum creatinine, CyA cessation of steroids.
immuno‐ publication (5‐ 12mg/kg/d levels. No serious SE observed. HT easily
suppressants with 28 months) controlled with dose reduction.
chronically active
disease avg 3 yrs
Zeller, Retrospectiv 6 Patients with Mean follow CyA Clinical markers of disease. CyA seems effective and should be
e case review refractory JDM up 51.5 Medication SE, Steroid doses considered in refractory cases. SE
1996[113]
months rare/minor
36
4.5 Azathioprine


Azathioprine is a purine analogue metabolised in the liver to its active metabolite 6‐
mercaptopurine (6‐MP). 6‐MP is then further metabolised via three major pathways, the
metabolites of which inhibit DNA synthesis through the suppression of guanine and adenine
synthesis. Azathioprine inhibits cell mediated immunity through inhibition of T cell growth
and results in reduced antibody production.

The bioavailability of azathioprine is approximately 50%. [114] It is rapidly metabolised in
the liver and its metabolite, 6‐MP, has a half life of 0.7 – 3 hours. Small amounts are
eliminated as unchanged drug and metabolites are predominantly renally excreted.

4.5.2 Efficacy of Azathioprine in SLE

Azathioprine has been used for the management of SLE in children for decades. Despite this
long experience, there are no controlled trials addressing its efficacy in paediatric lupus and
therefore its use remains controversial.

Azathioprine is used in a variety of clinical circumstances in SLE but most frequently in
combination with corticosteroids. The addition of azathioprine as second line therapy may
be indicated to permit steroid dose reduction in patients requiring unacceptably high doses
of corticosteroids. [2] In adult patients this was found to be associated with fewer
hospitalisations.[115]

The role of azathioprine in the management of paediatric lupus complicated by nephritis is
even less well defined. There is conflicting evidence in the adult literature about its use in
this context. Some studies are in favour of its use. A retrospective cohort study of 26 adult
patients with SLE and associated proliferative lupus nephritis were managed long‐term with
prednisolone and azathioprine. [116] This study concluded that azathioprine was well
tolerated and that 5‐10 year survival rates were similar to those of cyclophosphamide‐based
therapies. [116] One outcome study of children with lupus nephritis concluded that long‐
term outcome was excellent with 94% survival at mean followup of 11 years. In this group of
patients, azathioprine was the most frequently prescribed agent. [117]

Although there is limited evidence for the efficacy of azathioprine in SLE and in particular
paediatric SLE, many rheumatologists acknowledge that it does have a role in therapy. In
particular, it is used to control serologic disease flares, allow reduction of steroid doses and
maintain disease course after parenteral cyclophosphamide. [45]

37
4.5.3 Efficacy of Azathioprine in JIA

The evidence for the efficacy of azathioprine is based on case series, case reports and
uncontrolled trials. To date there is only one randomised double blind placebo controlled
trial addressing the efficacy of azathioprine in the treatment of 32 JIA [118] Statistically
significant improvement was only seen in two disease activity measurements and it is
therefore not considered to have greater efficacy than placebo. It is not used routinely in the
treatment of JIA. See table 8 for details of studies.

An uncontrolled prospective trial involving 129 patients with refractory JCA demonstrated
improvement in both clinical and laboratory outcomes with acceptable side effect profile.
[119] A further retrospective study of 24 patients demonstrated clinical improvement in
62.5% of patients and remission in 37.5%. [120] Whilst the strength of this evidence is not as
compelling as that of other DMARDs used in the treatment of JIA, these studies suggest that
there may be a role of azathioprine in JIA.


Azathioprine should be started at 1‐1.5 mg/kg/day increasing to a maximum dose of 2‐
2.5mg/kg/day. It is generally considered that a minimum of 12 weeks is required to achieve
adequate therapeutic response. Azathioprine should be administered with food to reduce
gastrointestinal disturbance.

4.5.5 Safety

Gastrointestinal side effects manifesting as nausea, vomiting, diarrhoea and epigastric pain
are common with azathioprine. These side effects can be diminished if the dose divided or if
administered with meals. Up to 12 % of patients experience these symptoms and in one
study 10% of adult patients with rheumatoid arthritis withdrew from therapy due to
gastrointestinal intolerance. [121]

Other less frequently observed side effects include: pancreatitis, liver toxicity (abnormal liver
function tests), interstitial pneumonitis and rash. It is difficult to estimate the incidence of
these side effects in the paediatric rheumatic disease population as studies of the use and
safety of azathioprine are frequently in the adult population and in conditions other than
rheumatic diseases.

Dose dependent effects on the bone marrow have also been well described in association
with azathioprine causing granulocyte arrest and leukopenia and, less frequently, anaemia
and thrombocytopenia. This is thought to be due to reduced activity of thiopurine
methyltransferase (TPMT). TMPT activity is low or absent in 0.3% of the population and
causes these haematological effects shortly after initiation of therapy. Lower TMPT activity
has been observed in African‐American individuals compared to Caucasian‐Americans.
[122] Distinct TMPT mutations have been identified and are detectable on PCR‐based
technique.

38

A number of medications, used concomitantly, have been reported to enhance the
myelosuppressive effect of azathioprine including trimethoprim. 5‐ASA derivatives may
decrease the metabolism of thiopurine analogs. The toxic effects of leflunomide may also be
enhanced when used with azathioprine and require more stringent monitoring of bone
marrow toxicity. Azathioprine may also decrease plasma cyclosporin levels.


Toxicity monitoring should occur throughout treatment. It is generally recommended that
clinical evaluation occur at 1‐2 months then 3 monthly thereafter or earlier if disease severity
warrants. Laboratory monitoring should include: weekly FBE with differential until stable
then monthly thereafter and monthly LFTs and UEC. [2] Analysis of TMPT genotype should
be considered for patients who develop severe leukopenia on azathioprine.

Azathioprine should be ceased if there is significant leukopenia, thrombocytopenia or
elevated liver enzymes.

4.5.8 Formulary

Australian brand name: Imuran® (tablets 25mg, 50mg, powder for reconstitution 50mg)
UK brand names: Imuran® (tablets 25mg, 50mg, powder for reconstitution 50mg)
US brand names: Imuran® (tablets 25mg, 50mg, powder for reconstitution 50mg); Azasan®
Canadian brand names: Alti‐Azathioprine; Apo‐Azathioprine®; Gen‐Azathioprine;
Imuran®; Mylan‐Azathioprine; Novo‐Azathioprine


Azathioprine appears to have a role in the management of both paediatric SLE and JIA
although conclusive strong evidence with RCTs is lacking. Azathioprine is associated with
potentially serious side effects in particular relating to bone marrow suppression.
Administration of azathioprine should be under the supervision of specialist care with access
to appropriate clinical and laboratory monitoring. Azathioprine is recommended for
inclusion on the complementary WHO essential medicines list.

39

Table 8. Evidence for the efficacy of Azathioprine in JIA
Author/ Type of Number Subjects Duration of Intervention Outcomes measured Conclusion and comments

of
Kvien, RDBPCT 32 JIA all types 16 weeks AZA 2‐2.5mg/kg/d Laboratory (ESR, FBE) Significant improvement only in
1986[118] Vs placebo Number of clinical measures patients’ subjective functional capacity
including active joint count, and subjective total assessment.
functional capacity, Trend in favour of azathioprine but not
physicians overall conclusive evidence of efficacy
assessment
Savolaine Uncontrolled 129 Refractory JCA Median 15% remission. 14% temporary
n treatment 13 remission (still on therapy).
1997[119] months, Sustained effect with acceptable SE
14% discontinued due to SE
Lin, Retrospectiv 24 JRA treated Mean duration AZA (avg max dose 62.5% showed clinical improvement.
e chart previously with treatment 13 1.9mg/kg/d) 37.5% clinical remission
2000[120]
review azathioprine months, mean 12 patients received Well tolerated.
follow up 45 DMARDs prior to start of Steroid sparing agent
months AZA
40
4.6 Hydroxychloroquine


Hydroxychloroquine is an antimalarial agent used in the treatment of rheumatic disease.
Hydroxychloroquine inhibits the synthesis of DNA, RNA and protein by interacting with
nucleic acid. Its immunosuppressive effect is via a number of mechanisms including:
alteration in lysosomal pH and interference in antigen processing; stabilization of lysosomal
membranes; inhibition of antigen‐antibody reactions; suppression of lymphocyte response
and inhibition of neutrophil chemotaxis. [2]

Hydroxychloroquine is rapidly absorbed from the intestine with an oral bioavailability of
74%. [123] The half‐life is 40 days, steady state is reached in 2 to 6 months and it is primarily
renally excreted. [123]

4.6.2 Efficacy of Hydroxychloroquine in JIA

Hydroxychloroquine has not been convincingly shown to be effective in the treatment of JIA.
There is one placebo controlled trial addressing the efficacy of hydroxychloroquine in the
treatment of JIA. [124] This randomised double blinded trial of 162 patients with
polyarticular JIA compared hydroxychloroquine with penicillamine or placebo. There was
no significant difference between groups.

Kvien et al demonstrated in an open randomised trial (not placebo controlled) of 72 patients
with oligo and polyarticular JIA, that hydroxychloroquine was not more efficacious than
gold or penicillamine.[125] Interestingly, a meta‐analysis in 2000 of all RCTs and CCTs
comparing hydroxychloroquine to placebo in adult patients with rheumatoid arthritis
revealed an overall moderate effect and with a low toxicity profile. [126]

4.6.3 Efficacy of Hydroxychloroquine in paediatric SLE

Hydroxychloroquine is frequently used as an adjunct to steroid therapy at the onset of
treatment of juvenile SLE. However, there are no trials addressing the effectiveness of
hydroxychloroquine in the paediatric population. Evidence for its efficacy was demonstrated
in a randomised, double blinded, placebo controlled withdrawal trial by the Canadian
Hydroxychloroquine Study Group. [127] Patients assigned to the placebo group had a
significantly higher relative risk of flare and that the time to flare was shorter compared to
those patients who continued HCQ.

There have since been many other studies supporting its use in SLE. Recent systematic
review demonstrated high levels of evidence that hydroxychloroquine prevents SLE flares an
increases long term survival.[128] There was moderate evidence of protection against
irreversible organ damage, thrombosis and bone mass loss. [128] Recommendations are that
hydroxychloroquine should be commenced in most patients and continued throughout the
course of the disease.

41


The usual dose of hydroxychloroquine in children is 3‐5 mg/kg kg/day divided 1‐2 times per
day with a maximum of 400mg per day. It should be administered with food to reduce the
occurrence of gastrointestinal intolerance.

4.6.5 Safety

Hydroxychloroquine is generally considered to be a very safe medication. The frequency and
severity of adverse effects is low even after prolonged use. There is a large amount of
supporting evidence for this in the adult literature.[128]

Gastrointestinal disturbance occurs in approximately 10% of adult patients. It is considered
less common in children. Central nervous system side effects are common and include:
headache, lightheadedness, insomnia, nervousness, nightmares and confusion.

The most concerning side effect is ocular toxicity. This occurs rarely but can cause blindness.
Retinal toxicity is thought not to occur in adults if the dose remains less than
6.5mg/kg/day.[129] Protocols and practices vary world wide, however it is generally
recommended that ophthalmological examinations are performed yearly. Local protocols
should be established between the prescribing physician and the treating ophthalmologist.
Retinal abnormalities should prompt immediate cessation of the medication.

Hydroxychloroquine is considered safe in pregnancy and breast feeding.


Hydroxychloroquine levels may be decreased by Echinacea. In addition there are a number
of medications that should be avoided or monitored carefully or increased or decreased
effect when used concomitantly with hydroxychloroquine. These include: beta blockers, anti‐
psychotics and others.

Whilst hydroxychloroquine is a safe medication, it does need regular monitoring. Full blood
examination is suggested on a regular basis and ophthalmology examination should occur at
least yearly.

4.6.8 Formulary

Hydroxychloroquine is not FDA approved for the use in paediatric SLE. In the UK
hydroxychloroquine is licensed for use in JIA, SLE and discoid LE and other dermatological
conditions caused by or aggravated by the sun.

Australian brand names: Plaquenil® (200mg tablets)
UK brand names: Plaquenil® (200mg tablets)
US brand names: Plaquenil®
42

Canadian brand names: Apo‐Hydroxyquine®; Gen‐Hydroxychloroquine; Plaquenil®; Pro‐
Hydroxyquine


Hydroxychloroquine appears to be a safe and effective treatment in the management of
juvenile SLE. It has no proven role in the management of JIA. Hydroxychloroquine is
recommended for the use in juvenile SLE provided patients have access to specialist care
including ophthalmological and laboratory assessments. It is recommended for inclusion on
the WHO essential medicines complementary list.

43

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18th Expert Committee on the Selection and Use of Essential Medicines

(21 to 25 March 2011)

Section 2 Analgesics, antipyretics, NSAIMs, DMARDs

2.4 Disease-modifying agents used in rheumatoid disorders

Author/ Pop’n Type of Number Subjects Duration of Groups/Intervention Outcomes measured Conclusion and

Author, Pop’n Type of Duration Number of Subjects Study groups Primary outcomes Conclusion and comments

Author Pop’n Type Duration Number Subjects Study groups Outcomes Conclusion and comments

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Author/ Type of Number Subjects Duration of Intervention Outcomes measured Conclusion and comments

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