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Juvenile idiopathic arthritis 

Juvenile idiopathic arthritis
Chapter:
Juvenile idiopathic arthritis
Author(s):

Brogan Foster

and Paul A. Brogan

DOI:
10.1093/med/9780198738756.003.0003
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date: 18 August 2019

Genetics and JIA: HLA and non-HLA/MHC associations with subtypes of JIA

Association studies in JIA

The association study is the standard methodology used in the search for genetic risk factors for JIA. There are a number of issues regarding study design that the clinician must be aware of, to understand and put into context the genetic findings to date for JIA (Fig. 3.1).

Genetic risk factors identified to date for JIA

Human leucocyte antigen (HLA)

The major histocompatibility complex (MHC) is the most consistently associated locus in JIA.

Multiple HLA class I and class II associations exist with JIA, with each ILAR subtype having a specific pattern of HLA associations, although it should be noted that there are also overlapping associations, particularly between oligoarthritis and RF−ve polyarthritis. HLA-DRB1*11 conferred the strongest risk in systemic JIA (sJIA).

Non-HLA/MHC loci

The candidate gene approach has previously been the main strategy used in the search for JIA susceptibility loci to date but large-scale mapping studies are now being performed. Most studies investigated association of regions known to be associated with other autoimmune diseases for association with JIA. Many regions show modest association but not all were replicated in independent cohorts. Only two non-HLA regions reached genome-wide significance (PTPN22 and PTPN2).

Some association studies performed in the past for JIA have suffered from inadequate sample sizes.

There have been three genome wide association study (GWAS) for JIA as a whole published to date. One identified the association of the VTCN1 (B7-Homolog 4 [B7-H4]) gene with JIA and was validated in an independent dataset. The second identified c3orf130/CD80 on chromosome 3 and IL15, and was validated in an independent dataset. The third identified CXCR4 on chromosome 2. None of these regions identified by GWAS reach genome-wide significance.

The largest study to date in JIA was published in 2013: a consortium of researchers brought together a sample size of 2816 cases with oligoarticular and RF-ve polyarticular JIA and 13,056 healthy controls. These were genotyped in a custom designed microarray, Immunochip. It confirmed 3 regions that have previously reached genome-wide significance threshold and identified 14 new loci, most notably a number of genes in the IL2 pathway. It also identified 11 regions at a suggestive significance threshold. These are highlighted in Table 3.1.

Table 3.1 Non-MHC regions reaching genome wide significant association with JIA and its subtypes

Gene Region

Chr

SNP

  • Best

  • p-value

Study population

Subtypes

Reference

Previous evidence for association

PTPN22

1

rs6679677

3.19 × 10–25

US, UK & Germany

O, RF-P

Hinks et al., 2013

Yes

STAT4

2

rs10174238

1.28 × 10–13

US, UK & Germany

O, RF-P

Hinks et al., 2013

Yes

PTPN2

18

rs2847293

1.44 × 10–12

US, UK & Germany

O, RF-P

Hinks et al., 2013

Yes

ANKRD55

5

rs71624119

4.40 × 10–11

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

IL2/IL21

4

rs1479924

6.24 × 10–11

US, UK & Germany

O, RF-P

Hinks et al., 2013

Yes

ANKRD30A

10

rs7100025

8.4 × 10–11

US, Aus, Nor

All JIA

Li et al., 2015

No

TYK2

19

rs34536443

1 × 10–10

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

IL2RA

10

rs7909519

8 × 10–10

US, UK & Germany

O, RF-P

Hinks et al., 2013

Yes

SH2B3/ATXN2

12

rs3184504

2.60 × 10–09

US, UK & Germany

O, RF-P

Hinks et al., 2013

Yes

ERAP2/LNPEP

5

rs27290

7.5 × 10–09

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

UBE2L3

22

rs2266959

6.2 x 10–09

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

C5orf56/IRF1

5

rs4705862

1.02 x 10–08

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

RUNX1

21

rs9979383

1.06 x 10–08

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

IL2RB

22

rs2284033

1.55 x 10–08

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

ATP8B2/IL6R

1

rs11265608

2.75 x 10–08

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

FAS

10

rs7069750

2.93 x 10–08

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

ZFP36L1

14

rs12434551

1.59 x 10–08

US, UK & Germany

O, RF-P

Hinks et al., 2013

No

Chr=chromosome. O=oligoarticular JIA, RF-P=RF negative polyarticular JIA. Aus=Australia, Nor=Norway

A recent investigation meta-analysis of paediatric onset autoimmune diseases, confirmed association with PTPN22, ANKRD55, IL2/IL21, and IL2RA in JIA and identified a novel locus for JIA, ANKRD30A. Large-scale GWAS and meta-analysis are still required in JIA to identify novel regions for the subtypes.

Subgroup-specific associations

There is an issue with association analysis by JIA subtype in that, for many JIA case cohorts, it results in small sample sizes that often are not sufficiently powered to detect the modest effects conferred by these complex disease genes. A few potential subtype specific effects are emerging:

Single nucleotide polymorphisms (SNPs) in the IL1 ligand cluster, IL1 receptor cluster and IL6 promoter show association with sJIA.

A SNP in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene, formerly known as ARTS1, which shows robust association with ankylosing spondylitis (AS) has been shown to be associated with the enthesitis-related arthritis subtype of JIA.

A SNP in the IL23 receptor gene shows association with the psoriatic arthritis subtype of JIA.

More recently a large GWAS for sJIA has been performed, which focused initially on the MHC, identified the strongest association with HLA-DRB1*11 and its defining amino acid residue glutamate at position 58.

What happens once a genetic effect has been identified?

Resequencing/fine-mapping

In most cases it is unlikely that the candidate gene study or GWAS will identify the actual causal variant, but they do detect SNPs which happen to be correlated with the causal variant.

In most situations it will be important to screen the whole region for all genetic variation, possibly by resequencing, and then fine-mapping the association by genotyping them in cases and controls (Box 3.1). This will identify all the possible causal variants.

Functional analysis

Once all the statistical analysis has been performed and the putative causal variants have been identified then the most likely functional SNPs can be identified using the multiple computational tools and online resources that are available. These give information from multiple independent experiments on what role the SNP may have biologically, for example, whether the SNP lies in regulatory regions of the genome, is an expression-trait locus (eQTL), lies in transcription factor binding site. This prioritizes SNPs for investigation and guides future functional experiments.

What can these genetic findings tell the clinician about JIA?

They will inform us of the important pathways involved in JIA disease pathogenesis. We are already seeing strong evidence to suggest a vital role for the IL-2 pathway in JIA and other autoimmune diseases. Once we know more about the biology of JIA, we may identify novel therapeutic targets.

Eventually they may help us predict disease risk. We are not at this stage yet as it is important to remember that for many of the loci identified to date the actual causative genetic variants have not yet been clearly defined.

Genetic susceptibility factors may be important in determining not only susceptibility to JIA but also to a child’s disease outcome. Prospective, long-term outcome studies, such as the CAPS (Childhood Arthritis Prospective Study) and Research in Arthritis in Canadian Children emphasizing Outcomes (ReACCh-Out) study, will be vital in exploring this hypothesis.

Conclusions

The last few years there has been great progress in the search for genetic risk factors for JIA, with many confirmed associations. Much larger sample sizes will need to be collected to enable more powerful analysis of the specific subtypes of JIA.

Further reading

Finkel TH, Li J, Wei Z, et al. Variants in CXCR4 associate with juvenile idiopathic arthritis susceptibility. BMC Med Genet 2016:17:24Find this resource:

Hinks A, Cobb J, Marion MC, et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet 2013;45(6):664–669.Find this resource:

Hinks A, Barton A, Shephard N, et al. Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysis. Arthritis Rheum 2009:60:258–63.Find this resource:

Li YR, Li J, Zhao SD, et al. Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases. Nat Med 2015;21:1018–27.Find this resource:

Moncrieffe H, Prahalad S, Thompson SD. Genetics of juvenile idiopathic arthritis: new tools bring new approaches. Curr Opin Rheumatol 2014;26:579–584.Find this resource:

Ombrello MJ, Remmers EF, Tachmazidou I, et al. HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. PNAS 2015: 112:15970–5.Find this resource:

Thompson SD, Marion MC, Sudman M, et al. Genome-wide association analysis of juvenile idiopathic arthritis identifies a new susceptibility locus at chromosomal region 3q13. Arthritis Rheum 2012;64:2781–91.Find this resource:

Aetiology of juvenile idiopathic arthritis

Pathogenesis

  • JIA is an autoimmune disorder; the immune system fails to distinguish between self and non-self and attacks synovium (membrane lining of the joint), leading to arthritis. Synovium becomes thickened, highly vascular and infiltrated with T cells, macrophages, dendritic cells, B cells, and NK cells, and secretes an inflammatory exudate (causing joint effusions).

  • Persistence of inflammation: cells are recruited into the joint by attaching to upregulated adhesion molecules on inflamed endothelium (inner layer of blood vessels). Resident fibroblasts (synoviocytes) and recruited immune cells secrete high levels of chemokines, which attract further inflammatory cells, and angiogenic factors (e.g. VEGF) causing highly vascular proliferation of synovium.

  • T cells are ↑ in synovium and synovial fluid and secrete several potent cytokines (see Table 3.2), leading to cartilage and bony damage. T cells secreting IL-17 (Th17 cells) are heavily implicated in psoriatic- and enthesitis-related arthritis. Remission in JIA is linked with high levels of synovial regulatory T cells (specialised T cells which counter inflammation).

  • B cells are ↓ in synovial fluid, but circulating B cells secrete cytokines and activate T cells. Specialized B cells, plasma cells, secrete auto-antibodies (rheumatoid factor (RF) and anti-cyclic citrullinated protein (CCP), and ANA) associated with specific disease sub-types but are not thought to be directly pathogenic.

  • sJIA has similar features with other auto-inflammatory disorders (see Juvenile idiopathic arthritis Chapter 4: autoinflammatory diseases, pp. [link][link]); high levels of IL-1β‎ and IL-6 cause systemic inflammatory features and growth retardation. Macrophage activation syndrome (MAS) in sJIA is associated with a defect in NK cell function, which prevents NK cells from killing activated lymphocytes and macrophages (see Chapter 4 on Macrophage activation syndrome, pp. [link][link]).

Table 3.2 Summary of cytokines and inflammatory mediators important in JIA

Cytokine/Mediator

Cell

Pathology

TNFα‎

Monocytes, T, B cells, PMN, mast cells, fibroblasts

  • Activates monocytes and neutrophils

  • Damages cartilage

  • ↑ Endothelial cell adhesion molecules

  • Inhibits regulatory T cells

IL-1β‎

Monocytes, fibroblasts

  • Activates osteoclasts (bone damage)

  • Fibroblast cytokine, chemokine release

  • ↑ Endothelial cell adhesion molecules

IL-17

T cells (Th17), mast cells

  • Chemokine release (recruit PMN)

  • Cartilage damage

  • Activates osteoclasts

  • Synergizes with TNFα‎ and IL-1β‎

IL-6

Monocytes, fibroblasts, B cells

  • B cell activation

  • Inhibits regulatory T cells

  • Growth retardation

  • Acute phase response and anaemia

IFNγ‎

T cells (Th1, CD8, NK cells)

  • Activates monocytes

  • ↑ Endothelial cell adhesion molecules

  • May assist recruitment of Th17 cells

  • Important in the pathogenesis of MAS

MRP8/14 (inflammatory mediator important in sJIA)

Monocytes, PMN

  • Activates monocytes,

  • Promotes pathological CD8+ T cells

  • Secretion of IL-1β‎

  • ↑ Endothelial cell adhesion molecules

Genetics

(see also Juvenile idiopathic arthritis genetics of JIA, pp. [link][link])

  • JIA is linked with several genetic polymorphisms (variations in the genetic code), but each only contributes a small risk of developing the disease.

  • Genes linked with JIA include:

    • Human Leukocyte Antigens (HLA, system of immune recognition, expressed on almost all cells): HLA-B27 is strongly associated with ERA; A*02 with oligoarthritis; and DRB1*11, DQB1 with rheumatoid factor (RF)–ve polyarthritis; DR4 with RF+ polyarthritis (as in adult RA).

    • Cytokine/chemokine-related genes: IL-10 with oligoarthritis; IL-6 with sJIA; and IL-23 receptor, CCL5, and TNFα‎ with psoriatic arthritis.

    • Immune-associated genes: PTPN22, TRAF1, STAT4, and CD25 are important in the control of T cell activation; mutations of MUNC13-4 and perforin in sJIA may be important in the development of MAS in select patients, but usually MAS in sJIA occurs without evidence of any monogenic cause.

Environment

  • Infection: There is no clear infectious trigger for JIA. DNA from several bacteria and viruses including parvovirus B19 have been detected in JIA serum and joints, but are of uncertain significance.

  • Family conditions: High parental income and being an only child are associated with JIA which relates to the hygiene hypothesis (lack of early childhood infection increases the risks of autoimmunity). Fetal exposure to smoking may increase the risk of JIA in girls.

Classification of JIA

Background

Historically, nomenclature and criteria had developed independently in Europe and North America. This hampered research and did not allow comparisons between publications. To address this, a Classification Taskforce of the Paediatric Standing Committee of International League of Associations for Rheumatology (ILAR) developed consensus criteria under an umbrella term Juvenile Idiopathic Arthritis (JIA).

The primary aim of the ILAR proposals for classification JIA was to delineate, for research purposes, relatively homogeneous, mutually exclusive categories of idiopathic childhood arthritis based on predominant clinical and laboratory features.

It is anticipated that the proposed classification will undergo further revision in order to correct anomalies, and in response to new information. Classification subtypes were last updated in 2001.

General definition of JIA

Juvenile idiopathic arthritis is arthritis of unknown aetiology that begins before the 16th birthday and persists for at least 6 weeks; other known conditions are excluded.

JIA subtypes

Seven subtypes of JIA are recognized in the current classification system. These are summarized in Table 3.3. Each subtype requires the presence of certain features (inclusion criteria) and the absence of others (exclusion criteria) during the first 6 months of the condition.

Table 3.3 Summary of ILAR classification of JIA

JIA subtype

Features

Exclusions

Systemic onset

Arthritis > 1 joint, with/preceded by fever (daily fever > 3 days) of at least 2 weeks’ duration + > 1 of:

A,B,C,D

Non-fixed erythematous rash; Generalized lymphadenopathy; Hepatomegaly +/or splenomegaly; Serositis

Oligoarthritis

Arthritis 1–4 joints in 1st 6 months. Subcategories:

A,B,C,D,E

Persistent: persists, 1–4 joints ; Extended: > 4 joints after 1st6 months

Polyarthritis RFve

Arthritis ≥ 5 joints during 1st 6 months; RF negative.

A,B,C,D,E

Polyarthritis RF+ve

Arthritis ≥ 5 joints during 1st 6 months of disease

A,B,C,E

>2 RF +,>3 months apart during 1st6 months of disease

Psoriatic arthritis

Arthritis and psoriasis, or arthritis + > 2:

B,C,D,E

Dactylitis; nail pitting / onycholysis; Psoriasis in 1st- degree relative

Enthesitis related arthritis

Arthritis and enthesitis, or arthritis / enthesitis + > 2:

A,D,E

Sacroiliac joint tenderness +/or inflammatory lumbosacral pain, currently or historically; HLA-B27 antigen; Onset in a male > 6 years old; Acute symptomatic anterior uveitis; Family history (1stdegree relative) of any of the following: Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, acute anterior uveitis

Undifferentiated arthritis

Arthritis that fulfils criteria in no category or > 2 categories

Exclusion criteria:

  1. A. Psoriasis or a history of psoriasis in the patient or first degree relative.

  2. B. Arthritis in an HLA-B27 positive male beginning after the 6th birthday.

  3. C. Ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis, or a history of one of these disorders in a first-degree relative.

  4. D. The presence of IgM rheumatoid factor on at least 2 occasions at least 3 months apart.

  5. E. The presence of systemic JIA in the patient. The application of exclusions is indicated under each category, and may change as new data become available.

Further reading

Petty, R.E. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390–2.Find this resource:

JIA subtypes and their clinical presentations

  • JIA is the most common form of chronic inflammatory joint disease in children and adolescents. It is defined as persistent joint inflammation (of >6 weeks duration) with onset before 16 yrs of age in the absence of infection or any other defined cause.

    • 95% of children with JIA have a disease that is clinically and immunogenetically distinct from RA in adults.

    • Newly presenting JIA is one of the commonest physically disabling conditions of childhood, with a prevalence of approximately 1 in 1000 children, (i.e. the same as diabetes or epilepsy) and amounting to over 12,000 affected children in the UK.

    • JIA is a heterogeneous group of conditions and clinical presentation varies with the disease subtype (Table 3.4).There are at least 7 different subtypes of JIA. The classification is essentially clinical and based on the number of joints affected in the first 6 months, the presence or absence of RF, HLA B27 tissue type, systemic features (such as fever or rash), and other extra-articular features (such as psoriasis or enthesitis).

    • Uveitis is an important complication of JIA and affects at least 1/3 of children; the highest risk is young children, females and those that carry antinuclear factor (see Juvenile idiopathic arthritis Uveitis screening pp. [link][link]).

  • JIA is essentially a clinical diagnosis and one of exclusion with a wide differential diagnosis (see Juvenile idiopathic arthritis Clinical skills p. [link]):

    • Classically a joint affected by arthritis is swollen and painful with some restriction of movement. In the younger child, however, a history of pain is often absent. Parents may describe a child who refuses to stand or has a limp first thing in the morning but runs about normally later in the day. In the youngest children, JIA may present as delay in walking or regression of achieved motor milestones (see Juvenile idiopathic arthritis Clinical skills p1). Examination may be limited by lack of cooperation and findings may be subtle. It is important to examine all joints even if symptoms are not volunteered and a pGALS assessment is needed as a minimum (see Juvenile idiopathic arthritis Clinical skills p. [link]). Joint involvement may include joints that are hard to assess clinically (e.g. temporomandibular joints, subtalar joints, hips) and imaging may be required; preferably by US or MRI (with gadolinium) as radiographs are often normal.

    • In the young child, joint involvement is usually asymmetrical and subtle loss of range of movement may be detected in comparison with the normal side.

    • Infection and malignancy are not uncommon and require careful consideration.

    • Consider septic arthritis in an unwell child with a single hot, swollen, painful joint (see Juvenile idiopathic arthritis pp. [link][link]).

    • Consider malignancy in child with severe joint pain, especially at night (see Juvenile idiopathic arthritis pp. [link][link]).

    • Consider haematological malignancy in a child presenting with suspected systemic JIA but with low white count and/or platelets and/or low ferritin (see Juvenile idiopathic arthritis pp. [link][link]).

    • Acute rheumatic fever and Lyme disease are both increasingly seen in the UK and should be remembered in the differential diagnosis (see Juvenile idiopathic arthritis pp. [link][link] and pp. [link][link] respectively).

Table 3.4 Summary of ILAR classification of JIA

Subtype

Systemic onset

Oligoarthritis

Polyarthritis RF–ve

Polyarthritis RF +ve

Psoriatic arthritis

Enthesitis-related arthritis

Other

Arthritis

In 1 or more joints with or preceded by daily (quotidian) fever for at least 3 days, accompanied by ≥1 of:

  • Evanescent erythematous rash

  • Generalized lymphadenopathy

  • Hepatomegaly and/or splenomegaly

  • Serositis

In 1–4 joints during first 6 months of disease

Subcategories:

  • Persistent—affecting no more than 4 joints throughout course

  • Extended—affecting a total of >4 joints after the first 6 months of disease

  • In 5 or more joints during the first 6 months of disease

  • RF test negative

  • In 5 or more joints during the first 6 months of disease

  • RF test positive

Arthritis and psoriasis, or arthritis and at least 2 of

  • Dactylitis

  • Nail pitting or onycholysis

  • Psoriasis in 1st-degree relative

Arthritis and enthesitis or arthritis with at least 2 of the following

  • Presence or history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain

  • Presence of HLA B27 antigen

  • Onset in ♂ >6yr

  • Acute anterior uveitis

  • Ankylosing spondylitis, enthesitis-related arthritis

  • Sacroiliitis with inflammatory bowel disease

  • Reiter syndrome

  • Acute uveitis in 1st-degree relative

Undifferentiated with no category or 2 or more categories

Exclusions

A,B,C,D

A,B,C,D,E

A,B,C,D,E

A,B,C,E

B,C,D,E

A,D,E

A: psoriasis or history of psoriasis in patient or 1st-degree relative, B: arthritis in HLAB27-positive male after 6th birthday, C: ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter syndrome or acute uveitis, or history of 1 of these in 1st-degree relative. D: presence of IgM RF on at least 2 occasions at least 3 months apart, E: the presence of systemic JIA.

Prognostic indicators in JIA

Despite the recent intensification of early treatment regimes for children with new-onset JIA, and the associated expectation of improved clinical outcomes, it remains difficult to predict the prognosis for an individual child. This is a huge challenge for children and their families.

Outcomes

An ideal outcome for a child or young person with JIA would be lifelong disease remission with no long-term functional or psychological effects. Suboptimal outcomes may result from:

  • Poorly controlled joint disease with resultant joint damage.

  • Visual loss from JIA-associated uveitis.

  • Psychosocial morbidity.

  • Delay in diagnosis and starting treatment.

The existing literature on long-term outcomes highlights a poor functional outcome for many young people with JIA. However, these studies reflect historical treatment regimens rather than current best practice. Evidence predicting outcomes from current therapeutic approaches is limited to anecdote and awaits validation from ongoing long-term outcome studies, e.g. the Childhood Arthritis Prospective Study (CAPS, UK) and Research in Arthritis in Canadian Children Emphasizing Outcomes Study (ReACCH-Out, Canada).

Prognosis

In predicting the prognosis for a child with JIA, two main factors require consideration:

  • Heterogeneity in the disease and its response to treatment.

  • Variability in access to optimal clinical care.

Disease heterogeneity

Indicators of poor outcome related to the disease itself are summarized in Table 3.5 and have traditionally been divided into:

  • Risk factors for continuing active disease.

  • Risk factors for long-term damage.

  • It should be noted that continuing active disease of any disease subtype can lead to long-term damage, and therefore division of indictors of poor outcome in this way may be obsolete.

Table 3.5 JIA subtypes and risk factors for poor disease outcomes

Risk factors for:

Continuing active disease

Long-term damage

Subtype of JIA

Psoriatic

  • Polyarticular onset: both onset and disease course (e.g. extended oligoarticular disease)

  • sJIA: ongoing active systemic features at 6 months defined as fever, need for corticosteroids, and thrombocytosis

Age

Young age in oligoarticular and RF−ve polyarticular

Blood markers

  • RF+ve

  • ANA+ve (↑ risk of uveitis)

  • Persistently raised platelet count in sJIA

  • RF+ve

  • Normal inflammatory markers with late diagnosis

Clinical features

  • Subcutaneous nodules

  • Late presentation

  • High CHAQ at presentation

  • Poor response to treatment at 4 months

  • Symmetrical joint disease

  • Hip or ankle involvement

  • Rapid & early involvement of small joints of hand and feet

  • Early radiographic changes

  • Presentation with uveitis as 1st symptom; or visual loss at 1st eye screen

Access to care

For any child with JIA, regardless of the disease subtype and features, there is increasing consensus that access to appropriate care is an important determinant of outcome. The British Society of Paediatric and Adolescent Rheumatology (BSPAR) Standards of Care for children and young people with JIA (see Juvenile idiopathic arthritis BSPAR, pp. [link][link]) emphasize the importance of:

  • Prompt diagnosis and referral to specialist care.1

  • Early aggressive treatment to control inflammation.

  • Support from a paediatric rheumatology MDT.

Success in achieving a good outcome mandates that the management must remain patient-centred, maximizing both physical and psychosocial wellbeing. Optimal disease control may require challenging drug regimens and compliance may be an issue during adolescence. The support of the MDT is essential for all children, young people and their families. It may be particularly important for lower socioeconomic groups where increased problems with daily activities and lower perception of disease consequences have been reported.

Adverse prognostic factors

Adverse prognostic factors for any child with JIA therefore include:

  • Delay in diagnosis.

  • Delay in referral to specialist team.

  • Late disease control.

  • Continued disease activity.

Future advances

Paediatric rheumatology is a rapidly changing specialty. In the near future improvements in our ability to predict prognosis for a child with JIA will likely result from further advances in our understanding of:

  • Genetic and molecular mechanisms involved in the immunological and inflammatory processes.

  • Genetic predictors of response to drugs.

  • Detection of subclinical disease with imaging.

  • Availability of new targeted therapeutic approaches.

Myeloid related proteins 8 and 14 (MRP 8/14) are calcium-binding proteins secreted by infiltrating phagocytes in inflamed synovium. MRP 8/14 may be a useful indicator in JIA, aiding prognostication, monitoring of treatment efficacy, and risk stratification for disease relapse on therapy cessation. Future targeted treatment trials will help to establish the role of MRP 8/14 as a prognostic indicator in children with JIA.

Uveitis screening in JIA: the approach to screening and guidelines

Rationale for screening

  • JIA is associated with a significant risk of developing asymptomatic chronic anterior uveitis (CAU).

  • JIA CAU is the leading cause of visual loss from childhood uveitis, and is associated with a high level of eye complications.

  • Early regular eye-screening is a key component in the care of JIA patients because it aims to reduce the incidence of visual impairment by early detection and intervention.

Justification for a screening programme

  • Provision of expensive screening is justified because it fulfils many, but not all, of the criteria for an effective screening programme, principally:

    • Slit lamp examination is a safe, effective screening test identifying CAU earlier in the disease course than children can themselves identify the subtle eye symptoms.

    • The incidence of CAU is high, affecting 10% of all JIA patients; the highest-risk subgroup of JIA, extended oligoarthritis, has an incidence of 35–57%.

    • 40% of CAU is present at the first eye screen.

    • The duration of persistent inflammation in the eye is a key poor prognostic factor which can be reduced by screening.

  • The outcome of JIA CAU remains poor despite screening, indicated by the following:

    • Bilateral disease in 67–85%; significant eye complications in >40% of cases—cataract, glaucoma, macular oedema, hypotony.

    • Early treatment is a key aim to improve outcomes. There is increasingly effective treatment for CAU available.

Population requiring screening

  • Screening should equally be offered to children with JIA (all subgroups), whether they have few or many affected joints, and despite some variation in risk.

    • Evidence of significant risk to warrant screening exists for persistent and extended oligoarthritis, RF−ve polyarthritis, psoriatic arthritis, and also undifferentiated arthritis.

  • Performing the first screen as early as possible is a key aim and in reality eye screening is often performed before the diagnosis of JIA is absolutely clear (e.g. in cases which are ultimately are diagnosed as reactive arthritis). Screening should be performed before the subgroup of JIA is confirmed as the classification evolves over time.

  • Uveitis is more common in the following:

    • Girls, younger age patients.

    • JIA patients who are ANA+ve (albeit of patients with uveitis, 50% are ANA−ve)—therefore children with JIA and who are ANA−ve also need eye screening).

    • Severe uveitis is associated with younger age and male sex.

  • Enthesitis-related arthritis (ERA) is usually associated with acute anterior uveitis (and often patients carry HLA B27) which presents promptly with a painful red eye. However, reports of asymptomatic CAU in ERA, leads to its inclusion in some screening programmes.

Exclusions to screening

  • Two subgroups of JIA are not associated with a high level of CAU, and are not offered screening in all programmes. A single eye screen at presentation of JIA is recommended, particularly where the diagnosis is unclear.

    • RF+ve polyarticular JIA (RF+JIA) is not associated with CAU, and as disease onset is usually in later adolescence may not be considered for screening in some programmes.

    • A small number of case reports exist of CAU in sJIA. Other conditions that could mimic sJIA, such as CINCA (amongst many others), do develop CAU, which raises a question about the diagnosis in these older case reports. As a rule of thumb developing CAU in sJIA should lead to the question: ‘Is this really sJIA?’.

Structure of the screening programme

  • The core principles of the screening programmes are listed in Table 3.6.

  • Variations in screening programmes between countries often relate to the lack of a clear evidence base to address these statements. Important points to consider are the following:

  • Those providing eye screening should be appropriately trained, skilled at examining young children, and should audit the robustness of their screening programme.

  • Most uveitis develops early in the disease course:

    • The first eye screen is critical, and should be made immediately after the diagnosis of JIA, or before certain diagnosis if JIA is likely.

    • Screening in the first and early years should be adhered to robustly.

    • Robust mechanisms to identify non-adherence to the screening programme are important.

  • Immediate access to advice and assessment should be offered should eye symptoms develop between screening visits or after discharge from the screening programme.

  • A revised screening schedule should be offered if the risk of uveitis increases, such as discontinuation of maintenance drugs (e.g. patients on biologics who stop taking methotrexate—anecdotally there are reports of de novo uveitis or flares occurring with etanercept use—see Juvenile idiopathic arthritis pp. [link][link]).

  • Children with JIA who are too young or otherwise unable (e.g. learning difficulties) to recognize subtle changes in their vision associated with the development of CAU must be offered eye screening.

    • Rapid access to an examination under anaesthetic (EUA) should be available for all children unable to comply with screening examinations. The children least likely to comply are at the highest risk for undetected disease, i.e. the youngest or those with learning disability.

  • Once considered high enough risk to merit inclusion in the screening programme, the screening interval offered should not be related to the risk of developing uveitis, but to the natural history of uveitis should it develop.

    • The screening intervals should be short enough so that should uveitis develop, no irreversible damage occurs between screening visits.

    • There is a poor evidence base for determining the screening interval.

  • Eye screening continues until the child is old enough to detect the symptoms of uveitis and this is usually considered 12yrs of age as a minimum.

    • Whilst the risk of developing uveitis falls with time from the date of last active arthritis, date of diagnosis, and with increasing age, children discharged from screening are still at risk of uveitis, and are discharged because they are considered old enough to identify subtle changes in their vision. In children with learning difficulties screening may be required for longer until the risk is low.

Table 3.6 Comparison of screening programmes between different countries

Core principle

Current UK guidance*

Current USA guidance

German variation on USA guidance

Rapid first eye screen

Within 6 weeks of referral to eye clinic

Within 1 month of diagnosis of arthritis

None given

Minimizing delay of symptom onset of JIA to diagnosis of JIA

Seen within 10 weeks of onset of symptoms and 4 weeks of the referral

Not discussed

Screening intervals

2-monthly for the first 6 months, then 3–4-monthly

3–12-monthly depending on risk category. No discussion of psoriatic arthritis at all

3–12-monthly depending on risk category. Recognizes psoriatic as important risk factor in addition to oligoarthritis and RF−ve JIA

Access to examination under anaesthetic as appropriate

‘Urgent’ if deemed high risk—no timescale given

Not discussed

Access if symptomatic

Within 1 week

Urgent access, no time interval given

Not discussed

Altered screening with altered risk

Return to 1st-year screening intervals on discontinuation of methotrexate

Complex algorithm dependent on age, ANA status, and disease duration

Adherence to screening

Priority to rebook (no time given)

Not discussed

Ages included, and duration of screening

Complex detail, summarized as until 12th birthday

Continue with 12-monthly screening throughout adolescence

Continue with 12-monthly screening throughout adolescence

Exclusions from screening

RF+ve JIA and sJIA offered baseline screen only

Uses 1986 classification, and screens only sJIA, oligoarthritis, and polyarthritis

None, RF positive JIA, ERA and sJIA offered 12-monthly screening

* Current UK guidance is based on the following: The Royal College of Ophthalmologists 2006 guidelines for screening for uveitis in juvenile idiopathic arthritis. Produced jointly by BSPAR and the RCPOphth (2006) available at Juvenile idiopathic arthritis http://www.rcophth.ac.uk/docs/publications.

Note: current screening programmes are not fully evidence-based because of lack of adequate study in large enough numbers of patients. There is little or no evidence to support different screening regimens between subgroups of JIA, nor to determine the best screening interval. This lack of evidence leads to some debate about the validity of the use of the term screening, suggest surveillance as a better term, and also discussion about the validity of guidelines which are not fully evidence-based. Nonetheless screening is performed in many countries with consensus that it is effective and worthwhile.

BSPAR Standards of Care 2010. BSPAR Standards of Care for JIA. Juvenile idiopathic arthritis http://www.bspar.org.uk/downloads/clinical_guidelines/Standards_of_Care.pdf.

Details of the screening assessment

  • Screening involves slit lamp examination of anterior, intermediate, and posterior chambers of the eye:

    • A slit lamp examination by a skilled operator is required, i.e. ophthalmologist (or optometrist) skilled and experienced at examining children’s eyes.

    • Examination by ophthalmoscope alone is not able to detect the presence of uveitis.

  • Anterior uveitis is by far the commonest presentation, but the other chambers are also affected.

  • Macular involvement, whilst rare, is associated with a poor prognosis and is particularly important to detect.

  • Some screening programmes also check visual acuity, and proceed to intraocular pressure measurements as indicated.

Further reading

Cassidy J, Kivlin L, Lindsley C, et al. Ophthalmological examination in children with juvenile rheumatoid arthritis Pediatrics 2006;117:1843–5.Find this resource:

Heiligenhaus A, Niewerth M, Ganser G, et al., and the German Uveitis in Childhood Study Group. Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines Rheumatology 2007; 46:1015–19.Find this resource:

JIA in the young adult

Background

A significant percentage of patients with JIA will continue with active disease into adulthood. Young adulthood (age group 16–25 years) is a time of profound personal change and development during which patients with JIA have specific needs which must be addressed in order to optimize their care and subsequent long-term health outcomes. The transition from adolescent to adult care can present challenges for the patient, their family and healthcare professionals–recognizing this and tailoring care appropriately offers the best chance of a healthy present and future.

What makes the young adult (YA) different?

Many new experiences and responsibilities are presented to the YA, often at a time of social upheaval. Life events may include moving out of the parental home, starting work or higher education, the desire for independence from their parents, and introduction of new sexual relationships. The YA may start to engage in behaviours such as substance use (legal and illegal).

Physiologically, middle adolescence (ages 14–17) is a period when there is a rapid increase in dopaminergic activity and so an increase in behaviours such as reward-seeking and risky behaviour where concerns about ‘the here and now’ predominate, (Steinberg, 2010). This is in contra-distinction to the maturation of the pre-frontal cortex, responsible for executive functions such as planning, abstract thought, problem-solving ability, and impulse control/delay of gratification, which is much slower and may not fully mature until the third decade of life. The YA with JIA may lack the executive functions and therefore skills required to manage their disease optimally. In adult services, such patients may be expected to start to attend appointments alone, take responsibility for their medications and drug monitoring, be encouraged to self-manage and take the initiative to report problems themselves and participate in decision-making with regards to treatment. These are skills which may not have been fully developed yet. In this context, it is perhaps not surprising that a high rate of unsuccessful transfer from paediatric to adult rheumatology care can occur. (Hazel et al., 2010). The YA Rheumatology team must tailor their services and the way in which they interact with the YA to engage patients successfully with healthcare and foster their skills and resilience to self-manage disease.

Specific areas to consider

General issues

  • Developmental stage: as part of an effective patient–professional relationship, assessment should be made of the ability of a YA to use executive functions in their interactions. This capability may vary from attendance to attendance but will shape the way information is presented and discussed.

  • Communication skills: some YA patients may not respond to reasoning about the health of their joints in 10-years time (remember: ‘the here and now’) but may respond better to arguments about what the treatment can provide for them in the immediate/short-term. Non-judgmental, honest, and jargon-free communication should be a cornerstone of the YA consultation and staff need specific training to develop such skills.

  • Knowledge: assess your patient’s knowledge of their disease and its management and fill in knowledge gaps. Provide information in paper and electronic form.

  • Confidentiality: should be discussed with the patient (and if necessary, explained to parents).

  • Developing self-advocacy: patients may begin to attend appointments alone. This should be supported but not forced upon the YA before they are ready. On the other hand, some parents/guardians as well as patients themselves may experience difficulty adjusting to this concept. A relationship of trust between the patient, physician, and parents/guardians is key in enabling the gradual shift towards the YA taking the primary role in consultations. The timing of this transition will vary between patients. The YA may also require guidance on developing skills to access rheumatology services independently (use of multimedia/technological resources may aid this) and to be their own advocate (Fig. 3.2).

  • Taking the lead in decision-making: use an individualized approach—some YAs may need more guidance than others when it comes to making decisions about their own treatment.

  • Attendance: Non-attendance is a common occurrence—reasons for non-attendance should be explored via a telephone consultation at the earliest opportunity—this will also enable you to make an, albeit limited, disease assessment, ‘troubleshoot’ and plan future care.

  • Adherence: barriers to adherence include busy social circumstances, long-distance travel, unwillingness to appear different to their peers, and (in the case of methotrexate [MTX]) alcohol use, as well as the usual problems of adverse side-effects. Needle phobia as well as MTX intolerance is common in this population and must be specifically addressed.


Fig. 3.2 Ideal structure of Rheumatology Services from childhood, through adolescence and into young adulthood and beyond.

Fig. 3.2 Ideal structure of Rheumatology Services from childhood, through adolescence and into young adulthood and beyond.

Medical issues

  • Medication

    • Patients may wish to consider a change from subcutaneous to oral MTX if they have not done so already.

    • Patients may wish to start self-injecting MTX/biologics, taking over this role from their parents or guardians.

    • Physicians should continue to use triamcinolone hexacetonide for intra-articular injections.

  • Osteoporosis: a risk assessment should be performed, risk factors addressed and vitamin D supplementation considered.

  • Recognizing adults with JIA as a separate disease group: disease phenotypes and treatments differ from adult disease. Re-labelling some sub-types of JIA as ‘rheumatoid arthritis’ or ‘ankylosing spondylitis’ may lead to patients being lost to follow-up in registry studies of biologics in JIA which contributes to the relative lack of knowledge of JIA in adulthood.

  • Reproductive health: an open, non-judgmental dialogue about sexual activity and contraception should be encouraged. Information about how to seek advice on contraception and safe sex should be provided. Patients on MTX should be reminded at regular intervals about teratogenicity.

Psychological issues:

  • Depression and anxiety: in a cohort study of 246 adults with JIA who had long-term follow-up, 31.6% were anxious, 5.2% were depressed, and 21.1% had previously suffered from depression (Packham et al., 2002). Chronic disease is a risk factor for depression and anxiety—physicians should enquire sensitively about these issues in the consultation—YA may not initiate discussions.

Social issues:

  • Further education and work: discussion about career aspirations and future work planning should be encouraged. The YA may seek advice on the impact of their arthritis on these issues.

  • Smoking, illicit drug use and alcohol: sensitive, non-judgmental enquiry is necessary. The impact on their specific disease as well as general health, in the immediate and long-term should be discussed. Excess alcohol is discouraged in the context of MTX and if the patient is unlikely to adhere to treatment for this reason, it may be worthwhile considering an alternative.

  • Clinics held in appropriate environments (i.e. dedicated Young Person’s Clinic space).

  • Clinics held at convenient times for the patient: consider evening clinics or weekend clinics to optimize chances of attendance.

  • Telephone consultations.

  • Accessibility: email/telephone/SMS contact and a service website/app.

  • Higher tolerance of non-attendance and clear plans for chasing non-attenders.

  • Built-in psychosocial assessment: consider using the HEADS approach: Home, Education/Employment, Activities outside school and home, Drugs, Sexual Health, Stress/suicidal intent/safety from violence and injury.

  • Individualize the consultation (concrete versus abstract) when it comes to communication and shared decision-making.

  • Encourage self-advocacy and self-management when developmentally appropriate.

Further reading

Steinberg, L A behavioural scientist looks at the science of adolescent brain development. Brain Cognit 2010;72:160–4.Find this resource:

Hazel, E et al (2010): High rates of unsuccessful transfer to adult care amongst young adults with juvenile idiopathic arthritis. Paediatr Rheumatol online 2010;11;8:2. doi: 10.1186/1546-0096-8-2.Find this resource:

Packham, JC et al Long-term follow-up of 246 adults with juvenile idiopathic arthritis: predictive factors for mood and pain. Rheumatology 2002;41(12):1444–9. doi: 10.1093/rheumatology/41.12.14Find this resource:

Transition from children’s to adults services for young people using health or social services NICE guidelines NG43Juvenile idiopathic arthritis http://www.nice.org.uk/guidance/ng43

Surgery in the young adult with JIA: practical issues

Introduction

  • Surgery has an important but diminishing part in the overall management of JIA.

  • Many young adults with JIA in their 20s will have limited physical function and continued disease activity. It should be remembered that current published outcome studies are retrospective and often pre-date the effects of newer treatments such as biologic drugs in combination with MTX. Better treatment has meant that growth has been completed with epiphyseal closure before joints fail and bone density has reached the adult peak.

  • Since the advent of these effective drugs, many centres have seen a reduction in need for certain types of surgery such as synovectomy and soft tissue release (tenotomies and capsulotomies), and delay in others such as joint replacement.

  • In most centres, surgery for joint failure now occurs into young adulthood, rather than in adolescence when maturation is incomplete.

  • There is currently a cohort of young adult patients who have received biologic drugs in their later years after a period of sustained disease activity and who present new problems for those providing services for people with arthritis. It is hoped that newer cohorts of patients who have had optimal control throughout their disease course will need less surgical intervention.

  • It is important that the orthopaedic surgeon has skills in this age group and JIA.

  • Combined management with a rheumatologist and surgeon is important and should ideally be in a dedicated setting.

Orthopaedic surgery in the young adult

  • There is now many years’ experience in young people in arthroplasty of the hip, knee, ankle, shoulder, elbow, and wrist. Cervical surgery and arthrodesis of various joints may still be considered.

  • The highest requirement for surgery is in RF+ve polyarticular JIA. Other patterns requiring surgery include systemic JIA with polyarticular course, RF−ve polyarticular disease, and extended oligoarticular arthritis, particularly if disease has been active for many years.

  • The best results are obtained in fully controlled disease with joints in a good position. If >1 joint needs surgery, the proximal one should be first, and lower limbs should precede upper limbs.

  • Intra-articular steroid may reduce synovial activity and fixed flexion deformity although should not be used within 3 months of surgery. Soft tissue release to obtain a good position is equally rarely necessary. Hydrotherapy may be needed to maintain muscle strength.

  • There is still a place for synovectomy (usually arthroscopic) if disease remains uncontrolled despite drug treatment.

  • Many orthopaedic surgeons are reluctant to operate on young people. However, hip and knee arthroplasty are now the commonest operations in this group with achievement of good 10-yr survival in specialist centres.

The key symptoms requiring surgery are:

  • Pain despite control of the other joints with active therapy.

  • Reducing exercise tolerance (walking distance in the legs or pain on movement in the arms.

  • Night pain or pain at rest.

  • Increasing disability and instability (locking or giving way of lower limb joints).

The threshold should be considerably above the level of immobility where the person has to regularly use a wheelchair.

Precautions with surgery in adults with JIA

  • Cervical spine: x-rays should be performed prior to surgery; if necessary this should be followed with MRI. PA and lateral views in flexion and extension should be obtained to assess for:

    • Atlanto-axial subluxation (see Fig. 3.3).

    • Cervical spondylolisthesis (slip of one vertebra on another which can be multiple).

    • Cervical fusion with limited range of movement of movement at one level.

  • Temporomandibular joint disease: micrognathia and abnormal/restricted jaw opening may cause intubation difficulty.

  • Occasionally there may have been previous intubation difficulty due to a small larynx or cricoarytenoid arthritis.


Fig. 3.3 Lateral X rays in flexion, neutral and extension position of 17-year-old man with a 2-yr history sero+ve polyarticular JIA on MTX and biologic drugs taken prior to hip surgery. The flexion view shows significant atlanto-axial subluxation of 6.0mm not visible in the neutral or extension views. MRI examination did not show significant cord compression. There were no neck symptoms.

Fig. 3.3 Lateral X rays in flexion, neutral and extension position of 17-year-old man with a 2-yr history sero+ve polyarticular JIA on MTX and biologic drugs taken prior to hip surgery. The flexion view shows significant atlanto-axial subluxation of 6.0mm not visible in the neutral or extension views. MRI examination did not show significant cord compression. There were no neck symptoms.

Medications:

  • MTX should not be stopped prior to surgery. Infection rates after replacement surgery are less if the drug is continued. Patients who have had MTX as a DMARD have a significantly better prosthesis survival.

  • It is better to be immunosuppressed and have controlled disease than have no immunosuppression and uncontrolled disease.

  • Biologics—the current advice is to stop anti-TNF therapy in the peri-operative period—the half-life of etanercept is 100h, adalimumab 15–19 days, infliximab 8–9.5 days, tocilizumab 11-13 days (subcutaneous 5–12 days), and abatacept 13 days.

    • A practical rule is to omit the biologic drug for 14 days before and 14 days after surgery for etanercept, adalimumab, infliximab, tocilizumab, and abatacept, providing the wound is healed and not infected. There is, however, a variation in advice with some studies recommending a 4-week interval for infliximab and tocilizumab. Ideally the timing of surgery should allow for the minimum period without the drug. The American College of Rheumatology recommends that the minimum interval is a week before and a week after surgery.

    • There is a balance between successful wound healing and reduction of infection by stopping anti-TNF therapy or other biologic therapy versus perioperative risk of disease flare.

    • There is some evidence that anti-TNF therapy has a higher incidence of infection and deep vein thrombosis in patients with RA undergoing surgery but the numbers studied were small.

Other considerations

  • Small stature—patients should be assessed against standard growth charts and consideration given to a need for greater anaesthetic care for small airways. Special surgical prostheses may be required (small standard prosthesis or a custom-made prosthesis).

  • Osteoporosis—bone densitometry is recommended prior to surgery with higher risk in those patients with long disease duration or previous high steroid requirement.

  • Down’s syndrome—higher risk of atlanto-axial subluxation and also an increased sensitivity to marrow suppression from immunosuppressant and other drugs.

  • Corticosteroid usage—steroid dosage may need to be adjusted over the perioperative period depending on the length and dosage of steroid use in the preceding months and years.

  • Preoperative assessment—blood counts and liver and renal chemistry should be performed prior to surgery, particularly if the patient is on disease-modifying therapy. Patients with systemic disease may need cardiac assessment with ECG and echocardiogram. Thrombosis risk should be assessed.

  • Amyloidosis—it is important not to dehydrate young people with amyloidosis with renal impairment undergoing surgery. An IV line will be needed prior to surgery to maintain hydration.

Perioperative care

  • Anaesthetists should be experienced in treating young people with JIA. They should be aware of potential intubation difficulties and the need for nasal intubation using a fibreoptic laryngoscope.

  • Pressure-reducing measures may be required to avoid skin ischaemia in vulnerable patients.

  • Early mobilization is important and hydrotherapy should be considered once the skin wounds have healed.

  • Preoperative physiotherapy assessments should alert the need for temporary or permanent aids and adaptations.

  • Written antibiotic advice needs to be given for future surgical and dental procedures.

Advice concerning pregnancy

Young women who have had arthroplasty are often unaware of issues related to pregnancy. All young people should be under consultant care. The physician and obstetrician will need to assess:

  • Pelvic size.

  • Stability of any hip or other joint prosthesis.

  • Neck issues as outlined on Juvenile idiopathic arthritis pp. [link][link].

  • Drug therapy in pregnancy and risk of postpartum disease flares.

  • Physical issues around breastfeeding and child care.

  • Timing of reintroduction of drug therapy in relation to delivery and breastfeeding.

Even if the mother has not had an arthroplasty, long labour should be avoided and the mother should be aware of the potential need for assisted delivery and Caesarean section.

Drugs in pregnancy, breastfeeding and paternal exposure

The reader is referred to the guideline reference below for detailed advice.

  • Prednisolone is compatible with each trimester of pregnancy, breastfeeding, and paternal exposure.

  • MTX should be avoided in pregnancy and stopped 3 months in advance of conception. It is not recommended with breastfeeding. Based on limited evidence it may be compatible with paternal exposure.

  • Anti TNF drugs. Infliximab may be continued until 16 weeks. Etanercept, adalimumab may be continued until the end of the second trimester. Women should not be discouraged from breastfeeding on anti-TNF but caution is recommended pending further information. Infliximab, etanercept, and adalimumab are compatible with paternal exposure.

  • Tocilizumab should be stopped at least 3 months prior to conception but unintentional exposure early in the first trimester is unlikely to be harmful. There is no data for breastfeeding. While there is no data regarding paternal exposure, it is unlikely to be harmful.

  • Abatacept. There is insufficient data to recommend this drug in pregnancy, breastfeeding, or paternal exposure. Unintentional exposure in the first trimester is unlikely to be harmful. Paternal exposure is unlikely to be harmful

Further reading

Ding T, Ledingham J, Luqmani R, et al. BSR and BHPR rheumatoid arthritis guidelines on the safety on anti-TNF therapies. London: BSR, 2010. Available at: http://www.rheumatology.org.uk/includes/documents/cm_docs/2010/d/draft_anti_tnf_safety_guideline_april_2010.pdf. (due for revision 2016)Find this resource:

Flint J, Panchal S, Hurrell A, van den Venne, M et al. BSR and BHPR Guideline on prescribing drugs in pregnancy and breast feeding. Part I: standard and biologic disease modifying anti-rheumatic drugs and corticosteroids. Rheumatology (Oxford). 2016;55(9):1693–7.Find this resource:

Hall MA, Surgical interventions. In Szer IS, Kimura Y, Malleson PN, et al. (eds) Arthritis in Children and Adults. Oxford: Oxford University Press, 2006; 403–14Find this resource:

Treatment approaches in JIA

  • JIA is a complex and chronic condition and is therefore optimally managed by an experienced MDT as part of a managed clinical network as outlined in the BSPAR Standards of Care (see Juvenile idiopathic arthritis pp. [link][link]).

  • The MDT is integral to the management with the patient and family at the centre (Fig. 3.4), with input from specialist consultant, specialist nurse, paediatric physiotherapist, and paediatric occupational therapist (with interests in musculoskeletal conditions if possible).

  • Access to ophthalmology for monitoring and treatment of JIA-associated eye disease is vital, with other services such as orthopaedic surgeons, radiology, social work, and psychology services able to be accessed readily as required; these disciplines all have to interlink efficiently to achieve the best possible outcome. See Juvenile idiopathic arthritis pp. [link][link] and related chapters for more information on MDT members and their specific roles.

  • The general treatment approach is to achieve early diagnosis and rapid control of the inflammatory process, whilst minimizing adverse effects of treatment and supporting general physical and mental health (Fig. 3.5).

  • Early and adequate treatment aims to prevent long-term joint damage and the need for joint replacement therapy.

  • Each member of the team contributes to the holistic management of the patient and family, with medical treatment forming only one strand of the overall picture.

  • Education and information form one of the most important features of management throughout the duration of disease and should be undertaken by all members of the team, although the nurse specialist often takes an ongoing role in this area.

  • Physiotherapy and occupational therapy have important roles in maintaining maximum function—the aim of treatment is as near to functional normality as possible. It is important to maintain muscle strength despite inflammatory processes within joints and these disciplines aim to achieve this by teaching specific exercises, pain management, and joint protection techniques as necessary.

  • A healthy balanced diet with particular emphasis on calcium and vitamin D intake for bone health are recommended in JIA but there is no evidence for dietary modification affecting the inflammatory process in this disease.


Fig. 3.4 Patient-centred MDT management of JIA.

Fig. 3.4 Patient-centred MDT management of JIA.


Fig. 3.5 General treatment approach in JIA.

Fig. 3.5 General treatment approach in JIA.

Rx=Treatment; DMARDS=Disease modifying anti-rheumatic drugs; BMT=Bone marrow transplant.

Specific medical management in subtypes of JIA

  • Table 3.7 illustrates some of the similarities and differences in the specific management of the different subtypes but should only be regarded as a guide to management.

  • There is a lack of good evidence for many aspects of JIA management, therefore variability in practice between specialists exists.

  • Particular management controversies remain around joint injection; dose, timing, number, and duration of treatment whilst in remission; and the use of specific disease-modifying drugs in particular disease types.

  • In future, the possibility of genetic and phenotypic subtyping may determine prognosis and more predictable response to particular drugs.

  • Further information is available (See Juvenile idiopathic arthritis Treatments used in paediatric rheumatism, p. [link]; Juvenile idiopathic arthritis Share guidance, pp. [link][link]; Juvenile idiopathic arthritis CARRA guidance, pp. [link][link]; Juvenile idiopathic arthritis Corticosteroids joint injections, pp. [link][link])

Table 3.7 Specific management of subtypes of JIA

Systemic onset JIA

Oligoarthritis

Polyarthritis

Established polyarthritis/oligoarthritis

Enthesitis related arthritis

Psoriatic arthritis

Early/mild disease

Medium-dose corticosteroids

  • Intra-articular steroids

  • NSAIDs

  • MTX

  • Steroids (intra-articular or systemic)

  • NSAID

  • IVMP/high-dose corticosteroids followed by 2–4 weeks of low dose

Established/ severe disease

  • Pulsed IV methyl prednisolone (IVMP)*.

  • Methotrexate (MTX) (usually given by subcutaneous (SC) route)

  • Consider ciclosporin, and biologics (e.g. anakinra or tocilizumab)

See next column

  • MTX (ensure maximum dose, SC route)

  • May need to add etanercept.

  • ± corticosteroids + joint injections

  • Disease >2–4 months’ duration

  • Sulphasalazine (may work better than other DMARDS)

  • MTX/anti-TNF

Remission

  • Wean prednisolone slowly

  • Reduce other treatment with extreme caution—high risk of relapse

Ongoing monitoring

  • Wean off Steroid first

  • DMARD continues longer then consider reduction or discontinuation

  • Continue treatment for several months

  • Wean and discontinue steroids first

  • Wait 1 year before weaning off DMARDs—off MTX last

Continue sulfasalazine 6 months–1yr

Relapse

  • Repeat high-dose corticosteroids

  • Consider other biologic agents

  • If previous IACs effect >4 months repeat injection

  • If lasted <4 months add NSAID, repeat IAC consider DMARD

Reintroduce all drugs on which remission was achieved.

  • Reintroduce all drugs that induced remission

  • Often requires step up in treatment to reinduce remission

  • Generally episodic course

  • Short courses of NSAID and sulphasalazine sufficient to obtain remission in recurrences

Persistent disease

  • Anti IL-6 and IL-1 directed treatments

  • Tocilizumab (anti-IL-6) canakinumab (anti-IL-1B), anakinra (IL1ra)

IAC targeted joints

  • Consider alternate biologic agents

  • In severe cases consider bone marrow transplant (see Juvenile idiopathic arthritis pp. [link][link])

* If macrophage activation syndrome develops (see Juvenile idiopathic arthritis pp. [link][link]).

MTX, methotrexate; IAC, intra-articular corticosteroid; DMARD, disease-modifying anti-rheumatic drug; NSAID, non-steroidal anti-inflammatory drug.

Disease activity scores in JIA

The purpose of disease activity scores is to guide and assess treatment strategies, whether pharmaceutical or other. These are formal, valid, typically composite measures that in adult rheumatology have been shown to be more effective than subjective assessment in routine practice to inform treat to target strategies. These validated tools include patient preferred outcomes, joint counts, visual analogue scales, and quality of life assessment.

The prime aim of disease management in juvenile arthritis has to be inactive disease or remission. With more aggressive use of DMARDS and access to biologics this has become a reality and is similar to adult experience.

Outcome measures in JIA

There are several measures for inactive disease in JIA and include core, or conventional, outcome variables (such as active joint count (AJC), ESR, and global assessments – see below) plus, importantly, features of systemic disease, uveitis, and morning stiffness (see Juvenile idiopathic arthritis Outcome measures in paediatric rheumatology, pp. [link][link]).

Once inactive disease (‘minimal disease activity’) has been achieved then the burden of chronic disease on quality of life (pain, anxiety, disability, sleep, loss of schooling and impact on family life) can be better understood. These parameters are currently measured in JIA by health related quality of life (HRQoL) tools (see Juvenile idiopathic arthritis Outcome measures in paediatric rheumatology, pp. [link][link])

Where there is persistent disease activity, further tools have been developed for use in clinical trials, to determine what meaningful improvement is and also what defines a flare. The principle tool for polyarticular course JIA is the American College of Rheumatology (ACR) Core Outcome Variables (COV) which compares a baseline disease activity to subsequent assessments in the form of a percentage improvement; e.g ACR-30 being 30% improvement in 3 of 6 variables. The ACR is based upon:

  • Active joint count (71-joints).

  • Restrictive joint count (71-joints).

  • CHAQ (see Juvenile idiopathic arthritis Chapter 1, p. [link]).

  • Parent (or patient) global evaluation (visual analogue scale of 0 to 10)—ParGE.

  • Physician global assessment (VAS of 0 to 10)—PhysGA.

  • ESR.

Core outcome variables are the gold standard for use in research trials although have limited use in clinical practice. They are not a measure of individual disease severity or status, have less responsiveness in oligoarticular disease, and are hampered by the use of CHAQ, which is often completed incorrectly (especially as a proxy measure completed by parents), and is influenced by comorbid conditions such as chronic pain. However, the CHAQ is useful in early disease assessment and has prognostic value in determining poor long term outcome.

The DAS28

In adults, DAS-28 has become the routine measure of disease activity using a complex formula that combines swollen joint count, tender joint count, ESR, or CRP, and a patient global assessment (VAS 1 to 100). A score of >5.1 after intensive therapy with a combination of conventional DMARDs, permits the use of a biologic and a moderate EULAR response (Table 3.8) after 6 months will allow drug continuation.

Table 3.8 EULAR response criteria to compare DAS at two different points in time

DAS28 improvement →

> 1.2

> 0.6 and ≤ 1.2

≤ 0.6

Present DAS28 ↓

≤ 3.2

Good response

Moderate response

No response

> 3.2 and ≤ 5.1

Moderate response

Moderate response

No response

> 5.1

Moderate response

No response

No response

In clinical practice the DAS-28 is now used to provide other targets whereby monthly assessment of RA disease activity is followed by a change in treatment (higher doses or new drugs) until disease activity is brought into remission (DAS<2.6) or low disease activity (DAS< 3.2) or to low CRP or ESR. Persistently high scores are associated with an increased likelihood of progressive joint damage, even in patients seemingly doing well.

A misleadingly low DAS-28 score may occur when the feet are predominantly involved or when neither the ESR nor the CRP have been ever high; these scenarios are both common in JIA. In addition, tenderness is not specific to active disease and it can be difficult to decide whether an individual joint is swollen or tender (leading to inter and intra observer error). The Simple Disease Activity Index (SDAI) has been developed to simplify the complex formulae required to calculate the DAS whilst maintaining sensitivity.

The JADAS

The problems with scoring systems are amplified in paediatric practice and the reliance of scores based on blood tests can be particularly problematic in JIA assessment. Nonetheless the Juvenile Arthritis Disease Activity Score (JADAS) has been developed and comprises PhysGE, ParGA, AJC, and ESR. The ESR is normalized (ESR (mm/hr)-20)/10) to give a score between 0–10.

The three versions of JADAS depend on the number of joints assessed:

  • JADAS-71 (all joints).

  • JADAS-27 (cervical spine, elbows, wrists, 1st–3rd MCPJs, PIPJs, hips, knees and ankles).

  • JADAS-10 (any joints up to a maximum of 10).

Defining active disease presents a challenge when in children joint restriction indicates activity rather than damage and there may be little swelling. JADAS-3 has proposed omitting the ESR to further improve clinical feasibility of the tool. This is equivalent to the Clinical Disease activity Index (CDAI) in adults.

The JADAS has good responsiveness to change and correlates well with ACR-Pedi 30, 50, and 70 in studies of polyarticular JIA. To accommodate the limitations in some forms of JIA, the JADAS scores have been defined as:

  • Inactive disease score of <1 in both oligo-JIA and poly-JIA.

  • Minimally active disease score of 1–2 in oligo-JIA and score of 1–3.2 in poly-JIA.

There is low correlation between JADAS and DAS-28 and CDAI.

Patient and parent reported measures

More recently, tools have included patient or parent reported outcome measures (PROMs) and in adults these multidimensional tools include the MDHAQ and the simpler form (called RAPID-3). There is good correlation between PROMs and AJC, ESR, and radiographic scores, and they are reproducible and informative to encompass impact of disease on the patient. Comparison of RAPID 3 and DAS-28 shows that they correlate well and in particular in defining disease states of remission, low, moderate, and high activity. Furthermore there is evidence that PROMs minimize the placebo effect of physician assessed AJC seen in trials.

In paediatrics, these tools have to accommodate development, growth and a disagreement between parent (or proxy) and child assessment of activity and PROMs. There is currently the Juvenile Arthritis Multidimensional Assessment Report (JAMAR) and Juvenile Arthritis Parent Assessment Index (JAPAI).

Disease activity in enthesitis-related arthritis

Currently there are no validated tools to measure disease activity in enthesitis-related arthritis or juvenile-onset spondyloarthritis. Although axial involvement is uncommon at presentation the adult tools such as Bath Ankylosing Spondylitis Disease Activity index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) show early promise with some degree of responsiveness and good correlation with CHAQ and PhysGA.

Imaging as a disease activity measure in JIA

Ultrasonography (US) is an important real-time diagnostic tool in diagnosis of joint swelling and synovitis. A number of studies suggest grey scale and power Doppler US are more sensitive to detect swelling and subclinical inflammation compared to clinical examination. MRI bone marrow oedema (as a precursor to erosive bone disease), is a good predictor of disease activity although due to the cost, availability and practical challenges in young children, routine use of MRI in clinical practice is limited. A number of scoring systems have been formulated using radiography of specific joints to evaluate joint activity in adult RA; however, measuring joint space narrowing, the number of erosions and cartilage loss in children is challenging due to changes of bone morphology and musculoskeletal maturation.

Further reading

Consolaro, A, Giancane G, Schiappapietra B, et al. Clinical outcome measures in juvenile idiopathic arthritis. Pediatr Rheumatol 2016;14:23 DOI 10.1186/s12969-016-0085-5Find this resource:

Ringold S et al. Performance of rheumatoid arthritis disease activity measures and juvenile arthritis disease activity scores in polyarticular-course juvenile idiopathic arthritis: analysis of their ability to classify the American College of Rheumatology pediatric measures of response and the preliminary criteria for flare and inactive disease. Arthritis Care Res 2010;62:1095–1102Find this resource:

McErlane F et al. Validity of a three-variable Juvenile Arthritis Disease Activity Score in children with new-onset juvenile idiopathic arthritis. Ann Rheum Dis 2013;72:1983–8.Find this resource:

Colebatch-Bourn et al. EULAR-PReS Points to consider for the use of imaging in the diagnosis and management if JIA in clinical practice Ann Rheum Dis 2015;74:1946–57.Find this resource:

Cardiovascular disease and JIA

Introduction

Individuals with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis have an increased risk of cardiovascular disease (CVD). The increased risk is due to a combination of:

  1. 1. high prevalence of traditional risk factors for CVD, such as hypertension and smoking

  2. 2. accelerated atherosclerosis and plaque instability caused by systemic inflammation

  3. 3. treatment, particularly long-term corticosteroids

Registry data and studies using surrogate cardiovascular outcome measures (examples are given in Table 3.9) suggest improved cardiovascular outcomes in adult-onset inflammatory arthritis with adequate disease control and the use of biologics.

Table 3.9 Examples of commonly used surrogate cardiovascular outcome measuresa

Outcome measure

Component of cardiovascular risk assessed

Pulse wave velocity

Arterial stiffness

Flow mediated dilatation

Endothelial dysfunction

Carotid intima-media thickness

Carotid atherosclerosis

Coronary computed tomography

Coronary artery calcium/atherosclerotic burden

aA surrogate outcome measure is a substitute for a clinical endpoint. It is a predicator for clinical outcome based on scientific evidence.

EULAR recommends annual cardiovascular risk factor screening for adults with rheumatoid arthritis. The recommendations are summarized in Box 3.2.

Evidence for cardiovascular risk in JIA

There is a paucity of data on cardiovascular risk either in children or adults with JIA. Preliminary evidence, however, suggests a higher prevalence of some traditional cardiovascular risk factors:

  • Children with JIA have higher systolic and diastolic blood pressure (although values remain within normal range).

  • Hypertension may be more prevalent in adults with JIA.

  • Some studies found ↓ HDL and ↑ triglycerides in JIA. The lipid profile is difficult to interpret in JIA: variability occurs with disease activity and medications (e.g. steroids, anti-TNFa and anti-IL6 agents).

  • Children with JIA may be less physically active.

  • Individuals with JIA may have higher total body fat for a given BMI.

  • Medications used frequently in JIA are known to increase cardiovascular risk in adults (eg steroids, NSAIDs).

  • There is insufficient evidence to comment on the prevalence of smoking, diabetes or family history of CVD in JIA.

Different subtypes may have different cardiovascular risk profiles: the JuMBO registry (see Further reading) found a high prevalence of CVD in systemic onset JIA but not in other subtypes. High disease activity is likely to be associated with increased cardiovascular risk, as observed in adult-onset inflammatory arthritides. Long-term cohort studies spanning several decades would be needed to determine the cardiovascular event risk in JIA. Surrogate cardiovascular outcomes (Table 3.10) have potential for assessing cardiovascular risk in JIA prior to such studies being available.

Guidelines for cardiovascular risk assessment in JIA

In the absence of clear increased cardiovascular risk in JIA, no evidence-based guidelines for managing risk are available. Atherosclerosis begins in childhood hence there is potential to improve cardiovascular outcomes from a young age. Extrapolated from the evidence in adult-onset inflammatory arthritides and other childhood conditions associated with increased cardiovascular risk (e.g. diabetes mellitus, familial hypercholesterolaemia, obesity), the following are pragmatic suggestions:

  • Determine relevant family history: cardiovascular event <55 years (male) or <60 years (female) in first-degree relatives.

  • Review family history for obesity, hyperlipidaemia, diabetes mellitus, and hypertension.

  • Commence active anti-smoking advice at an early age and advise against passive smoking including a smoke-free home environment.

  • Growth/diet—monitor height/weight/BMI and promote healthy nutrition.

  • Measure blood pressure annually for all children and young people.

  • Physical activity promotion—recommend >1hr moderate-to-vigorous physical activity per day.

  • Cardiovascular health assessment and promotion should be a routine part of transitional care, including serum lipid and glucose measurement.

  • Health care professionals involved in the care of children and young adults with JIA should be aware of the potential for increased cardiovascular risk.

Further reading

Coulson EJ, Ng WF, Goff, I, Foster HE. Cardiovascular risk in juvenile idiopathic arthritis. Rheumatology (Oxford) 2013;52(7):1163–71.Find this resource:

Bohr, AH, Fuhlbrigge RC, Pedersen FK, de Ferranti SD, Mu¨ller K. Premature subclinical atherosclerosis in children and young adults with juvenile idiopathic arthritis. A review considering preventive measures. Pediatric Rheumatol 2016:14:3 DOI 10.1186/s12969-015-0061-5.Find this resource:

Kerekes G, Soltész P, Nurmohamed,MT, et al. Validated methods for assessment of subclinical atherosclerosis in rheumatology. Nature Rev Rheumatol 2012;8(4):224–34.Find this resource:

Minden K, Klotsche J, Nieworth M, et al. Biologics register JuMBO. Long-term safety of biologic therapy of juvenile idiopathic arthritis. Z Rheumatol. 2013;72(4):339–46. doi: 10.1007/s00393-012-1063-z.Find this resource:

Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics 2011;128(suppl 5):S213–S256.Find this resource:

Peters, MJ, Symmons DP, McCarey D, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis 2010;69:325–31.Find this resource:

Notes:

1 Defined as: all children in whom JIA is suspected should be seen by a specialist paediatric rheumatology MDT within 10 weeks from onset of symptoms and 4 weeks from date of referral in order to facilitate early diagnosis, eye screening, and commence appropriate treatment.