Indian ] Pediatr 1996; 63 : 275-282

Juvenile Rheumatoid Arthritis - 'iinical Manifestations A.N. Malaviya and Khaled ALsaeid

Department of Medicine, Kuwait University, Kuwait Abstract. Chronic inflammatory arthritis in childhood could be due to an obvious cause (e.g. sepsis, rheumatic fever, systemic lupus erythematosus etc.), or it could be idiopathic. After excluding those with obvious cause there still remains a large group of chronic inflammatory arthritis in childhood. This category has been variously called 'juvenile rheumatoid arthritis', 'juvenile arthritis', 'juvenile chronic arthritis', and more recently, 'idiopathic arthritis of childhood', The present article reviews the various classification criteria used for defining this group of disorders with emphasis on the common features as well as the major differences between these criteria. The major classes withtn this group with their characteristic clinical and laboratory features are also discussed. (Indian J Pediatr 1996; 63 : 275-282)

Key words : Juvenile rheumatoid arthritis; Classification; Clinical manifestations C h r o n i c arthritis is one of the major clinical problems in pediatric age group. There are a number of causes of arthritis in children. Some of them m a y be obvious e.g. septic arthritis, rheumatic fever, and systemic lupus erythematosus (SLE). In others, further investigations w o u l d help in finding the cause of arthritis e.g. congenital/developmental problems, hematological conditions, neoplasia and others. After excluding the known causes, a large group of idiopathic arthritides is left behind. This group has been traditionally called Juvenile Rheumatoid Arthritis (JRA) in USA ~ while in United Kingdom it has been referred as Still's disease s, This group is characterised b y marked clinical heterogeneity. Therefore, several attempts have .been made in the past for classifying these diseases. Thus, Cassidy in USA suggested

Reprint requests : Dr. A.N. Malaviya, Professor of Medicine, Consultant Physician & Rheumatol0gist, Department of Medicine, Kuwait University, Kuwait

the term 'juvenile arthritis' in 19883, while the term 'Juvenile Chronic Arthritis' (JCA) was suggested b y Wood in Europe*. The problems of classifying this group of disorders and giving it a proper name has been well highlighted b y Southwood and Woo s. Tlll to-date 6 such attempts have been made

TABLE1. Different Classification Criteria for JRA/JCA/IAC

1. Taplowcriteria for Still's disease (1959)2. 2. 3. 4. 5. 6.

7.

New York Criteria for JRA (Still's disease) (1968)9. American Rheumatism Association (ARA) criteria (1972)1. Revised ARA criteria for JRA (1977)z~ American College of Rheumatology (ACR) criteria (1986)s. European League Against Rheumatism (EULAR) criteria for juvenile chronic arthritis (1988)4. Proposal for the development of classification criteria for Idiopathic Arthritides of Childhood (1995)6.

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and a 7th a t t e m p t is in process ~ (Table 1). TABt~3. Criteria for Diagnosis of Juvenile Chronic Arthritis (JCA)4 Even the latest attempt has been criticised 7 indicating that the subject of idiopathic ar* Age at onset < 16 yr. thritides in children is still in a state of flux. * Arthritis in 1 or more joints In spite of these limitations there are broad Duration of disease 3 months or longer a g r e e m e n t s on major clinical sub-catego9 Type defined by characteristic at onset ries. Pauciarticular < 5 joints D E F I N I T I O N A N D CLASSIFICATION

-

-

-

-

Polyarticular > 4 joints, rheumatoid tac-

tor negative

The t w o p o p u l a r classification criteria in wide usage have been: 1. 2.

A m e r i c a n College of R h e u m a t o l o g y criteria for JRA M. E u r o p e a n League A g a i n s t R h e u m a tism (EULAR) criteria for juvenile chronic arthritis 4.

These 2 classification criteria are given in Table 2 and 3 respectively. C o m m o n features in different classifications include: 1. 2. 3. 4.

Arthritis in one or more joints in children below 16 years of age. W h e r e no obvious cause can be defined. Persistent arthritis. Heterogeneous category with at least 3

TABLE2. Criteria for Classification of Juvenile Rheumatoid Arthritis (.IRA)8 1. 2.

3. 4.

5.

Age at onset < 16 yr. Arthritis (swelling or effusion, or presence of two or more signs : limitation of range of motion). Duration of disease 6 weeks or longe~. Onset type defined by type of disease in first 6 months a. Polyarthritis : 5 or more inflamed joints b. Oligoarthritis < 5 inflamed joints c. Systemic arthritis with characteristic fever Exclusion of other forms of juvenile arthritis

Systemic arthritis with characteristic fe-

ver --

Juvenile rheumatoid arthritis > 4 joints,

---

]uvenile ankylosing spondylitis Juvenile psoriatic arthritis

rheumatoid factor positive

major a n d several f u r t h e r subsets of clinical forms. The m a i n difference b e t w e e n ACR and EULAR classification is in defining duration of arthritis before it is classified in the category u n d e r discussion. This problem arises because the,pattern of disease takes variable time to evolve into a stable clinical sub-set. Most classification criteria have u s e d onset-type for d e f i n i n g sub-sets. While ACR classification criteria suggest a period of 6 m o n t h s to define onset-type, EULAR criteria suggest o n l y 3 m o n t h s to define onset-type. Over p e r i o d of time, it has also t~een realised that other forms of chronic arthritis such as psoriasis-related arthritis n e e d to be i n c l u d e d in this category. To accommodate these forms and to clearly define the time period, onset-types, course sub-types, serological status and effect of genetic factors, a task force fob classification criteria was set up b y the Pediatric Standing C o m m i t t e e of International League of Association for R h e u m a t o l o g y (ILAR). P r e l i m i n a r y proposals for the development of classification criteria have been published recentlyL It is

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TABLE4. ILAR Task Force Proposal for the Development of Classification Criteria for the Idiopathic Arthritides of Childhood (7) I.

Systemic arthritis

Definite 1. 2. 3.

Documented quotidian fever for at least 2 weeks Evanescent, non-fixed, erythematous rash. Arthritis

2. Positive family history of spondyloarthropathy 3. Positive rheumatoid factor V. Extended oligoarthritis Arthritis affecting 1 to 4 joints during the first 6 months of the disease, and a cumulative total of 5 joints or more after the first 6 months of the disease.

Probable

1. 2. 3.

In the absence of arthritis, the presence of criteria 1 and 2 above, together with any 2 of the following: Generalised lymph node enlargement Hepatosplenomegaly or splenomegaly Serositis

Specific exclusions 1.

Neonatal multisystem inflammatory disease, hyper-IgD, FAPA (fever, aphthous ulceration, pharyngitis, adenopathy) and other periodic syndromes including familial Mediterranean fever. Drug hypersensitivity

Specific exclusions 1. Positive family history of psoriasis 2. Positive rheumatoid factor VI. Enthesis-related arthritis Arthritis and enthesitis, or arthritis and at leas~ two of the following

Arthritis affecting 5 or more joints during the first 6 months of the disease.

Sacroiliac joint tenderness Inflammatory spinal pain HLA B27 Positive family history (first or 2nd degree relatives) of at least I of (i) anterior uveitis with pain, redness, or photophobia (ii) spondyloarthropathy confirmed by a rheumatoiogist (iii) inflammatory bowel disease. 5. Anterior uveitis that is usually associated with pain, redness or photophobia.

Specific exclusion

Specific exclusions

Positive rheumatoid factor

1. Positive rheumatoid factor or antinuclear antibody 2. Arthritis related to inflammatory bowel dis-

2.

II. Polyarthritis : rheumatoid factor negative

III. Polyarthritis : rheumatoid factor positive Arthritis affecting 5 or more joints during the first 6 months of the disease, associated with positive rheumatoid factor tests on at least 2 occasions 3 months apart. Specific exclusion : Family history of psoriasis

1. 2. 3. 4.

ease

VII.

Psoriatic arthritis

Arthritis affecting 1 to 4 joints during the first 6 months of the disease.

Arthritis and psoriasis, or arthritis and a positive family history of psoriasis in parents or siblings, in addition to: 1. Dactylitis in the patient, or 2. Nail abnormalities (pitting or onycholysis) in the patient

Specific exclusions

Specific exclusions

1. Positive family history of psoriasis

Positive rheumatoid factor

IV. Oligoarthritis

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r roposed to identify this category as "Idiopathic Arthritides of Childhood" (IAC). It includes 7 diseases with onset before 16th birthday (Table 4). The problem of duration has been solved by a 2-step approach. It proposes that on step 1, the disease can be classified as IAC if it persists for more than 6 weeks. Further, classification into any of the 7 sub-types is done only after 6 months of onset of disease. Between 6 weeks to 6 months the disease remains as unclassified IAC. The "Taskforce' has not yet recommended this classification for use except as part of a formal process of evaluating this proposed classification. Therefore, in this short review a consensus approach is given describing clinical features of main well-defined subtypes of IAC. CLINICAL MANIFESTATIONS

The following varieties of idiopathic arthritides in children will be discussed: 1. Systemic-onset--JCA/JRA 2. Oligoarticular 4isease of y o u n g girls with eye involvement 3. Seronegative polyarticular--JCA/JRA 4. Seropositive polyarticular-- JCA/JRA 5. Juvenile spondarthritis (including juvenile ankylosing spondylitis 6. Other varieties of oligoarticular diseases 7. Psoriatic -- JCA/JRA CLINICAL FEATURES

Systemic Onset JCA/JRA By definition this form of IAC is diagnosed in the presence of fever, rash and arthritis. The characteristic fever is quotidian in nature persisting for at least 2 weeks. The fe-

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ver occurs mainly in the afternoon or evening in conjunction with' a non-fixed erythematous evanescent rash most commonly seen on the trunk and proximal extrimities. The third component is arthritis which could be oligoarthritis or polyarthritis. Rarely, the arthritis may not be n0n-persistent. There could be a rare case where there is no arthritis (anarthritic presentation). "Probable" diagnosis of IAC of systemic variety can still be m a d e is such a case in the presence of documented quotidian fever of at least 2 weeks along with evanescent, non-fixed, erythematous rash along with 2 of the following 3 : (i) Generalised l y m p h n o d e enlargement (ii) Hepatomegaly a n d / o r splenomegaly (iii) Serositis. Systemic manifestations m a y occur months after the onset of arthritis, but usualy within the first 6 months. Systemic form of IAC has no particular peak age of onset, it occurs throughout childhood. Boys and girls are involved with almost equal frequency. N u m b e r of joints involved is variable presenting primarily as peripheral arthritis with frequent involvement of upper cervical spine. Chronic involvement of temporomandibular joints may cause micrognathia with characteristic appearance of face on profile view showing u n d e r d e v e l o p e d chin. Systemic manifestations are prominent with generalised lymphadenopathy hepatosplenomegaly, pleuritis and pericarditis. Children may appear toxic during spike of fever but between fever spikes they may appear and feel quite normal. Eye involvement in this type of IAC is rare. In about 40% of cases the disease is nonerosive, oligoarticular in nature with good prognosis. Polyarticular disease is seen in 60% of patients frequently associated with erosive arthritis causing

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functional incapacitation. Thus, severe limitation was seen at the end of 15 years in 4%, moderate limitation in 25%, while only slight incapacitation was seen in about 60% (Taplow). Tenosynovitis is occasionally seen around, the wrist joint presenting as masses seen on the dorsal aspect of both wrist joints. Sometimes the disease is severe with complications including amyloidosis. Death has been reported in 14% of cases in a large study with long term follow-upL Investigations show marked neutrophilic leukocytosis occasionally even higher than 30,000/mmL It can cause confusion with leukemia, which can cause leukemic arthritis. Other features of acute phase reaction are present including high erythrocyte sedimentation rate (usually above 50-60 m m 1st hr.), high platelet count (> 400,000/mm 3) normocytic normochromic anemia, increased C-reactive protein (CRP), decreased albumin and increased globulin with reversed albumin/ globulin ratio. Rheumatoid-factor is uniformly negative, antistreptolysin 'O' titer is not elevated but a minority (< 10%) may show the presence of anti-nuclear antibody (ANA) in low titers. Synovial fluid, when present in demonstrable amounts, show nonspecific features of inflammatory joint fluid. Diseases which m a y be confused with systemic form of IAC include leukemia and SLE. Mis-diagnosing leukemia as systemic IAC is common, hence, in many patients, bone marrow examination is an essential part of the diagnostic work-up required before establishing a diagnosis of systemic IAC. Other diseases that may create diagnostic problems include rheumatic fever, drug reactions, syndrome of feveraphthous ulceration-pharyngitis, adenopathy (FAPA), neonatal onset multisystem

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27~)

inflammatory diseases, systemic infections (e.g. infective endocarditis, chronic viral infections) and hyper IgD syndr6me.

Oligoarthritis of Young Girls with Eye Involvement This form of arthritis represents the commonest variety of IAC. It is a disease of early childhood with a peak incidence between 1-3 years. Clinical presentation is frequently monoarthritis with the knee joint as the predominant site of affection. Females predominate in a ratio of 5 : 1. ANA is positive in 75-85% of patients. Chronic uveitis is one of the most important, potentially debilitating extra-articular manifestation of IAC particularly oligoarticular disease of young girls 1". Eye involvement is almost always restricted to y o u n g children before they are able to read, and if left undiagnosed may lead to blindness. Since chronic uveitis is initially asymptomatic, routine slit-lamp examinations are recommended. The frequency of visits to the ophthalmologist is based on presence of certain risk factors. The predisposing factors include oligoarticular onset, young age of onset, female gender, and detection of anti-nuclear antibodies in the patient serumL Because of the severity of eye involvement prognosis is generally considered moderate to poor in this form of IAC.

Seronegative Polyarticular JCA/JRA Children with arthritis affecting 5 or more joints during the first 6 months of disease with only mild to moderate systemic involvement are classified under this category. Disease occurs throughout childhood with peak at 1-3 years of age with female to male ratio of 3 : 1. Arthritis in-

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volves peripheral joints in symmetrical or asymmetrical pattern. Upper cervical spine may be affected in some patients but lumbodorsal spine involvement is not seen. T e m p o r o m a n d i b u l a r involvement causing real-development of joint can also occur. Occurrence of chronic uveitis is seen in about 5% of cases. Generally the disease is mild. Witb nonerosive disease with only slight to moderate incapacitation, death is rare. By definition it is a seronegative disease. Therefore, RF must be negative for classifying a patient under this category. Features of acute phase reaction including high ESR, CRP, high platelets, reversed A / G ratio, may be present. However, in contrast to systemic variety, leukocyte count is generally not high. ANA may be positive in a minority.

involvement with subIuxation and involvement of odontoid (erosio.n and subluxation) may also occur. Arthritis is progressive deforming and in majority, destructive with unremitting course. Functional incapacitation is common. Joint erosions are seen over period of time in majority. Most patients cross over to adult age group and then classified as typical seropositive, erosive, progressive adult RA. In India extra-articular features are uncommon. These include mildconstitutional symptoms, pleuritis, pericarditis rheumatoid nodules, vasculitic complications like periungual infarcts, pyoderma gangrenosum. Although fatal outcome is distinctly uncommon, severe incapacitation with abnormal growth and development is seen often. Complications like systemic vasculitis and amyloidosis are rare but could be fatal. Laboratory investigations show the usual features of acute-phase reaction including high ESR (usually above 50-60 mm 1st hr.), elevated platelet count, normocytic normochromic anemia, elevated CRP, low albumin, high globulins with reversed A / G ~atio. Patientsl by definition, have persistently high titers of RF: ANF may also be positive in about 20%.

280

Seropositive PolyarticularJCA/JRA In the early stages of illness this category of polyarthritis is clinically indistinguishable from RF negative polyarthritis. But, by definition such patients are persistently RF test positive (seropositive). These patients are older in age, majority being above 10 years of age. Females predominate 3-4"times over males. Constitutional manifestations are minimal. Polyarthritis is symmetrical peripheral involving small joints in hands which resemble seropositive RA of adults, except that distal interphalangeal joints (DIP) are often involved as against adult RA where DIP are not involved. Other joints which are involved include proximal interphalangeal joints (PIP), metacarpophalangeal joints (MP), wrists, elbows, shoulders, temporomandibular joints, hips, knees, ankles and joints in feet. Atalanto--axial joint

Juvenile Spondarthritis (Including Juvenile Ankylosing Spondylitis) This variety of arthritic disorder is seen in older boys much more often than girls, the usual age of onset being 8-12 years. Joints in the lower segment of the b o d y are affected m u c h more frequently. Hip, knee and ankle involvement in prominently asymmetrical pattern is characteristic. Inflammation of sites of insertion of ligaments and tendons (enthesitis) is anothel

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characteristic feature. Thus, tenderness and pain at the site of insertion of tendoAchilles, quadriceps tendon insertion at tibial tubercle, attachment of planter fascia on the planter aspect of calcaneum, are common. Inflammatory lower back pain d u e to involvement of sacroiliac joints a n d / o r apophyseal joints is another characteristic clinical feature. There are several other typical extraarticular features including acute intermittent uveitis, conjunctivitis, features suggestive of inflammatory bowel disease and skin lesions (keratoderma blenorrhagica, pscrriatiform rash). Family history of any one of the dise a s e / m a n i f e s t a t i o n s of spondarthritis in family members (including 1st or 2nd degree relatives) is present in about one-third of the patients. Some of these boys may, over the years, slowly evolve into typical ankylosing spondylitis with extensive spinal involvement. In major'~ty, prognosis is good with only mild deterioration in functional capacity. A minority may have poor prognosis. Investigations m a y show features of acute-phase reaction. Sacroiliitis (unilateral or bilateral) is demonstrable on iadiological examination. Tissue type HLA B27 is present in a large proportion of cases. OTHER VARIETIES OF OLIGOAi~TICULAR DISEASES Over the years it is becoming obvious that the so-called oligoarticular JCA/JRA belong to a heterogeneous group with several subsets, some of which need to be defined further. Thus, symmetrical knee involvement of chronic type in young girls is probably a separate subset. The other subset is the so-called 'extended oligarthritis' affecting 1 to 4 joints during the first 6 months of disease, and a cumulative total

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of 5 joints or more a f a r first 6 months of disease. This subset of oligoarticular disease also needs to be defined further. Psoriatic Arthritis In Pediatric Age-Group Inflammatory arthritis in the presence of psoriasis is included in this group. In the absence of psoriasis a positive history of psoriasis in parents or siblings in the presence of dactylitis and nail abnormalities (pitting or onycholysis) can still be taken as indicative of psoriatic arthritis. There are several patterns of psoriatic arthritis including a mild oligoarticular variety, a peripheral polyarthritis resembling potyarticular JRA/JCA (but rheumatoid factor is negative), spondarthritis variety resembling category 4 above and a prominent distal interphalangeal pattern with severe nail involvement. Prognosis is generally good except in some of those with spondarthritis variety. These patients may develop severe deforming multilating diseases over a period of time (arthritis mutilans). REFERENCES

1. Brewer EJ, Bass J, Cassidy JT et al. Criteria for classification of jLIvenile rheumatoid arthritis. Bull Rheum Dis 1972; 23 : 712719. 2. Ansell BM, Bywaters EGL. Prognosis in Still's disease. Bull Rheum Dis 195q; 9 : 189-92. 3. Cassidy JT, Nelson AM. The frequency of juvenile arthritis. J Rheumatol 1988; 15 : 535-536. 4. Wood PHN. Nomenclature and classification criteria for idiopathic arthritis in children. EULAR Bull 1988; 4 : 101. 5. Southwood TR, Woo P. Childhood arthritis : The name game. Br J Rheumatol 1993; 32 : 421-423. 6. Fink CW. Proposal for the development

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of classificatio~ criteria for idiopathic arthritides of childhood, j Rheumatol I995; 22 : 1566-1569. 7. H o c h b e r g MC. Classification criteria for childhood arthritic diseases. J Rheumatol 1995; 22 : 1445-1446. 8. Cassidy JT, Levinson JE, Bass JC et aL A s t u d y of classification criteria for a diagnosis of juvenile rheumatoid

arthritis. Arthritis Rheum 1986; 29 : 27428I. 9. Cassldy JT,.Petty RE. Juvenile rheumatoid arthritis. I n : Textbook of Pediatric Rheumatology. N e w York : Churchchill Livingstone, 1995. 10: Rosenberg AM. Uveitis associated with juyenile rheumatoid arthritis. Sere Arth Rheum 1987; 16 : 158-173.