Recent advances in the diagnosis and
care of the child with arthritis

LAUREN M. PACHMAN, MD
ANDREW K. POZNANSKI, MD

aSpring 1998

WE HAVE BEEN TAKING  care of children with arthritis for the past two and a half decades. It has been a very rewarding experience to participate in the progress that has been made in the treatment of these children and the resultant improvement in function. The emergence of the discipline of pediatric rheumatology (first sub-speciality certification awarded in 1992) has been associated with an increased understanding of some of the factors that regulate the inflammatory process leading to the use of a wider variety of therapies. The combination of earlier, more aggressive intervention with more informative diagnostic tools (serologic and radiologic) has resulted in better patient outcomes. In this brief article, we review some of the symptoms of the child with juvenile rheumatoid arthritis, diagnostic tests that may be helpful (old and new) and summarize data concerning newer modes of therapy and their pitfalls.

How do we know it's arthritis? It's not always easy

In the United States, children are designated as having juvenile rheumatoid arthritis if they have symptoms of arthritis involving one or more joints for a period of at least six consecutive weeks and the symptoms are not part of another well defined disease. Added to this definition is the concept of onset types (Table 1) that describe the pattern of disease in the first six months of illness. Children with systemic onset juvenile arthritis (SO-JRA) must have documented intermittent fever of at least 39ºC for two weeks. Children who have polyarticular JRA (Poly JRA) have involvement of five or more joints, while youngsters who have pauciarticular JRA (Pauci-JRA) have involvement of four joints or fewer. Clinicians have also recognized that the pattern of arthritis can change over time, and that defining the course, or type of disease 6 to 12 months after disease onset might better predict the consequences of the various types of chronic inflammatory arthritis. For example, the child with systemic onset of disease could either follow a polyarticular course, or the symptoms could resolve. Each of these entities is discussed below. Exciting new data about the genetic markers (Histocompatibility Locus Antigens [HLA]) may ultimately redefine disease-susceptible populations and have some predictive value concerning their disease course.¹ For example, our new data that show that children who present with SO-JRA at the onset of their symptoms, who are positive for HLA DR4, are more likely to evolve into a polyarticular course.²

Common symptoms of arthritis

Most pediatricians are familiar with the overt symptoms of arthritis in children: decreased ability to walk or run, intermittent complaints of pain and/or swelling (often worse in the morning, or exacerbated by intercurrent illness or fatigue).³ For most children with arthritis, the duration of morning stiffness is a reasonable indicator of disease activity and severity. More subtle signs are increased irritability, intermittent low grade fevers, and "falling off" the individual's growth curve for both height and weight. Obvious evidence of bruising may occur as the child has an increase in falls, which are more likely to be accompanied by bone fracture if the arthritis has been undiagnosed and therefore untreated for a longer period of time. Other children may have some emotional regression and become decidedly less independent. Here we describe the characteristics of each of the main types of chronic arthritis in children, and then review the useful diagnostic laboratory tests that help differentiate many of the other potential causes of similar symptoms. To make the diagnosis of JRA, an increasing number of other diseases must be excluded (Table 2). The physician examining the child with musculoskeletal complaints must be aware of the norms for age for development, the presence of hyperextensibility, trauma, and a wide spectrum of previous infectious exposures that can lead to similar complaints.

What kind of arthritis is it?

Systemic Onset JRA (SO-JRA)

The child with SO-JRA is most likely to be admitted to a hospital as a "fever of unknown origin," for the assessment of spiking temperatures,⁴ which may antedate the onset of arthritis by several weeks to months. These fevers often occur in an idiosyncratic, almost predictable pattern, returning to the baseline, thus helping to differentiate the entity from systemic infection. The evanescent, migratory, maculopapular salmon-pink rash (usually located over joints, as well as on the palms and soles) may emerge with fever or immersion in warm water and may persist long after other symptoms have abated (Figures 1a and 1b).

FIGURES 1A, B. The rashes of systemic onset JRA. On the infant, the rash appears blotchy and is evanescent; on the older child, the rash is more discrete with temperature elevations. The infant also has marked joint swelling of wrists, hands and feet, characteristic of a systemic onset to polyarticular course.

Occasionally, the symptoms have a pruritic component, which can be exacerbated by dry skin and the Koebner phenomenon — erythema elicited by rubbing or lightly scratching the skin — with the subsequent appearance of macular lesions. Activation of the reticuloendothelial system with splenomegaly is a frequent sign, as is lymphadenopathy, which has the usual pattern of reactive hyperplasia. Hepatomegaly is a frequent feature of this type of presentation, and hepatic dysfunction is reflected by low albumin levels and a prolonged PT. Cardiopulmonary complications are frequent: pericarditis occurs in about 36% of children with SO-JRA, aortic valve regurgitation can occur, and cardiac tamponade can be a life-threatening complication if untreated Sometimes the smaller child with SO-JRA seems inconsolable and does not want to be held. This may be a consequence of an inflammatory myopathy that can accompany severe systemic vasculitis and result in pain when the muscle is compressed. Joint manifestations at onset vary from none to severe polyarticular arthritis (95% develop arthritis by the end of the first year of illness). A striking finding is the progressive involvement of carpal bones, with loss of joint space, occurring over as long a time span as 25 years.⁵

Polyarticular Onset

Polyarticular onset: rheumatoid factor-negative

This mode of presentation involving four joints or more is found in 30 to 40% of JRA; females are primarily affected (4:1), and this type of onset can occur at any age, although two peaks are seen at 1 to 3 years and 8 to 10 years. The onset of the illness may be insidious, or it may be precipitated by an immunological stimulus (intercurrent infection, immunization, trauma). The child may occasionally have a low-grade (under 102ºF) intermittent fever, fatigue, mild anorexia, and complain of progressive early-morning stiffness. The pattern of joint involvement is often additive over time, localizing symmetrically to multiple joints—typically, the small joints of the hands and feet (Figure 2).

FIGURE 2 [left]. The hands of a child with polyarticular JRA showing joint and soft tissue swelling, with some swan neck deformity. FIGURE 3A [right]. A 2-year 3-month-old girl with JRA. The wrist appears relatively small when compared to the size of the hand. Note also the angular contours of the developing ossification centers of the carpals which are a sign of destructive changes in the cartilaginous part of the carpals. There is also some periosteal reaction in the fourth metacarpal.

In the JRA child with incomplete ossification and arthritis involving the small joints of the hands, there may be destruction of the cartilaginous part of the carpals or deficient cartilage formation so that the intercarpal distance is closer than normal. This provides a convenient way to document the presence of arthritis in the absence of overt bone erosion, (Figures 3a, 3b⁶ ).

FIGURE 3B. The carpal size can be quantitated by the relation of the distance from the mid radial epiphysis to the base of the third metacarpal (RM) to the length of the second metacarpal (M2). In this girl it is well below 2SD.

In the knee, erosive disease can be severe, but may be difficult to document early in the disease course. In polyarticular disease, the temporomandibular joint (TMJ) is often altered, with facial asymmetry on opening the mouth, deviation of the jaw, and micrognathia. Progressive destruction of the joint, accompanied by diminished inter-incisor distance (less than 4 cm is severe), is a cause of inanition because the child cannot open her mouth to eat. Severe headaches may accompany TMJ pain, and middle ear function can be compromised. Involvement of any joint may be rapidly progressive in either IgM rheumatoid factor positive or negative disease, and if untreated, results in loss of range of motion and function.

Non-articular manifestations include subcutaneous nodules. These are a poor prognostic sign, developing in areas of pressure or friction; they are frequently found at the olecranon process of the elbow, on flexor tendons, and the back of the heel. Benign rheumatoid nodules with palisading on histological examination (granuloma annulare) may occur in healthy children. These are usually located in subcutanous tissue, such as the scalp and in the pretibial areas. They often recur following excision, making surgery and other forms of therapy futile in this benign, self-limited disease.

Polyarticular onset; rheumatoid factor-positive:
juvenile rheumatoid arthritis

This group, as opposed to the rheumatoid factor-negative group, is relatively homogeneous, comprising about 7 to 10% of the total JRA population. This onset type, primarily composed of females, is indistinguishable from the adult form of classic rheumatoid disease and is more likely to develop severe debilitating arthritis. Sixty percent of children are DR4 positive and often have an extensive family history of arthritis and/or other connective tissue diseases. Like their adult counterparts, these children may require medication for most of their lives to control disease symptoms. Therefore, it is necessary to balance the risks of lifelong therapy with the consequences of early joint destruction.

Pauciarticular Arthritis

This mode of onset is common in females under four years of age and involves 4 or fewer joints. In the United States, about 40 to 50% of the total group of children with JRA have this onset. The first signs of pauciarticular disease may be insidious, such as refusal to walk in the morning, increased fatigue, and reversion to crawling. The joint that is involved initially and most frequently in the course of disease is the knee, which may exhibit painless swelling. One of the most common findings is overgrowth of the affected limb (attributed to increased blood flow to the area of inflammation), which can result in a severe positional scoliosis, as seen in Figure 4.

FIGURE 4. A child with pauciarticular arthritis and scoliosis secondary to overgrowth of the right knee.

Involvement of the knee may be hard to document radiologically; an MRI with gadolinium may be required. This test can differentiate fluid accumulation from inflammed synovia and detect early cartilage destruction (Figures 5a–c).

FIGURE 5. Magnetic resonance imaging of a knee of a 15-year-old girl with arthritis. [Left] T1 weighted sequence. [Middle] T1 weighted sequence following gadolinium injection. [Right] T2 weighted sequence. A portion of the low signal areas (dark areas) on the T1 image in the suprapatellar region as well as around the joint have high signal (become white) after administration of gadolinium [middle]. These high signal areas represent synovitis. In the T2 image the entire suprapatellar area has high signal since both joint fluid and synovitis have a similar appearance. The low signal area remaining on the post gadolinium study which has high signal on the T2 image represents fluid.

The onset of pauciarticular arthritis has relatively few systemic signs. Fever and cardiopulmonary symptoms are rare, but there is an increased risk of anterior chamber uveitis; 50% to 75% of patients have a positive ANA, usually seen in a speckled pattern (Figure 6), which is highly associated with uveitis. The uveitis may precede or follow the observation of arthritis by months to years.

FIGURE 6. A positive ANA in a speckled pattern using ANA HEp2 cells as an indicator.

Spondyloarthropathy

This brief discussion is limited to the children who have definite JRA. However, for many years a different subset of children, those with a spondyloarthropathy/enthesiopathy (tenderness at insertion of tendons) was included in this group, and their symptoms often improve with exercise. We now know that these children with asymmetrical arthritis, often below the waist (knee, hip, ankle), may also have involvement of the axial skeleton, resulting in decreased spine expansion on forward flexion. Unlike other subsets of chronic arthritis, in which there is a female predominance, these children (with one or two joints involved and are HLA-B27⁺ ) are 75% male and are slightly older at the disease's onset (mean age about 9 years).⁷ Family history of illnesses that are associated with HLA-B27⁺ arthritis includes psoriasis, ulcerative colitis, or other bowel-related arthritis. It is important to differentiate this group of children from those with JRA, because concomitant findings, acute anterior uveitis (red painful eye), cardiac valve involvement, and progressive spine involvement may be components of this illness and require specific care. This group of children is also prone to reactive arthritis (following an infectious process, such as with Salmonella, Shigella, or Yersinia).

Disease progression

About 20% of all youngsters with JRA have SO-JRA onset, which does not appear to differ from adult-onset systemic arthritis; hip involvement may be severe, and occur as late as 10 years after onset. Only fifty percent of the SO-JRA patients develop polyarticular disease; usually their symptoms develop by one year after disease onset. At 5-year follow-up, the most severe prognostic signs are early age of onset, persistence of disease activity, and wrist damage on radiography. In contrast, in RF⁺ polyarticular JRA, about 20% have no or slight disability at 15 years after onset with a mortality of 12%. In the United States, poly-onset patients have a 31% remission rate at 5 years, pauci-onset patients 17% and those with systemic onset have a 47% rate of remission. Pauciarticular disease is not associated with any risk factors for death, and about 80% have no limitations at 15 years after onset; about 20% evolve into polyarticular disease.

Diagnostic testing

Children with systemic onset JRA usually have leukocytosis: elevations of the ESR and platelet count and a white blood cell count of more than 25,000/mm3 are not uncommon, with an associated microcytic anemia that may be Coombs positive. The presence of vasculopathy is reflected by an increased von Willebrand factor antigen (indicating endothelial cell damage) and platelet factor 4 (indicating intravascular thrombosis);⁸ vasculopathy can be life threatening. Often an associated low serum albumin complicates the administration of nonsteroidal anti-inflammatory drugs which bind to albumin and results in a rise in liver-derived enzymes. An inflammatory myopathy may be accompanied by increased serum levels of muscle-derived enzymes and may be accompanied by myocarditis. The most exciting area of diagnostic testing that is currently under development is the study of the mediators of inflammation in children with arthritis (sera, synovial fluid).⁹ The observation that a macrophage-derived product, tumor necrosis factor alpha (TNF-a ), is increased in JRA has led to experimental trials of therapies to lower this cytokine.

In polyarticular JRA, the serological findings are less dramatic. The usual serological indicators of disease activity are a microcytic anemia (often non-hemolysis); less commonly, an elevated ESR (normal in more than 40% of these youngsters) and an elevated platelet count. In rheumatoid factor-positive (RF⁺) adults and in about 7% of children, the DR4 antigen and its epitopes are associated with a more severe, persistent, polyarticular course and the presence of IgM rheumatoid factor.

In Pauciarticular JRA, the most common serological abnormality is positive antinuclear antibody (ANA), which usually exhibits a speckled or homogeneous pattern (Figure 6) in the indicator HEp2 cell. Multiple attempts to characterize the antigenic specificity of this ANA have been uniformly unsuccessful.

Some children with repeated infections are deficient in immunoglobulins; the association of hypogammaglobulinemia and JRA is about 1.2%, and about 4% have an IgA deficiency. The IgA level may return to normal with disease remission. The arthritis of hypogamma-globulinemia often resolves with replacement IgG.

A certified pediatric diagnostic immunology laboratory plays an important role in the assessment of children with rheumatic disease. This is not only because of care in specimen processing (small volumes), but also because of the requirement for age-related (often region-related) standards. For example, ANAs performed by the Diagnostic Immunology Laboratory of Children's Memorial on sera from 150 healthy children (not taking medications associated with antibodies against nuclear components [e.g. dilantin]) showed that only 4% were positive at a titer of 1:80 and were usually in a speckled pattern. None were positive for known disease-associated patterns, such as anti-centromere (CREST syndrome), or homogeneous (SLE). IgG levels also must be compared with age-related normal values to avoid the common misdiagnosis of hypogammaglobulinemia when adult values are used as standards.

Therapy of children with JRA

The mainstay of treatment of children with JRA is nonsteroid anti-inflammatory drugs. Because children often balk at pills, new preparations in liquid form are being developed to add to those already available. Of concern are gastric irritation, hepatotoxicity, nephrotoxicity, cutaneous reactions or other evidence of drug sensitivity that require drug withdrawal. For children with severe arthritis or a rapid progression of symptoms, the use of two more modalities appears to have altered the disease course. Methotrexate, given in doses that are lower than used in cancer chemotherapy, has been very useful in arresting disease if given early in the disease course.¹⁰ Folic acid (1 mg/day) should be considered to help maintain rapidly dividing cells. Minor variations in the regimen of drug administration and/or antiemetics can reduce the occasional adverse reactions of nausea or abdominal discomfort.

One of the most useful adjuncts in disease control has been the implementation of high-dose intermittent intravenous methyl-prednisone (IVMP). This modality has allowed rapid disease suppression, gaining time to permit the slower acting agents to obtain sufficient blood levels to control inflammation. Some of the adverse reactions to this regimen have just been described in a study of 213 children over a four-year period; the 46 children received 2,622 doses of IV steroids. The most common reactions were behavioral changes in 10% of the children within 24 hours of steroid administration. There was a significant association between histories of drug-induced cutaneous reactions and adverse reactions to IV corticosteroids (p<.01).¹¹

As with most rheumatic diseases, the children must have a calcium-sufficient diet, and when steroids are given, a preparation of vitamin D aids in calcium absorption (which is retarded by steroids). Active physical/occupational therapy includes evaluation of specific joint utilization, and orthotics and splinting can aid the child's gait and restore elements of function. Also integral to the team approach to the treatment of children with arthritis is social work evaluation to help families cope with the stress of a chronic illness. Management of pain (through relaxation, imaging, exercise) as well as recognition of the impact of the illness on the child and his or her family hastens the youngster’s return to normal activities.

Now that better diagnostic tools and more effective therapies are in place for the treatment of children with arthritic diseases such as juvenile rheumatoid arthritis, we have seen a marked decrease in their needs for joint replacements. (Only one hip replacement has been performed in the past 11 years). Other than this child, none of the youngsters with JRA we care for require a wheel chair, in contrast to the clinics of years gone by. So far, it has been a very rewarding experience! But just wait until the next chapter!

REFERENCES

1. Nepom, B: The immunogenetics of juvenile rheumatoid arthritis. Rheum Dis Clin N Amer 1991;17:825–842.

2. Pachman LM, Goronzy JJ, Miller ML, Liotta M, Mendez E, and Weyand CM: HLADRB1 antigens in children with symptoms of systemic onset juvenile rheumatoid arthritis (S0–JRA). Arthritis Rheum 1997;40:S241(Abstr.)

3. Pachman LM, Poznanski AK: Juvenile (rheumatoid) arthritis. In Arthritis and Allied Conditions, WJ Koopman (ed), Baltimore: Williams and Wilkins, 1996;1155–72.

4. Miller ML, Szer IS, Yogev R, and Bernstein BH: Fever of unknown origin.Pediatr Clin N Amer 1995;42:999–1015.

5. Ekon KB, Hughes GR, Bywaters EGL, et al: Adult-onset Still's disease: Twenty-year follow up and further studies of patients with active disease. Arthritis Rheum 1982;25:647–654.

6. Poznanski AK, Hernandez RJ, Guire KE, Bereza UL, and Garn SM: Carpal length in children — A useful measurement in the diagnosis of rheumatoid arthritis and some congenital malformation syndromes. Radiology 1978;129:661–668.

7. Burgos-Vargas R, Pacheo-Tena C, and Vazquez-Mellado J: Juvenile-onset spondyloarthropathies. Rheum Dis Clin N Amer 1997;23:569–598.

8. Scott JP, Gerber P, Maryjowski MC, and Pachman LM: Evidence for intravascular coagulation in systemic onset, but not polyarticular, juvenile rheumatoid arthritis. Arthritis Rheum 1985;28:256–261.

9. Woo P: The cytokine network in juvenile chronic arthritis. Ann Med 1997;491–498.

10. Singsen BH, and Goldbach-Mansky R: Methotrexate in the treatment of juvenile rheumatoid arthrtitis and other pediatric rheumatic and nonrheumatic disorders. Rheum Dis Clin N Amer 1997;23:811–840.

11. Klein-Gitelman MS, Pachman LM: IV pulse corticosteroids (CS): Adverse reactions are more variable than expected in children. Arthritis Rheum 1995;38:S338; in press, J Rheumatology, 1998.

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