Symposium on Adolescent Medicine

Juvenile Rheumatoid Arthritis and Systemic Lupus Erythematosus in the Adolescent Edward M. Sills, M.D. *

JUVENILE RHEUMATOID ARTHRITIS A discussion of juvenile rheumatoid arthritis in the adolescent must be divided into those instances in which the onset of the disease is in early childhood and those instances in which the onset of the disease is at age 12 years or older. In the first instance the child's disease has been diagnosed, the chronic patterns of the illness have been established, and the major objective is to assist the child and his family in coping with adolescence within the limits of the illness. In the later case, in addtion to the above, the problem of differential diagnosis, education of the child, his family and school teachers about the disease, and the initiation, titration, and manipulation of medical, surgical and physical therapy. The discussion here will focus on the latter instance. For this discussion juvenile rheumatoid arthritis is defined as a disease of varying clinical manifestations; an infrequent occurrence of rheumatoid factor and rheumatoid nodules, the frequent occurrence of arthritis limited to a few joints, usually large joints, the association with iridocyclitis and the occasional prominence of systemic symptoms. It is useful to divide rheumatoid arthritis into two major groupings: seronegative, usually with onset before age 16, although series of this seronegative disorder in adults has been reported,2. 4 and seropositiv~, usually with the onset after age 16 and characterized by minimal incidence of the systemic and ophthalmologic abnormalities associated with the seronegative group. In the adolescent, this type of classification is most useful, for the presence or absence of rheumatoid factor is a more reliable predictor of disease evolution than is the arbitrary division based upon age of onset. In addition to these rheumatoid arthritides, the physician treating the adolescent must be aware of a third group which *Assistant Professor of Pediatrics, The Johns Hopkins University School of Medicine; Direc-

tor, Children's Collagen-Vascular and Pediatric Referral Services, The Johns Hopkins Hospital, Baltimore, Maryland

Medical Clinics of North America- VoL 59, No. 6, November 1975

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is largely seronegative and consists of the non-rheumatoid arthritides, idiopathic ankylosing spondylitis, psoriatic arthritis, Reiter's disease, the intestinal arthropathies (ulcerative colitis, Crohn's disease, Whipple's disease), and Beh~et's syndromeY There has been a recent deluge of evidence that this third group of diseases are Closely interrelated to one another and to seronegative juvenile onset arthritis on the basis of HL-A antigen typing, which indicates that susceptibility to these arthropathies may be linked to the major histocompatibility genes. L 10, 11 The onset of juvenile rheumatoid arthritis has two peaks, the first occurring prior to age 4 years and the second just following the attainment of peak height velocity in early adolescence. This latter group makes up about 30 per cent of our total group of youngsters with rheumatoid arthritis. Of these 28 patients with onset in adolescence, there are 19 girls and 9 boys. Three presented with an acute systemic onset, 1 with a prominent pericarditis; two with uveal tract symptoms, both female and both developing pauciarticular synovial disease within 3 years of first eye symptoms; 9 with polyarticular disease (4 or more joints involved) and 14 with pauciarticular presentations (three or fewer joints). Two of the children with polyarticular disease had rheumatoid nodules. Six of the 9 polyarticular presentations including the two with nodules were seropositive for rheumatoid factor(s). The multiple manifestations of juvenile rheumatoid arthritis make it a prime candidate for confusion with other disorders. We 12 recently reviewed 50 consecutive children referred to the Children's Medical and Surgical Center of the Johns Hopkins Hospital with a presumptive diagnosis of juvenile rheumatoid arthritis. The children ranged in age up to 15 years. In all but 7 instances, medical therapy for rheumatoid arthritis had been instituted. On the basis of physical and laboratory examinations, one third of the children had a disorder other than juvenile rheumatoid arthritis. Seventy-five per cent of the misdiagnosed patients had monarticular complaints. Of particular concern is the existence of malignancy, chronic infection, and other connective tissue disorders that mimic arthritis. The important task of the physician is to recognize diseases of potentially serious consequence. The diagnostic problems essentially fall into two groups: patients with monarticular arthritis and those with polyarticular involvement. In children with monarticular disease the major confusion is with trauma when fever is not present and with septic arthritis when it is. The misdiagnosis of traumatic arthritis is frequently followed by bed rest, immobilization, or even casting. This can lead to muscle atrophy, flexion contractures, and osteoporosis, all of which are exaggerated in the child with rheumatoid disease. In febrile patients with monarticular arthritis one must always suspect septic arthritis. Whenever there is a question of septic arthritis, the joint must be aspirated and the synovial fluid analyzed and appropriately cultured. It is not unusual for osteomyelitis with or without concomitant septic arthritis to be mistaken early in its course for juvenile rheumatoid arthritis. When dealing with polyarticular arthritis, one must stiit consider septic arthritis although other diagnoses are more likely. It should be

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remembered, however, that even when patients with compromised host responses, such as in sickle cell disease, are excluded septic arthritis is polyarticular in about 20 per cent of cases. When multiple joints are involved, the differential diagnosis is extensive and includes acute rheumatic fever without carditis, malignancies (especially leukemias), various osteochondroses and a host of nonrheumatoid arthritides which include ankylosing sypondylitis, psoriatic arthritis, Reiter's disease, the intestinal arthropathies (the inflammatory bowel disorders) and Behcet's syndrome. In most instances of rheumatoid arthritis the burden of diagnosis rests largely on the history and physical findings. Laboratory and radiographic studies are most useful in excluding other disorders but-fail to definitively diagnose rheumatoid disease. The diagnostic criteria proposed by Bywaters 3 are useful in organizing one's approach to diagnostic evaluation. These include the onset of disease before age 16 with 2 or more joints involved for a minimum of 3 months with swelling or pain and limited motion. If monarticular involvement is the case, the joint must be involved for a minimum of 3 months with swelling or pain and limited motion and there should be biopsy evidence consistent with rheumatoid arthritis, showing synovial hyperplasia and a predominant infiltration of lymphocytes and plasma cells. If there are several other factors present including radiographic, serologic, rash, fever, ophthalmologic, and cervical findings, diagnosis can be made after 6 weeks in either monarticular or polyarticular disease. When the diagnosis is not clinically apparent, one should rapidly exclude malignancies, infections, and rheumatic fever, and then carefully observe and evaluate the patient's course. So long as immediately hazardous conditions are excluded, the several weeks or even months required for a firm diagnosis are appropriate. It is not unusual for the initial investigation to exclude urgent causes, yet leave the diagnosis unclear; consequently, one must astutely observe and re-evaluate the patient at a later date. Sufficient manifestations will ultimately allow the diagnosis to be made if an open mind is maintained. Of particular concern in seronegative rheumatoid disease is the chronic iridocyclitis. It is potentially the most disabling aspect of this disease because if undiagnosed and untreated, it can eventuate in blindness. The iridocyclitis can have its onset many years before or after the appearance of joint manifestations. Approximately one third of patients who develop eye disease do so within one year of the onset of joint disease. The remaining two thirds develop it at variable times and frequently at long intervals before or after the appearance of joint disease. Iridocyclitis occurs in approximately 15 per cent of all patients with this form of rheumatoid disease. There are, however, several factors which favor its occurrence. In females with early disease onset, pauciarticular disease and antmuclear antibodies the risk factor approaches 100 per cent for the development of iridocyclitis at one time or another. The iridocyclitis is chronic, is usually severe, and tends to develop independently of the activity of the arthritis. Early signs are often, if not usually, missed. The disease is usually confined to the anterior seg-

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ment and is usually bilateral. Primary inflammation occurs in the iris and the ciliary body and inflammatory cells and protein appear in the anterior chamber. Clumps of cells may be deposited on the posterior surface of the cornea and on the anterior surface of the lens. Fine adhesions form between the anterior lens and the posterior iris. These synechiae may become permanent, creating an irregular, nonreactive pupil which cannot be dilated. Secondary glaucoma usually results as the synechiae close off communication between the anterior and posterior chambers. Band keratopathy and cataract formation are sequelae of this disorder. The slit lamp is the sole instrument used in detection of early iridocyclitis. Routine ophthalmoscopic examination may detect decreased visual acuity, gross amounts of protein and cells in the anterior chamber, irregular pupil pigment deposits on the anterior lens, and lens opacity. These, however, occur late in the disease after most of the damage has taken place. Treatment in early stages with topical antiinflammatory and dilating agents will suppress progression of the eye disease. It is, therefore, absolutely essential that patients with juvenile onset rheumatoid arthritis be examined with a slit lamp at least twice yearly. In high risk cases, slit lamp examination should be performed every 3 to 4 months.

TREATMENT

In addition to relief of inflammation and pain, the preservation of growth potential and functional capacity are major objectives of therapy. Constant awareness of the potential for disabling iridocyclitis and for the overwhelming psychological and social problems must be maintained in the setting of medical, surgical, physical, and occupational therapy. Excellent physical and occupational therapy is required to prevent and correct deformities. The aims are to maintain and increase the range of joint motion as well as to maintain and increase muscle strength and tone. In addition to supervised exercises, night splinting assists in correcting or preventing deformity. Moist heat is useful for stiffness, swelling, and joint pain. The adolescent, with concerns of self and body image, is easily discouraged and constant reassurance is necessary. Therapy should be established with definite attainable goals. We actively encourage patients to stay in school for both scholastic and social reasons. In secondary schools where there is frequent changing of 'classrooms, arrangements should be made to allow the adolescent with a restricted gait extra time for changing rooms. Teachers and school nurses should be informed of the patient's condition and limitations, but at the same time we must remind them to avoid overprotection and isolation of the patient. The tendency of school officials to overprotect the arthritic child is particularly significant in the areas of college and vocational counseling All too frequently the image of a wheel-chair bound, heavily braced adult arthritic is so prevalent that it

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tends to limit the opportunities to which youngsters with arthritis are exposed. This is an inappropriate attitude. If capacity and motivation are present, there is virtually no area of educational or vocational training which should be closed to teenagers with rheumatoid disease. Drug therapy centers about agents which effectively suppress the inflammatory response, relieve pain, and control fever. Aspirin is the preferred agent to achieve these ends. We attempt to achieve a serum level close to 25 mg per cent which usually requires about 100 mg per kg of aspirin daily in 4 divided doses during waking hours. These levels are maintained until the joint disease is quiescent for at least 6 months, at which point the salicylates are gradually tapered. We have found problems of salicylism and salicylate toxicity to be minimal and infrequent, provided there is assiduous monitoring. The major difficulties with chronic salicylate administration is compliance. Water-soluble gold salts are used in instances where severe polyarthritis does not improve or its progression is not halted in the face of 4 to 6 months of adequate salicylate therapy or in patients who have been placed on steroids and are resistant to withdrawal from the steroids. Unfortunately, gold is not absorbed well from the gastrointestinal tract and cannot be administered orally. Weekly intramuscular injections are required and are relatively painful. The liabilities of heavy metal toxicity, the potential for hypersensitivity reaction, the discomforts of frequent intramuscular injections and the frequent surveillance of hematologic and renal status must be weighed against the risks of progressive functional and growth deterioration. The most convincing study on the beneficial role of gold in rheumatoid arthritis is the doubleblind trial conducted by the Research Subcommittee of the Empire Rheumatism Council in 24 British centers reported in 1961.5,6 In seriously ill patients systemic steroids are occasionally used. Steroids do not prevent complications of the disease nor do they appear to ultimately influence prognosis. The only absolute, clear-cut indication for steroids is iridocyclitis. The toxicity of glucocorticoids especially in the growing adolescent is awesome. Attempts to reduce dosages frequently lead to arthritic withdrawal rebounds in which the symptoms are usually more severe than the initial indications for the use of steroids. Antimalarial drugs tend to produce severe adverse reactions in the retina and can compromise peripheral vision as well. Accordingly we avoid their use. Indomethacin is an effective drug whose usefulness is often minimized by the frequent vomiting and nausea experienced by some patients. It shourd not be used in patients under the age of 14 years.We have found it particularly useful in relieving symptoms of those adolescents who have sacroiliac arthritis or ankylosing spondylitis. A dose of 25 to 50 mg at bedtime effectively relieves the following morning's joint stiffness in many of our rheumatoid patients. Surgical treatment is controversial and depends on the talent and enthusiasm of local orthopedic colleagues. Total synovectomy effect-

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tively suppresses synovitis. Excellent rehabilitation including manipulations and physical therapy are essential following synovectomy and depend upon the availability of appropriate staff support. Once linear growth is completed, tendon lengthening, reconstructive surgery, and insertion of hip and knee prostheses are useful procedures in selected patients. Juvenile onset rheumatoid disease is a situation in which the physician must pay careful attention not only to drugs but to careful, frequent re-evaluation of the diagnosis, frequent ophthalmologic evaluation, renewal of physical therapy, splinting, and ascertainment of optimal educational and socializing opportunities for the patient.

SYSTEMIC LUPUS ERYTHEMATOSUS At the Johns Hopkins Children's Medical and Surgical Center in the period during which 28 new cases of juvenile rheumatoid arthritis were diagnosed in adolescents, there were 13 cases of systemic lupus erythematosus diagnosed in teenagers. Ten patients were females of which 4 presented with hepatosplenomegaly and 3 with myocarditis. Sclerodactyly was present in all 3 male patients. Femoral artery thrombosis occurred in 2 girls. Thrombocytopenia was a persistent problem in 5 patients. All 13 had positive tests for antinuclear factors and 12 of the 13 had low serum complement levels. Nine of the girls and 1 of the boys had renal involvement. Seven experienced synovial disease. Most of our patients have required prolonged treatment but can lead useful lives. We carefully establish with the patient and family at the outset that long-term medical supervision is required and that there are no spontaneous remissions or sudden cures. In addition to drug treatment, the patient with systemic lupus erythematosus requires careful management of the arthritis, possible ultraviolet sensitivity, and liabilities associated with immunosuppressive and/or corticosteroid therapy. Patients should be given full benefit of active physical therapy to maintain joint range of motion and allow for maintenance of muscle strength and tone. Sun screening lotions and creams are effective at excluding ultraviolet light and should be used on exposed skin tluring the summer months. The patient with systemic lupus erythematosus who is treated with prednisone is at risk for the development of many infetions. Tuberculosis is a notorious complication and patients should be carefully observed for this. Fungal infections should be anticipated and aggressively treated when they occur. The patient with lupus who is on steroids and develops arthritis is likely to have a septic joint process rather than "benign lupus arthritis." Each child with lupus taking steroids who develops synovial disease should have joint aspiration. About 46 per cent of these taps in our experience have revealed pyarthrosis. The clinical manifestations of infected and non-infected patients are identical and even in retrospect it is usually impossible to adequately identify which patient was infected without

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joint aspiration. A high index of suspicion, therefore, and constant vigilance in seeking evidence of infection must be maintained. TREATMENT

Medication is directed at stopping inflammation due to antiDNA-DNA complexes and complement fixation. Attempts have been made to release DNA complexes from the tissues of patients, to prevent antiDNA-DNA binding and to diminish the production of antiDNA-DNA antibodies. Corticosteroid drugs potently affect the disease by reducing inflammation and perhaps preventing the fixation of circulating complexes in tissues since antiDNA antibodies disappear and serum complement levels return to normal. The usual starting dose of prednisone is in the range of 2 mg per kg per day. The dose should be tapered when signs of continued disease activity have been eradicated. In addition to clinical manifestations, evidence of complement elevation and decreasing titer of antinuclear antibodies are indications that the disease is being suppressed and that the prednisone dose can be tapered. At the first sign of exacerbation during the course of tapering the dose should be increased by about 5 mg per day which is often adequate to regain control. The ultimate aim is to maintain the patient on the lowest possible dose at which clinical symptoms are absent. If possible, the dose should be tapered until the patient is off the drug. Antimalarial drugs have been used in systemic lupus erythematosus and are effective in providing long-term suppression. They are occasionally useful in reducing the daily dose of prednisone. Their use, however, must be tempered by the recognition that an irreversible and self-perpetuating retinopathy caused by the deposition of the drug in the pigmented epithelium of the retina can occur. The abnormalities usually begin in the macula and progress rapidly in a radial distribution. These abnormalities do not appear to reverse after the drug is discontinued. In those patients in whom joint symptoms are the major manifestations of the disease, aspirin is an effective agent when used as detailed for use in juvenile rheumatoid arthritis. Additional medications are usually not necessary in this setting. In those patients with lupus nephritis complicated by the nephrotic syndrome and increasing renal insufficiency with an elevated serum urea nitrogen, immunosuppressive therapy may be considered. At this stage in patient management we strongly encourage referral to a major center where kidney biopsy can be performed and appropriate administration of immunosuppressive therapy can be instituted. If the biopsy reveals a diffuse, widespread disease within and among glomeruli, the patient should be started on a controlled administration of one of the immunosuppressive agents such as azathioprine or cyclophosphamide. The use of these immunosuppressive agents is not without significant

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potential danger in terms of their oncogenic potential and the occurrence of overwhelming sepsis and aplastic anemia.

OTHER COLLAGEN-VASCULAR DISORDERS In addition to the rheumatoid and lupus disorders in adolescents, we have observed patients with dermatomyositis, scleroderma, polyarteritis, and anaphylactoid purpura on our adolescent service. In the time span included in assembling the series of patients reported above, there have been seven teenagers presenting with an illness ultimately diagnosed as having a systemic angiopathy involving multiple organ systems, dermatomyositis. Our experience has been encouraging with the use of high dosage corticosteroids and active, aggressive physical therapy. The tragic and frustrating disorder, scleroderma, has been resistant to various attempts at aggressive therapy over the years. Spontaneous remissions however do occur in both the localized and systemic forms and do not appear to be more frequently correlated with one or another form of treatment. The treatment of scleroderma is focused on the control and prevention of infection and attempts to prevent or retard restriction of joint motion. Aggressive physical therapy, splinting and surgical procedures when indicated should be employed. Polyarteritis is rare but is often susceptible to treatment with corticosteroid drugs. The diagnosis is made solely on the basis of biopsy findings as the clinical manifestations are variable and often suggest a host of other disorders, most importantly, systemic lupus erythematosus. Anaphylactoid purpura is a disease involving skin, joints, intestinal tract and kidneys and may begin with anyone or combination of these organs involved. There is no evidence that treatment with steroids alters the outcome of renal involvement. The kidney disease is common in this disorder, and a review of the literature reveals an incidence of from 20 to 60 per cent of cases. 7 ,8 Kidney biopsy shows alternating normal and diseased glomeruli with interspersed focal hyaline glomerular scarring. Renal function must be carefully monitored in patients with anaphylactoid purpura and appropriate symptomatic therapy should be employed if arterial hypertension or diminished glomerular function develops. The arthritis of this disease is non-erosive and self-limiting; consequently there is no indication for the use of corticosteroids in treating this symptom. Gross or occult intestinal bleeding occurs in about 50 per cent of patients and in 5 per cent intussusception occurs. Because of the danger of these complications prednisone is suggested for a period of 1 week followed by 2 weeks of gradual tapering in patients with intestinal hemorrhage or severe abdominal pain.

REFERENCES 1. Brewerton, D. A., et al.: Ankylosing spondylitis and HL-A27. Lancet, 1 :904,1973. 2. Bujak, J. S., et al.: Juvenile rheumatoid arthritis presenting in the adult as fever of unknown origin. Medicine, 52:431,1973.

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3. Bywaters, E. G.: Diagnostic Criteria for Juvenile Rheumatoid Arthritis. Proceedings of Third International Symposium on Population Studies of the Rheumatic Diseases, Exerpta Medica Foundation, New York, 1968. 4. Bywaters, E. G. L.: Still's disease in the adult. Ann. Rheum. Dis., 30:121,1971. 5. Empire Rheumatism Council Subcommittee: Ann. Rheum. Dis., 19:95, 1960. 6. Empire Rheumatism Council Subcommittee: Ann. Rheum. Dis., 20:315,1961. 7. Hurley, R. M., and Drummond, K. N.: Anaphylactoid purpura nephritis. J. Pediat., 81: 904, 1972. 8. Meadows, S. R., et al.: Schonlein-Henoch nephritis. Quart. J. Med., 41 :241, 1972. 9. Moll, J. M. H., et al.: Associations between ankylosing spondylitis, psoriatic arthritis, Reiter's disease, the intestinal arthropathies and Behc;:et's syndrome. Medicine, 53 :343, 1974. 10. Morris, R., et al.: HL-A W27: A useful discriminator in the arthropathies of inflammatory bowel disease. New Eng. J. Med., 290:1117, 1974. 11. Rachelefsky, G. S., et al.: Increased prevalence of W27 in juvenile rheumatoid arthritis. New Eng. J. Med., 290:892, 1974. 12. Sills, E. M.: Errors in diagnosis of juvenile rheumatoid arthritis. Johns Hopkins Med. J., 133:88,1973. The Johns Hopkins Hospital Baltimore, Maryland 21205