Current Medication Choices in Juvenile Rheumatoid Arthritis II - Update of a Survey Performed in 1993

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Current Medication Choices in Juvenile Rheumatoid Arthritis II –Update of a Survey Performed in 1993

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Hermine I. Brunner; Kwan N. Kim; H. Ballinger; Suzanne L. Bowyer; A. ; Gloria C. Higgins; Mier; Murray H. Passo; Rennebohm; Schikler; J. Lovell

Children’s Hospital Medical CenterCincinnati, Ohio (HB, KK, TG, MP, DL) Whitcomb Riley HospitalIndianapolis, Indiana, (SHB, SLB)Children’s Hospital, ColumbusOhio (GH, RR)Shriner’s HospitalLexington, Kentucky (RM)Department of PediatricsUniversity of Louisville, LouisvilleKentucky (KS).

JCR: JOURNAL OF CLINICAL RHEUMATOLOGY 2001;7:295-300

[Click here for reference links. (6 references linked.)]

The documentation of treatments used for Juvenile Rheumatoid Arthritis (JRA) is important to allow for the evaluation of practice patterns for future outcome studies. A survey of nine pediatric rheumatologists was performed between September 1999 and February 2000. Each of the physicians prospectively recorded demographic and treatment information on consecutively sampled JRA patients (n=395). Pauciarticular onset JRA was present in 46%, polyarticular onset JRA in 35%, and systemic onset JRA in 19% of the children. Naproxen was the most frequently prescribed medication (55% of the patients), followed by methotrexate (MTX), which was used in 39% of the patients. Folic acid supplementation (1 mg/day) was provided to 69% of the patients treated with MTX. Etanercept was used in 11% of the children. Eleven percent of the patients received corticosteroids, and 13% of children on corticosteroids took calcium supplements. Uveitis was present in 8% and had a chronic course in 79% of those cases. Although systemic medications were used in 50% of the children with uveitis to control eye inflammation, severe damage to the eyes developed in 30% of them. Fourteen percent of the patients required gastroprotective medications. Compared with findings of a similar survey performed in 1993, there was no significant change in the frequency of use of naproxen, but nabumetone is now more often prescribed, and COX-2 inhibitors have been introduced in the therapy of JRA. Changes among second-line agents used for JRA have also occurred, although there was no change in the frequency of use of MTX or corticosteroids. JRA continues to be a treatment challenge for the practicing pediatric rheumatologist. Patients often show incomplete response to the currently available medications. Therefore, new therapeutic agents need to be evaluated for their use in JRA, and the treatment of JRA associated uveitis especially needs to be improved.

Key words: Juvenile rheumatoid arthritis; Juvenile idiopathic arthritis medications; Treatment; Children

Juvenile Rheumatoid Arthritis (JRA) is a group of chronic inflammatory autoimmune diseases of childhood. In JRA especially the joints are affected, and no curative therapy is available at the current time (1). Changes of therapies used for JRA occur regularly but are poorly documented. Surveys of JRA patients seen in clinical practice are more suitable than clinical trials of highly selected patient populations to evaluate treatment patterns in JRA. Documentation of therapies is required for the estimation of costs associated with JRA. The documentation of treatment patterns is also important to evaluate practice variation, to provide information for future studies, and to help explain differences in long-term outcomes based on the treatments used in the past. The survey may also help to estimate the duration of the enrollment periods of future studies based on the estimated number of patients treated with certain medications.

PATIENTS AND METHODS

Nine board-certified pediatric rheumatologists, all of whom practice in the Midwestern United States, participated in the survey performed between September 1999 and February 2000. All were experienced clinicians and attending physicians at pediatric rheumatology referral centers. Data were obtained from consecutively sampled patients seen in clinics. All included patients fulfilled the American College of Rheumatology (ACR) diagnostic criteria for JRA (2). Information was collected regarding onset and course type of JRA, some complications associated with JRA and its treatment, and the medications used for therapy.

Statistical analysis to test for differences between disease subtypes of JRA and among physicians was done by using chi-square tests, Fisher-exact tests when appropriate, and the Kruskal-Wallis statistic.

RESULTS

Demographic Data

Composition of cohort.

The nine physicians actively follow a total of approximately 1000 JRA patients. Three hundred and ninety-five of these patients were surveyed (Table 1). The onset-type of 7 patients was not reported, and in 20 patients no information was available regarding the disease course. Thirty-eight of the 179 (21%) patients with pauciarticular onset JRA had a polyarticular course, whereas 133 out of 179 (74%) continued to have no more than 4 inflamed joints (disease course was unknown in eight patients with pauciarticular onset JRA). The youngest patient included was diagnosed at age 6 months, and 132 patients with pauciarticular JRA patients were diagnosed before 6 years of age (Table 1). Twenty-three patients with polyarticular JRA were at least 12 years of age at the time of diagnosis.

Table 1. Demographics of the surveyed patients with Juvenile Rheumatoid Arthritis (JRA).

Ophthalmologic lesions.

Overall, 33 out of 395 (8%) patients had a history of uveitis, and 26 of them still had active eye disease at the time of assessment (Table 2). Therefore, remission of uveitis was observed only in about 21% ( 733) of the cases. Therapy of uveitis often required ( 1326, 50%) systemic medications, i.e., systemic medications were specifically commenced to treat active uveitis unresponsive to topical therapy only. Thirteen percent ( 23179) of the patients with pauciarticular JRA, but only 7% ( 10134) of those with polyarticular JRA developed inflammatory eye disease. None of the patients with systemic JRA had uveitis. Thirty-nine percent ( 1333) of the JRA patients with uveitis developed significant ocular complications. There were 10 ( 1033, 30%) cases of cataracts and 9 cases ( 933, 27%) of glaucoma. Decreased visual acuity was present in 11 out of 33 ( 33%) patients. Eight patients (833, 24%) with uveitis developed band keratopathy.

Table 2. Treatment of inflammatory eye disease in patients with Juvenile Rheumatoid Arthritis (JRA).

Medications

Forty-three of the 395 patients (11%) were in remission and off therapy. NSAIDs alone were sufficient to control the arthritis in 95 children ( 95395, 24%), 20 children ( 20395, 5%) were only treated with intraarticular steroids, and another 20/395 patients (5%) were treated only with MTX. Thus, including the 4 patients on etanercept alone, single-agent therapy was employed in 139 of the 395 patients (35%). Second-line agents were used in 195 patients. The majority of these patients ( 135195, 69%) received only one second-line agent, but in some patients up to four different agents were used concurrently (average number of second-line drugs per patient: 1.45 = 284195). Gastroprotective agents were given to 57 of the 395 (14%) patients, and 54 of these 57 patients were treated with NSAIDs and/or corticosteroids. Calcium supplements were prescribed to only 13% of the 45 children treated with corticosteroids.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

NSAIDs were prescribed to 303 of the 395 patients (77%). Among the NSAIDs, naproxen was the most frequently prescribed, followed by nabumetone (Table 3). There were 353 patients in the cohort that had been treated with naproxen at some point in time during their disease. While exposed to naproxen, 46 out of 353 (13%) children experienced side effects from this medication (16 patients with skin fragility and/or scarring, 25 patients with nonlife-threatening gastrointestinal (GI) side effects, and 1 patient each with hives, nonspecific rash, hair loss, headaches, and somnolence). Eleven of the 16 patients ( 1116, 69%) with skin fragility and/or scarring secondary to naproxen had fair skin, while the prevalence of fair skin of all patients exposed to naproxen was only 43% Therefore, fair skin seemed to predisposed to the dermal side effects of naproxen (p=0.04). In all but 2 of the 16 children with skin fragility and/or scarring, naproxen was subsequently discontinued and replaced by another NSAID in some (n= 8). No information is available regarding side effects associated with the use of NSAIDs besides naproxen.

Table 3. Nonsteroidal anti-inflammatory medications (NSAIDs) used for the treatment of patients with Juvenile Rheumatoid Arthritis (JRA).

Second-line agents.

Second-line agents were used in 195 of the 395 patients (49%). MTX was the most frequently prescribed second-line agent, followed by etanercept and oral corticosteroids (Table 4).

Table 4. Use of secondline agents in patients with Juvenile Rheumatoid Arthritis (JRA) in 1993 and 2000.

Methotrexate (MTX).

A total of 153 patients were treated with MTX (Table 5). In 51 of 153 (33%) MTX-treated patients, the drug was given in combination with other second-line agents. MTX was taken orally in 59% of the patients, and administered by subcutaneous injection in 41% of the patients. The weekly subcutaneous injection of MTX was most commonly done by family members (76%), followed by nurses (7%) and the patients themselves (7%). MTX was used in the majority of the patients with polyarticular-course (57%) or with systemic JRA (52%) (Table 5). Patients with systemic JRA received, on average, higher doses of MTX as compared with children with polyarticular or pauciarticular JRA.

Table 5. Methotrexate (MTX) use in patients with Juvenile Rheumatoid Arthritis (JRA).

Corticosteroids.

Oral or pulse intravenous corticosteroids were used in 45 patients ( 45395, 11%). Forty percent of all patients with systemic-course JRA ( 2050), but only 14% ( 19134) of JRA patients with a polyarticular course required oral or intravenous corticosteroids for disease control. Daily oral dosing, as opposed to every other day corticosteroids, was used in 42 of the 45 patients, and all 4 patients treated with intravenous methylprednisolone had systemic JRA and also received daily oral corticosteroids (Table 6). Intraarticular steroids (triamcinolone hexacetonide) had been used for the therapy of 44% ( 174395) of the JRA patients in the past, and 11% ( 43395) of them received joint injections within the three-month period preceding the survey. No information was collected regarding possible side effects associated with intraarticular corticosteroid therapy.

Table 6. Oral and intravenous corticosteroid use in patients with Juvenile Rheumatoid Arthritis (JRA).

Etanercept.

This biologic agent was used in 45 out of 395 (11%) patients. Thirty-one children treated with etanercept concomitantly received another second-line agent (MTX in 10 patients, MTX plus corticosteroids in 8 patients, and various other combinations including leflunomide, hydroxychloroquine, sulfasalazine, and cyclosporine in others).

Variation of treatments among the surveyed physicians

There were no important differences in the groups of patients surveyed by each of the physicians, i.e., patient groups did not differ significantly with regard to the onset type or course type of JRA and had similar disease duration and age at the time of assessment. There were no important differences among physicians regarding the frequency of prescribing MTX, but they differed significantly in the dose of MTX used (p<0.05), as well as the route chosen for its administration (orally versus subcutaneous) (p<0.05). Overall, 69% of the patients on MTX received concomitant folic acid supplementation. However, there was a large (range 0%–100%) and statistically significant (p<0.002) variation among physicians in prescribing folic acid (1mg daily) to MTX-treated patients. These highly statistical significant differences in suggesting folate supplements among physicians persist, even if the 400g of folate contained in generic multivitamins were to be considered as sufficient folate supplements for children treated with MTX. There was no difference among physicians with regard to the use of corticosteroids, irrespective of the route of administration used. However, physicians varied significantly in the frequency with which they prescribed etanercept (range: 2%–20% of the patients; p<0.001).

Differences of treatments in the same physician group when compared with 1993

Compared with a study of consecutively sampled JRA patients treated by the same group of physicians in 1993, cyclooxygenase-2 (COX-2) inhibitors, leflunomide, etanercept, and minocycline were introduced in the treatment of the JRA patients surveyed, while the use of intravenous immunoglobulins and gold was no longer reported. Overall, there were no important differences in the frequency of use of NSAIDs, corticosteroids, or MTX since 1993. Although the frequency of the use of naproxen did not change significantly, nabumetone is now more often prescribed to patients ( 6266=, 2% in 1993 compared with 46/303, 15%) than in the past (Table 4). In addition, MTX is now more often given subcutaneously (26% in 1993 versus 41% in 2000), and there is a trend toward using higher doses of MTX (in polyarticular JRA: 0.32mg/kg in 1993 versus 0.39 mg/kg in 2000; in systemic JRA: 0.47 mg/kg in 1993 versus 0.50 mg/kg in 2000).

DISCUSSION

Treatments in JRA change over time due to the development of new medications and based on results of studies investigating their effects. Currently, NSAIDs remain the most common medication group used for the therapy of JRA, but almost half of the patients also require second-line agents. Steroids are still important second-line agents. Etanercept, a newly available TNF- blocking agent that was approved by the Federal Food and Drug Administration (FDA) for JRA in May of 1999, is already being used frequently in clinical practice in the US.

Unlike treatment regimens before 1996 (3–5), gold was no longer used for the treatment of JRA by these physicians. Likewise, intravenous immunoglobulins, cyclophosphamide, and penicillamine were used by some to treat JRA in the past (3–5). These medications were not given to any of the 395 JRA patients surveyed for the current study. This likely constitutes an overall change in the treatment of JRA, since the more effective TNF- blocking agents have become available (6). No difference in the frequency of use of naproxen, MTX, or prednisone was observed between 1993 and 2000. Although this consistency might be based on persisting individual treatment customs of the surveyed physicians, it is more likely that naproxen, MTX, and prednisone are still being used in clinical practice because of their superior effectiveness, side-effect profiles, and possibly lower costs when compared with other available medications.

The patients from each of the nine physicians lived in the Midwestern United States and had similar JRA demographics. Thus, differences in the frequency of prescribing etanercept, the dosing of MTX, and the use of folic acid likely constitute true differences in clinical practice patterns of the physicians surveyed.

Despite the use of topical and new systemic medications, the therapy of JRA-associated uveitis continues to be a challenge, as supported by the observation that inflammatory eye disease still often results in permanent damage.

As previously reported in 1993 (3) and 1996 (4), NSAIDs are the most commonly prescribed medications for JRA therapy. Naproxen and nabumetone are the two most frequently prescribed NSAIDs used by the surveyed physicians. Because naproxen is also available as a suspension, it can be used in very young patients. In contrast, nabumetone, a COX-2 preferential NSAID, is only available in tablet form, which limits its use to older patients. Nabumetone is frequently used for the treatment of arthritis in adults because of its twice-daily dosing regimen and its superior GI safety profile when compared with other NSAIDs (7). MTX also continues to be important (3, 4) for JRA treatment. This study demonstrates that MTX is often administered subcutaneously (versus orally) and in higher doses than in the past (3, 4).

Calcium supplements may help to prevent bone loss in children, which is especially observed when higher doses of corticosteroids are used (8). However, calcium supplements were prescribed to only 13% of patients treated with systemic corticosteroids (average corticosteroid dose in patients with calcium supplements was 0.16 mg/kg/d versus 0.29 mg/kg/d in corticosteroid-treated patients without calcium supplements).

A limitation of this study is the relatively small sample size compared with other surveys (4,5). However, the composition of the cohort is similar to previously examined cross-sectional JRA cohorts with respect to the disease-onset subtypes, course of the disease (9), and the prevalence of uveitis (10, 11). In addition, about 40% of the JRA patients followed by the physicians are reported, and all included patients were consecutively sampled from clinic to avoid selection bias.

The survey was performed by a group of pediatric rheumatologists from a single geographic region of the United States. Therefore, the observed trends in treatment patterns can only be documented for this part of the country. However, we are unaware of published data describing current treatment approaches of pediatric rheumatologists that are practicing in other parts of the United States.

This study supports that treatments of JRA change over time, especially with regard to the type of second-line agents used. MTX, corticosteroids, and etanercept are the most frequently used second-line agents at the current time. Despite the development of new drugs, corticosteroids are still used to treat some children with active JRA. Although commonly used, NSAIDs alone suffice to control the disease in only about 25% of the patients with JRA.

REFERENCES

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Address correspondence to: Hermine I. Brunner, MD, MSc, Children’s Hospital Medical Center - PAV 2-129, S. Rowe Division of Rheumatology, 3333 Burnet Avenue, Cincinnati, OH 45229. Fax: 513-636-4116. E-mail: brus9z@...

Journal of Clinical Rheumatology 2001 October;7(5):295-300 Copyright © 2001 Lippincott & Wilkins All rights reserved