The combination of methotrexate and infliximab, a chimeric monoclonal anti–tumor necrosis factor α (TNFα) antibody, has been shown to be very effective in reducing the signs and symptoms of rheumatoid arthritis (RA) (1, 2). There are theoretical reasons why early use of anti-TNF might interrupt monocyte/macrophage function, producing long-lasting clinical benefits (3). If these theories are correct, then early use of high-dose remission-induction therapy could become standard treatment. Currently, some clinically important questions about this therapeutic approach need to be addressed. First, is nonresponsiveness to anti-TNF attributable to insufficient doses, and, if so, can poor clinical response be overcome by use of an adequately high dose? Second, can use of very high-dose anti-TNF therapy early in the course of disease have a profound influence on outcome, allowing drug-free remission to be achieved? To answer these questions, we conducted a pilot study using high-dose infliximab, with reinduction if no remission occurred. State-of-the-art imaging modalities were used.
The study group comprised 5 patients with newly diagnosed inflammatory arthritis. All patients fulfilled the American College of Rheumatology (ACR; formerly, the American Rheumatism Association) criteria for RA (4) and had not previously received any disease-modifying antirheumatic drugs (DMARDs). Other inclusion criteria were RA of <12 months duration and ≥3 poor prognostic criteria (based on sex, C-reactive protein [CRP] level, rheumatoid factor [RF], shared epitope, and Health Assessment Questionnaire score ). The protocol was approved by the local ethics committee, and all patients gave informed consent.
Methotrexate therapy (increasing to a maximum dosage of 15 mg/week) began at baseline. Patients received infliximab, 10 mg/kg, at weeks 0, 2, 6, and 10. If remission had not occurred by week 12, they received a repeat, “reinduction” regimen. Standard clinical and laboratory outcome evaluations were performed at all time points. Magnetic resonance imaging (MRI) scans and high-resolution ultrasonography of the dominant hand (2nd to 5th metacarpophalangeal joints) were performed at weeks 0, 12, and 48, as previously described (6). The MRI sequences and scoring method were consistent with recent expert recommendations (7). Bone densitometry scans (spine, both femoral necks, and hands) were also performed at 0 and 48 weeks.
The mean duration of symptoms of the 5 patients was 7.3 months. Four patients were female, 4 had a positive family history of RA, 4 were RF-positive, and all 5 possessed the shared epitope (previously known as HLA–DR4 and DR1). At baseline, 1 patient had erosions on conventional radiographs of the hands and feet. The clinical and imaging outcomes are presented in Table 1. After the initial administration of 4 infusions of high-dose infliximab (3 times higher than the conventional dose), 1 patient was in remission, 3 showed highly significant improvement (2 ACR 70% response and 1 ACR 50% response ), and 1 demonstrated no improvement. The 3 patients who underwent reinduction of high-dose infliximab (1 patient did not undergo reinduction because of a previous infusion reaction) did not achieve further remission or improvement. In particular, the patient who showed no improvement following initial therapy also showed no response to reinduction, and that patient's serum CRP level increased after treatment. No patient achieved drug-free remission.
|Outcome measure||Week 0||Week 12||Week 48, responders|
|Early morning stiffness, minutes||105||300||0||300||10|
|Tender joint count||12||33||3||26||7.5|
|Swollen joint count||8.8||9||1.3||13||1.3|
|Patient's global assessment on 100 mm VAS||62||80||6||40||11|
|C-reactive protein, mg/ml||46||48||6||41||10|
|Health Assessment Questionnaire, raw score||11.8||19||3||15||2.8|
|MRI synovitis global score†||7||7||3||6||5|
|MRI bone edema sites‡||2.5||0||0.5||0||0.5|
|Ultrasound synovitis global score†||4||2||1.5||3||2.8|
Imaging modalities demonstrated a reduction in global synovitis (see Figure 1) in all 4 patients who responded clinically but not in the nonresponding patient, in whom the degree of synovitis was unaltered by therapy. The reduction in synovitis was accompanied by a dramatic reduction in bone edema as seen on MRI, and no joints with reduced synovitis according to MRI scans developed new erosions. Bone densitometry in the 4 responding patients demonstrated a small loss over 48 weeks compared with the nonresponder (average loss 1.6% versus 3.4%).
This unique experiment examined the effect of very high-dose TNF blockade at the time of presentation followed by reinduction in RA patients who did not achieve remission. We specifically included patients with a poor prognosis, who may be candidates for more aggressive initial therapy. Results of this study answered the questions initially posed. One of 5 patients did not respond to therapy, but the variable clinical response clearly was not attributable to an insufficient dose of infliximab. Repeat induction with high-dose therapy did not produce any greater response in the partial responders, and the nonresponder had no improvement whatsoever. A more likely explanation for the variable response may be the known heterogeneity of synovial TNF expression observed in patients with RA (9).
With respect to the disparity between nonresponse and radiologic damage, imaging showed a close correlation between response and reduction of synovitis in the imaged joints. Among patients who had a good response to therapy, synovitis was reduced, and no further joint damage occurred. The nonresponding patient had no reduction in synovitis and was withdrawn from the study at 6 months, after failed reinduction.
Prevention of damage is clearly relevant to long-term outcome. All previous studies of conventional DMARDs have indicated that bone loss, as measured by bone densitometry, continues despite aggressive therapy. Although this bone loss was slowed in our patients, it was not completely abolished, perhaps because true remission was not achieved in all cases. Finally, although a good response was seen in all but 1 patient (nonresponder), a more profound effect on the disease, allowing drug-free remission, was not seen. All patients had continued disease activity that required treatment with anti-TNF. It is therefore clear that the forces driving RA were not stopped by early administration of high-dose anti-TNF therapy.