LONDON – Tumor necrosis factor may play a role in erosive hand osteoarthritis, and treatments such as etanercept that target this cytokine may help prevent progression of the condition, according to the results of two studies presented at the European Congress of Rheumatology.

In one of the studies, immunoscintigraphic detection of radiolabeled certolizumab pegol was used to show that tumor necrosis factor (TNF) was present in swollen finger joints. In another study, researchers looked to see if treatment with etanercept would have any specific effects on the joints of patients with erosive hand osteoarthritis (OA) and performed a separate analysis of the potential effect on synovitis and the effect on bone marrow lesions.

“We previously had the idea that TNF is an important cytokine in the pathogenesis of erosive [hand] osteoarthritis; but there have been no animal studies, and it’s very difficult to take biopsies or fluid aspiration from these small finger joints,” Dr. Ruth Wittoek, a staff rheumatologist at Ghent University Hospital in Belgium and a coauthor of all three studies, explained in a precongress interview. “We needed to look for other possibilities to really identify the presence of TNF in those affected joints.”

Dr. Wittoek and her associates used immunoscintigraphy to take static images of both hands of five patients with erosive OA immediately (less than 15 minutes) after administration of radiolabeled certolizumab pegol (early phase) and 4-6 hours following the injection (late phase).

The patients studied had erosive OA for a median of 8.4 years, and their median age was 55.6 years. All patients underwent clinical examination for presence of tenderness and palpable swelling of the joints and ultrasound 1 day prior to undergoing immunoscintigraphy.

All 18 interphalangeal (IP) finger joints were scored according to the anatomical phase scoring system on x-ray, and 90 IP finger joints were studied in total. The uptake of radiolabeled certolizumab pegol was semiquantitatively described as being absent, weak, or strong.

During the early phase following administration, uptake of the radiolabeled TNF inhibitor was seen in seven (7.8%) joints, although the uptake was described as weak in all cases. The radiolabeled TNF inhibitor was seen in 24 (26.7%) joints during the late phase following administration, with five instances described as strong uptake and the remaining 19 instances being weak uptake. No uptake of the radiolabeled TNF inhibitor was seen in metacarpophalangeal joints.

Uptake of the radiolabeled TNF inhibitor was linked to signs of disease activity, including tender, swollen, and radiographically active joints.

Late uptake was present in 12 (36.4%) of 33 tender joints and in 12 (21.1%) of 57 nontender joints (odds ratio, 2.1; 95% confidence interval, 0.8-5.6; P was nonsignificant).

The relationship was most pronounced with palpable joint swelling: Late uptake was present in 14 (61%) of 23 swollen joints and 10 (14.9%) of 67 nonswollen joints (OR, 8.9; 95% CI, 3.3-26.0; P less than .001).

Late uptake was present in 18 (29%) of 62 sonographically active joints (defined as any presence of effusion or synovial proliferation) but just 6 (21.4%) of 28 noninflamed joints (OR, 1.5; 95% CI, 0.5-4.3; P was nonsignificant).

Uptake of the radiolabeled TNF inhibitor was observed in all anatomical phases of erosive hand OA, Dr. Wittoek noted, but the strongest association was found during the final remodeling (R) phase.

“Soft-tissue swelling strongly correlated with uptake of certolizumab, meaning in these joints a lot of TNF was present,” Dr. Wittoek said. “These data further solidify the rationale for cytokine-directed therapies in erosive OA.”

Although the data provide proof of concept that TNF may be involved in erosive hand OA, the lack of a control tracer was noted as a limitation of the study after the investigator’s presentation. Dr. Wittoek conceded that it would be interesting to examine that in a future study.

So, if TNF is present, what effect does anti-TNF therapy have on the joints in erosive hand OA?

That question was addressed in a multicenter, double-blind, randomized, placebo-controlled trial involving 90 patients who were randomized to receive either 50 mg of subcutaneous etanercept weekly for 24 weeks, then 25 mg weekly for the remainder of 1 year (45 patients), or placebo (45 patients). Participants were a mean age of 60 years, 81% were women, and 96% fulfilled the American College of Rheumatology hand OA criteria.

“Synovial inflammation is often present in erosive hand OA; moreover, synovitis is associated with pain and with structural damage after around 2 and a half years,” the lead study author, Dr. Margreet Kloppenburg, a professor of rheumatology at Leiden University Medical Centre in the Netherlands, said in an interview.

“Therefore, we wanted to know whether blocking of synovial inflammation by a well-known drug such as etanercept would also have a positive effect on outcomes in erosive hand OA,” Dr. Kloppenburg explained.

The primary outcome measure was the level of OA pain assessed on a visual analog scale (VAS) at 24 weeks.

Secondary endpoints included assessment of hand function, quality of life, the number of tender joints, and grip strength after 4, 8, 12, 24, and 36 weeks, and after 1 year. Radiographic progression of IP joints was scored blindly at baseline, 24 weeks, and 1 year following the quantitative Ghent University Scoring System (GUSS). VAS pain was compared between treatment groups at 24 weeks and 1 year in intention-to-treat analyses.

Although etanercept was not superior to placebo on VAS pain at 24 weeks, it was superior to placebo both on pain and structural damage assessed by GUSS in the symptomatic and inflammatory patients who completed the study. The drug was especially effective in joints with signs of inflammation.

Overall, VAS pain in all patients decreased by 24.8 mm (95% CI, –29.2 to –20.5; P less than .001) at 24 weeks. In intention-to-treat analysis, differences in pain between the groups were in favor of etanercept but did not reach statistical significance. The per-protocol analysis of GUSS showed a mean difference in favor of etanercept, indicating more remodeling in the etanercept group.

Additional analyses showed an interaction between soft swelling/erythema and etanercept treatment on GUSS, resulting in a statistically significant (P less than .05) mean difference between the two treatment groups. More patients dropped out on placebo than on etanercept (six vs. three) because of inefficacy, whereas more dropped out on etanercept than on placebo (six vs. one) because of adverse effects.

“Synovial inflammation is an interesting target for treatment in OA patients with an inflammatory hand osteoarthritis phenotype,” Dr. Kloppenburg said.

A separate analysis of the same multicenter study suggests that etanercept is effective in inhibiting bone marrow lesions (BMLs) in patients with erosive hand OA.

The researchers studied 20 participants with symptomatic erosive OA with clinical and ultrasonographic signs of inflammation in at least one IP joint. The patients underwent contrast-enhanced MRI of the eight distal and proximal IP joints of one hand at baseline and 1 year. Images were scored for synovitis and BMLs (0-3 per joint, total score 0-24), blinded for patient characteristics.

Radiographs of the same hand were scored according to the Verbruggen-Veys system. Logistic regression was used to associate the presence of an MRI feature in a joint with being in an erosive versus nonerosive anatomical phase.

“Although erosive hand OA is a condition with a high disease burden, no disease-modifying treatments are available yet,” explained Féline Kroon, a PhD student in the department of rheumatology at Leiden University Medical Center in the Netherlands, in an interview. “Research to find a new form of therapy is partly hindered by our limited knowledge on the pathophysiology of the disease.”

However, “new imaging modalities like MRI enable us to study the pathophysiology of erosive OA more closely,” she said. “This study also gave us the unique opportunity to investigate whether anti-TNF, which is known to lead to clinical improvement and improvement of inflammatory lesions on MRI in other rheumatic diseases like rheumatoid arthritis, might also be effective in erosive OA.”

The presence of BMLs, but not synovitis, was associated with the presence of an erosive anatomical phase in a joint, and treatment with etanercept appeared to be effective in inhibiting these lesions. That suggests a role for TNF in the pathophysiology of erosive OA.

The inhibitory effect of etanercept on BMLs was more pronounced in IP joints with severe synovitis at baseline, suggesting that inflamed synovial tissue could be a source of TNF production in erosive OA.

The total synovitis score was similar at baseline and 1 year in both study groups. For BMLs, the median total score at baseline was 5.4 (range 2-9) and 7.0 (0-9) at 1 year in the placebo group, versus 4.5 (3-9) and 3.7 (0-8), respectively, in the etanercept group.

The presence of BMLs was associated with being in the erosive and remodeling anatomical phases of erosive hand OA. Synovitis was not associated with those phases.

“We think that TNF-alpha plays a role in the pathophysiology of erosive OA via an effect on the subchondral bone,” Ms. Kroon said. “Because we saw that the beneficial effect of etanercept on BMLs was more pronounced in joints with synovitis at baseline, we think that, in an inflamed synovial hand joint, an interaction takes place between synovium and subchondral bone, which could be influenced by blocking TNF.”

Pfizer and UCB supported the investigator-initiated studies and provided the study drugs. Dr. Kloppenburg has received lecturing, consultancy, and investigator fees or grants from AbbVie, APPROACH, GlaxoSmithKline, Levicept, Pfizer, Servier, and UCB, all paid to her institution. All other authors declared no conflicts of interests.

rhnews@frontlinemedcom.com

Anti-TNF agents may slow erosive hand osteoarthritis