Tumor Necrosis Factor Inhibitors May Slow the Progression of Spondyloarthritis

Rheumatologists prescribe tumor necrosis factor inhibitors (TNFi’s) to manage axial spondyloarthritis (axSpA) for some patients. In addition to their anti-inflammatory effects, TNFi’s have a wide range of direct effects on bone turnover, some of which may benefit axSpA patients. Example: A study in mice that overexpress TNF on the cell surface suggests that TNF may play a role in the ankylosis that occurs in patients with axSpA.¹

A 2021 study suggests that, for patients with axSpA, TNFi’s may reduce spinal disease progression, as measured by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS)—a radiographic, but not clinical, measure of disease progression. The findings by Alexandre Sepriano, MD, PhD, a rheumatologist at Egas Moniz Hospital, Lisbon, Portugal, and a researcher at the Leiden University Medical Center, the Netherlands, and colleagues from the University of Alberta, Canada, indicate TNFi’s may affect progression, as measured by the Ankylosing Spondylitis Disease Activity Score (ASDAS), a clinical measure of disease activity. TNFi’s may also have a direct effect on the progression of disease in the spine that is not captured by the ASDAS. The study results were published in the July issue of Arthritis & Rheumatology.²

Study Details

The cross-Atlantic collaboration recruited 314 patients with axSpA from both academic and community-based practices in northern Alberta, Canada, and followed the patients in clinical practice. The investigators evaluated treatment with a TNFi at each visit (yes/no; time-varying). They also analyzed treatment with TNFi according to the following definitions: treatment with TNFi at any time during the follow-up interval (yes/no; time-varying), duration of treatment with any TNFi during the follow-up interval (yes/no; time varying), proportion of time receiving TNFi treatment during the follow-up interval (continuous variable as a proportion of follow-up; time varying), duration of TNFi treatment <50% vs. or greater of the follow-up interval (yes/no; time-varying), and duration of continuous TNFi treatment (allowing for interruptions of a maximum of six months) ≤4 years vs. >4 years (yes/no; time-fixed).

“What we found,” says Dr. Sepriano, “is that there’s an effect of these drugs on the progression of disease in the spine.”

This observational study documented a reduction in clinical symptoms as measured by the ASDAS in patients treated with TNFi. The investigators were surprised to find the symptom reduction as measured by the ASDAS did not fully explain the beneficial effect of TNFi’s on structural progression. Thus, the researchers hypothesized TNFi’s affected progression indirectly by suppression of inflammation, as measured by the ASDAS, and directly, by inhibiting radiographic mSASSS progression. The authors propose that it does this through direct biologic actions on the bone. Example: TNFi may be acting on granulation tissue in the subchondral bone marrow.³ The cells that line the granulation tissue express typical markers of osteoblasts and osteoclasts. The invasion of the granulation tissue into the subchondral bone and the colocalization of aberrant bone formation with this tissue are consistent with the hypothesis that that this granulation tissue plays an important role in the progressive joint remodeling and ankylosis in radiographic axial SpA and may respond directly to TNFi.⁴ This direct effect does not appear to be captured by the ASDAS. In a caveat, the authors acknowledge this direct effect of TNFi’s on mSASSS scores may still be an effect of TNFi’s on inflammation not captured by the ASDAS.

When the investigators evaluated both the direct and indirect effects using longitudinal models adjusted for time-varying confounders, they found treatment with TNFi’s over time modified the longitudinal association between clinical ASDAS and radiographic mSASSS.The researchers documented a higher progression of ASDAS in patients never treated with TNFi’s compared with those continuously treated. In contrast, treatment with non-steroidal anti-inflammatory drugs (NSAIDs) during follow-up was not associated with a decreased progression of ASDAS. Although the study is limited by its observational nature, the investigators were able to perform robust estimates of the treatment effect, which reinforced the plausibility of the findings.

In their discussion, the authors emphasize the potential of managing axSpA via strategies that target suppression of the clinical symptoms measured by ASDAS and other measures of inflammation, such as magnetic resonance imaging (MRI).

Need for New Treatments

Walter P. Maksymowych, MD, a rheumatologist at the University of Alberta, Canada, and senior investigator of the study says, “What we lack in treating patients with SpA is the ability to prevent the progression of their disease.”

Disease progression is slow and can take years to be reliably visualized using radiography, which makes outcomes difficult to measure in clinical trials. Untreated, the disease can lead to bone fusion in the spine. Because randomized controlled trials are difficult to justify in axSpA, the investigators turned to an observational study to address this unmet need of patients.

“We cannot allow patients to be on a placebo for two years,” says Dr. Maksymowych. The authors explain that, although patients with rheumatoid arthritis can realistically enroll in a randomized controlled trial, it’s unreasonable to expect the same of patients with SpA, especially given the fact that TNFi’s are effective in treating symptoms and may even prevent disease progression through direct biological actions on the bone, as demonstrated by the inhibition of radiographic mSASSS progression.

Identifying Patients

Thankfully, not all patients with axSpA will develop ankylosis. And TNFi’s are associated with an increased risk of infection—a risk not all patients should take on.

“We don’t have good prognostic tools, and the difference between patients is quite substantial and not easy to monitor because you have to follow people for at least two years to reliably see the change,” says Dr. Maksymowych.

Thus, he emphasizes the importance of carefully evaluating the prognostic profile of each patient. According to Dr. Maksymowych, individuals at high prognostic risk of developing ankylosis include men who have the HLA-B27 haplotype and have active inflammation, as well as patients who already have new bone formation evident on radiographs when they are first seen.⁵

“You should be prepared to pull the trigger in these patients that much quicker when prescribing TNFi’s,” says Dr. Maksymowych. “Don’t waste time. … We certainly don’t want to see a patient developing ankylosis.”

Although Dr. Maksymowych points to findings on MRI, a consistent risk factor for disease severity that is affected by treatment and has been used as an outcome in clinical trials, he notes, generally, the field lacks risk factors for different stages of disease progression. “This is an area we think requires a lot more investigation and study,” he says. “We’re all looking for something that is a consistently strong predictor of radiographic progression.”

Dr. Maksymowych especially emphasizes the need to validate surrogates for new bone formation, which can serve as early warning signals of ankylosis. This approach could be a test for gene expression or production of a protein that is consistently associated with radiographic progression and is more responsive to intervention than the mSASSS instrument used to monitor change on radiographs.

References

1. Kaaij MH, van Tok MN, Blijdorp IC, et al. Transmembrane TNF drives osteoproliferative joint inflammation reminiscent of human spondyloarthritis. J Exp Med. 2020. 217:e20200288.
2. Sepriano A, Ramiro S, Wichuk S, et al. Tumor necrosis factor inhibitors reduce spinal radiographic progression in patients with radiographic axial spondyloarthritis: A longitudinal analysis from the Alberta Prospective Cohort. Arthritis Rheumatol. 2021 Jul;73(7):1211–1219.
3. Bleil J, Maier R, Hempfing A, et al. Histomorphologic and histomorphometric characteristics of zygapophyseal joint remodeling in ankylosing spondylitis. Arthritis Rheumatol. 2014 Jul;66(7):1745–1754.
4. Bleil J, Maier R, Hempfing A, et al. Granulation tissue eroding the subchondral bone also promotes new bone formation in ankylosing spondylitis. Arthritis Rheumatol. 2016 Oct;68(10):2456–2465.
5. MC Hwang Ridley L, Reveille JD. Ankylosing spondylitis risk factors: a systematic literature review. Clin Rheumatol. 2021 Aug;40(8):3079–3093