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Ankylosing Spondylitis

TNF Inhibitor Therapy

Muhammad Asim Kahn, MD, FRCP, MACP; Nurullah Akkoç, MD 
Reviewed on July 15, 2024
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Introduction

Biologics targeting tumor necrosis factor α (TNF-α), tumor necrosis factor inhibitors (TNFis) have transformed the management of ankylosing spondylitis (AS) and related spondyloarthritis (SpA), and have become the cornerstone for management by improving functional outcomes and decreasing disease activity in those who do not adequately respond to or are intolerant of conventional therapies. In 2011, the Assessment of Spondyloarthritis International Society (ASAS) published an updated consensus statement on the use of TNFis for treatment of patients with definitive AS and also for those fulfilling the ASAS criteria for axial spondyloarthritis (axSpA) to allow for the earlier use of TNFis in the disease process. This recommendation set was updated and aggregated with the 2010 ASAS- European League Against Rheumatism (EULAR) recommendations on the management of AS into one set of management recommendations applicable to the full spectrum of patients with axSpA; the…

Introduction

Biologics targeting tumor necrosis factor α (TNF-α), tumor necrosis factor inhibitors (TNFis) have transformed the management of ankylosing spondylitis (AS) and related spondyloarthritis (SpA), and have become the cornerstone for management by improving functional outcomes and decreasing disease activity in those who do not adequately respond to or are intolerant of conventional therapies. In 2011, the Assessment of Spondyloarthritis International Society (ASAS) published an updated consensus statement on the use of TNFis for treatment of patients with definitive AS and also for those fulfilling the ASAS criteria for axial spondyloarthritis (axSpA) to allow for the earlier use of TNFis in the disease process. This recommendation set was updated and aggregated with the 2010 ASAS- European League Against Rheumatism (EULAR) recommendations on the management of AS into one set of management recommendations applicable to the full spectrum of patients with axSpA; the latest updated version of the ASAS-EULAR recommendations was released in 2022. The 2019 Update of the ACR/SAA/SPARTAN recommendations addressed the treatment of AS and non-radiographic axial spondyloarthritis (nr-axSpA) in two separate sets.

Inhibition of TNF-α is currently achieved by using a circulating receptor fusion protein named etanercept (Enbrel), or by monoclonal antibodies, such as infliximab (Remicade), adalimumab (Humira), golimumab (Simponi) and certolizumab pegol (Cimzia). Etanercept is a TNF-receptor–fusion protein conjugated to the Fc portion of human IgG. Infliximab, adalimumab and golimumab are monoclonal antibodies directed toward TNF-α. Certolizumab pegol is essentially different from these other TNFis since it is not a full antibody and does not include an Fc portion. It is a recombinant, polyethylene glycolylated, antigen-binding fragment of a humanized monoclonal antibody that selectively targets and neutralizes TNF-α.

Efficacy of TNF Inhibitors in AS

These biologics are now approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of adult patients with active AS unresponsive to conventional therapy based on the successful results of the pivotal phase 3 trials (Table 15-1). The EMA has approved the use of four TNFis (etanercept, adalimumab, certolizumab pegol and golimumab) also for the treatment of patients with non-radiographic axial spondyloarthritis (nr-axSpA) based on the successful results of the pivotal phase 3 trials (Table 15-1). The FDA approved only certolizumab pegol to treat nr-axSpA, based on a later study which addressed and resolved the key concerns raised by the FDA after reviewing the application files of adalimumab and certolizumab submitted for approval for this indication.

All TNFis show similarity in their efficacy in treating AS (Table 15-1), although no head-to-head studies have been published; the ASAS40 response at Week 24 varies between 39% and 48%. They lead to rapid and remarkable improvement in the symptoms and signs, including back pain and stiffness, peripheral arthritis and enthesitis. They also improve health-related quality of life, patient-reported outcomes, anemia, sleep quality, fatigue and bone density. Clinical improvement is accompanied by a significant decrease in inflammation, as evidenced by a dramatic reduction in C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). But it remains to be clearly established whether early effective treatment with TNFis can retard or prevent new bone formation.

TNFis are effective as monotherapy (without the need for concomitant methotrexate or other conventional synthetic DMARDs) and often maintain long-term efficacy. However, they may have a primary inefficacy or lose efficacy with time in some patients. Switching to an alternative TNFi or increasing the dose or frequency of administration may sometimes overcomes this problem.

The choice of TNFis should be guided by the presence of extra-articular manifestations and the patient’s preference because of differences in mode of administration (intravenous (IV) infusion vs subcutaneous (SC) self-injection) and the frequency of administration. Unlike etanercept, the TNF inhibiting monoclonal antibodies have been shown to be effective in treating IBD and they are also relatively more effective in preventing recurrent episodes of acute anterior uveitis than etanercept.

Elevated CRP and active sacroiliitis on magnetic resonance imaging (MRI) are the strongest predictors of structural damage in the sacroiliac joints (SIJs) and, therefore, of progression from a nonradiographic to a radiographic stage. The same parameters predict a good and a sustained clinical response in patients with AS/axSpA, especially if used in nonradiographic disease. Obese and overweight patients have a lower response rate to TNFis, and weight loss may improve response rate. There is impaired response to treatment with TNFis in smokers with AS/axSpA, and smoking is associated with a worse outcome.

For patients who attain good disease control, the best strategy for maintenance of disease control has not been established. Response to TNFis may be sustained over several years, but symptoms almost invariably return due to disease flare-up when anti-TNF therapy is completely stopped. It is unclear how long biologic-free remission is likely to be sustained or whether NSAID treatment might aid in maintenance of remission after the TNFi is discontinued. Because of the high cost of long-term treatment, some studies have shown that good disease control has been maintained with a reduction in anti-TNF dose in some patients. In a real-world setting, 60% of individuals with severe AS who achieve low disease activity can successfully reduce the dose of TNFi therapy by a third for a mean of 1 year.

The 2022 ASAS/EULAR recommendations advise to taper the biologic treatment in patients in sustained remission, while warning about increased flare risk in complete discontinuation. The 2019 American College of Rheumatology (ACR) guideline somewhat differs from the ASAS/EULAR recommendation. It recommends against the discontinuation of anti-TNF treatment in patients with stable disease and also against the tapering of biologics as a standard approach. However, the ACR guideline does admit that tapering could be considered in patients with prolonged stable AS. Withdrawal of biologic therapy in early axSpA patients with sustained remission results in more flares than the continuation of the therapy. However, the majority of those who flare are able to regain inactive disease state within 12 weeks.

Studies have established the efficacy of TNFis in the symptomatic treatment of juvenile SpA, although their efficacy for halting progression of structural damage is less clear. Treatment guidelines for juvenile arthritis, including juvenile SpA, have been published by the ACR and are based on active joint count and presence of sacroiliitis. The 2019 update of this guideline provided recommendations for different phenotypes of juvenile idiopathic arthritis. The new guideline recommended the use of biologics based on the disease activity and the risk of disabling joint damage in patients with polyarthritis, initial therapy with biologics being justified in the presence of high disease activity or involvement of high-risk joints. According to the new guideline, the addition of a TNFi was strongly recommended over NSAID monotherapy in patients with sacroiliitis and TNFi was suggested to be the preferred treatment in patients with active enthesitis despite NSAID therapy.

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Etanercept (Enbrel)

Etanercept 50 mg once weekly (or 25 mg twice weekly) as a SC injection has been shown to be tolerable and efficacious in decreasing symptoms and signs of active AS, as well as improving function, spine mobility and quality of life. The ASAS response criteria have been used to demonstrate sustained, long-term efficacy of all TNFis. For example, all patients with AS in a multicenter, open-label extension of a previous 24-week, double-blind, randomized-controlled study of etanercept, who subsequently enrolled in the open-label extension study (n=257), were followed for up to 192 weeks during the open-label portion of the study (Figure 15-1). Not shown in the figure are the Assessment of Spondyloarthritis International Society criteria for 20% improvement (ASAS20) and Assessment of Spondyloarthritis International Society criteria for 40% improvement (ASAS40) responses when calculated for the subjects who had at least one post-dose assessment, using last observation carried forward (LOCF) for missing data imputation. These responses were 67% for ASAS20 and 49% for ASAS40.

Enlarge  Figure 15-1: ASAS20 and ASAS40 Response in Patients With AS Treated With Etanercept. Results in patients treated with etanercept (A). Results in patients treated with placebo for the first 24 weeks and then switched to etanercept (B). After 192 weeks of etanercept exposure, the ASAS20 response was 81% and the ASAS40 response was 69% in the completer analysis (for all patients remaining in the trial at that time). Not shown in this figure are the ASAS20 and ASAS40 responses when calculated for the subjects who had at least one post-dose assessment, using LOCF for missing data imputation. These responses were 67% for ASAS20 and 49% for ASAS40. Source: Adapted from Davis JC Jr, et al. Ann Rheum Dis. 2008;67(3):346-352.
Figure 15-1: ASAS20 and ASAS40 Response in Patients With AS Treated With Etanercept. Results in patients treated with etanercept (A). Results in patients treated with placebo for the first 24 weeks and then switched to etanercept (B). After 192 weeks of etanercept exposure, the ASAS20 response was 81% and the ASAS40 response was 69% in the completer analysis (for all patients remaining in the trial at that time). Not shown in this figure are the ASAS20 and ASAS40 responses when calculated for the subjects who had at least one post-dose assessment, using LOCF for missing data imputation. These responses were 67% for ASAS20 and 49% for ASAS40. Source: Adapted from Davis JC Jr, et al. Ann Rheum Dis. 2008;67(3):346-352.

Infliximab (Remicade)

Infliximab (5 mg/kg by IV infusion at weeks 0, 2 and 6 and subsequently every 6 weeks) has shown consistent efficacy in controlling the symptoms and signs of AS, as well as improving productivity and reducing workday loss. Continuous treatment of AS with infliximab is more efficacious than on-demand treatment and the addition of methotrexate (MTX) to infliximab provides no significant benefit. Figure 15-2 shows results of a study of the long-term efficacy of infliximab over 5 years in 69 patients with active AS. After completing the 3-month, placebo-controlled, randomized phase of the study, 65 of the 69 patients entered an open-label study and received IV infliximab (5 mg/kg every 6 weeks). Completer analysis of all 35 patients who completed the entire 5-year period is shown in Figure 15-2A. There were significant and sustained reductions (indicating clinical improvement) in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Functional Index (BASFI) and Bath Ankylosing Metrology Index (BASMI) scores and also significant improvement in the percentage of AS patients who achieved ASAS40 and ASAS 5/6 improvement criteria (ASAS5/6) responses during 5 years of infliximab treatment in the open-label portion of the study. At 5 years, ASAS40 and -5/6 response rates were 63.4% and 68.3%, respectively and 65% showed at least 50% reduction in the BASDAI score (BASDAI 50 response) (Figure 15-2B).

In a report of follow-up after 8 years of treatment with infliximab, >85% patients still remained on the same treatment without any major safety events. Furthermore, both the infusion intervals and also the mean infliximab dose were modestly reduced in at least 70% of the patients without the loss of clinical efficacy.

Enlarge  Figure 15-2: Long-Term Efficacy of Infliximab in Treating Patients With AS. There were significant and sustained reductions (indicating clinical improvement) in BASDAI, BASFI, and BASMI (A). There were also significant and sustained improvements as judged by the percentage of patients achieving ASAS40 or ASAS5/6 responses, or at least 50% reduction in BASDAI score (B). a Completer analysis of all 35 patients who completed the entire 5-year study period. Source: Adapted from Braun J, et al. Ann Rheum Dis. 2008;67(3):340-345
Figure 15-2: Long-Term Efficacy of Infliximab in Treating Patients With AS. There were significant and sustained reductions (indicating clinical improvement) in BASDAI, BASFI, and BASMI (A). There were also significant and sustained improvements as judged by the percentage of patients achieving ASAS40 or ASAS5/6 responses, or at least 50% reduction in BASDAI score (B). a Completer analysis of all 35 patients who completed the entire 5-year study period. Source: Adapted from Braun J, et al. Ann Rheum Dis. 2008;67(3):340-345

Adalimumab (Humira)

Adalimumab dosage is 40 mg every other week, and the percentage of patients with active AS who achieved an ASAS20 and an ASAS5/6 response obtained in its registration trial were similar to the response to the other TNFis. Adalimumab is also clinically effective in patients with early axial SpA, before the occurrence of radiographically confirmed sacroiliitis. In a 52-week, randomized, controlled trial of 46 patients with NSAID-refractory nr-axSpA, patients were randomized to placebo (n=24) or adalimumab (n=22) for 12 weeks, followed by an open-label extension for up to 52 weeks (Figure 15-3). After 12 weeks, ASAS40 responses and ASAS partial remissions were achieved in 54.5% and 22.7%, respectively, of the adalimumab-treated patients compared with 12.5% and 0% of the placebo-treated patients (P=0.004 and P=0.019, respectively).

At 52 weeks, ASAS40 responses and ASAS partial remissions were sustained in patients continually treated with adalimumab throughout the study (45.5% and 18.2%, respectively). Patients who switched from placebo to adalimumab at 12 weeks during the open-label extension showed significant improvements in ASAS40 and ASAS partial remission (50.0% and 37.5%, respectively; P=0.004 and P=0.002). The fact that a substantial percentage of patients achieved partial remission suggest that TNFis may be even more effective in early forms of axial SpA. An analysis of 71 trials involving a very large number of patients with nearly 12 years of adalimumab exposure indicates long-term safety.

Adalimumab has the most FDA-approved indications for treatment compared with the other TNFis. It is indicated for treatment of:

  • To reduce the signs and symptoms of:
    • Moderate to severe RA in adults
    • Moderate to severe polyarticular juvenile idiopathic arthritis in children 2 years of age and older
    • PsA in adults
    • AS in adults
    • Moderate to severe CD
    • Moderate to severe CD in children 6 years of age and older
    • Moderate to severe hidradenitis suppurativa in adults
  • In adults, to help induce remission in moderate to severe UC and sustain remission when other medicines have not worked well enough
  • To treat moderate to severe chronic plaque psoriasis in adults who are ready for systemic therapy or phototherapy
  • To treat noninfectious intermediate posterior and panuveitis in adults.
Enlarge  Figure 15-3: Results of Adalimumab in Pre-radiographic Axial Undifferentiated Spondyloarthritisa. Forty-six patients completed the 12-week randomly controlled trial, and 38 completed the 52-week open-label extension phase of the study. At week 12, 54.5% of patients receiving adalimumab showed ASAS40 response vs 12.5% on placebo (P = 0.004). After switching to adalimumab, those patients who were initially on placebo also showed a similar degree of efficacy. At week 52, the efficacy was maintained in all patients. The bars indicate the percentage of patients who achieved ASAS40 and ASAS partial-remission responses at 12 weeks and at 52 weeks. Young age and an elevated CRP were the best predictors of the ASAS40 response (not shown in this figure). a- Early AS without x-ray defined sacroiliitis. Source: Adapted from Haibel H, et al. Arthritis Rheum. 2008;58(7):1981-1991.
Figure 15-3: Results of Adalimumab in Pre-radiographic Axial Undifferentiated Spondyloarthritisa. Forty-six patients completed the 12-week randomly controlled trial, and 38 completed the 52-week open-label extension phase of the study. At week 12, 54.5% of patients receiving adalimumab showed ASAS40 response vs 12.5% on placebo (P = 0.004). After switching to adalimumab, those patients who were initially on placebo also showed a similar degree of efficacy. At week 52, the efficacy was maintained in all patients. The bars indicate the percentage of patients who achieved ASAS40 and ASAS partial-remission responses at 12 weeks and at 52 weeks. Young age and an elevated CRP were the best predictors of the ASAS40 response (not shown in this figure). a- Early AS without x-ray defined sacroiliitis. Source: Adapted from Haibel H, et al. Arthritis Rheum. 2008;58(7):1981-1991.

Golimumab (Simponi)

Golimumab has demonstrated significant efficacy and an acceptable safety profile in a large cohort of patients with active AS as well as in a cohort of patients with active non-radiographic axial SpA at a dose of 50 mg subcutaneously every 4 weeks (Figure 15-4).

Enlarge  Figure 15-4: Proportions of Chinese Patients Achieving ASAS Responses Through Week 52 in a Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial with Golimumab. Key: CO, crossover; EE, early escape. a) P <0.001. Responses include (A) at least 20% improvement (ASAS20), (B) at least 40% improvement (ASAS40), and (C) at least 20% improvement in five of six ASAS domains (ASAS5/6), as well as (D) an ASAS score <2 (ASAS partial remission). Source: Bao C, et al. Rheumatology. 2014;53:1654-1663.
Figure 15-4: Proportions of Chinese Patients Achieving ASAS Responses Through Week 52 in a Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial with Golimumab. Key: CO, crossover; EE, early escape. a) P <0.001. Responses include (A) at least 20% improvement (ASAS20), (B) at least 40% improvement (ASAS40), and (C) at least 20% improvement in five of six ASAS domains (ASAS5/6), as well as (D) an ASAS score <2 (ASAS partial remission). Source: Bao C, et al. Rheumatology. 2014;53:1654-1663.

Certolizumab Pegol (Cimzia)

Certolizumab pegol is equally effective in treating AS at a dose of 200 mg every 2 weeks or 400 mg every 4 weeks. A placebo-controlled trial of certolizumab, called the RAPID-axSpA double blind to Week 24, dose-blind to Week 48 and open-label to Week 204. The RAPID-axSpA trial has documented the efficacy and safety of certolizumab pegol over 24 weeks in patients with ax-SpA, including AS and nr-axSpA (Figure 15-5). A subsequent report described its efficacy and safety up to week 96 of the study. A 52-week controlled trial confirmed its effectiveness in nr-axSpA.

Enlarge  Figure 15-5: RAPID-axSpA Trial: Mean BASMI, BASDAI, and BASFI to Week 96 of Certolizumab Pegol Treatment in Patients With axSpA, AS, and nr-axSpA. Key: LOCF, last observation carried forward; OC, observed case [data]. BASMI linear score (A), mean BASDAI score (B), and mean BASFI score (C) to week 96 of certolizumab pegol (CZP) treatment in patients with axSpA, patients with AS, and patients with nr-axSpA. Graphs show LOCF data. Results are reported for the randomized set (all patients randomized at baseline to receive either CZP 200 mg Q2W or CZP 400 mg Q4W). OC data for week 96 (n = 171 patients with axSpA; n = 97 patients with AS; n = 74 patients with nr-axSpA. Source: Sieper J, et al. Arthritis Rheumatol. 2015;67(3):668-677.
Figure 15-5: RAPID-axSpA Trial: Mean BASMI, BASDAI, and BASFI to Week 96 of Certolizumab Pegol Treatment in Patients With axSpA, AS, and nr-axSpA. Key: LOCF, last observation carried forward; OC, observed case [data]. BASMI linear score (A), mean BASDAI score (B), and mean BASFI score (C) to week 96 of certolizumab pegol (CZP) treatment in patients with axSpA, patients with AS, and patients with nr-axSpA. Graphs show LOCF data. Results are reported for the randomized set (all patients randomized at baseline to receive either CZP 200 mg Q2W or CZP 400 mg Q4W). OC data for week 96 (n = 171 patients with axSpA; n = 97 patients with AS; n = 74 patients with nr-axSpA. Source: Sieper J, et al. Arthritis Rheumatol. 2015;67(3):668-677.

Efficacy of TNFis in nr-axSpA

AS and nr-axSpA share common epidemiologic, genetic and clinical characteristics, that support the use of the term axSpA as a better name for an old disease called AS. But, as has been discussed in Ankylosing Spondylitis: Axial Spondyloarthritis and Non-Radiographic axSpA, nr-axSpA is characterized by a higher prevalence of females, lower efficacy of treatment with TNFis and a lower level of CRP in comparison to AS that probably reflects the inclusion of a certain subgroup of patients with a rather mild, nonprogressive disease course.

It has been reported than men with nr-axSpA had polygenic risk score (PRS) that was similar to AS and distinct from healthy subjects, but women with nr-axSpA had similar PRS to healthy subjects and distinct from women with AS. This indicates that women clinically diagnosed with axSpA, but who are x-ray negative, as a group have a disease that is genetically distinct from AS overall, and from nr-axSpA in men. This study also demonstrates that PRS has good discriminatory performance for men with nr-axSpA from healthy controls. Relatively a small percentage (26%) of the patients with nr-axSpA progress to AS over as long as 15 years of follow-up. Elevated CRP and active sacroiliitis on MRI are the strongest predictors for such a progression. The disease burden in patients with nr-axial SpA is comparable to that of AS.

Patients with nr-axSpA and AS who show inadequate responses to NSAIDs respond similarly well to therapy with TNFis if their level of inflammation at baseline is also similar. Therefore, the use of TNFis in the treatment of nr-axSpA were approved by the EMA (for etanercept, adalimumab, certolizumab pegol and golimumab) based on the positive results of short-term trials (Table 15-2). However, the FDA withheld approval for the use of TNFi in patients with nr-axSpA due to the discrepancies in the central and local reading of the radiographs of the patients involved in the ABILITY trial of adalimumab and RAPID-axSpA trial of certolizumab pegol submitted to the FDA for approval and to the uncertainty on the spontaneous remission and progressions rates during the natural course of nr-axSpA.

The C-axSpAnd study, a 52-week, randomized, placebo-controlled trial of certolizumab pegol in nr-axSpA was planned in a specific controlled trial design which also addressed the issues raised by the FDA. The trial included 317 adult nr-axSpA patients with active disease and objective signs of inflammation despite the use of NSAIDs. Patients were assigned to receive either placebo or certolizumab pegol 200 mg SC every 2 weeks after a loading dose of 400 mg at Weeks 0, 2 and 4, in addition to nonbiologic background medication. Primary outcome measure was Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement, defined as an ASDAS decrease of at least two points from baseline or reaching lowest possible value at Week 52. Compared with placebo, a significantly higher proportion of patients treated with certolizumab pegol demonstrated ASDAS-MI response (47.2% vs 7%) at Week 52. ASAS40, a key secondary endpoint, was also significantly better with certolizumab pegol relative to placebo at Weeks 12 and 52 (Figure 15-6).

Switching to open-label treatment before Week 52 occurred in about 61% of patients in the placebo group and 13% in the certolizumab pegol group, indicating that remission in nr-axSpA occurs infrequently. Based on the results of the C-axSpAnd trial, certolizumab has been approved by the FDA for its use in adult patients with nr-axSpA with objective signs of inflammation. The requirement of positive MRI and/or elevated CRP in patients with nr-axSpA has been substantiated by the results of the randomized controlled PrevAS study which found similarly low ASAA20 response rates after 16 weeks of treatment with etanercept or placebo (17% vs 11%, respectively) in patients suspected of nr-axSpA with high disease activity but without the requirement of positive MRI and/or elevated CRP.

Long-term efficacy of TNFis in patients with nr-axSpA beyond 1 year need to be seen. Three years of anti-TNF therapy resulted in similar clinical outcomes and treatment adherence in nr-axSpA (with the exception of those with constantly lower CRP levels) and AS. CRP elevation at baseline was similarly associated with superior clinical outcomes and anti-TNF treatment persistence in both groups.

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Enlarge  Figure 15-6: C-axSpAnd Study: Proportion of Patients Achieving (A) Major Improvement in ASDAS-MI and (B) 40% Improvement in Disease Activity According to ASAS40 by Week 52. Key: P<0.0001 for certolizumab pegol (CZP) vs placebo (PBO) at week 12 and week 52 for both ASDAS-MI and ASAS40. Source: Deodhar A, et al. Arthritis Rheumatol. 2019;71(7):1101-1111.
Figure 15-6: C-axSpAnd Study: Proportion of Patients Achieving (A) Major Improvement in ASDAS-MI and (B) 40% Improvement in Disease Activity According to ASAS40 by Week 52. Key: P<0.0001 for certolizumab pegol (CZP) vs placebo (PBO) at week 12 and week 52 for both ASDAS-MI and ASAS40. Source: Deodhar A, et al. Arthritis Rheumatol. 2019;71(7):1101-1111.

Improvements Observed on Imaging

A characteristic feature of AS is the progression of axial inflammation from the SIJs to the intervertebral discs, facet joints and ligamentous structures of the spine. This progression is typically assessed in clinical practice using plane radiography: however, scoring methods to measure radiographic structural change have shown poor sensitivity to change. MRI of the spine in patients with AS has shown abnormalities of the spine before the development of typical features on plane radiographs.

Treatment with TNFis is associated with a decrease in spinal inflammation as detected by MRI. Disease activity parameters do not directly correlate with MRI, but both point in the same direction, indicating that both the disease activity parameters and the MRI response may be useful for defining response to anti-TNF therapy. The treatment increases bone density in patients with AS.

Halting or reducing radiographic progression of disease is essential in the management of AS; this has already been shown when patients with RA and PsA were treated with TNFis. This treatment does target sites of active inflammation, but it remains controversial whether they also directly inhibit osteoproliferation. Studies generally show better structural outcomes in axSpA especially when treatment with TNFis initiated in early stage of the disease and provided for a long period of time. A study of certolizumab demonstrated low modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) progression rates over 4 years and non-progression in 80.6% of patients. One systematic review and meta-analysis suggest a protective effect of TNFis on spinal radiographic progression in AS after at least 4 years of treatment, but only when the analysis was restricted to six studies of TNFi with low risk of bias. However, others suggested that the conclusion of this meta-analysis might be misleading due to selective reporting, heterogeneity and risk of bias assessment.

Therefore, there is still a need to study a larger number of AS patients with early disease and to treat them for a longer period to firmly confirm the promising observational data. Moreover, a better scoring method is also needed to assess structural damage. There is increasing evidence that TNFis do increase bone density in patients with active AS.

Safety and Tolerability

TNF-α is a pleiotropic cytokine that is broadly involved in immune-mediated diseases with impact on both innate and adaptive immunity. Thus, targeting TNF-α may impair the immune system’s capacity to mount protective responses against intracellular bacteria and granulomatous infections. Availability of TNFis on the commercial market for a prolonged period of time has now provided information about long-term safety from postmarketing surveillance, registries, long-term follow-up studies and voluntary reporting. Some of the main safety issues with TNFis and contraindications to their use are listed in Table 15-3. This treatment is associated with increased risk of infections; a large majority of these are upper respiratory tract infections. But they also include opportunistic infections and also activation of some of the preexisting bacterial (such as tuberculosis [TB]) or viral infections (e.g., hepatitis B virus). A phase 2 open-label short-term study reported that etanercept appeared to be safe in patients with articular manifestations associated with hepatitis C virus infection. Patients with active infection or those at high risk of infection are more vulnerable; examples of such patients include those with:

  • Septic arthritis of a native joint within the past 12 months
  • Sepsis of a prosthetic joint within the past 12 months (or indefinitely if the prosthesis remains in situ)
  • Chronic leg ulcers
  • Indwelling urinary catheter
  • Persistent or recurrent chest infections.

The increased risk of opportunistic infections, particularly fungal infections, is included in a “Black Box” warning with these agents. A 2011 Cochrane review of adverse effects of treatment of rheumatic diseases with biologics reported a best estimate of what happens to people who take biologics in the short term (range: 1 to 63 months). They reported statistically significantly higher rates of occurrence of serious infections, including opportunistic infections and TB reactivation, total adverse effects and withdrawals due to adverse effects when compared with controls. A serious adverse effect is a life-threatening adverse event that can result in death or hospitalization and disability or permanent damage. Its occurrence was 12.7 per 100 patients who took any biologics compared to 11.8 per 100 patients who took placebo (1% absolute harm).

Total adverse effects occurrences were 77 per 100 patients who took any biologics compared to 72.4 per 100 patients who took placebo (5% absolute harm). Among people who took any biologic, 13.7 out of 100 dropped out of the study due to side effects compared with 9.8 out of 100 on placebo (4% absolute harm). Corresponding figures for serious infections were 3.5 vs 2.6 (1% absolute harm) and 0.2 vs 0.04 (0.16% absolute harm).

Some biologics show a statistically higher association with certain adverse outcomes compared with control, but there was no consistency across the outcomes, so caution is needed in interpreting these results. Indirect comparisons revealed that certolizumab pegol was associated with a statistically significantly higher odds of serious infections compared with adalimumab, etanercept and golimumab. Moreover, certolizumab pegol was associated with a statistically significantly higher odds of serious adverse effects compared with adalimumab. No statistically significant differences were noted between biologics in total adverse effects or withdrawals due to adverse effects in indirect comparisons. A study analyzing the data involving slightly less than 20,000 patients from the British Society for Rheumatology Biologics Register (BSRBR) found similar rates of serious infection between all of the TNFis.

All patients should receive pneumococcal vaccination and also consideration should be given to zoster vaccine before starting TNFi therapy. A yearly influenza vaccination is advised. An interferon-γ–based testing or purified protein derivative (PPD) skin test (induration of 5 mm or more) is recommended to screen for prior exposure to Mycobacterium tuberculosis, and patients showing a positive result need to be treated before starting TNFi therapy. Neither test can differentiate active from latent TB. Physicians should monitor patients receiving TNFis for signs and symptoms of active TB (including patients who tested negative for latent TB infection) or other opportunistic infections. Treatment of latent TB should be initiated according to country-specific guidelines prior to (or concurrent with) starting therapy with a TNFi, and continued surveillance remains imperative.

Because studies of individual TNFis differ in details of study design, it has been difficult to discern differences in reactive TB rates among each discrete agent. However, it appears monoclonal antibodies to TNF carry a higher risk of reactivating latent TB. One US study demonstrated that infliximab has a higher rate of TB compared to etanercept (54 and 28 per 100,000 treated patients for infliximab and etanercept, respectively). Based on the French Research Axed on Tolerance of Biotherapies (RATIO) registry, which includes patients with a variety of inflammatory and autoimmune diseases on biologic therapies, 69 cases of TB were reported over a total of 57,711 patient-years; these cases were related to infliximab and adalimumab use, but none of them had received the currently recommended chemoprophylactic treatment for latent TB.

The British Society for Rheumatology Biologics Register (BSRBR) confirmed similar results in a cohort of 10,712 patients over a median of 3.2 years, finding a three to four times higher rate of TB in RA patients on infliximab and adalimumab compared to etanercept. The RATIO registry also has found that infliximab and adalimumab carry a higher risk of a variety of serious non-tuberculous opportunistic infections compared to etanercept. The same registry found a significantly higher risk of herpes zoster infection with monoclonal antibodies to TNF (adalimumab and infliximab) compared to the soluble TNF-α receptor, OR 3.49 (95% CI 1.12-10.90, P=0.0316). A similar trend was seen in the same registry regarding Legionella pneumophila infection; the standardized incidence ratio (SIR) for all TNFis was 13.1 compared to the general French population. However, the SIR for infliximab and adalimumab were higher, 15.3 and 31.8, respectively, in comparison to etanercept, SIR 2.4.

There has been a concern for increased risk of lymphomas and solid tumors with the use of TNFis. Rate of lymphomas with adalimumab, has been noted in to be 0.1/100 patient-years and the rate of non-melanoma skin cancer to be 0.2/100 patient-years. The French RATIO registry observed a discrepancy among agents; in a series of 38 cases of lymphoma in patients with a variety of autoimmune diseases on anti-TNF therapy, a significant risk was found to be related to infliximab or adalimumab use vs etanercept, OR 4.12 (95% CI 1.36-12.49) and OR 4.73 (95% CI 1.27-17.65), respectively. Unfortunately, this relationship remains unclear as conflicting data abound.

In the psoriasis literature, it is reported that the risk of lymphoma as a result of therapy with TNFis is approximately equivalent to the lifetime risk without TNF-blocker therapy. Studies investigating the lymphoma risk associated with the anti-TNF therapy in large cohorts of rheumatoid arthritis (RA) patients from the BSRBR and the Swedish databases found no increase as compared to the background RA population.

One long-term use report indicates that the observed number of malignancies in AS and PsA were similar to the number expected for age- and sex-matched populations. Over 10 years, in one Belgian population, the incidence of malignancy after one or more anti-TNF therapies for SpA was noted to be 500.1 per 100,000 patient years, higher than the general population. However, it is noted that this controversial relationship stems from the concern that some increased risk may be disease related and not treatment related. Most data in patients with AS and related SpA show that treatment with a TNFi was not associated with increased risks of cancer, neither overall nor for the six most common cancer types.

Rare postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF-blocking agents. This rare type of T-cell lymphoma has a very aggressive disease course and is usually fatal. Nearly all of the reported TNF-blocker–associated cases have occurred in patients with Crohn’s disease (CD) or ulcerative colitis (UC). The majority were in adolescent and young adult males. Almost all of these patients had received treatment with azathioprine (AZA) or 6-mercaptopurine (6-MP) concomitantly with a TNF blocker at or prior to diagnosis. The potential risk with the combination of AZA or 6-MP and TNFis should be carefully considered. A risk for the development for hepatosplenic T-cell lymphoma (HSTCL) in patients treated with TNFis cannot be excluded.

Other possible adverse effects include injection site reactions with SC administration and allergic reactions, especially with IV infliximab administration. Injection site reactions are seen more often with etanercept than with infliximab and adalimumab. Paradoxical occurrence of a new-onset psoriasis, particularly palmo-plantar pustular psoriasis has been noted. The cause of this is unclear, but they can be managed conservatively without drug withdrawal and changing to another biologic agent. A few other autoimmune diseases rarely induced by TNF-targeted therapies include uveitis, eczema, demyelinating disease, lupus-like syndromes, vasculitis, interstitial lung disease, sarcoidosis, autoimmune hepatitis and myopathy. Exacerbation of congestive heart failure has also been reported. Laboratory abnormalities include mild transaminitis, bilirubinemia and creatinine kinase elevations, as well as generally mild and transient cytopenias (including thrombocytopenia, lymphocytopenia and neutropenia) have been noted.

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Use in Pregnancy

TNFis carry an FDA class B pregnancy risk, suggesting that although no risk is apparent from animal studies, there are no controlled studies of pregnant women receiving these agents. A European League Against Rheumatism (EULAR) task force was established to define points to consider on use of antirheumatic drugs before pregnancy, and during pregnancy and lactation. Based on a systematic literature review and pregnancy exposure data from several registries, statements on the compatibility of antirheumatic drugs during pregnancy and lactation were developed. The task force came to the conclusion that among biologics, TNFis are best studied and appear reasonably safe until gestational Week 20 for infliximab and adalimumab, until Week 30-32 (throughout pregnancy, if indicated) for etanercept and throughout pregnancy for certolizumab.

Two post-marketing trials of certolizumab, CRIB and CRADLE, showed no to minimal placental transfer of certolizumab from mother to child during pregnancy and minimal mother-to-infant transfer from breast milk during lactation, respectively. These results, as well as the post-marketing pregnancy outcomes data led to the approval of a label change in the product information of certolizumab by the EMA in January 2018, which allowed its use in pregnancy and during lactation, in clinically indicated cases. The FDA also consented a label update in March 2018 to include the pharmacokinetic data showing negligible to low transfer of certolizumab pegol through the placenta and minimal transfer to breast milk from mother to infant. 

Guidelines for the Use of TNFis for AS

The ACR in collaboration with Spondylitis Association of America (SAA) and SPARTAN combined guidelines that provide two different sets of recommendations for AS and nonradiographic axSpA. It is recommended to start anti-TNF therapy in patients diagnosed with axSpA who have a high disease activity determined by either a BASDAI score of at least 4 or an ASDAS of at least 2.1. Initiation of such treatment requires distinguishing symptoms that reflect active disease from symptoms of a mechanical or psychological nature (“expert opinion” based on additional supportive clinical findings) and presence of refractory disease based on failure of at least two NSAIDs during a minimum of 4-week period in total. ACR/SAA/SPARTAN guidelines recommend use of TNFis in adult patients with active AS despite treatment with NSAIDs, without describing specific objective criteria for active disease (Figure 13-2). They explicitly recommend the use of monoclonals in patients with uveitis and IBD. The 2022 ASAS/EULAR guideline update also acknowledges the differences between the monoclonals and etanercept in their efficacy regarding the extra-muscular manifestations of the disease.

Treatment must be continued on a long-term basis to maintain disease control. Validated disease activity measures, such as BASDAI or ASDAS score (see Imaging) should be followed for monitoring the response to treatment with TNFis. ASAS/EULAR guideline recommends the treatment to be guided according to a predefined treatment target, while ACR/SAA/SPARTAN guidelines recommend against a treat to target approach based on ASDAS measurements. Response is defined as improvement of at least 50% or 2 units (on a 0-to-10 scale) of the BASDAI score. Discontinuation of anti-TNF treatment should be considered if the patient fails to respond after 12 weeks of treatment. When one TNFi has not succeeded or adverse effects developed that are not related to the TNFis as a class, switching to another anti-TNF agent should be preferred over switching to an IL-17i. However, in patients who have experienced primary treatment failure or class related adverse effects with TNFis, IL-17is should be the choice of treatment, as well as in patients with active disease who have heart failure or demyelinating disease.

Enlarge  Figure 13-2: Summary of the ACR/SAA/SPARTAN Recommendations for the Treamtent of Patients With A) Active Ankylosing Spondylitis and B) Stable Ankylosing Spondylitis. The bracketed numbers represent the numbers preceding the recommendations in Tables 13.2 through 13.10. Source: Ward MM, et al. Arthritis Rheumatol. 2019;71(10):1599-1613.
Figure 13-2: Summary of the ACR/SAA/SPARTAN Recommendations for the Treamtent of Patients With A) Active Ankylosing Spondylitis and B) Stable Ankylosing Spondylitis. The bracketed numbers represent the numbers preceding the recommendations in Tables 13.2 through 13.10. Source: Ward MM, et al. Arthritis Rheumatol. 2019;71(10):1599-1613.

Biosimilars for TNFis

Biosimilars are subsequent versions of innovator biologics made by a different pharmaceutical company following patent expiration on the innovator product. A biological product may be demonstrated to be “biosimilar” if the manufacturer can provide evidence that shows that, among other things, their product is “highly similar” to an already-approved biological product, but the two products are not considered interchangeable and are therefore not called generics. Preliminary evidence supports the biosimilarity and interchangeability of biosimilars and reference TNFis. Biosimilars promise to provide comparable clinical results to innovator biologics but at a lower cost.

In 2016, FDA approved Inflectra, a biosimilar for Remicade (infliximab-dyyb) for use for the seven indications of the reference product, including AS, psoriasis and PsA (Table 15-4). It was previously known as CT-P13; it has equivalent pharmacokinetics to infliximab and is well tolerated, with an efficacy and safety profile comparable to that of infliximab up to Week 30 in patients with active AS.

The FDA approved the first biosimilar for Enbrel known as Erelzi (etanercept-sass) in 2016, for the five indications of the reference product, including AS, psoriasis and PsA.

Also in 2016, the FDA approved the first biosimilar for Humira; it is named Amjevita. Amjevita was approved across all eligible indications of the reference product, except for the treatment of pediatric CD, hidradenitis suppurativa, or uveitis. The FDA has later approved many other biosimilars of TNFis, many of which have not been launched in the US (Table 15-4). The uptake of biosimilars in patients with rheumatic diseases, including AS remains low, comprising 3.5% of all TNF prescriptions, as suggested by an analysis of the registry data from rheumatology practices across the US, despite the similar treatment persistence rates of infliximab‐dyyb and infliximab bio‐originator.

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Biologics Therapy Beyond TNFis

As discussed, secukinumab and ixekizumab selective anti-IL-17A monoclonal antibodies are the first biologic agents beyond TNFis to demonstrate efficacy in AS and nr-axSpA in randomized, placebo-controlled trials. They will be discussed in detail in Biologics Targeting IL-17.

Studies on tocilizumab, sarilumab and abatacept were negative. Rituximab was not effective in patients with AS that did not respond to TNFis but it had only modest efficacy in TNFi-naïve patients.

Concluding Remarks

Physical functioning can be markedly affected by AS/axSpA, leading to limitations in the patient’s ability to work. NSAIDs and physical therapy are the traditional first-line treatments for AS, but many patients fail to respond adequately to these interventions. MTX and other conventional DMARDs are not effective as second-line treatments for managing the axial manifestations of AS. The demonstrated efficacy of TNFis in patients with AS who show an inadequate response to conventional therapy has enabled physicians to manage treatment more effectively.

TNFis are highly effective in AS in alleviating pain and reducing clinical disease activity, both axial and peripheral arthritis, reducing spinal and SIJ inflammation as visualized on MRI, alleviating extra-articular manifestations, improving quality of life and maintaining long-term efficacy out to more than 10 years. The response is greater in patients with earlier disease and less damage. All current TNFis are approved in the EU but only certolizumab is approved in the US for the treatment of nr-axSpA and one hopes of slowing, if not preventing, radiologic progression and ankylosis. The untoward effects of anti-TNF therapy in AS do not appear to be much different from those in RA and PsA. Unfortunately, many AS patients who meet the criteria for anti-TNF treatment according to the published guidelines do not receive a treatment for one reason or another (including cost and possible side effects).

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