Therapeutic Controversies




Tumor necrosis factor α inhibitors (TNF blockers) have revolutionized the treatment of patients with anklyosing spondylitis. Despite clinical efficacy, there are questions and controversies treating rheumatologists face, which this review discusses: whether there are specific indications for specific TNF blockers; whether the dose of TNF blockers can be decreased; whether immunogenicity plays a role; what the role of residual active inflammation MRI might be; and whether there is a window of opportunity to treat patients with anklyosing spondylitis and prevent radiographic progression. This article summarizes evidence for switching between TNF blockers and addresses the question of malignancies.








  • Four TNF blockers are available for the treatment of ankylosing spondylitis (AS), including infliximab, etanercept (ETN), adalimumab, and golimumab.



  • For the treatment of active AS, only nonsteroidal anti-inflammatory drugs (NSAIDs) and the tumor necrosis factor α (TNF-α) inhibitors (in this article, termed TNF blockers ) are recommended if patients primarily present with axial manifestations.



  • Approximately 40% to 50% of AS patients treated with TNF blockers show a marked improvement of their disease activity, as measured by the Assessments in Spondyloarthritis International Society (ASAS) 40 percent response criterion.



Key Points


Introduction


For the treatment of active AS, only NSAIDs and the TNF blockers are recommended if patients primarily present with axial manifestations. Approximately 40% to 50% of AS patients treated with TNF blockers show a marked improvement of their disease activity, as measured by the BASDAI.


This review aims at discussing the role of TNF blockers in the treatment of AS/axial spondyloarthritis (SpA) with a special focus on limitations and controversies. Although the introduction of TNF blockers has revolutionized treatment of AS, treating physicians are aware of certain limitations. When looking for answers to controversial questions about TNF blockers in AS, experience shows that part of the answer is derived from treatment with RA, because in RA there is longer experience with TNF blockers. RA and AS are substantially different diseases, however, which share the common feature that TNF-α plays a major role in disease. This review outlines and discusses 8 major controversies that focus on treatment efficacy, treatment strategies involving the use of TNF blockers in real-world practice, and safety aspects specific to their use in SpA.




Controversy 1: Are there specific indications for using specific TNF blockers because of differences in efficacy? What is the evidence for differences in treatment efficacy for extra-articular manifestations of SpA?


As described previously, the efficacy of TNF blockers in AS for treating axial disease is similar. It is also known, however, that patients with AS suffer from peripheral arthritis and a substantial proportion of patients from extraarticular manifestations, such as enthesitis, psoriasis, inflammatory bowel disease (IBD), or acute anterior uveitis (AAU).


Acute Anterior Uveitis


AAU represents one of the most common extraarticular manifestations, affecting approximately 30% to 50% of AS patients. In cases of failure of topical glucocorticosteroids, TNF blockers are considered an effective treatment option. The question, however, is whether there is evidence that one TNF blocker is more efficacious than another.


A few case series described new onset or flares of AAU in patients on TNF blocker treatment, which was ETN in many cases. Consistent with these case reports, 3 retrospective case series reported a lack of impact of ETN on AAU. Guignard and colleagues reported data from French patients with SpA, showing differences in the efficacy of TNF blockers in reducing AAU flares. Of 46 patients with AAU, 33 patients were treated with anti-TNF monoclonal antibodies (infliximab [IFX] [n = 25] or adalimumab [ADA] [n = 8]) and 13 patients received ETN. Subgroup analysis showed that the incidence of AAU remained unchanged with ETN treatment (54.6 vs 58.5 per 100 patient years), whereas there was a statistically significant reduction during treatment with IFX (47.4 vs 9.0 per 100 patient-years) or ADA (60.5 vs 0 per 100 patient years).


Cobo-Ibanez and colleagues reported approximately 150 patients with SpA on TNF blocker therapy of whom 19 (12.7%) had AAU before starting treatment (15 had AS, 2 had undifferentiated SpA, and 2 had psoriasis). Of these 19 patients, 10 received ETN and 9 received IFX, and 1 patient was switched from ETN to IFX because of recurrent uveitis flares. The incidence of AAU in IFX-treated patients was 61.7 and 2.6 per 100 patient-years before and after treatment, respectively. In the ETN group, however, an increase of AAU flares from 34.3 before treatment to 60 per 100 patient-years after starting therapy was observed.


A 12-week open-label study with ADA demonstrated reduced rates of AAU in patients with AS (n =1250). A significant reduction in AAU rates was found when treatment before and during ADA was compared (15 vs 7.4 per 100 patient-years) in the whole group of patients and flare rates were reduced by 50%. Subgroup analysis showed consistent findings in several subgroups, including patients with a history of AAU or patients with symptomatic AAU at baseline. The strength of this study was the large sample size and prospective study design but no comparator was used and study duration was limited to 12 weeks.


Braun and colleagues compared AAU flare data from different AS clinical trials that included 4 placebo-controlled studies with TNF blockers (2 with ETN and 2 with IFX) and 3 open-label studies. Further information about the course of AAU was provided for 397 of 717 initially identified patients, of whom 90 were exposed to IFX and 297 to ETN for a total of 146 and 430 patient years, respectively. Although the frequency of AAU in the placebo group was 15.6 per 100 patient-years, for patients treated with TNF blockers a mean of only 6.8 AAU flares per 100 patient-years was found. In this study, a nonsignificant lower frequency of AAU flares was observed in patients treated with IFX compared with patients treated with ETN (3.4 per 100 patient-years vs 7.9 per 100 patient-years, respectively).


Finally, Sieper and colleagues assessed the frequency of AAU in an analysis of different clinical trials of ETN in patients with AS (3 open label, 1 active controlled [sulfasalazine as comparator], and 4 placebo controlled). A significant difference was found in AAU event rates per 100 patient years in favor of ETN versus placebo: 8.6 versus 19.3. Compared with sulfasalazine, similar AAU event rates were found for ETN: 10.7 for ETN versus 14.7 for sulfasalazine.


Fig. 1 summarizes some of the data about AAU event rates per 100 patient years from several trials.




Fig. 1


Illustration of rates of AAU flares per 100 patient-years during treatment with different TNF-α–blocking agents in different studies. py, patient years; uveitis, acute anterior uveitis.

( Data from ( A ) Guignard S, Gossec L, Salliot C, et al. Efficacy of tumour necrosis factor blockers in reducing uveitis flares in patients with spondylarthropathy: a retrospective study. Ann Rheum Dis 2006; 65(12):1631–4; ( B ) Rudwaleit M, Rodevand E, Holck P, et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann Rheum Dis 2009; 68(5):696–701; ( C ) Sieper J, Koenig A, Baumgartner S, et al. Analysis of uveitis rates across all etanercept ankylosing spondylitis clinical trials. Ann Rheum Dis 2010; 69(1):226–9; ( D ) Cobo-Ibanez T, del Carmen Ordonez M, Munoz-Fernandez S, et al. Do TNF-blockers reduce or induce uveitis? Rheumatology (Oxford) 2008; 47(5):731–2)


In conclusion, there seems little doubt that ETN does not increase the AAU event rate, as originally suggested by retrospective data. Whether ETN is efficacious in reducing AAU event rates is difficult to establish with certainty because exposure to placebo was short term (12–24 weeks) in clinical trials and the AAU event rate varied widely in placebo patients between clinical trials. Consequently, estimation of AAU event rate in placebo patients by summing data from different trials and presenting event rate per 100 patient years may not reflect an appropriate event rate. Overall, the data suggest that either IFX or ADA is a better choice in the minority of patients with frequent attacks of AAU.


Inflammatory Bowel Disease and Psoriasis


Several studies have demonstrated that IFX substantially improves gastrointestinal signs and symptoms of Crohn disease (CD) and ulcerative colitis as well as associated axial and peripheral joint inflammation. The same is true for ADA, which was approved in 2007 for treatment of CD. Conversely, treatment of patients with IBD and associated SpA with ETN showed that signs and symptoms of IBD worsened after 12 weeks of treatment even though articular symptoms had improved. This is not surprising because ETN is not indicated for the treatment of CD. For ETN there are even some case reports that CD persists or even flares during ETN therapy. IFX and ADA are, therefore, preferred anti-TNF agents compared with ETN in the setting of IBD.


The 3 TNF blockers, IFX, ETN and ADA, are approved and indicated for treatment of psoriasis and no head-to head comparisons are available. The weight of evidence does not support a preferred TNF blocker agent.


Enthesitis


Enthesitis is a characteristic finding in SpA patients and is considered an ASAS core outcome domain for the evaluation of AS. The frequency of enthesitis differs in AS/SpA, ranging between approximately 40% and 50% in different cohorts. For the assessment of enthesitis by clinical examination different indices have been developed, such as the Mander index, the Stoke Enthesitis Index, the University of San Francisco index, the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), the Berlin enthesitis score, and the Spondyloarthritis Research Consortium of Canada (SPARCC) score. None of these clinical indices has been fully validated. Most placebo-controlled trials of TNF blockers have not shown a consistent impact of treatment on enthesitis scores with the exception of ADA in the Adalimumab trial evaluating long-term efficacy and safety for ankylosing spondylitis (ATLAS) trial. IFX did not significantly decrease enthesitis scores measured by either the Mander index in the ankylosing spondylitis study for the evaluation of recombinant infliximab therapy (ASSERT) study or the Berlin enthesitis score in the German study. Several different indices were assessed in the GO-RAISE trial of golimumab in AS, including the MASES, Berlin, and San Francisco scores, with a significant effect observed only using the San Francisco score. There was also no effect of ADA on the MASES in a placebo-controlled trial of patients with nonradiographic axial SpA (ABILITY I). In contrast to the lack of effect on clinical enthesitis, there is evidence that enthesitis evident on MRI improves after TNF blocker treatment as shown in the HEEL study, in which patients with SpA and MRI-proved heel enthesitis were successfully treated with ETN, or a trial in which whole-body MRI was able to show that enthesitis at various sites is significantly reduced by ETN in patients with early axial SpA (ESTHER trial).


The discrepancy in the impact of TNF blocker therapy on clinical and MRI features of enthesitis may reflect the complete lack of correlation between clinical and MRI features and the importance of training and a standardized approach to the clinical assessment of enthesitis. The available data do not support the case for preferential use of any specific TNF- blocker in patients with active enthesitis.




Controversy 1: Are there specific indications for using specific TNF blockers because of differences in efficacy? What is the evidence for differences in treatment efficacy for extra-articular manifestations of SpA?


As described previously, the efficacy of TNF blockers in AS for treating axial disease is similar. It is also known, however, that patients with AS suffer from peripheral arthritis and a substantial proportion of patients from extraarticular manifestations, such as enthesitis, psoriasis, inflammatory bowel disease (IBD), or acute anterior uveitis (AAU).


Acute Anterior Uveitis


AAU represents one of the most common extraarticular manifestations, affecting approximately 30% to 50% of AS patients. In cases of failure of topical glucocorticosteroids, TNF blockers are considered an effective treatment option. The question, however, is whether there is evidence that one TNF blocker is more efficacious than another.


A few case series described new onset or flares of AAU in patients on TNF blocker treatment, which was ETN in many cases. Consistent with these case reports, 3 retrospective case series reported a lack of impact of ETN on AAU. Guignard and colleagues reported data from French patients with SpA, showing differences in the efficacy of TNF blockers in reducing AAU flares. Of 46 patients with AAU, 33 patients were treated with anti-TNF monoclonal antibodies (infliximab [IFX] [n = 25] or adalimumab [ADA] [n = 8]) and 13 patients received ETN. Subgroup analysis showed that the incidence of AAU remained unchanged with ETN treatment (54.6 vs 58.5 per 100 patient years), whereas there was a statistically significant reduction during treatment with IFX (47.4 vs 9.0 per 100 patient-years) or ADA (60.5 vs 0 per 100 patient years).


Cobo-Ibanez and colleagues reported approximately 150 patients with SpA on TNF blocker therapy of whom 19 (12.7%) had AAU before starting treatment (15 had AS, 2 had undifferentiated SpA, and 2 had psoriasis). Of these 19 patients, 10 received ETN and 9 received IFX, and 1 patient was switched from ETN to IFX because of recurrent uveitis flares. The incidence of AAU in IFX-treated patients was 61.7 and 2.6 per 100 patient-years before and after treatment, respectively. In the ETN group, however, an increase of AAU flares from 34.3 before treatment to 60 per 100 patient-years after starting therapy was observed.


A 12-week open-label study with ADA demonstrated reduced rates of AAU in patients with AS (n =1250). A significant reduction in AAU rates was found when treatment before and during ADA was compared (15 vs 7.4 per 100 patient-years) in the whole group of patients and flare rates were reduced by 50%. Subgroup analysis showed consistent findings in several subgroups, including patients with a history of AAU or patients with symptomatic AAU at baseline. The strength of this study was the large sample size and prospective study design but no comparator was used and study duration was limited to 12 weeks.


Braun and colleagues compared AAU flare data from different AS clinical trials that included 4 placebo-controlled studies with TNF blockers (2 with ETN and 2 with IFX) and 3 open-label studies. Further information about the course of AAU was provided for 397 of 717 initially identified patients, of whom 90 were exposed to IFX and 297 to ETN for a total of 146 and 430 patient years, respectively. Although the frequency of AAU in the placebo group was 15.6 per 100 patient-years, for patients treated with TNF blockers a mean of only 6.8 AAU flares per 100 patient-years was found. In this study, a nonsignificant lower frequency of AAU flares was observed in patients treated with IFX compared with patients treated with ETN (3.4 per 100 patient-years vs 7.9 per 100 patient-years, respectively).


Finally, Sieper and colleagues assessed the frequency of AAU in an analysis of different clinical trials of ETN in patients with AS (3 open label, 1 active controlled [sulfasalazine as comparator], and 4 placebo controlled). A significant difference was found in AAU event rates per 100 patient years in favor of ETN versus placebo: 8.6 versus 19.3. Compared with sulfasalazine, similar AAU event rates were found for ETN: 10.7 for ETN versus 14.7 for sulfasalazine.


Fig. 1 summarizes some of the data about AAU event rates per 100 patient years from several trials.




Fig. 1


Illustration of rates of AAU flares per 100 patient-years during treatment with different TNF-α–blocking agents in different studies. py, patient years; uveitis, acute anterior uveitis.

( Data from ( A ) Guignard S, Gossec L, Salliot C, et al. Efficacy of tumour necrosis factor blockers in reducing uveitis flares in patients with spondylarthropathy: a retrospective study. Ann Rheum Dis 2006; 65(12):1631–4; ( B ) Rudwaleit M, Rodevand E, Holck P, et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann Rheum Dis 2009; 68(5):696–701; ( C ) Sieper J, Koenig A, Baumgartner S, et al. Analysis of uveitis rates across all etanercept ankylosing spondylitis clinical trials. Ann Rheum Dis 2010; 69(1):226–9; ( D ) Cobo-Ibanez T, del Carmen Ordonez M, Munoz-Fernandez S, et al. Do TNF-blockers reduce or induce uveitis? Rheumatology (Oxford) 2008; 47(5):731–2)


In conclusion, there seems little doubt that ETN does not increase the AAU event rate, as originally suggested by retrospective data. Whether ETN is efficacious in reducing AAU event rates is difficult to establish with certainty because exposure to placebo was short term (12–24 weeks) in clinical trials and the AAU event rate varied widely in placebo patients between clinical trials. Consequently, estimation of AAU event rate in placebo patients by summing data from different trials and presenting event rate per 100 patient years may not reflect an appropriate event rate. Overall, the data suggest that either IFX or ADA is a better choice in the minority of patients with frequent attacks of AAU.


Inflammatory Bowel Disease and Psoriasis


Several studies have demonstrated that IFX substantially improves gastrointestinal signs and symptoms of Crohn disease (CD) and ulcerative colitis as well as associated axial and peripheral joint inflammation. The same is true for ADA, which was approved in 2007 for treatment of CD. Conversely, treatment of patients with IBD and associated SpA with ETN showed that signs and symptoms of IBD worsened after 12 weeks of treatment even though articular symptoms had improved. This is not surprising because ETN is not indicated for the treatment of CD. For ETN there are even some case reports that CD persists or even flares during ETN therapy. IFX and ADA are, therefore, preferred anti-TNF agents compared with ETN in the setting of IBD.


The 3 TNF blockers, IFX, ETN and ADA, are approved and indicated for treatment of psoriasis and no head-to head comparisons are available. The weight of evidence does not support a preferred TNF blocker agent.


Enthesitis


Enthesitis is a characteristic finding in SpA patients and is considered an ASAS core outcome domain for the evaluation of AS. The frequency of enthesitis differs in AS/SpA, ranging between approximately 40% and 50% in different cohorts. For the assessment of enthesitis by clinical examination different indices have been developed, such as the Mander index, the Stoke Enthesitis Index, the University of San Francisco index, the Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), the Berlin enthesitis score, and the Spondyloarthritis Research Consortium of Canada (SPARCC) score. None of these clinical indices has been fully validated. Most placebo-controlled trials of TNF blockers have not shown a consistent impact of treatment on enthesitis scores with the exception of ADA in the Adalimumab trial evaluating long-term efficacy and safety for ankylosing spondylitis (ATLAS) trial. IFX did not significantly decrease enthesitis scores measured by either the Mander index in the ankylosing spondylitis study for the evaluation of recombinant infliximab therapy (ASSERT) study or the Berlin enthesitis score in the German study. Several different indices were assessed in the GO-RAISE trial of golimumab in AS, including the MASES, Berlin, and San Francisco scores, with a significant effect observed only using the San Francisco score. There was also no effect of ADA on the MASES in a placebo-controlled trial of patients with nonradiographic axial SpA (ABILITY I). In contrast to the lack of effect on clinical enthesitis, there is evidence that enthesitis evident on MRI improves after TNF blocker treatment as shown in the HEEL study, in which patients with SpA and MRI-proved heel enthesitis were successfully treated with ETN, or a trial in which whole-body MRI was able to show that enthesitis at various sites is significantly reduced by ETN in patients with early axial SpA (ESTHER trial).


The discrepancy in the impact of TNF blocker therapy on clinical and MRI features of enthesitis may reflect the complete lack of correlation between clinical and MRI features and the importance of training and a standardized approach to the clinical assessment of enthesitis. The available data do not support the case for preferential use of any specific TNF- blocker in patients with active enthesitis.




Controversy 2: Is it possible to reduce the dose of a TNF blocker (eg, by increasing dosing intervals) or even stop treatment with a TNF blocker so that drug-free remission becomes possible?


A few clinical trials have dealt with the question of whether patients can remain in a low disease activity state or remission with a reduced dose of a TNF blocker or even after discontinuation of active treatment with a TNF blocker.


In a Spanish study, dose reduction of ETN was performed according to the treating rheumatologist and patient preference in patients with well-controlled disease activity defined as a BASDAI less than 4 and normal C-reactive protein (CRP) values; dose reduction was possible in 16 of 51 (32%) patients with different dose reduction schemes.


Another retrospective study from South Korea assessed 109 AS patients in a real-life setting in whom dosing intervals for ETN were increased from 4.7 days at 3 months to 12.1 days at 21 months. BASDAI values declined from 8.5 to 0.6 after 21 months, which was accompanied by a decrease in CRP. A dose reduction of ETN from 50 mg once weekly to a maintenance dose of 25 mg once weekly has been investigated in another Korean study, including 27 AS patients.


A recent analysis of a retrospective French study assessed dose changes in clinical practice in 189 AS patients where the mean follow-up was 45.5 months. In these patients, a state of low disease activity/remission was achieved in 65 patients (35%). The adjustment of TNF blocker dose was observed approximately 50 times and resulted in keeping the state of low disease activity in the majority of patients. For IFX, the mean dose intervals ranged between 7 and 15 weeks (mean interval for IFX increased from 8.3 weeks at 6 months to 9.7 weeks at 36 months). The most frequently performed dose modification for ADA was increasing the dose interval from 2 to 3 weeks (mean intervals for ADA application was 3.1 weeks at 6 months and 3.5 weeks at 24 months). For ETN, the most frequently observed dose modification was the use of 25 mg once weekly or 50 mg every 10 to 14 days (mean intervals for ETN 25 mg/50 mg application were 6.6 days/12.3 days at 6 months and 8.0 days/10.0 days at 36 months). Among patients reaching remission, no dose increase was necessary until the end of follow-up for 13 of 26 patients on IFX, 4 of 17 patients on ETN, and 2 of 5 patients on ADA. The cumulative probability of continuation of the TNF blocker after dose adjustment was approximately 80% at 12 months, approximately 70% at 24 months, and approximately 60% at 36 months.


The studies where TNF blockers were completely discontinued in patients who reached a state of inactive disease or remission showed flare rates of approximately 100% in patients with AS after several years of therapy with IFX or ETN, 83% in patients with nonradiographic axial SpA after 1 year of ADA, and 60% of patients with axial SpA with a symptom duration of less than 3 years after 16 weeks of IFX.


The latest trial providing data on drug-free remission are from the 2-year data of the ESTHER trial, which assessed ETN versus sulfasalazine in early axial SpA. All patients had to have an MRI showing active inflammatory lesions on MRI at baseline. After 1 year of treatment, only those patients who were in ASAS remission and free of active inflammation on MRI were followed without active treatment for 1 more year. Although 33% of ETN patients retained this strict remission criterion (MRI and clinical remission) at year 1, only 8% of ETN-treated patients stayed in drug-free remission at year 2.


A reservation with the evaluation of studies that assessed flare rates is that different definitions for low disease activity or remission as well as flare were used. In longstanding disease in AS, it may be difficult for patients to attain a BASFI of less than or equal to 20 of 100, which is necessary for the ASAS remission criteria. It has been proposed that remission may be more appropriately defined by using the Ankylosing Spondylitis Disease Activity Score definition for low disease activity state (score <1.3).


The opposite question is whether some AS patients would benefit from a dose increase. For golimumab, 100 mg subcutaneously every 4 weeks was not superior to 50 mg subcutaneously every 4 weeks. For ETN, a recent study evaluated whether 50 mg subcutaneously twice weekly is more efficacious than 50 mg subcutaneously once weekly in a randomized placebo-controlled setting. At week 12, ASAS 20 and ASAS 40 response rates were not statistically different between the 2 treatment groups (31% vs 30% and 23% vs 18%, respectively).


To summarize, there are data that dose reduction may be possible in some patients. Treatment discontinuation may be possible in a small minority (10%) of patients with early axial SpA although the vast majority of patients clinically show a relapse, requiring resumption of TNF blocker treatment.




Controversy 3: Antichimeric antibodies—are they of clinical significance in patients receiving TNF blockers?


In RA, it has been shown that antibodies against TNF blockers may develop, which is associated with reduced efficacy of TNF blockers.


In AS, a few smaller studies have investigated the development of antibodies to TNF blockers. For example, one study assessed 60 AS patients, of whom 20 patients per treatment group were treated with IFX, ETN, and ADA and then followed prospectively for 12 months. Antibodies against IFX, ETN, and ADA were found in 20%, 0%, and 30%, respectively.


Another small study that assessed 8 AS patients treated with IFX for 24 weeks found that 2 patients developed antibodies to IFX and low trough IFX levels and this was associated with a lack of clinical response and infusion reactions. In contrast, Krzysiek and colleagues did not find any association of anti-IFX antibodies or trough IFX concentration and response to treatment. A similar study with a higher number of AS patients (n = 35) and a slightly longer follow-up (6 months) assessed the relationship between antibody formation against ADA and efficacy and side effects. Of 11 patients (31%) who developed antibodies to ADA with low or undetectable ADA levels, 9 were clinical nonresponders and 1 suffered from an allergic reaction.


When the same group of researchers evaluated antibody formation against ETN, in a group of 53 AS patients, serum drug levels increased to 2.7 mg/L after 3 months to 3.0 mg/L after 6 months with no difference between responders and nonresponders and no antibodies to ETN were identified. This has also been noted in other rheumatic diseases, so failure of clinical response in AS patients cannot be due to anti-ETN antibodies.


In the most recent study from a Spanish group, Plasencia and colleagues conducted a 4-year retrospective study of 94 patients with axial SpA (50 with AS, 12 with undifferentiated SpA, 22 with psoriatic arthritis [PsA], and 10 with IBD]). All patients were treated with IFX (5 mg/kg). Antibodies to IFX were found in approximately 25% of patients, mostly after the sixth infusion, and patients with antibodies presented with higher disease activity at follow-up, shorter drug survival (4.3 years vs 8.2 years), and more adverse events. Anti-IFX antibodies developed less frequently in patients taking concomitant methotrexate (MTX) (11% vs 35%) and patients taking MTX had higher IFX serum concentrations. A limitation of this study is that data were not stratified according to diagnosis and it is unclear whether treatment with MTX had any beneficial clinical effects. In addition, it is unclear to what degree the development of anti-IFX antibodies was an independent factor contributing to lack of treatment response because no regression analysis was performed. For instance, the patients on MTX at baseline may have been started on this treatment for indications, such as peripheral arthritis and elevated CRP that could be associated with a better treatment response. Fig. 2 summarizes the frequency of antibodies against TNF blockers.




Fig. 2


Frequency of development of antibodies against TNF-α–blocking agents.


A second retrospective study from France evaluating 91 patients with SpA treated with IFX came to similar conclusions. High concentrations of IFX during treatment initiation reduced the development of antibodies to IFX and the absence of such antibodies was associated with prolonged maintenance of IFX. Those who were treated concomitantly with MTX had a lower risk of developing anti-IFX antibodies than patients not taking MTX. Infusion reactions occurred in 52% of those with anti-IFX antibodies compared with only 1% without. It was unclear, however, whether treatment with MTX had any beneficial clinical effect.


In summary, several studies now show that patients with AS develop antibodies against ADA or IFX and the most recent data indicate that this is delayed compared with rheumatoid arthritis (RA) and that at least a year of follow-up is appropriate. The question is whether this is clinically relevant and whether antibody formation could be prevented by adding an immunosuppressant drug (such as MTX or azathioprine), which has been associated with a lower frequency of antidrug antibody expression in RA and CD.


This question arises because there are some studies with IFX in AS indicating that there is no difference whether or not IFX is combined with MTX in patients with AS, including data from the Norwegian registry suggesting that drug survival in AS after 1 year is not different between patients who receive a combination of a TNF blocker plus MTX or TNF blocker alone, which is different in PsA or RA registries. Moreover, a recent extensive pharmacokinetic analysis has shown that combination of MTX and IFX does not increase the exposure to IFX over IFX alone in patients with AS and the 2 groups did not differ in disease activity or biomarkers of inflammation.


To summarize, although evidence supporting a role for anti-IFX antibodies in reduced clinical response to IFX is compelling, there is insufficient evidence to warrant institution of MTX therapy as concomitant treatment for SpA, particularly because there are no controlled data that show that this agent has a beneficial effect in SpA. Because there is no proved intervention mitigating the development of anti-TNF blocker antibodies, the role of measuring these antibodies in routine clinical practice remains unclear.




Controversy 4: What is the implication of residual active inflammation on MRI in patients treated with TNF blockers in relation to radiographic progression and does MRI constitute an appropriate endpoint for a treat-to-target therapeutic strategy?


With the use of TNF blockers, a marked decrease of active inflammation on MRI can be observed of approximately 40% to 50% in the sacroiliac joints and approximately 60% in the spine. Nevertheless, this indicates that a significant amount of inflammatory burden remains and raises the question as to its impact on the course of disease. In particular, is there a relationship between inflammation and structural progression, and does the apparent lack of impact of TNF blocker therapies on structural progression reflect insufficient control of inflammation?


Several studies have now shown that vertebral inflammation as detected on short tau inversion recovery sequence (STIR) MRI predicts the development of new syndesmophytes. But it has also been shown that the majority of syndesmophytes develop from vertebral corners, which appear normal on the STIR sequence. It has thus been argued that inflammation and ankylosis are uncoupled. It should be noted, however, that sample size calculations show that the TNF blocker trials of ETN, IFX, and ADA are only powered to detect treatment group differences of at least 80% in the modified Stokes Ankylosing Spondylitis Spinal Score and lesser degrees of reduction in that score with active therapy would not be captured. The most recent study has confirmed the link between inflammation and new bone formation at vertebral corners but also shows that acute inflammatory lesions resolve completely without sequelae whereas more complex mature lesions, especially those where there is evidence of fat metaplasia as well as inflammation, resolve but are still associated with development of new syndesmophytes. The majority of new syndesmophytes develop from vertebral corners with either inflammation on STIR images or fat metaplasia on T1-weighted sequence. Two reports have shown that inflammatory lesions undergo fat metaplasia. The data, therefore, support a window of opportunity hypothesis for disease modification whereby early and effective intervention with anti-inflammatory therapy may prevent structural progression. The typical patients recruited to clinical trials of TNF blockers have a mix of acute and more complex inflammatory lesions and the overall development of new bone during TNF blocker therapy may, therefore, depend on the balance between the number of early and more mature inflammatory lesions. This hypothesis also predicts that with prolonged follow up it should be possible to demonstrate a beneficial effect of anti-TNF therapy on structural progression because continued treatment will prevent development of new inflammatory lesions.


Because recent data also suggest that NSAIDs may slow down radiographic progression in AS patients with pre-existing syndesmophytes and elevated CRP levels, it is of special interest to know whether a combination of a TNF blocker and an NSAID is superior to TNF blocker monotherapy.

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Therapeutic Controversies
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