Which patients respond particularly well to therapy with TNF inhibitors?

Ankylosing spondylitis was also a topic at the EULAR Congress in Rome. In addition to non-pharmacological approaches, NSAIDs, local steroids, and TNF inhibitors are the most commonly used. What must be considered when using them and which patients benefit particularly from therapy with biologics? Prof. Dr. med. Martin Rudwaleit, Clinic for Internal Medicine and Rheumatology at the Bielefeld Rosenhöhe Clinic, gave a practical and comprehensive insight into the current practice of Morbus Bechterew treatment.

Ankylosing spondylitis is an inflammatory rheumatic disease characterized by sacroiliitis, spondylitis, and ankylosis. Extraspinal manifestations such as arthritis, enthesitis, uveitis, or psoriasis are also possible. Men are affected twice as often as women, onset of disease is usually between 20-30 years of age. Unfortunately, diagnosis is delayed by an average of 5-10 years. 80-90% of affected individuals are HLA-B27 positive.

According to Prof. Dr. med. Martin Rudwaleit, Clinic for Internal Medicine and Rheumatology at the Rosenhöhe Hospital in Bielefeld, physical exercises and physiotherapy are essential in ankylosing spondylitis, as they effectively reduce pain and improve mobility and performance. Disease-specific exercises should be performed regularly; possible forms include weekly supervised group physical therapy or daily home exercises.

Validated measurement methods

According to the recommendations of the international task force around Prof. Dr. med. Josef Smolen, a treat-to-target approach in spondyloarthritides is possible and reasonable [1]. An important goal is clinical remission and disease inactivity with respect to musculoskeletal involvement (arthritis, dactylitis, enthesitis, axial) – this taking into account extra-articular manifestations.

The regular use of validated measurement procedures to assess disease progression is recommended. This can be used to justify treatment decisions and adjustments. Examples include the “Bath Ankylosing Spondylitis Disease Activity Index” (BASDAI) to assess disease activity, e.g. combined with the “Bath Ankylosing Spondylitis Functional Index” (BASFI) to assess functional limitations, or the “Ankylosing Spondylitis Disease Activity Score” (ASDAS).

“It must be borne in mind that the patient’s view and the physician’s view of disease activity can differ greatly. According to one study, patients see in particular a painful spine and painful joints, functional limitations (BASFI) and fatigue (BASDAI) as important parameters for disease activity,” explained Prof. Rudwaleit [2].

NSAIDs – what can they do, where should caution be exercised?

According to a survey, non-steroidal anti-inflammatory drugs (NSAIDs) lead to very good pain control (or even pain cessation) in about 46% of patients, they cause a noticeable improvement, i.e. a 50% reduction in pain, in 34%, and no effects are seen in as many as one fifth [3]. Problems with drug tolerability are relatively common, with 24% of patients reporting severe side effects and more than half exchanging NSAIDs. Reasons for switching were predominantly lack of efficacy, abdominal pain, nausea, headache, and dizziness.

According to a 2013 meta-analysis that included 280 studies of NSAIDs, the increase in risk of serious vascular events was significant for certain drug classes: coxibs increased risk by 37% and diclofenac by 41% (compared with placebo). No increase in risk was associated with naproxen [4]. Ibuprofen also shows a relevant interaction with low-dose aspirin: taken two hours beforehand, it significantly inhibits its antiplatelet effect [5].

Local corticosteroids

In spondyloarthritis patients with sacroiliitis, CT-controlled steroid injections directly into the sacroiliac joint help – this was shown in a 1996 study [6]. Both the subjectively perceived pain and the objectively measured inflammation were significantly reduced.

TNF inhibitors

ASAS recommendations for the use of TNF inhibitors in patients with axial spondyloarthritis are summarized in Figure 1 . Looking at the studies in ankylosing spondylitis – caveat: no head-to-head studies – the various TNF inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab) show response rates (ASAS 40) of about 40-50% after 24 weeks. “Response should be assessed no later than twelve weeks of therapy. It is based on an improvement in BASDAI of ≥50% or of ≥2 (0-10) and on expert-based assessment,” Prof. Rudwaleit explained.

Are there certain predictors of response? According to a 2004 study, the following parameters make a clinical response (BASDAI 50) more likely [7]:

Shorter duration of illness/younger age
Elevated CRP/ESR
deeper BASFI
MRI: spinal inflammation.

“Also relevant is a response to TNF inhibitors. Remission at twelve weeks predicts whether remission is still present years later,” the speaker said. “Early remission is the best predictor of its sustainability and duration [8,9].” Based on current studies, TNF inhibitors tend not to prevent radiographic progression in ankylosing spondylitis – NSAIDs are more likely to do so (especially as continuous therapy). However, the study situation is inconsistent in this respect for both groups of active substances.

Non-radiographic axial spondyloarthritis.

With the introduction of the ASAS classification criteria, axial spondyloarthritis has been subdivided into nonradiographic axial spondyloarthritis (nr-axSpA) and classic ankylosing spondylitis. Study data show that TNF inhibitors are also effective in nr-axSpA. For example, with adalimumab, a significant ASAS 40 response of 36.3% vs. 14.9% (placebo) was achieved at week 12. Patients with shorter disease duration, younger age, elevated CRP, and higher SPARCC-MRI sacroiliac joint score performed best [10]. Positive data on nr-axSpA are also available for certolizumab [11].

Several birds with one stone?

“In addition to the benefits mentioned so far, TNF inhibitors also reduce the incidence of acute anterior uveitis, by 50-60%. Infliximab probably works best in this regard. In addition, there are the known positive effects in the field of psoriasis,” says Prof. Rudwaleit.

Source: EULAR Congress, June 10-13, 2015, Rome.

Literature:

Smolen JS, et al: Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force. Ann Rheum Dis 2014 Jan; 73(1): 6-16.
Spoorenberg A, et al: Measuring disease activity in ankylosing spondylitis: patient and physician have different perspectives. Rheumatology (Oxford) 2005 Jun; 44(6): 789-795.
Zochling J, et al: Nonsteroidal anti-inflammatory drug use in ankylosing spondylitis – a population-based survey. Clin Rheumatol 2006 Nov; 25(6): 794-800.
Coxib and traditional NSAID Trialists’ (CNT) Collaboration: Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials. Lancet 2013 Aug 31; 382(9894): 769-779.
Meek IL, et al: Interference of NSAIDs with the thrombocyte inhibitory effect of aspirin: a placebo-controlled, ex vivo, serial crossover study. Eur J Clin Pharmacol 2013 Mar; 69(3): 365-371.
Braun J, et al: Computed tomography guided corticosteroid injection of the sacroiliac joint in patients with spondyloarthropathy with sacroiliitis: clinical outcome and follow-up by dynamic magnetic resonance imaging. J Rheumatol 1996 Apr; 23(4): 659-664.
Rudwaleit M, et al: Prediction of a major clinical response (BASDAI 50) to tumor necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis 2004 Jun; 63(6): 665-670.
Sieper J, et al: Early response to adalimumab predicts long-term remission through 5 years of treatment in patients with ankylosing spondylitis. Ann Rheum Dis 2012 May; 71(5): 700-706.
Baraliakos X, et al: Persistent clinical efficacy and safety of infliximab in ankylosing spondylitis after 8 years – early clinical response predicts long-term outcome. Rheumatology (Oxford) 2011 Sep; 50(9): 1690-1699.
Sieper J, et al: Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 2013 Jun; 72(6): 815-822.
Landewé R, et al: Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled phase 3 study. Ann Rheum Dis 2014 Jan; 73(1): 39-47.
van der Heijde D, et al: 2010 Update of the international ASAS recommendations for the use of anti-TNF agents in patients with axial spondyloarthritis. Ann Rheum Dis 2011 Jun; 70(6): 905-908.