Treatment of Axial Spondyloarthritis (Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis) in Adults - UpToDate

2/19/2021 Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults - UpToDate
Official reprint from UpToDate®

www.uptodate.com ©2021 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
Treatment of axial spondyloarthritis (ankylosing

spondylitis and nonradiographic axial spondyloarthritis)
in adults
Authors: David T Yu, MD, Astrid van Tubergen, MD, PhD
Section Editor: Joachim Sieper, MD
Deputy Editor: Paul L Romain, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2021. | This topic last updated: Nov 20, 2020.
INTRODUCTION
Axial spondyloarthritis (SpA), which includes ankylosing spondylitis (AS) and nonradiographic
axial SpA (nr-axSpA), is a chronic inflammatory condition manifested by back pain and
progressive spinal stiffness. AS and nr-axSpA differ in that significant abnormalities of affected
sacroiliac joints are observed by conventional radiography in patients with AS but not in those
with nr-axSpA.
Axial SpA characteristically presents in young adults with a peak age of onset between 20 and
30 years. Although primarily thought of as a spinal disease, enthesitis, as well as arthritis of
peripheral joints, which is sometimes transient, occur in up to 50 percent of patients. In
addition, other organs such as the eyes, bowel, lungs, heart, and kidneys can be affected.
The treatment, monitoring, and prognosis of axial SpA in adults are presented here. The clinical
manifestations and diagnosis of axial and peripheral SpA in adults, the treatment of peripheral
SpA, and a detailed discussion of SpA in children are presented separately. (See "Clinical
manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial
spondyloarthritis) in adults" and "Diagnosis and differential diagnosis of axial spondyloarthritis
(ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults" and "Clinical
manifestations and diagnosis of peripheral spondyloarthritis in adults" and "Treatment of
peripheral spondyloarthritis" and "Spondyloarthritis in children".)
https://www.uptodate.com/contents/treatment-of-axial-spondyloarthritis-ankylosing-spondylitis-and-nonradiographic-axial-spondyloarthritis-in-adults/p… 1/38
GOALS AND GENERAL PRINCIPLES OF MANAGEMENT
The primary goals of management for patients with axial spondyloarthritis (SpA) are to optimize
short- and long-term health-related quality of life through the following [1]:
● Relief of symptoms – To eliminate symptoms such as pain, stiffness, and fatigue or to

reduce them to the minimal possible level
● Maintenance of function – To maintain the best possible functional capacity
● Prevention of complications of spinal disease – To prevent flexion contractures, especially

dorsal kyphosis
● Minimization of extraspinal and extraarticular manifestations and comorbidities – To

reduce the impact of axial SpA-associated disorders such as uveitis and aortic valve
insufficiency
● Maintenance of effective psychosocial functioning – To preserve social participation,

prevent job loss, and improve health status and function
General principles of management and approach to therapy in axial SpA include [1-4]:
● Most patients benefit from care by an expert in rheumatologic disease, such as a

rheumatologist, and care should be coordinated with appropriate clinical specialists,
depending upon the clinical features, such as a dermatologist for psoriasis, a
gastroenterologist for inflammatory bowel disease (IBD), and an ophthalmologist for
uveitis.
● Disease activity should be regularly measured and therapy adjusted accordingly to improve
outcome.
● All patients should receive nonpharmacologic measures, including patient education,

physical therapy and exercise, encouragement to participate in support groups, and
encouragement and support of smoking cessation. (See 'Nonpharmacologic interventions'
below.)
● Pharmacologic treatment of the axial and peripheral articular manifestations can help to
reduce and prevent functional limitations that can result directly from disease activity.
Pharmacotherapy includes one or more of the following: nonsteroidal antiinflammatory
drugs (NSAIDs), non-NSAID analgesics, nonbiologic (conventional synthetic [cs]) disease-
modifying antirheumatic drugs (DMARDs), and biologic (b)DMARDs. Unlike rheumatoid
arthritis, oral (low-dose) glucocorticoids have no role in axial SpA, but intraarticular
injections may be helpful to some patients.
The choice of therapy is based upon the selection of agents that will be effective alone or in
combination for the clinical manifestations that are present in a given patient. Most of the
treatments for the different clinical manifestations overlap, but some are more effective for
one or another feature. Treatment choices, particularly the use of bDMARDs such as a
tumor necrosis factor (TNF) inhibitors and interleukin 17 (IL-17) inhibitors, may also be
influenced by the presence of findings of another disease associated with axial SpA that
may require one of these agents, such as psoriasis, IBD, and uveitis.
● In addition to control of disease activity, symptoms that require recognition and

appropriate treatment include anxiety, depression, fatigue, sleep disturbance, and
helplessness, which also contribute to functional limitations in some patients with axial SpA
[5].
Active patient engagement in shared decision-making with their clinical team regarding
their treatment is important in the management of axial SpA, which is usually lifelong.
Patients vary greatly in their disease pattern, response to different therapies, rate of
disease progression, and goals and preferences.
INITIAL THERAPY
The initial treatment interventions for most patients with axial spondyloarthritis (SpA;
ankylosing spondylitis [AS] and nonradiographic axial SpA [nr-axSpA]) include a series of
nonpharmacologic measures (see 'Nonpharmacologic interventions' below) and nonsteroidal
antiinflammatory drug (NSAID) therapy. (See 'Initial drug therapy with NSAIDs' below.)
Nonpharmacologic interventions — All patients newly diagnosed with axial SpA should

receive the following initial and ongoing interventions:
● Patient education – Patients should receive education about the nature of their disease
and advice about the need for a lifelong exercise and posture-training program and about
their working and leisure habits relevant to axial SpA. Patients should also be educated
about the importance of regular follow-up and management of comorbidities. Any patients
receiving pharmacologic treatment should be instructed about their medications, the need
for adhering to regular drug administration, and the monitoring of disease activity and for
potential side effects of therapies.
● Counseling regarding smoking cessation – Smoking cessation should be advised because

cigarette smoking is generally believed to have an adverse effect on SpA, in addition to its
adverse effects upon cardiovascular risk and other aspects of health [6]. (See "Overview of
smoking cessation management in adults".)
● Depression screening and psychosocial support – Patients should undergo screening for
anxiety and depression and be encouraged to participate in patient support groups and
arthritis self-help programs [7]. (See "Screening for depression in adults".)
● Exercises and physical therapy – Exercise improves the disease activity of SpA patients
[8,9].Patients newly diagnosed with axial SpA should be referred to a physical therapist for
an initial evaluation and training. Exercises include postural training, range of motion
exercises, stretching, recreational activities, and sometimes hydrotherapy. Spinal
manipulation should be avoided in patients with spinal fusion or advanced spinal
osteoporosis [4].
Home exercises are effective, but supervised exercise programs or formal physical therapy
can be of greater benefit, and exercise therapy combined with hydrotherapy might be more
effective than exercises alone [10]. Inpatient rehabilitation is rarely needed but may be a
solution for those patients with concomitant psychosocial problems or for encouraging
work reintegration [11].
Even those patients who are doing well clinically with pharmacologic treatment will also
benefit from education and exercise [12-15]. A randomized trial involving 62 patients
clinically stable on anti-tumor necrosis factor (TNF) therapy showed statistically significant
benefit in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and in spinal
range of motion after two and six months from the combination of an intensive
rehabilitation exercise treatment program with an educational-behavioral program,
compared with the educational-behavioral treatment alone or the results of a control group
[12].
Additional instructional materials for exercising are available from patient support
organizations, such as the Spondylitis Association of America and the National Ankylosing
Spondylitis Society in the United Kingdom, including guidebooks and audio and video aids,
such as video demonstrations of exercises for axial SpA [16].
Initial drug therapy with NSAIDs — In most patients with symptomatic axial SpA, we
recommend a nonsteroidal antiinflammatory drug (NSAID) as initial therapy. Examples include
naproxen (up to 500 mg twice daily), celecoxib (up to 200 mg twice daily), or ibuprofen (up to
800 mg three times daily), although any non-aspirin NSAID may be effective ( table 1).
Regardless of the NSAID used, the maximum dose is often required. The potential
gastrointestinal, renal, cardiovascular, and other risks of NSAIDs need to be considered when
using these agents. The potential adverse effects of NSAIDs are reviewed in detail separately.
(See "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective
NSAIDs", section on 'Toxicities and possible toxicities'.)
Each NSAID tried should be assessed for its efficacy in alleviating symptoms such as pain and
stiffness at a full antiinflammatory dose on a regular continuing basis for at least two to four
weeks before switching to a second NSAID [17].
In many patients, NSAIDs are the only medications required. Approximately 70 to 80 percent of
AS patients report substantial relief of their symptoms, including back pain and stiffness, with
NSAIDs [18]. By comparison, this is significantly more than the 15 percent observed in patients
with chronic mechanical low back pain. NSAIDs are also helpful for reducing the symptoms of
peripheral arthritis [19].
There is no evidence that one NSAID is more effective than another in axial SpA [4,20-22]. A
2015 systematic review and meta-analysis of multiple randomized trials showed benefits from
both nonselective and cyclooxygenase-2 (COX-2) selective NSAIDs and little evidence that harm
from NSAID use differed from placebo after 12 weeks of therapy [21]. The use of NSAIDs in axial
SpA is also consistent with expert guidelines of major organizations [1,2].
One case-control study found that current use of diclofenac, compared with remote use, was
associated with an elevated risk of myocardial infarction in patients with SpA (odds ratio [OR]
3.32, 95% CI 1.57-7.03) [23]. There was also evidence of increased cardiovascular risk in patients
with osteoarthritis (OA), but the increased risk with diclofenac was greater in patients with SpA
compared with that seen with OA (OR 2.64, 95% CI 1.24-5.58). Such risk was not seen in patients
on naproxen. Cardiovascular risk associated with diclofenac and with other NSAIDs is reviewed
in detail separately. (See "NSAIDs: Adverse cardiovascular effects".)
Duration of NSAID therapy — Once a particular nonsteroidal antiinflammatory drug (NSAID)

has been determined to be effective within two to four weeks, it is usually then used on
demand (as needed) according to symptoms, although some patients require ongoing daily
therapy to maintain benefit. Some data have suggested that treating patients continuously with
NSAIDs even though patients are asymptomatic might prevent formation of growth of
syndesmophytes in the spine [24]. However, this could not be verified in a subsequent study
[25]. We do not use NSAIDs continuously in asymptomatic patients.
Prevention of syndesmophyte formation was suggested in a 2005 trial involving 215 patients
treated with celecoxib (100 to 200 mg twice daily) either continuously or as needed, those
receiving continuous therapy exhibited less radiographic progression in the spine at two years
[24]. By contrast, another randomized trial, in which 167 patients with AS were treated with
diclofenac either continuously or as needed, found no evidence at two years for reduced
radiographic change in the group assigned to continuous therapy [25].
INADEQUATE RESPONSE TO NSAIDs
In patients with symptoms due to active axial spondyloarthritis (SpA) and an inadequate
response to initial therapy with two different nonsteroidal antiinflammatory drugs (NSAIDs)
used consecutively in an adequate dose for at least two to four weeks each, we recommend a
tumor necrosis factor (TNF)-alpha inhibitor rather than continuing treatment with NSAIDs
alone. Any of the TNF inhibitors is an acceptable option (see 'TNF inhibitors' below); the choice
between them is based upon patient preferences regarding the route and frequency of
administration, physician preference and experience, regulatory and cost constraints, and
possible coexisting conditions such as inflammatory bowel disease (IBD). These biologics do not
need to be used together with a conventional synthetic (cs) immunosuppressive agent such as
methotrexate (MTX) as there is no evidence this offers greater benefit. (See 'Efficacy of TNF
inhibitors' below.)
In patients who have contraindications to the use of TNF inhibitors, we suggest treatment with
an anti-IL-17 antibody, secukinumab or ixekizumab, [4]. Secukinumab and ixekizumab, two anti-
interleukin 17 (IL-17) monoclonal antibodies, are reasonable alternatives to a TNF inhibitor, with
a similar level of efficacy (see 'Secukinumab' below and 'Ixekizumab' below). However, there is
much more experience in clinical practice with TNF antagonists than with secukinumab or
ixekizumab.
The use of a biologic agent for active axial SpA is particularly appropriate for those with high or
very high disease activity, although they are effective in patients with mild to moderate
symptoms as well (see 'Efficacy of TNF inhibitors' below). The high cost of these therapies and
efforts by regulators or payers to control such costs are major impediments to wider availability
of these agents for use in symptomatic SpA [26]. High disease activity can be defined as a Bath
Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥4.0 or Ankylosing Spondylitis Disease
Activity Score (ASDAS) ≥2.1 [17]. (See 'Evaluation and monitoring' below.)
Before proceeding with a biologic agent, it is also important to clinically exclude other causes of
the patient's symptoms, including fibromyalgia, which is present in a substantial minority of
patients with axial SpA and can mimic symptoms of SpA as well [27,28]. The differential
diagnosis of SpA and the diagnosis and treatment of fibromyalgia are described separately.
(See "Diagnosis and differential diagnosis of axial spondyloarthritis (ankylosing spondylitis and
nonradiographic axial spondyloarthritis) in adults", section on 'Differential diagnosis' and
"Clinical manifestations and diagnosis of fibromyalgia in adults" and "Initial treatment of
fibromyalgia in adults".)
In patients with symptoms and findings predominantly of peripheral arthritis, we use a disease-
modifying antirheumatic drug (DMARD) first before switching to a biologic. Use of sulfasalazine
(SSZ) as an alternative to TNF inhibitors is limited to patients with prominent peripheral arthritis
[4]. (See 'Peripheral arthritis and periarticular disease' below.)
TNF inhibitors
Use of TNF inhibitors
● Dosing – The typical doses of the TNF inhibitors for both ankylosing spondylitis (AS) and
nonradiographic axial SpA (nr-axSpA) are:
• Etanercept – 50 mg weekly, administered as a subcutaneous injection of 50 mg once a

week or 25 mg twice a week
• Infliximab – 5 mg/kg by intravenous infusion at zero, two, and six weeks followed by a
maintenance dose of 5 mg/kg every six to eight weeks
• Adalimumab – 40 mg by subcutaneous injection every two weeks
• Golimumab – 50 mg by subcutaneous injection every four weeks
• Certolizumab pegol – 400 mg by subcutaneous injection at zero, two, and four weeks,
followed by 200 mg every other week or 400 mg every four weeks
There is little information on whether higher doses of any of these TNF antagonists would
confer greater efficacy [29].
Biosimilar agents (eg, for infliximab, etanercept, and adalimumab) have the same dosing
regimen as originators and seem to have a similar efficacy [30]. (See "Overview of biologic
agents and kinase inhibitors in the rheumatic diseases", section on 'Biosimilars for biologic
agents'.)
● Contraindications – The contraindications to TNF inhibitor use are the same as those for
use in other diseases, such as rheumatoid arthritis. Briefly summarized, these include:
• Active infection
• Latent (untreated) tuberculosis (TB)
• Demyelinating disease (eg, multiple sclerosis, optic neuritis)
• Heart failure
• Malignancy
These agents are probably safe in patients who are pregnant or breastfeeding, but the
evidence is limited. The risks of these biologics in general and also individually are
discussed in detail separately. (See "Safety of rheumatic disease medication use during
pregnancy and lactation", section on 'Tumor necrosis factor inhibitors'.)
The safety of these agents and risk of recurrent malignancy in patients with a history of
prior malignancy is less well established than in patients without such a history; the
available data are discussed in detail separately. (See "Tumor necrosis factor-alpha
inhibitors: Risk of malignancy".)
● Adverse effects – The risks and adverse effects of the TNF inhibitors are described in detail
separately. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects"
and "Tumor necrosis factor-alpha inhibitors: Bacterial, viral, and fungal infections" and
"Tumor necrosis factor-alpha inhibitors and mycobacterial infections" and "Tumor necrosis
factor-alpha inhibitors: Risk of malignancy" and "Tumor necrosis factor-alpha inhibitors:
Induction of antibodies, autoantibodies, and autoimmune diseases".)
● Monitoring – (See 'Evaluation and monitoring' below.)
● Duration of therapy – (See 'Duration of therapy with biologics' below.)
Efficacy of TNF inhibitors — The ability of the TNF inhibitors to reduce disease activity in
patients with axial SpA, including both AS and nr-axSpA, has been demonstrated in multiple
randomized trials and several meta-analyses of randomized trials [31-33]. Trials have been
performed with each of the five widely available TNF inhibitors (ie, infliximab, etanercept,
adalimumab, certolizumab, and golimumab), as well as a number of biosimilars to these drugs,
which are becoming increasingly available in the United States, Europe, and other regions
worldwide. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases",
section on 'Biosimilars for biologic agents'.)
As examples of the available evidence:
● The efficacy of TNF inhibitors (including etanercept, adalimumab, infliximab, certolizumab,

and golimumab) in the treatment of axial SpA was documented in a 2015 systematic review
and meta-analysis of randomized trials involving over 2400 patients in which substantial
improvements in disease activity and function were seen [31]. Patients treated with these
agents, compared with placebo, were significantly more likely to achieve at least 40 percent
improvement from baseline, measured with the Assessment of SpondyloArthritis
international Society (ASAS) 40 percent (ASAS40) composite response measure (odds ratio
[OR] 4.73, 95% CI 3.75-5.98).
The ASAS response is a composite measure, which includes:
• Patient global assessment

• Patient assessment of pain
• A functional assessment, such as ability to carry out certain activities with which the
patient had difficulty prior to treatment
• Degree of inflammation as assessed by morning stiffness
● A 2007 meta-analysis indicated that all three of the TNF inhibitors then available
(adalimumab, etanercept, and infliximab) were similar in efficacy in patients with AS [34].
These medications have not been compared directly with each other, but indirect
comparisons were unable to demonstrate differences between them. At week 12 of trials,
patients treated with the TNF inhibitors were 3.6-fold more likely, compared with those
treated with placebo, to achieve 50 percent improvement using the ASAS50 composite
measure [35].
The clinical responses are typically rapid. Eighty percent of patients who experienced a >50
percent response according to the BASDAI (see 'Evaluation and monitoring' below) by 12 weeks
did so within the first six weeks of treatment. The number needed to treat (NNT) to achieve a
partial remission is estimated to be from 2.3 to 6 [36]. In patients with advanced AS, treatment
with TNF inhibitors was also found to be effective [37]. The long-term benefit of TNF inhibitor
therapy appears to be durable [38].
Patients with a shorter duration of disease, and to a lesser extent those with elevated C-reactive
protein (CRP) levels or younger age, are most likely to have a good response [39,40].
Improvement of greater than 50 percent may be seen in up to 80 percent of such patients [41].
TNF inhibitors are also effective in patients with clinically symptomatic nr-axSpA who failed
treatment with NSAIDs [42-49].
Concomitant use of an immunomodulatory drug, such as MTX, is not required as most of the
limited evidence indicates that this provides no additional benefit in patients with SpA but may
increase the cost and the risk of adverse effects [50-53].
Pooled data from 12 European registries, including a total of 24,195 axial SpA patients, found
that disease becomes inactive in routine care after six months of treatment with a first TNF
inhibitor in approximately one-fourth of treated AS patients and one-fifth of nr-axSpA patients,

with drug retention rates at 12 months of 80 and 73 percent, respectively [54].
The frequency of an inadequate response to the initial TNF inhibitor has also been analyzed in
the United States using an insurance claims database; of patients newly started on a TNF
inhibitor from 2009 to 2013, only approximately one-third of males and less than one-fourth of
females with AS continued to use the initial TNF inhibitor over a two-year follow-up period [55].
Interleukin 17 inhibitors
Secukinumab — Secukinumab, an anti-IL-17A monoclonal antibody, is an alternative to TNF

inhibitors for patients with axial SpA. Secukinumab is administered in a dose of 150 mg by
subcutaneous injection; patients should be treated weekly for four weeks as a loading dose,
then once every four weeks thereafter [56,57]. In AS patients with an insufficient response to
secukinumab 150 mg per month, in particular in those patients with a previous inadequate
response to TNF inhibitors, an increase in the dose to 300 mg every four weeks can be
considered [58]. Patients should be screened for latent TB prior to use of this agent and should
be treated appropriately, if screening positive, by initiation of anti-TB therapy before starting
secukinumab. However, there are no reports, in contrast to TNF inhibitor therapy, of latent TB
reactivation under secukinumab treatment. Hence, an IL-17 inhibitor, such as secukinumab (or
ixekizumab (see 'Ixekizumab' below)), is the preferred biologic in patients in whom there is high
risk for TB. (See "Approach to diagnosis of latent tuberculosis infection (tuberculosis screening)
in adults" and "Treatment of latent tuberculosis infection in HIV-uninfected nonpregnant
adults".)
Secukinumab became commercially available in the United States in 2016 for use in AS
irrespective of prior use of TNF inhibitors. This drug is also available for use in active AS in
Europe and other parts of the world; and since 2020, also for patients with active nr-axSpA.
Because of its more recent release and more limited number of indications, there is less
experience with this agent than with the TNF inhibitors as a class and with the individual TNF
inhibitors; it is also available for use in psoriasis and psoriatic arthritis. (See "Treatment of
psoriasis in adults", section on 'Secukinumab' and "Treatment of psoriatic arthritis", section on
'Secukinumab'.)
In contrast to psoriatic arthritis and axial SpA, secukinumab was found to be ineffective in
patients with Crohn disease, and secukinumab and other anti-IL-17 biologics have been
reported to induce or exacerbate IBD [59]. Hence, it should be used with particular caution if
needed for the treatment of SpA in patients with probable coexistence of IBD.
https://www.uptodate.com/contents/treatment-of-axial-spondyloarthritis-ankylosing-spondylitis-and-nonradiographic-axial-spondyloarthritis-in-adults/… 10/38
The efficacy and relative safety of secukinumab has been demonstrated in three randomized
trials in AS that compared the efficacy of secukinumab in several dosing regimens (75 mg, 150
mg, and 300 mg subcutaneously every four weeks following weekly doses for the first four
weeks of therapy) with placebo [60,61]. In addition, secukinumab was beneficial, compared with
placebo, both in patients who were naïve to TNF inhibitor therapy and those with prior TNF
inhibitor exposure [60-63]. As an example, in one trial, these differences were 68 versus 31 and
50 versus 24 percent, respectively [63]. Responses were sustained after two to three years [64-
66].
It is unclear whether a loading dose adds further benefit. A fourth trial was designed to test the
efficacy of 150 mg secukinumab with or without loading doses. The ASAS20 and other
endpoints were not reached at a level that was statistically significantly greater than the
placebo response at week 16. This was attributed to a higher-than-expected placebo response
[67]. Subsequent open-label treatment responses were sustained or further improved from
week 16 through week 104 for both secukinumab regimens, regardless of previous TNF
inhibitor therapy.
The efficacy and safety of secukinumab 150 mg every four weeks has also been demonstrated
in a randomized trial in patients with nr-axSpA [68]. In total, 555 patients were randomly
assigned to receive secukinumab 150 mg every four weeks with or without a loading dose, or to
placebo. The proportion achieving an ASAS40 among TNF inhibitor-naïve patients was greater
for the loading dose group (41.5 percent) at week 16 and non-loading dose group (39.8 percent)
at week 52 compared with placebo (29.2 percent at week 16 and 19.9 percent at week 52) [68].
Infections, including candidiasis, were more common in patients receiving secukinumab during
the placebo-controlled period of the first 16 weeks of the trials; during the entire period of
treatment, the rates of neutropenia, candida infection, and Crohn disease were each just below
one case per 100 patient-years among the secukinumab-treated patients.
Ixekizumab — Ixekizumab, like secukinumab, is another anti-IL-17A monoclonal antibody

available in the European Union and also the United States, where it has been approved by the
US Food and Drug Administration (FDA) for the treatment of active AS and nr-axSpA. In AS, it is
administered as a subcutaneous injection of 160 mg once, for the initial dose, followed by 80
mg every four weeks. In nr-axSpA, the initial dose is 80 mg. Subsequent doses are 80 mg every
four weeks. It may be administered alone or in combination with conventional DMARDs (eg,
SSZ). Similar to secukinumab, patients should be tested for latent tuberculosis prior to starting
therapy, and patients should be monitored for symptoms of IBD, which has been described as a
complication during the treatment.
Ixekizumab has been shown in randomized phase 3 trials to be effective in patients with active
AS and active nr-axSpA [69-71].
● In a trial involving 341 patients with active AS/radiographic axial SpA with inadequate
responses or intolerance to NSAIDs who had not previously received a biologic DMARD,
patients randomly assigned to receive ixekizumab (80 mg subcutaneously every two or four
weeks) or adalimumab (40 mg subcutaneously every two weeks) were more likely at week
16 to achieve an ASAS40 composite response measure compared with those receiving
placebo (52, 48, and 36 versus 18 percent; differences of 33, 30, and 17 percent; 95% CI of
20-47, 16-43, and 4-30, respectively) [70].
● In a trial involving 316 patients with active AS/radiographic axial SpA with an inadequate
response or intolerance to one or two TNF inhibitors, patients randomly assigned to receive
ixekizumab (80 mg subcutaneously every two or four weeks) were more likely at week 16 to
achieve an ASAS40 compared with those receiving placebo (31 and 25 versus 13 percent, p
= 0.003 and 0.017, respectively) [69].
● In a trial involving 303 patients with active nr-axSpA with inadequate responses or
intolerance to NSAIDs, patients were randomly assigned to receive ixekizumab (80 mg
every two or four weeks) or placebo. Patients receiving ixekizumab were more likely to
achieve an ASAS40 response (40 and 35 versus 19 percent, respectively) [71].
In all three trials, treatment-emergent adverse effects, largely minor to moderate infections,
were similar in frequency among the actively treated groups and more common than with
placebo. Injection site reactions were seen in some patients as well.
A systematic review of the randomized trials comparing IL-17 inhibitors with placebo showed
similar responses and safety in AS patients treated with secukinumab and ixekizumab, although
no studies directly compared the two agents [72].
Role of systemic glucocorticoids for axial disease — Systemic glucocorticoids are not

indicated for patients with axial SpA. Very limited data suggest that only very high doses of
prednisolone may have some benefit for very short-term therapy [73].
INADEQUATE RESPONSE OR INTOLERANCE TO INITIAL BIOLOGIC
Definitions — One should distinguish between two categories as the reason for switching
agents [38]:
● Primary failure – A patient can be considered as having an inadequate response,

conventionally described as that biologic "failing," after starting a particular TNF or
interleukin 17 (IL-17) inhibitor and receiving therapy for at least 12 weeks, if they never
experience an improvement (primary failure for lack of efficacy). (See 'Evaluation and
monitoring' below.)
● Secondary failure – Patients in whom there is initial improvement with drug therapy, but
who experience a subsequent relapse (ie, worsening or recurrence of disease activity) are
described as experiencing secondary failure for loss of efficacy. Patients who do not
tolerate the particular TNF or IL-17 inhibitor (eg, due to an adverse event) are defined as
experiencing a form of secondary drug failure as well.
Primary and secondary failures are characterized by continuing symptoms of pain and/or
stiffness that affect routine activities [1,74]. (See 'Evaluation and monitoring' below.)
Approach to switching biologic agents — The choice of therapy in patients with inadequate

efficacy or intolerance of a first or subsequent biologic is based in part upon the reason for
drug discontinuation; it is also substantially influenced by an assessment of individual factors in
a process of active shared decision-making involving the patient and their clinician, which is
also affected by factors such as patient preferences for route and frequency of administration,
the duration and severity of disease, and coexisting diseases or comorbidities, as well as
regulatory and patient cost concerns [75].
The major options are a TNF inhibitor (see 'TNF inhibitors' above); secukinumab or ixekizumab,
which are anti-IL-17 agents (see 'Interleukin 17 inhibitors' above); or a medication not formally
approved by regulators for use in patients with this disorder. (See 'Resistant to standard
therapies' below.)
We take the following general approach [38]:
● Primary failure to an initial TNF inhibitor – In patients with an inadequate response,

even after three months of therapy, we suggest an anti-IL-17 antibody as the next agent.
This approach is also consistent with 2019 expert guidelines and findings documenting the
efficacy of these agents in axial spondyloarthritis (SpA) [1,4]. Anti-IL-17 antibodies have the
theoretical appeal that the mechanisms of action are different from TNF inhibitors.
● Secondary failure to an initial TNF inhibitor – In patients with secondary drug failure
from loss of efficacy to the initial agent, we prefer treatment with a second TNF inhibitor,
given the evidence of benefit, at least initially, with this class of drug.
● Intolerance to an initial TNF inhibitor – In patients who develop intolerance to the initial
agent, especially if the intolerance is considered to belong to the TNF inhibitor class (eg,
rash, injection site reactions), switching to an anti-IL-17 antibody is a reasonable option.
● Secondary failures of two consecutive TNF inhibitors – Secondary failure to two

consecutive TNF inhibitors does not preclude a response to a third TNF inhibitor or to an
anti-IL-17 antibody. Both are reasonable options, although the likelihood of responding to a
third TNF inhibitor is lower after two failures.
● Primary drug failures with both a TNF inhibitor and anti-IL-17 antibodies – In patients
who have had an inadequate response to at least one TNF inhibitor and to anti-IL-17
antibodies, we repeat the diagnostic evaluation to assure that the diagnosis is correct.
Findings consistent with previously undiagnosed psoriasis involving skin or nails may
suggest a diagnosis of psoriatic arthritis with axial SpA; in patients in whom a diagnosis of
psoriatic SpA is likely, trials of agents that have proven effective in psoriatic arthritis, but
that are typically not effective (or of unproven efficacy) in ankylosing spondylitis (AS) and
nonradiographic axial SpA (nr-axSpA), may be reasonable options. Such agents include anti-
IL-23 monoclonal antibodies [76]. (See "Diagnosis and differential diagnosis of axial
spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in
adults" and "Treatment of psoriatic arthritis" and 'Resistant to standard therapies' below.)
Treatment options in patients with AS or nr-axSpA who lack signs of another condition
(such as psoriasis), who have responded inadequately to at least one TNF inhibitor and to
an anti-IL-17 antibody, include any of the other TNF inhibitors or the alternate anti-IL-17
antibody. As an example, patients may benefit from switching to infliximab, if this has not
been used, which has the possibility of measuring trough levels of the drug to confirm
therapeutic serum concentrations. An additional strategy is to use an agent with a different
inhibitor mechanism (ie, etanercept, which is a soluble TNF receptor, rather than one of the
other TNF inhibitors, which are monoclonal anti-TNF antibodies, or vice versa). (See 'Agents
of possible benefit' below.)
● Inadequate response or intolerance of secukinumab or ixekizumab as initial agent – In

the patients who may receive secukinumab or ixekizumab as the initial drug, but need to
switch, we would use a TNF inhibitor as the next agent. In those unable to use a TNF
inhibitor, an alternative agent would be required (see 'Resistant to standard therapies'
below). There is a lack of evidence that compares options for these specific patient
populations.
Efficacy of switching — In general, the frequency of good responses to TNF inhibitors is still
substantial but decreases with the use of subsequent agents, compared with the first. This is
well studied in patients with rheumatoid arthritis (see "Treatment of rheumatoid arthritis in
adults resistant to initial biologic DMARD therapy") but has also been examined in patients with
AS. There is little evidence and a lack of randomized trials to serve as a guide in managing these
patients. Most reports are based on registry studies [38].
As an example, a 12-week, open-label study involving 1250 patients with AS evaluated the
effectiveness of switching to adalimumab when patients failed etanercept or infliximab because
of either an inadequate response or an adverse effect [77]. Such patients were compared with
those begun on adalimumab who had never received etanercept or infliximab. After 12 weeks,
a 50 percent improvement in the BASDAI response (BASDAI 50) from baseline was observed
more often in patients who had never received TNF antagonists, compared with those who had
received a prior TNF inhibitor (63 versus 41 percent, odds ratio [OR] 0.40, 95% CI 0.31-0.53).
Other studies involving patients with AS have also shown levels of benefit with second agents
that approach those with the first drug. In one study, efficacy of etanercept in a large
proportion of 23 patients with AS who were switched from infliximab due to loss of benefit or
intolerance was shown at 54 weeks (ASAS20, ASAS50, and ASAS70 response rate of 74, 61, and
39 percent, respectively) [78]. As another example, benefits of a subsequent TNF inhibitor were
described in a study of 47 patients with SpA (19 of whom had AS) that found similar good
outcomes in patients who were switched from either infliximab or etanercept to adalimumab as
a second or third agent, regardless of the reason for discontinuation [79].
One registry-based analysis in patients with an inadequate response to an initial TNF inhibitor
found a subsequent TNF inhibitor to have comparable efficacy to switching to secukinumab
[80].
RESISTANT TO STANDARD THERAPIES
Agents of possible benefit — Little evidence and no randomized trials are available to

determine the best treatment options for patients in whom two to three different tumor
necrosis factor (TNF) inhibitors and interleukin 17 (IL-17) inhibitors have all been inadequate. A
third (but investigational) IL-17 inhibitor, bimekizumab, has been reported to be effective in
patients with active ankylosing spondylitis (AS) [81]. Additional drugs have been reported in
limited studies, but typically without confirmation, to be somewhat effective in
spondyloarthritis (SpA).
Used in other disorders
● Tofacitinib – Tofacitinib, a Janus kinase (JAK) inhibitor with preferential effects on JAK-3 and
-1 over JAK-2, is available for use in psoriatic arthritis, rheumatoid arthritis, and ulcerative
colitis and has been reported in a proof-of-concept multiple-dosing study in 207 patients in
a 12-week phase 2 trial in AS. It had greater benefit than placebo in the tofacitinib groups in
a phase 2 trial [82,83]. (See "Treatment of rheumatoid arthritis in adults resistant to initial
biologic DMARD therapy", section on 'Tofacitinib' and "Treatment of rheumatoid arthritis in
adults resistant to initial conventional nonbiologic DMARD therapy", section on 'Tofacitinib'
and "Treatment of psoriatic arthritis", section on 'Tofacitinib'.)
● Upadacitinib – Upadacitinib is a JAK inhibitor with preferential effects on JAK-1, which is

being investigated in patients with AS [84]. It is available for use in rheumatoid arthritis and
is also under investigation for use in psoriatic arthritis and inflammatory bowel disease
(IBD). (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD
therapy", section on 'Upadacitinib' and "Treatment of rheumatoid arthritis in adults
resistant to initial conventional nonbiologic DMARD therapy", section on 'Upadacitinib'.)
The benefits of upadacitinib in AS were shown in a randomized phase 2/3 trial involving 187
patients with active AS and inadequate responses or intolerance to nonsteroidal
antiinflammatory drug (NSAID) therapy, in which patients treated with upadacitinib,
compared with placebo, were more likely to achieve a SpondyloArthritis international
Society (ASAS) 40 percent (ASAS40) response at 14 weeks (52 versus 26 percent) [84].
Improvements in function and magnetic resonance imaging (MRI) findings of inflammation
were also seen. No herpes zoster, serious infections, or venous thromboembolic events
were seen; elevations in levels of creatine kinase were observed with upadacitinib and
placebo in 9 and 2 percent of patients, respectively.
● Thalidomide – The potential benefit of thalidomide has been examined in AS because of its
immunomodulatory properties, including its effects on TNF [85-87]. A 2002 review of
observational studies reported that among more than 50 patients treated with thalidomide,
68 percent improved and 19 percent withdrew from treatment due to lack of efficacy or
adverse effects [87]. Thalidomide has also been reported to reduce relapses after the
discontinuation of etanercept [88]. However, the seriousness of the potential side effects
will need to be considered in determining whether it has a role in therapy, and randomized
trials have not been reported. It is rarely, if ever, used in the United States or Europe for AS.
Investigational agents not yet available for any conditions
● Filgotinib – Filgotinib, an investigational selective JAK-1 inhibitor, has been shown to be

effective in a trial involving 116 patients with active AS with inadequate responses or
intolerance to NSAIDs [89]. In a randomized phase 2 trial, patients receiving filgotinib (200
mg orally once daily) showed a greater reduction in Ankylosing Spondylitis Disease Activity
Scores (ASDAS) at week 12 compared with placebo responses (mean change from baseline
-1.47 versus-0.57, least squares mean difference 0.85, 95% CI -1.17 to -0.53). A clinically
significant improvement in ASDAS was also more likely in the filgotinib-treated patients (66
versus 26 percent, 40 percent difference, 95% CI 22-54). Approximately 40 percent of
patients were receiving a conventional synthetic (cs) disease-modifying antirheumatic drug
(DMARD). Adverse effects were similar in the two groups. Filgotinib has also been under
investigation for several other inflammatory rheumatic diseases.
Biologic and other agents effective in other diseases but not axial SpA — Several agents
that have been shown to be effective in patients with psoriatic arthritis, rheumatoid arthritis, or
other forms of inflammatory arthritis have been found to be ineffective in patients with axial
SpA or insufficiently effective to warrant further development for this condition, including:
● Abatacept, a T-cell costimulation blocker [90]

● Tocilizumab and sarilumab, IL-6 inhibitors [91,92]
● Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody [93]
● Risankizumab, an anti-IL-23 p19 monoclonal antibody [94]
● Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor [95,96]
● Rituximab, a monoclonal anti-CD20 antibody that depletes B cells [97]
Role of non-NSAID analgesics — In patients who need additional temporary pain relief, not
adequately provided by NSAIDs, we most often use acetaminophen (500 to 1000 mg up to three
times daily), which can be added to NSAIDs if required temporarily [98].
Opioids should generally be avoided and used, if needed, for only a short period of time. As an
example, tramadol (25 to 50 mg up to four times daily) has sometimes been used if opioids are
required, but other opioid medications should be avoided in axial SpA, and such situations are
rare.
There are few studies describing the usefulness of analgesics or opioids in axial SpA, whether
alone or in combination with other drugs [99].
Isolated active sacroiliitis — A treatment option used by one of the authors (DY) in patients
refractory to NSAIDs with severe isolated sacroiliitis is injection of long-acting glucocorticoids
(eg, 40 mg triamcinolone) into the sacroiliac joints. Small studies with methodologic limitations
suggest this approach may be beneficial in patients who complain of marked pain at the
sacroiliac joints that is unresponsive to systemic medications [2]. It is preferable to carry out the
injections under imaging (usually computed tomography [CT]) guidance [100].
Benefit of injection of long-acting glucocorticoids has been found in some but not all studies
[101,102]. However, one randomized trial reported more than 70 percent relief in over 80
percent of injected sacroiliac joints [102]. Relief persisted for as long as six months or more
after the injection and no complications were seen.
EVALUATION AND MONITORING
Patients should be followed regularly for monitoring of disease activity and medication safety.
The frequency of visits and laboratory assessment depend upon the patient's response to
therapy and the risks of the medications being used. Patients initially require evaluation every
two to four weeks to assess the response to nonsteroidal antiinflammatory drugs (NSAIDs),
then monthly to every three months once stable or when starting a biologic agent. Patients
should be evaluated after at least 12 weeks of tumor necrosis factor (TNF) inhibitor or anti-
interleukin 17 (IL-17) therapy. Subsequent monitoring can take place every three to six months
when the disease is under control.
Imaging should be repeated only when the results might alter the treatment strategy [4]. For
patients with nonradiographic axial spondyloarthritis (nr-axSpA), it is not necessary to repeat
magnetic resonance imaging (MRI) of the spine or the pelvis to confirm that there is a response
to therapy. Neither is it necessary to repeat radiographs of the spine at a fixed scheduled
interval.
Clinical assessment should include a focused history and examination directed at the patient's
known manifestations and screening for other features associated with axial spondyloarthritis
(SpA) (see "Clinical manifestations of axial spondyloarthritis (ankylosing spondylitis and
nonradiographic axial spondyloarthritis) in adults"). The adequacy of the response is based
upon a combination of measures:
● Disease activity assessment with either the Bath Ankylosing Spondylitis Disease Activity
Index (BASDAI) or the Ankylosing Spondylitis Disease Activity Score (ASDAS):
• BASDAI – The BASDAI is an instrument for the assessment of disease activity that is
presented in a questionnaire format. A BASDAI score of ≥4 (on a scale of 0 to 10) is
indicative of active disease that warrants consideration of biologic therapy ( table 2).
Clinically significant improvement is defined as either a 50 percent improvement of the
BASDAI score (BASDAI 50) or an absolute change of ≥2 on a scale of 0 to 10 and a

clinical "expert" opinion that a particular patient has improved.
• ASDAS – The ASDAS is a composite instrument to measure disease activity. Unlike the
BASDAI, the ASDAS also incorporates information from the level of acute phase
reactants in addition to clinical parameters (a patient global score and several
questions also used for the BASDAI). An ASDAS calculator is accessible at the
Assessment of SpondyloArthritis international Society (ASAS) website (which can also
be downloaded on mobile devices through an ASAS app, available in several
languages), together with information regarding its use and interpretation. The ASDAS
categorizes the disease activity as inactive, low, high, or very high [103]. The disease
activity should at least be high (≥2.1) to warrant consideration of biologic therapy. A
change of ≥1.1 in the ASDAS score is considered a significant improvement, while a
change of ≥2.0 is a major improvement.
● Individualized contextual judgment – Over the course of therapy and at key decision points,
each patient's personal goals and preferences should be incorporated in treatment
decisions, particularly regarding the targets of treatment, and patients should be assessed
individually in the context of their own psychological, social, and clinical history; physical
examination; previous therapies; laboratory tests; results of imaging; and degree of
response to prior therapies [3,75]. Use of a serial quantitative measure is of particular
benefit; scoring the patient global assessment on a scale of 0 to 10, which is included in the
ASDAS calculation, should be performed even if an ASDAS or BASDAI is not.
PERIPHERAL ARTHRITIS AND PERIARTICULAR DISEASE
The approach to patients with predominantly peripheral spondyloarthritis (SpA) differs from
that for patients with symptomatic axial SpA, whether or not peripheral SpA is also present in
such patients, because of the potential benefit of traditional (conventional synthetic [cs])
disease-modifying antirheumatic drugs (DMARDs) for peripheral joint manifestations but not
for the axial disease. By contrast, treatments for the axial disease, including biologic agents, are
typically also quite effective for the peripheral manifestations. (See "Treatment of peripheral
spondyloarthritis", section on 'Resistant to nonbiologic DMARD'.)
The treatment of peripheral articular and periarticular manifestations of SpA is briefly reviewed
here but discussed in detail separately (see "Treatment of peripheral spondyloarthritis"). The
management of peripheral arthritis in patients with SpA depends upon the degree of
involvement, whether involved joints are accessible to injection, and the medications being
used for other disease manifestations.
The following summarizes our approach:
● Mono- or oligoarthritis – In patients with only one to three peripheral joints affected, we
perform joint aspiration and intraarticular glucocorticoid injection (eg, with triamcinolone
acetate or methylprednisolone acetate) using the same general approach and medications
as in patients with rheumatoid arthritis. (See "Use of glucocorticoids in the treatment of
rheumatoid arthritis", section on 'Intraarticular therapy' and "Intraarticular and soft tissue
injections: What agent(s) to inject and how frequently?".)
● Persistent peripheral arthritis – In patients with peripheral arthritis that is not adequately
controlled with nonsteroidal antiinflammatory drugs (NSAIDs), but whose axial disease is
controlled with these medications, we suggest a traditional nonbiologic csDMARD, such as
sulfasalazine (SSZ; 2 to 3 g in two or three divided doses daily) or methotrexate (MTX; 15 to
25 mg once weekly).
In randomized trials comparing SSZ with placebo, efficacy was shown for peripheral joint
disease, but only very modest to no benefit was shown for axial manifestations [104,105].
Tumor necrosis factor (TNF) inhibitors appear more effective than SSZ; in one randomized
trial in patients with ankylosing spondylitis (AS), SSZ was less effective in reducing disease
activity compared with etanercept, whether or not peripheral joint involvement was present
[106]. Use of SSZ in patients with predominantly peripheral manifestations is also
supported by major guidelines [1,2,4]. Data supporting the use of MTX in patients with AS
are more mixed and the data are very limited, but reductions in peripheral joint
manifestations have been seen in some of the trials [107,108]. Limited data suggest that
leflunomide is of little or no benefit for patients with AS [109,110].
However. in patients with axial disease not adequately controlled with an NSAID, biologic
agents are indicated because csDMARDs are ineffective for the axial inflammatory disease
(see 'TNF inhibitors' above). Moreover, peripheral arthritis in such patients is likely to be
adequately controlled by the biologic agent that is effective for the axial disease, and a
csDMARD is not then required. The treatment of peripheral arthritis in SpA with these
agents is described separately. (See "Treatment of peripheral spondyloarthritis" and
"Treatment of peripheral spondyloarthritis", section on 'Arthritis'.)
● Enthesitis and dactylitis – In patients with persistent symptoms of enthesitis despite

NSAID therapy, we use local glucocorticoid injections, with the exception of disease
affecting the Achilles tendon. Glucocorticoid injections should be avoided in the area of the
Achilles tendon, as they might induce tendon rupture. Patients with an inadequate
response to NSAIDs and local injections often respond to the biologic DMARD being
employed for the treatment of axial or poorly responsive peripheral disease. The treatment
of enthesitis and dactylitis in SpA is described in detail separately. (See "Treatment of
peripheral spondyloarthritis", section on 'Enthesitis' and "Treatment of peripheral
spondyloarthritis", section on 'Dactylitis'.)
DURATION OF THERAPY WITH BIOLOGICS
In patients on biologic agents who have been stable for at least a year in remission or with low
disease activity, it is reasonable to cautiously attempt dose reduction but not drug
discontinuation; the latter may be more appropriate in patients for whom the treatment is a
significant burden and if at least several potential treatment options remain, but patients
should be informed of the risk of a disease flare and of the associated risk of not regaining their
prior level of disease control. By contrast, tumor necrosis factor (TNF) inhibitors and other
biologics, such as secukinumab, should be discontinued if response criteria are not met or if
adverse effects limit usage.
Among patients with ankylosing spondylitis (AS) who have substantial clinical responses, the
majority will relapse soon after completely stopping their TNF inhibitor [111]. However, a
number of randomized trials and observational studies have shown that in stable patients with
axial SpA and low disease activity, the dosing interval for TNF inhibitors can be prolonged or the
dose reduced in approximately half of the patients without losing disease control [51,112-114].
It is not clear which dose reduction strategy (either dose reduction at the same interval or
increased spacing between doses) is more successful. No studies have investigated the
potential risk of immunogenicity with dose reduction or looked in detail at effects upon
associated comorbidities with this approach [115].
Similar observations have been made in patients with nonradiographic axial spondyloarthritis
(nr-axSpA) in a well-designed randomized trial of drug discontinuation, as well as in several
much smaller trials and observational studies that had some methodologic limitations. The risk
of disease flare in patients discontinuing adalimumab after induction of stable remission of
previously active nr-axSpA was examined in a trial involving 305 such patients who were
randomly assigned to continue adalimumab or receive placebo [45]. A higher proportion of
those remaining on the drug did not experience a flare during the 40-week trial period (70
versus 47 percent). Rescue therapy with adalimumab was given in 44 percent of those
withdrawn from the drug (ie, most of those who flared), but 43 percent of this group did not
regain a disease remission during the trial period. Smaller, mostly observational, studies have
also examined the effect of withdrawal of TNF inhibitors after the patients have entered
remission and similarly had indicated that approximately 80 percent of these patients had flares
of their disease, and approximately 60 to 80 percent of these patients achieved substantial
improvement over time with resumption of therapy [116].
One trial has demonstrated the benefits of tapering of a TNF inhibitor (by increasing the
interval between doses) over discontinuation among patients with early (defined as symptom
duration five years) radiographic and nonradiographic axial SpA who had achieved remission
with certolizumab pegol (CZP; 200 mg every 2 weeks for 48 weeks) [117]. In the trial, 313
patients in sustained remission were randomly assigned to continued full-dose CZP (200 mg
every 2 weeks), reduced-dose CZP (200 mg every 4 weeks), or drug discontinuation. After an
additional 48 weeks (week 96) a sustained flare-free state was more common in patients in both
CZP groups (83.7 and 79.0 percent versus 20.2 percent, respectively). Patients who escaped
from remission were restarted on the full-dose regimen with only approximately 60 percent of
those who flared being able to regain clinical remission.
SURGERY
Hip and spine surgery may be beneficial in selected patients with axial spondyloarthritis (SpA).
Clinicians and anesthesiologists should be cautioned about perioperative risks such as reduced
chest expansion and more rigid cervical spines. Indications for surgery are:
● Severe hip involvement, with persistent pain or severe limitation in mobility and quality of
life
● Atlantoaxial subluxation with neurologic impairment
● Severe flexion deformities with impaired ability to look in a forward direction
Total hip arthroplasty — Total hip arthroplasty (THA, total hip replacement) is indicated
whenever there is severe, persistent pain or severe limitation in mobility and quality of life due
to hip involvement. THA is more common in patients with early onset of disease, axial, and
entheseal involvement [118]. (See "Total hip arthroplasty".)
Almost 90 percent of patients will experience pain relief from the hip arthroplasty, with
improved ranges of motion, 90 percent survival of the replaced hip for 10 years, and 72 percent
for 15 years [119].
Patients with ankylosing spondylitis (AS) may be at higher risk of developing heterotopic
ossification following joint replacement, but this remains an unusual complication [120]. If,
however, this complication has occurred following a prior joint arthroplasty, prophylactic
therapy has been recommended, such as a nonsteroidal antiinflammatory drug (NSAID)

beginning on the day of surgery or radiation therapy (pre- or postoperative) [119]. (See
"Complications of total hip arthroplasty", section on 'Heterotopic ossification'.)
Spinal surgery — There are several indications for spinal surgery. The first is acute fracture.
The most common spinal fracture is in the cervical spine. Approximately 25 percent of cervical
fractures are associated with spinal cord injuries [121].
Cervical fusion is indicated for the very small number of patients who develop atlantoaxial
subluxation with impairment in neurologic function. This problem is managed in a fashion
similar to that in rheumatoid arthritis. (See "Cervical subluxation in rheumatoid arthritis".)
Corrective wedge osteotomy is an effective surgical treatment for those with kyphosis with
functional impairment [122].
SPECIAL POPULATIONS
Patients with axial spondyloarthritis and extraarticular manifestations — Extraarticular

manifestations such as uveitis, psoriasis, and inflammatory bowel disease (IBD) frequently
occur in patients with axial spondyloarthritis (SpA). The presence of an extraarticular
manifestation may add complexity to care and influence treatment decisions, which should be
coordinated with the other clinicians caring for the patient.
● Uveitis – Unilateral anterior uveitis is the most common extraarticular complication of axial
SpA, occurring in 25 to 40 percent of patients [123]. The evaluation and management of
uveitis are discussed in detail separately (see "Uveitis: Etiology, clinical manifestations, and
diagnosis" and "Uveitis: Treatment", section on 'Noninfectious uveitis'). Use of anti-tumor
necrosis factor (TNF) therapy may also decrease the frequency of recurrences of uveitis in
patients with axial SpA [124,125].
● Psoriasis – Psoriasis is present in up to approximately 10 percent of patients with axial SpA

[123]. Patients with concomitant psoriasis have more frequent peripheral joint involvement
and possibly a more severe axial SpA disease course compared with axial SpA patients
without psoriasis [126,127]. Peripheral arthritis is usually treated initially with conventional
synthetic disease-modifying antirheumatic drugs (csDMARDs) such as sulfasalazine (SSZ) or
methotrexate (MTX). Patients resistant to DMARDs or with axial disease that failed
treatment on two nonsteroidal antiinflammatory drugs (NSAIDs) can be treated with a
biologic. The presence of psoriasis can influence the choice of biologic agents. (See
"Treatment of psoriatic arthritis".)
● Inflammatory bowel disease – Overt IBD occurs in approximately 5 to 10 percent of

patients with axial SpA, and approximately 4 to 10 percent of patients with IBD have
concomitant findings of axial SpA [123,128]. The presence of IBD impacts the management
approach. The clinical manifestations, diagnosis, and treatment of peripheral and axial SpA
associated with IBD are described in detail separately. (See "Clinical manifestations and
diagnosis of arthritis associated with inflammatory bowel disease and other
gastrointestinal diseases" and "Treatment of arthritis associated with inflammatory bowel
disease".)
Pregnancy — Hormonal status and fertility are normal. The effect of pregnancy on disease
activity is variable [129]. Considerations relevant to the use of medications for axial SpA during
pregnancy and lactation are reviewed separately. (See "Safety of rheumatic disease medication
use during pregnancy and lactation".)
Axial spondyloarthritis and osteoporosis — Low bone mineral density (BMD) and bone loss
have been documented in patients with axial SpA and are evident within the first 10 years of
disease [130-132]. Screening and treatment of osteoporosis are discussed in detail elsewhere.
(See "Screening for osteoporosis in postmenopausal women and men" and "Evaluation and
treatment of premenopausal osteoporosis" and "Overview of the management of osteoporosis
in postmenopausal women" and "Treatment of osteoporosis in men".)
PROGNOSIS
Axial spondyloarthritis (SpA) is a chronic disease, although a minority of patients may

experience a spontaneous remission. Most axial SpA patients with mild disease that is restricted
to a small area of involvement are able to maintain almost full functional and employment
capacity. The most serious musculoskeletal consequences are unremitting spinal pain, hip
destruction, and spinal fusion. Only a minority of patients develop life-threatening
extramusculoskeletal complications.
A questionnaire survey done prior to the availability of the biologic agents found that
employment was affected in approximately 30 percent of the males with ankylosing spondylitis
(AS) [133]. However, the majority of patients were able to work well into their fifties. Without
biologic therapies, disease activity usually fluctuated in the individual patient, with symptoms
usually persisting over decades, and approximately 1 percent of patients developed a stage of
"burnt-out" disease activity and entered long-term remission [134].
The prognosis for axial SpA may have improved since the 1990s. This may relate to the
availability of tumor necrosis factor (TNF) inhibitors beginning at the end of that decade, but
the evidence is indirect and does not prove causality. In a longitudinal study of 350 patients
with AS, approximately a quarter of the patients showed radiographic progression of spinal
disease over two years [135]. The rate of radiographic progression was reduced by 20 percent in
patients using TNF inhibitors. TNF inhibitors might be more effective in controlling
inflammation when used early in the disease course, prior to the development of changes on
plain radiographs [41].
Effects of treatment on radiographic progression — Whether long-term use of anti-TNF

agents can halt the radiographic progression of the disease has long been uncertain because
such effects may not be evident until patients have been followed for more than two years after
starting the medication [136-139], and the arrest of progression might not start appearing until
more than two years after starting the TNF inhibitors [140]. An increasing number of studies
provide evidence of such benefit. The range of evidence is illustrated by the following:
● Data from 432 AS patients from the Swiss Clinical Quality Management cohort analyzed the
impact of TNF inhibitors on spinal radiographic progression [141]. This study could
demonstrate that TNF inhibitors are associated with a reduction of spinal radiographic
progression in patients with AS, but this effect is mediated through the inhibiting effect of
TNF inhibitors on disease activity measured by the Ankylosing Spondylitis Disease Activity
Score (ASDAS). The odds ratio (OR) of radiographic progression halved in patients who have
used TNF inhibitors for more than two years (OR 0.50, 95% CI 0.28-0.88). In patients who
achieved an inactive disease status (ASDAS ≤1.3), radiographic progression was entirely
inhibited. Longer duration of TNF inhibition was associated with more reduction in
radiographic progression (≥4 years of treatment showed a 70 percent lower estimate in
radiographic progression; in ≤4 years of treatment, this was 45 percent) [141].
● In a prospectively followed cohort of 334 patients treated with standard therapies for AS, in
whom TNF inhibitors were administered to 201 patients, treatment with a TNF inhibitor was
associated with a 50 percent reduction in the odds of radiographic progression (OR 0.52,
95% CI 0.30-0.88) [142]. Such benefit was more evident in patients in whom these agents
were begun earlier in the disease course and in whom the follow-up was at least four years.
● In an 18-year real-world study in Korea, the analysis was limited to patients who were
initiated on TNF inhibitors, but compared radiographic progression during the follow-up
intervals in which patients were on TNF inhibitors with intervals when they were not [143].
Radiographic assessments were performed at average intervals of 2.4 years. Radiographic
progression was lower during the on-TNF inhibitors intervals compared with the off-TNF
inhibitors intervals, consistent with a therapeutic effect. Additionally, radiographic

progression was less severe in women than men, and more severe in those with associated
eye involvement.
● Although anti-IL-17 can lead to improvement in clinical disease activity, it will probably
require studies of more than two years to determine whether they can affect radiographic
spinal progression [144].
Some evidence also suggests that biologic therapy may prevent or reduce the need for joint
arthroplasty. As examples:
● An analysis of data from the national arthroplasty registry in Norway compared surgical
rates from 1988 to 2002 with those from 2003 to 2010 [145]. It described a trend since 2002
for a reduced frequency of hip replacement surgery in patients with AS compared with a
continued increase in hip replacements in patients with osteoarthritis (OA) during this same
time period. The onset of the apparent decline in need for joint replacement coincided with
the introduction of TNF inhibitors in Norway between 2000 and 2003.
● Similarly, a study from the United States compared rates of hip, knee, and shoulder
arthroplasties from 1991 to 2005 using data from large administrative databases in New
York and California; the rate of arthroplasties for noninflammatory conditions increased by
nearly 200 percent from 1991 to 2005, compared with an increase in rates of arthroplasty
for SpA of only approximately 50 percent during the same interval [146]. The mean age at
the time of arthroplasty decreased for noninflammatory causes (age 71.5 versus 69.0) but
increased for patients with SpA (age 54.3 versus 60.4), also consistent with a reduction in
the rate of joint injury for SpA since the introduction of TNF inhibitors.
Prognostic indicators — A number of prognostic indicators were identified before the

availability of biologics in patients with AS. One study, for example, evaluated 328 patients with
SpA; seven variables at entry correlated with increased disease severity [147]:
● Hip arthritis – OR 23
● Sausage-like finger or toe – OR 8
● Poor efficacy of nonsteroidal antiinflammatory drugs (NSAIDs) – OR 8
● High erythrocyte sedimentation rate (ESR; >30 mm/h) – OR 7
● Limitation in range of motion of the lumbar spine – OR 7
● Oligoarthritis – OR 4
● Onset less than 16 years of age – OR 3
A mild outcome was likely if none of these factors was present at entry (sensitivity 93 percent,
specificity 78 percent). However, a severe outcome was predictable if the hip was involved or if
three factors were present (sensitivity 50 percent), and mild disease could be virtually excluded
(specificity 98 percent).
The following parameters have been found to be independent baseline predictors of a good
response to TNF inhibitor therapy after three to six months of therapy [148] (see 'TNF inhibitors'
above):
● Increased acute phase reactants

● Higher disease activity
● Higher functional status
● Younger age
● Human leukocyte antigen (HLA)-B27 positivity
Other factors have also been associated with a poor outcome in patients with AS [149-151].
These include cigarette smoking, increasing severity of radiographic changes, active disease as
assessed by a disease activity index, functional impairment as assessed by a self-report, lower
educational attainment, presence of other diseases related to SpA (eg, psoriasis, inflammatory
bowel disease [IBD]), male sex, a history of uveitis, and occupational activities involving either
dynamic flexibility (ability to quickly and repeatedly bend, twist, and stretch) or exposure to
whole-body vibration (such as driving a truck or operating heavy equipment). Other predictors
of poor outcome are presence of HLA-B27, older age, the presence of enthesitis, poor
functional ability, and elevated C-reactive protein (CRP) [152].
Elevated CRP levels are associated with increased risk of radiographic progression both in the
sacroiliac joints and in the spine [153,154]. Other factors associated with an increased degree of
radiographic progression include the baseline severity of radiographic change and cigarette
smoking [142,155]. A 12-year prospective follow-up study involving the Outcome in Ankylosing
Spondylitis International Study (OASIS) cohort found that progressive radiographic spinal
changes occurred significantly faster in men, HLA-B27-positive patients, and those with greater
radiographic change at baseline [156]. Although long-term radiographic progression varied
between patients (ranging from some showing no progression at all to others progressing
rapidly over short periods of time), it continued over decades and followed a roughly linear
course for the cohort as a whole.
Complications
● Spinal cord injury – Patients with AS suffer an increased rate of spinal fractures [121]. In
Finland, the incidence of spinal cord injury among those with AS has been estimated to be
increased more than 10-fold compared with the general population [157]. In those with AS,
a majority of spinal cord injuries resulted from slips and falls, an event that was rarely the
cause of cord damage in those without AS (53 versus 7 percent, respectively).
● Cardiovascular risk – AS is associated with an increased risk of cardiovascular diseases,

including disease of the aortic root and rarely of the aortic valve, acute coronary syndromes
(ACS), strokes, venous thromboembolism, and conduction abnormalities. Although
cardiovascular involvement has been examined in patients with AS in several studies [158-
160] and evaluated in patients with SpA in general [161], it has not been examined
specifically in patients with nonradiographic axial SpA (nr-axSpA). Most but not all studies
show increases in ischemic heart disease compared with the general population. The
increased risk has been attributed to the systemic inflammation and increased prevalence
of traditional cardiovascular risk factors, but also the use of NSAIDs. (See "Clinical
manifestations of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial
spondyloarthritis) in adults", section on 'Cardiovascular disease'.)
● Absence of increased risk of lymphoma – In contrast to some other chronic rheumatic

diseases (eg, rheumatoid arthritis and Sjögren's syndrome), the risk of developing
lymphoma does not appear to be significantly increased in patients with AS [162].
● Mortality – Mortality among patients with AS admitted to the hospital for medical care is
approximately 1.5 times higher than that of the general population [163]. Overall, mortality
may be modestly increased. This was illustrated in a review of eight studies on mortality in
AS that concluded that there was an increase in mortality rates compared with the general
population (standardized mortality ratios ranging from 1.32 to 2.62) [164]. The major
causes of death in patients with AS were infections, cancer, and diseases of the respiratory
and cardiovascular systems [165].
GUIDELINES OF MAJOR ORGANIZATIONS
Management recommendations for ankylosing spondylitis (AS) and non-radiographic axial

spondyloarthritis (nr-axSpA) have been developed jointly by the Assessment of Spondylo-
Arthritis international society (ASAS) and by the European League Against Rheumatism (EULAR)
[1,3] and jointly by the American College of Rheumatology (ACR), the Spondylitis Association of
America (SAA), and the Spondyloarthritis Research and Treatment Network (SPARTAN) [2,4]. Our
approach is generally consistent with these guidelines. The ACR/SAA/SPARTAN 2019 update and
supplement to the previous guideline document addresses the use of agents not discussed in
their older publication (eg, secukinumab, ixekizumab, tofacitinib, and tumor necrosis factor
[TNF] biosimilars) and cautions regarding discontinuation or tapering of biologic agents in

patients with stable AS, among other recommendations [4].
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Spondyloarthritis".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Ankylosing spondylitis (The Basics)")
● Beyond the Basics topic (see "Patient education: Axial spondyloarthritis, including
ankylosing spondylitis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● The primary goals of management are to optimize short- and long-term health-related
quality of life through relief of symptoms, maintenance of function, prevention of spinal
complications, minimization of extraspinal and extraarticular manifestations and
comorbidities, and maintenance of effective psychosocial functioning. Most patients
benefit from care by an expert in rheumatologic disease, such as a rheumatologist; care
should be coordinated with appropriate specialists, depending upon the clinical features;
and active patient engagement in shared decision-making with their clinical team is an
important element of care. (See 'Goals and general principles of management' above.)
● All patients with axial spondyloarthritis (SpA) should receive education about their disease
and its management; counseling regarding smoking cessation, depression screening and
psychosocial support, and physical therapy with instruction in home exercises. (See
'Nonpharmacologic interventions' above.)
● In most patients with symptomatic axial SpA, we recommend a nonsteroidal

antiinflammatory drug (NSAID) as initial therapy, rather than starting a disease-modifying
antirheumatic drug (DMARD). Examples include naproxen (up to 500 mg twice daily) or
ibuprofen (up to 800 mg three times daily), although any NSAID may be effective ( table 1
). Regardless of the NSAID used, the maximum dose is usually required, and the response
should be assessed after a sustained dose on a daily basis for at least two to four weeks. In
patients with an inadequate response, we switch to a second NSAID. (See 'Initial drug
therapy with NSAIDs' above and 'Duration of NSAID therapy' above.)
● In patients with symptoms due to active axial SpA and an inadequate response to initial
therapy with at least two NSAIDs consecutively, we suggest adding a tumor necrosis factor
(TNF)-alpha inhibitor rather than treatment with NSAIDs alone. Any of the TNF inhibitors
(eg, subcutaneous adalimumab 40 mg every other week or infliximab 5 mg/kg by
intravenous infusion at zero, two, and six weeks followed by a maintenance dose of 5
mg/kg every eight weeks) is an acceptable option; the choice between drugs is based upon
patient preferences regarding the route and frequency of administration, physician
preference and experience, and regulatory and cost constraints. These biologics do not
need to be used together with a conventional synthetic (cs) immunosuppressive agent such
as methotrexate (MTX). (See 'Inadequate response to NSAIDs' above and 'TNF inhibitors'
above.)
The interleukin 17 (IL-17) inhibitors secukinumab and ixekizumab are reasonable

alternatives to a TNF inhibitor as initial biologic therapy (for example, in case of
concomitant psoriasis), although there is much more experience and evidence of long-term
efficacy and safety with the TNF inhibitors. (See 'Secukinumab' above.)
● In patients with an inadequate response to one TNF inhibitor, we suggest a second TNF
inhibitor or a switch to an IL-17 inhibitor (secukinumab or ixekizumab). We prefer an IL-17
inhibitor in patients with primary failure to the initial TNF inhibitor. Any of the TNF
inhibitors are reasonable options. (See 'Inadequate response or intolerance to initial
biologic' above and 'TNF inhibitors' above and 'Secukinumab' above and 'Ixekizumab'
above.)
TNF inhibitors and anti-IL-17 inhibitors have not been directly compared in patients with
axial SpA; however, both have similar levels of efficacy and similar safety profiles compared
with placebo, and use of a biologic agent with a different mechanism of action provides an
additional rationale for its use, especially in patients who have already not responded to
two TNF inhibitors.
• A reasonable alternative to a TNF inhibitor in patients with axial SpA and an inadequate
response to a first TNF inhibitor is to switch to secukinumab or ixekizumab, particularly
in patients with primary treatment failure to an initial TNF inhibitor.
• We use a TNF inhibitor in patients who were initially treated with secukinumab or
ixekizumab and responded inadequately after three months.
• A TNF inhibitor would also be preferred in patients with inflammatory bowel disease
(IBD), for which the anti-IL-17 agents lack efficacy.
● In all patients who respond inadequately to biologic therapies, we reassess the diagnosis.
Options for patients in whom two different TNF inhibitors and secukinumab or ixekizumab
have been inadequate include other TNF inhibitors or anti-IL-17 agents not previously used
by the patient or drugs that are available for other disorders for which evidence of benefit
in axial SpA exists, such as tofacitinib, a Janus kinase (JAK) inhibitor. (See 'Resistant to
standard therapies' above and 'Agents of possible benefit' above.)
● In patients with axial SpA, there is an extremely limited role, if any, for the use of opioid
analgesics. Systemic glucocorticoids (eg, prednisone) are ineffective for axial SpA in low to
moderate doses and are not indicated. (See 'Role of non-NSAID analgesics' above and 'Role
of systemic glucocorticoids for axial disease' above.)
● The treatment of peripheral arthritis and periarticular disease in patients with axial SpA is
discussed in detail separately. (See 'Peripheral arthritis and periarticular disease' above and
"Treatment of peripheral spondyloarthritis".)
Use of UpToDate is subject to the Subscription and License Agreement.
Topic 7790 Version 50.0
GRAPHICS
Orally available nonopioid analgesic and nonsteroidal antiinflammatory drugs (NSAIDs): Usual
dosing for adults with pain or inflammation
Optional Usual
Maximum
initial analgesic Selected characteristics and role in
Drug dose per day
loading dose therapy
(mg)
dose (oral)
Para-aminophenol derivative
Acetaminophen* None 325 to 650 mg 3000 mg Effective for noninflammatory pain; may be
(paracetamol, every 4 to 6 opioid-sparing.
APAP) hours Doses <2000 mg per day do not increase
Or risk of serious GI complications.
1000 mg every 6 Does not alter platelet functioning.

hours up to Can cause hepatotoxicity in chronic or
three times per acute overdose.
day Avoid or use a lower total daily dose
(maximum 2000 mg per day) in older
adults, patients at risk for hepatotoxicity
(eg, regular alcohol use, malnourished) or
with organ dysfunction.
For short-term or one-time use, may use a
total dose of up to 4000 mg per day in
selected medically supervised patients.
Interacts with warfarin (prolongs INR),
isoniazid, and CYP450-inducing drugs ¶
(transaminitis).
Warn patients about acetaminophen
content in combination prescription (eg,
oxycodone-acetaminophen) and OTC
preparations.
NSAID agents
Applies to all nonselective NSAIDs:

Effective for treatment of acute and chronic painful and inflammatory conditions. May decrease opioid requirements.
Short- to moderate-acting NSAIDs (eg, naproxen, ibuprofen) are preferred for most patients.
Dose- and age-related risk of gastropathy.
May cause or worsen renal impairment.
Nonselective NSAIDs reversibly inhibit platelet functioning and can alter cardioprotective effects of aspirin.
Avoid NSAIDs in patients with renal insufficiency (CrCl <60 mL/minute), GI bleeding, platelet dysfunction, reduced cardiac
output, difficult-to-control hypertension, hypovolemia, hyponatremia, aspirin-sensitive asthma, or cirrhosis.
Safety concerns of NSAID use in patients with, or at elevated risk for, cardiovascular disease or thrombotic events are
addressed in a separate topic in UpToDate.
Use with caution or avoid in patients receiving comedication with anticoagulants, systemic glucocorticoids, lithium, loop
diuretics, and other interacting drugs. Δ
Though some older adults may benefit from a brief course of NSAIDs at the lowest effective dose, use in most older
adults should be avoided. Refer to the UpToDate topics on treatment of pain in older adults and older adults with organ
dysfunction.
Salicylate (acetylated)
Aspirin* 2600 mg 325 to 650 mg 4000 mg Standard for comparison, but now used
every 4 to 6 infrequently for treatment of chronic pain
hours and inflammation.
Unlike other NSAIDs, irreversibly inhibits

platelet functioning for life of the platelet (7
to 10 days).
Salicylates (nonacetylated)
Diflunisal 1000 mg 500 mg every 8 1500 mg Applies to all nonacetylated salicylates:

to 12 hours No significant effect on platelet function
at usual analgesic doses.
Less frequently associated with GI
Choline 1500 mg 750 mg every 8 3000 mg
bleeding than nonselective NSAIDs at
magnesium to 12 hours
usual analgesic doses.
trisalicylate
Generally tolerated by adults with
asthma at lower daily doses: Diflunisal
≤1000 mg, choline magnesium
Salsalate 1500 mg 750 to 1000 mg 3000 mg trisalicylate and salsalate ≤2000 mg.
every 8 to 12 Relatively slow onset.
hours 500 mg dose of diflunisal has a
comparable analgesic effect with 650
mg acetaminophen or aspirin.
Propionic acids (phenyl-propionic acid)
Naproxen* 500 mg 250 to 500 mg 1250 mg acute, A good choice for treatment of acute or
(naproxen base) every 12 hours 1000 mg chronic chronic pain and inflammation in most
550 mg (naproxen base) (naproxen base) patients if NSAID therapy is indicated.
(naproxen 275 to 550 mg 1375 mg acute, High doses (eg, 500 mg twice daily) may
sodium) every 12 hours 1100 mg chronic have less cardiovascular toxicity than
(naproxen (naproxen comparable doses of other NSAIDs. ◊
sodium) sodium) For the treatment of rheumatologic
disorders, total daily dose may be increased
to a maximum of 1500 mg base (1650 mg
naproxen sodium), when needed.
Naproxen sodium has more rapid
absorption and onset of effect than
naproxen base.
Ibuprofen* 800 mg 400 mg every 4 3200 mg (acute), 200 to 400 mg dose has a comparable
to 6 hours 2400 mg analgesic effect with 650 mg
(chronic) acetaminophen or aspirin.
Short duration of effect.
Useful alternative to naproxen in patients
without cardiovascular risks.
Ketoprofen 100 mg 50 mg every 6 300 mg 25 mg dose has a comparable analgesic

hours or 75 mg effect to 400 mg ibuprofen.
every 8 hours Short duration of effect.
Flurbiprofen 100 mg 50 to 100 mg 300 mg Lozenge preparation available in some

every 6 to 12 countries.
hours
Oxaprozin None 1200 mg once 26 mg/kg up to Long duration of effect.

daily 1800 mg
(whichever is
lower)
Acetic acids (pyrano-indoleacetic acid)
Diclofenac 75 or 100 mg 50 mg every 8 150 mg Diclofenac is also available as a topical

(conventional hours Approved patch, solution, and gel for treatment of
tablets) maximum daily musculoskeletal pain and osteoarthritis of
superficial joints, which may be useful in
combination with or as an alternative to
dose in Canada systemic NSAIDs. Refer to the UpToDate

is 100 mg topic on initial treatment of osteoarthritis
and separate table.
Interacts with drugs that are strong
inhibitors or inducers of CYP2C9 drug
metabolism; use Lexi-Interact to determine
specific interactions.
Etodolac 400 to 600 mg Immediate Immediate Relatively COX-2 selective at lower total
release: 200 to release: 1000 daily dose of 600 to 800 mg.
400 mg every 6 mg 200 mg dose has a comparable analgesic
to 8 hours Extended effect with 400 mg of ibuprofen.
Extended release: 1200
release: 400 to mg
1000 mg once
daily
Indomethacin 75 mg Immediate 150 mg Useful for treatment of acute gout and

release: 25 to 50 specific types of headache.
mg every 8 to Potent inhibitory effects on renal
12 hours prostaglandin synthesis.
Controlled More frequently associated with CNS side
release: 75 mg effects (eg, headache) compared with other
once or twice NSAIDs.
daily Carefully select and monitor patients to
reduce risk of renal and cardiovascular
toxicities.
Tolmetin 600 mg 400 to 600 mg 1800 mg

every 8 hours
Sulindac 300 mg 150 to 200 mg 400 mg More frequently associated with hepatic
every 12 hours inflammation (idiosyncratic or with features
of hypersensitivity) compared with other
NSAIDs.
Sulindac metabolites implicated in the
formation of renal calculi; refer to the
UpToDate topic on nonselective NSAID
adverse effects.
Prescribing should be limited to specialists
with experience in treatment of chronic
pain and inflammation.
Oxicams (enolic acids)
Meloxicam 7.5 mg 7.5 to 15 mg 15 mg Long duration of effect; slow onset.

(conventional once daily Relatively COX-2 selective and minimal
tablets) effect on platelet function at lower total
daily dose of 7.5 mg.
Rarely associated with serious cutaneous
allergic reactions, including Stevens-
Johnson syndrome.
Piroxicam 10 mg 10 to 20 mg 20 mg A long-acting option for treatment of

once daily chronic pain and inflammation poorly
responsive to other NSAIDs.
Daily doses ≥20 mg increase risk of serious
GI complications.
Concurrent pharmacologic
gastroprotection is suggested.
Rarely associated with serious cutaneous
allergic reactions, including Stevens-
g g
Johnson syndrome.
Prescribing should be limited to specialists
with experience in treatment of chronic
pain and inflammation.
Fenamates (anthranilic acids)
Meclofenamate 150 mg 50 mg every 4 400 mg Alternate NSAID choice for treatment of

(meclofenamic to 6 hours acute or chronic pain, inflammation, and
acid) dysmenorrhea.
Appears to be associated with higher
incidence of GI disturbance (including
diarrhea) compared with other nonselective
NSAIDs.
Mefenamic 500 mg 250 mg every 6 1000 mg Alternate NSAID choice for treatment of
acid hours acute pain and dysmenorrhea.
Duration of use not to exceed seven days
(acute pain) or three days (dysmenorrhea).
Antiinflammatory efficacy is comparatively
low.
Not indicated for treatment of chronic pain
or inflammation.
Nonacidic (naphthylalkanone)
Nabumetone 1000 mg 500 to 750 mg 2000 mg Moderate duration of effect; slow onset.
every 8 to 12 Relatively COX-2 selective at lower total
hours or 1000 to daily dose of 1000 mg or less.
1500 mg once Minimal effect on platelet function at total
daily daily dose of 1000 mg or less.
Selective COX-2 inhibitors §
Celecoxib 400 mg 200 mg daily or 400 mg Relative reduction in GI toxicity compared

100 mg every 12 with nonselective NSAIDs.
hours No effect on platelet function.
Cardiovascular and renal risks are dose-
related and appear similar to those of
nonselective NSAIDs.
Patients with indications for
cardioprotection require aspirin
supplement; individuals may require
concurrent gastroprotection.
Etoricoxib (not None 30 to 60 mg 60 mg (chronic May be associated with more frequent and
available in the once daily pain and severe dose-related cardiovascular effects
United States) inflammation) (eg, hypertension) compared with
120 mg (acute nonselective and other COX-2 selective
pain for up to 8 NSAIDs.
days) Otherwise, risks and benefits as with
celecoxib (see above).
For specific uses, patient selection, and precautionary information, refer to the appropriate treatment topic(s) in UpToDate and
the Lexicomp drug monographs.
GI: gastrointestinal; INR: international normalized ratio; CYP450: cytochrome P450; OTC: over-the-counter, available without prescription;
CrCl: creatinine clearance; COX-2: cyclooxygenase, isoform 2; CYP2C9: cytochrome 2C9; CNS: central nervous system; SSRIs: selective
serotonin reuptake inhibitors.
* Available without a prescription in the United States.
¶ A list of CYP450-inducing drugs is available separately in UpToDate.
Δ NSAIDs may interact with aspirin, warfarin, methotrexate, antihypertensives, serotonin reuptake inhibitor antidepressants (eg, SSRIs,
cyclic antidepressants, venlafaxine), and other drugs. For specific interactions, use the Lexi-Interact program included with UpToDate.
◊ Refer to the UpToDate topic on the cardiovascular effects of nonselective NSAIDs.
§ For additional information on gastroprotective strategies, including selective COX-2 inhibitors and other options, refer to the UpToDate
topics on the overview of selective COX-2 inhibitors and on NSAIDs (including aspirin) and the primary prevention of gastroduodenal
toxicity.
Prepared with data from:

1. Anon. Drugs for pain. Treatment guidelines from the Medical Letter; 2013. 11:31.
2. Castellsague J, Riera-Guardia N, Calingaert B, et al. Individual NSAIDs and upper gastrointestinal complications: A systematic review.
Drug Saf 2012; 35:1127.
3. Lexicomp Online. Copyright © 1978-2021 Lexicomp, Inc. All Rights Reserved.
Graphic 70067 Version 53.0
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
1. How would you describe the overall level of fatigue/tiredness you have experienced?
none | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | very severe
2. How would you describe the overall level of AS neck, back, or hip pain you have had?
none | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | very severe
3. How would you describe the overall level of pain/swelling you have had in joints other than neck, back, and hips?
none | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | very severe
4. How would you describe the level of discomfort you have had from an area tender to touch or pressure?
none | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | very severe
5. How would you describe the level of morning stiffness you have had from the time you wake up?
none | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | very severe
6. How long does your morning stiffness last from the time you wake up?
0 (0 hours) | 1 | 2 | 3 | 4 | 5 (1 hour) | 6 | 7 | 8 | 9 | 10 (2 or more hours)
Calculation of BASDAI:
Compute the mean of questions 5 and 6
Calculate the sum of the values of question 1-4 and add the result to the mean of questions 5 and 6
Divide the result by 5
Originally published in: Garrett S, Jenkinson T, Kennedy LG, et al. A new approach to deﬁning disease status in ankylosing spondylitis: the Bath
Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994; 21:2286. Reproduced with permission from: the Royal National Hospital for
Rheumatic Diseases NHS Foundation Trust, Bath. www.rnhrd.nhs.uk. Copyright © 1994.
Graphic 57638 Version 3.0

Treatment of Axial Spondyloarthritis (Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis) in Adults - UpToDate

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Treatment of Axial Spondyloarthritis (Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis) in Adults - UpToDate

Uploaded by

Copyright:

Available Formats

2/19/2021 Treatment of axial spondyloarthritis (ankylosing spondylitis and nonradiographic axial spondyloarthritis) in adults - UpToDate

Official reprint from UpToDate®

Treatment of axial spondyloarthritis (ankylosing

GOALS AND GENERAL PRINCIPLES OF MANAGEMENT

● Relief of symptoms – To eliminate symptoms such as pain, stiffness, and fatigue or to

● Maintenance of function – To maintain the best possible functional capacity

● Prevention of complications of spinal disease – To prevent flexion contractures, especially

● Minimization of extraspinal and extraarticular manifestations and comorbidities – To

● Maintenance of effective psychosocial functioning – To preserve social participation,

● Most patients benefit from care by an expert in rheumatologic disease, such as a

● All patients should receive nonpharmacologic measures, including patient education,

● In addition to control of disease activity, symptoms that require recognition and

Nonpharmacologic interventions — All patients newly diagnosed with axial SpA should

● Counseling regarding smoking cessation – Smoking cessation should be advised because

Duration of NSAID therapy — Once a particular nonsteroidal antiinflammatory drug (NSAID)

INADEQUATE RESPONSE TO NSAIDs

Use of TNF inhibitors

• Etanercept – 50 mg weekly, administered as a subcutaneous injection of 50 mg once a

● Monitoring – (See 'Evaluation and monitoring' below.)

● Duration of therapy – (See 'Duration of therapy with biologics' below.)

As examples of the available evidence:

● The efficacy of TNF inhibitors (including etanercept, adalimumab, infliximab, certolizumab,

The ASAS response is a composite measure, which includes:

• Patient global assessment

inhibitor in approximately one-fourth of treated AS patients and one-fifth of nr-axSpA patients,

Secukinumab — Secukinumab, an anti-IL-17A monoclonal antibody, is an alternative to TNF

Ixekizumab — Ixekizumab, like secukinumab, is another anti-IL-17A monoclonal antibody

Role of systemic glucocorticoids for axial disease — Systemic glucocorticoids are not

INADEQUATE RESPONSE OR INTOLERANCE TO INITIAL BIOLOGIC

● Primary failure – A patient can be considered as having an inadequate response,

Approach to switching biologic agents — The choice of therapy in patients with inadequate

We take the following general approach [38]:

● Primary failure to an initial TNF inhibitor – In patients with an inadequate response,

● Secondary failures of two consecutive TNF inhibitors – Secondary failure to two

● Inadequate response or intolerance of secukinumab or ixekizumab as initial agent – In

RESISTANT TO STANDARD THERAPIES

Agents of possible benefit — Little evidence and no randomized trials are available to

Used in other disorders

● Upadacitinib – Upadacitinib is a JAK inhibitor with preferential effects on JAK-1, which is

Investigational agents not yet available for any conditions

● Filgotinib – Filgotinib, an investigational selective JAK-1 inhibitor, has been shown to be

● Abatacept, a T-cell costimulation blocker [90]

EVALUATION AND MONITORING

BASDAI score (BASDAI 50) or an absolute change of ≥2 on a scale of 0 to 10 and a

PERIPHERAL ARTHRITIS AND PERIARTICULAR DISEASE

The following summarizes our approach:

● Enthesitis and dactylitis – In patients with persistent symptoms of enthesitis despite

DURATION OF THERAPY WITH BIOLOGICS

therapy has been recommended, such as a nonsteroidal antiinflammatory drug (NSAID)

Patients with axial spondyloarthritis and extraarticular manifestations — Extraarticular

● Psoriasis – Psoriasis is present in up to approximately 10 percent of patients with axial SpA

● Inflammatory bowel disease – Overt IBD occurs in approximately 5 to 10 percent of

Axial spondyloarthritis (SpA) is a chronic disease, although a minority of patients may

Effects of treatment on radiographic progression — Whether long-term use of anti-TNF

inhibitors intervals, consistent with a therapeutic effect. Additionally, radiographic

Prognostic indicators — A number of prognostic indicators were identified before the

● Increased acute phase reactants

● Cardiovascular risk – AS is associated with an increased risk of cardiovascular diseases,

● Absence of increased risk of lymphoma – In contrast to some other chronic rheumatic

GUIDELINES OF MAJOR ORGANIZATIONS

Management recommendations for ankylosing spondylitis (AS) and non-radiographic axial

[TNF] biosimilars) and cautions regarding discontinuation or tapering of biologic agents in

SOCIETY GUIDELINE LINKS