Clinical Topic A-Z Clinical Speciality

Ankylosing spondylitis

Ankylosing spondylitis
D013167Spondylitis, Ankylosing
Musculoskeletal
2013-02-01Last revised in February 2013

Ankylosing spondylitis - Summary

Ankylosing spondylitis is a chronic inflammatory rheumatic disease of unknown cause and varying clinical presentation. The principal features (not all of which are present at onset, or in all people) are:

Inflammatory low back pain, (pain and stiffness worse at night and in the morning).

Inflammation of the spinal joints and the junction (enthesis) of the intervertebral spinal ligaments and vertebrae, leading (after many years) to ankylosis (i.e. fusion from fibrosis and calcification).

Inflammation of the sacroiliac joints (on X-ray or other radiological imaging such as MRI), which presents as alternating buttock pain.

Enthesitis (inflammation of the sites where tendons and ligaments attach to bone), costochondritis (inflammation where cartilage joins the ribs), and epicondylitis (inflammation of an epicondyle of bone).

Arthritis of peripheral joints, usually involving the large joints of the lower limbs, or asymmetric arthritis of peripheral joints.

Insidious onset (over a period of at least 3 months, and often several years) usually beginning in late adolescence or early adulthood.

Fatigue.

Association with the human leukocyte antigen B27 (HLA-B27).

Ankylosing spondylitis is not uncommon:

About 2% of people in a general practice will present with back pain and up to 5% of these will show features of ankylosing spondylitis.

It is about three times more common in men than women.

It most commonly begins between 20 and 30 years of age, but also occurs in children and older adults.

Common complications include:

Progressive involvement of the lumbar, thoracic, and cervical spine, leading to a fixed and flexed posture.

Damage to peripheral joints.

Anterior uveitis (iritis).

If ankylosing spondylitis is suspected:

The presence of inflammation should be confirmed with erythrocyte sedimentation rate (ESR), and/or C-reactive protein (CRP), and full blood count (FBC) tests.

Local referral protocols should be followed on imaging the sacroiliac joints and spine, or specialist advice sought on imaging before referral. In well-established cases, radiographs of the sacroiliac joints and spine are diagnostic. Magnetic resonance imaging can detect early changes in sacroiliac joints. Ultrasound scanning can confirm a clinical impression of enthesitis.

Referral to a rheumatologist should be arranged.

Treatment should be started with a nonsteroidal anti-inflammatory drug (NSAID).

Treatments available from rheumatologists for ankylosing spondylitis include:

For sacroiliitis: injection of corticosteroids.

For enthesitis (inflammation where bone joins tendon or ligament): injection of corticosteroids.

For uncontrolled disease in general: tumour necrosis factor (TNF)-alpha inhibitors such as etanercept and adalimumab or oral or intravenous bisphosphonates.

Have I got the right topic?

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This CKS topic covers the management of people with ankylosing spondylitis in primary care.

This CKS topic does not cover the treatment of complications of ankylosing spondylitis such as uveitis, or give details of the use of disease-modifying anti-rheumatic drugs or the new 'biologic' drugs as these would usually be started and managed in secondary care.

There are separate CKS topics on Back pain - low (without radiculopathy), Dyspepsia - proven peptic ulcer, Dyspepsia - unidentified cause, DMARDs, NSAIDs - prescribing issues, Sciatica (lumbar radiculopathy), and Uveitis.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in February 2013

February 2013 — reviewed. A literature search was conducted in December 2012 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. Changes have been made to the sections on diagnosis and referral.

Previous changes

February 2013 — minor update. The 2013 QIPP options for local implementation have been added to this topic [NICE, 2013].

October 2012 — minor update. The 2012 QIPP options for local implementation have been added to this topic [NPC, 2012].

January 2012 — minor update. Information from the manufacturer's Summary of Product Characteristics about the possible interaction between pantoprazole and warfarin has been added to drug interactions [ABPI Medicines Compendium, 2011]. Information from the British National Formulary about the potentially serious interaction between proton pump inhibitors and protease inhibitors (atazanavir and saquinavir) has also been added [BNF 62, 2011]. Issued in January 2012.

May 2011 — minor update. The 2010/2011 QIPP options for local implementation have been added to this topic [NPC, 2011]. Issued in June 2011.

February 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

June 2010 — minor update. In people at risk of cardiovascular adverse events, ibuprofen up to 1200 mg per day or naproxen up to 1000 mg per day are recommended as first-line NSAIDs. Issued in July 2010.

July 2009 — minor update. The Medicines and Healthcare products Regulatory Agency (MHRA) has issued advice on the interaction between clopidogrel and proton pump inhibitors. Healthcare professionals are advised to avoid concomitant use of these drugs unless considered essential [MHRA, 2009]. Issued in July 2009.

June 2009 — minor update. The intra-articular corticosteroid prescriptions have been updated. Issued in June 2009.

March to July 2008 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

There are no major changes to the recommendations on managing ankylosing spondylitis. However, there are some changes in the recommendations on the use of nonsteroidal anti-inflammatory drugs (NSAIDs), with clearer advice on balancing the benefits and risks of treatment.

October 2005 — minor technical update. Issued in November 2005.

April 2005 — reviewed. Validated in June 2005 and issued in July 2005.

June 2001 — reviewed. Validated in November 2001 and issued in April 2002.

July 1999 — written. Validated in October 1999 and issued in January 2000.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 December 2012.

HTAs (Health Technology Assessments)

No new technology appraisals since 1 December 2012.

Economic appraisals

No new economic appraisals since 1 December 2012.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Machado, M.A., Barbosa, M.M., Almeida, A.M., et al. (2013) Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis. Rheumatology International 33(9), 2199-2213. [Abstract]

Wang, H., Zuo, D., Sun, M., et al. (2014) Randomized, placebo controlled and double-blind trials of efficacy and safety of adalimumab for treating ankylosing spondylitis: a meta-analysis. International Journal of Rheumatic Diseases 17(2), 142-148. [Abstract]

Yang, Z., Zhao, W., Liu, W. et al. (2014) The efficacy evaluation of methotrexate in the treatment of ankylosing spondylitis using meta-analysis. International Journal of Clinical Pharmacology and Therapeutics epub ahead of print. [Abstract]

Primary evidence

No new randomized controlled trials published in the major journals since 1 December 2012.

New policies

No new national policies or guidelines since 1 December 2012.

New safety alerts

No new safety alerts since 1 December 2012.

Changes in product availability

No changes in product availability since 1 December 2012.

Goals and outcome measures

Goals

To diagnose early in the course of the disease

To promptly implement effective management

To identify people in whom the disease is inadequately controlled, but who have not been offered referral for tumour necrosis factor (TNF)-alpha inhibitor treatment

To recognize and minimize the occurrence and effects of complications of the disease such as anterior uveitis (iritis) and osteoporosis, and of adverse effects of treatment such as hypertension and renal impairment

To recognize peripheral manifestations of ankylosing spondylitis such as enthesitis-related conditions

To help people remain in employment

QIPP - Options for local implementation

QIPP - Options for local implementation

Non-steroidal anti-inflammatory drugs (NSAIDs)

Review the appropriateness of NSAID prescribing widely and on a routine basis, especially in people who are at higher risk of both gastrointestinal (GI) and cardiovascular (CV) morbidity and mortality (e.g. older patients).

If initiating an NSAID is obligatory, use ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review patients currently prescribed NSAIDs. If continued use is necessary, consider changing to ibuprofen (1200 mg per day or less) or naproxen (1000 mg per day or less).

Review and, where appropriate, revise prescribing of etoricoxib to ensure it is in line with MHRA advice and the NICE clinical guideline on osteoarthritis [CSM, 2005; NICE, 2008].

Co-prescribe a proton pump inhibitor (PPI) with NSAIDs for people with osteoarthritis, rheumatoid arthritis, or low back pain (for people over 45 years) in accordance with NICE guidance [NICE, 2008; NICE, 2009a; NICE, 2009b].

Take account of drug interactions when co-prescribing NSAIDs with other medicines (see Summaries of Product Characteristics). For example, co-prescribing NSAIDs with ACE inhibitors or angiotensin receptor blockers (ARBs) may pose particular risks to renal function; this combination should be especially carefully considered and regularly monitored if continued.

[NICE, 2013]

Background information

Definition

What is it?

Ankylosing spondylitis is a chronic inflammatory rheumatic disease of unknown cause and varying clinical presentation. The principal features (not all of which are present at onset, or in all people) are [Elyan and Khan, 2006; McVeigh and Cairns, 2006; Zochling et al, 2006a]:

Inflammatory low back pain (pain and stiffness worse at night and in the morning).

Inflammation of the spinal joints and the junction (enthesis) of the intervertebral spinal ligaments and vertebrae, leading (after many years) to ankylosis (i.e. fusion from fibrosis and calcification).

Inflammation of the sacroiliac joints (on X-ray or other radiological imaging such as magnetic resonance imaging [MRI]), which presents as alternating buttock pain.

Enthesitis (inflammation of the sites where tendons and ligaments attach to bone), costochondritis (inflammation where cartilage joins the ribs), and epicondylitis (inflammation of an epicondyle of bone).

Arthritis of peripheral joints, usually involving the large joints of the lower limbs, or asymmetric arthritis of peripheral joints.

Insidious onset (over a period of at least 3 months, and often several years) usually beginning in late adolescence or early adulthood.

Fatigue.

Association with the human leukocyte antigen B27 (HLA-B27).

Axial spondyloarthritis is a term used to describe people with the symptoms of ankylosing spondylitis, but without the radiographic changes. Over a 10 year period, more than half of these people will progress to radiographic sacroiliitis and ankylosing spondylitis [Kain et al, 2008].

Causes

What causes it?

The cause of ankylosing spondylitis is not known.

It is thought that ankylosing spondylitis is triggered by an environmental factor (or factors) in people who are genetically predisposed [Kim et al, 2005].

There is a strong and complex association with the gene for human leukocyte antigen B27 (HLA-B27).

The prevalence of HLA-B27 varies considerably between different populations [Mijiyawa et al, 2000; Bakland et al, 2005].

In white western Europeans, the prevalence of HLA-B27 is about 90–95% in people with ankylosing spondylitis compared with about 8% in the general population.

In sub-Saharan Africans, the prevalence of HLA-B27 is low and ankylosing spondylitis is rare (but more common in the presence of HIV infection).

Non-HLA-B27 genes also play a role in susceptibility to ankylosing spondylitis [Wellcome Trust Case Control Consortium et al, 2007].

Prevalence

How common is it?

Ankylosing spondylitis is not uncommon:

Incidence. It is estimated that each year about 2% of people in a general practice will present with back pain and up to 5% of these will show features of ankylosing spondylitis [Underwood and Dawes, 1995].

Prevalence. Estimates of the prevalence of ankylosing spondylitis vary between 0.1% and 2% in different populations [Gran and Husby, 2003]. There are around 200,000 diagnosed cases in the UK [DH, 2006].

Sex. It is about three times more common in men than women.

Age. It most commonly begins between 20 and 30 years of age, with 90–95% of people aged less than 45 years at disease onset [Sieper, 2012].

Familial association. It is more common in people with the HLA-B27 antigen, and in this group, the risk of ankylosing spondylitis or similar type of arthritis (i.e. spondyloarthropathy) is three times more common in first degree relatives [Khan, 2002].

Complications

What are the complications?

Common complications

Progressive involvement of the lumbar, thoracic, and cervical spine can lead to a fixed and flexed posture. However, this seldom causes severe disability unless there is also severe arthritis of the hips.

Damage to peripheral joints.

Anterior uveitis (iritis).

Less common complications

Fracture of spinal vertebrae:

People with mild ankylosing spondylitis have a higher risk of fractures compared with the normal population and this increases with the duration of disease [Ralston et al, 1990; Cooper et al, 1994; Mitra et al, 2000].

Cardiac complications:

The risk of atherosclerotic cardiovascular events is increased in ankylosing spondylitis. It is therefore particularly important to identify and manage modifiable cardiovascular risk factors [Peters et al, 2004].

Aortic regurgitation, mitral regurgitation, atrioventricular block, fibrosis.

Apical fibrosis of the lung.

Cauda equina syndrome: altered bladder and bowel function, saddle anaesthesia, widespread or progressive motor weakness in the legs or gait disturbance.

Amyloidosis — in long term and severe disease.

Secondary osteoarthritis.

Secondary osteoporosis.

Blindness from uveitis.

[Elyan and Khan, 2006; McVeigh and Cairns, 2006]

Prognosis

What is the prognosis?

Many people with ankylosing spondylitis do relatively well, although progression of the disease varies widely between different individuals, and a significant proportion are at risk of long term disability.

After an initial period of inflammation, the disease tends to settle down, and 70–90% of those affected remain fully independent or minimally disabled in the long term. This is despite eventual severe restriction of spinal flexibility in 40% of those affected.

However, if the spine becomes fixed with flexion, this can be significantly disabling. If spinal deformities do arise, they do so after at least 10 years. The mortality rate is increased only in people who have had severe disease for at least 20 years.

Every attempt should be made to keep the person in employment until symptoms have been controlled. Once out of a job, people with ankylosing spondylitis rarely get back to work.

The appropriate use of anti-TNF treatments for patients with severe persistent disease is likely to greatly reduce disability in this group in the shorter and longer term.

Most people have mainly spinal symptoms, with occasional episodes of peripheral joint arthritis or anterior uveitis. A minority have spinal symptoms and recurrent extra-spinal problems (such as anterior uveitis).

Rarely, fusion of the spine can lead to severe deformities and disability, especially if the hips are also involved. Replacements of affected hip joints will not only relieve pain in the hips and improve mobility, but will also allow flexion of the lower limb to compensate for restricted movement of the spine.

Fusion of vertebral bodies and costovertebral joints may lead to a frozen thorax, which may cause respiratory impairment. This may be prevented by anti-TNF treatment.

The risk of vertebral fractures is increased in people with ankylosing spondylitis. The spine is made brittle by rigidity and weak by osteoporosis, and fractures can occur with minimal force [Ralston et al, 1990; Cooper et al, 1994; Mitra et al, 2000].

Factors that can affect outcomes

Gender

Women tend to have milder spinal disease than men, but more symptoms in knees, wrists, ankles, hips, or pelvis.

Men tend to have more severe disease than women, with involvement of the spine, pelvis, chest wall, hips, shoulders, or feet.

Women are more likely to present with anterior uveitis.

Age of onset

Early onset of peripheral arthritis or intractable iritis is associated with more severe spinal restriction.

Heredity and HLA-B27

If the parent has ankylosing spondylitis and is HLA-B27-positive, the chance of a child developing ankylosing spondylitis is less than 2 in 10.

If the parent has ankylosing spondylitis and is HLA-B27-negative, the chance of a child developing ankylosing spondylitis is less than 1 in 10.

Radiotherapy

Radiotherapy has not been used to treat ankylosing spondylitis for many years. However, those who have been irradiated are at increased risk of developing leukaemia in the early post-radiation stage, and carcinomas in the irradiation field at later stages.

[Elyan and Khan, 2006; McVeigh and Cairns, 2006]

Diagnosis

Diagnosis of ankylosing spondylitis

Diagnosis

How do I make a working diagnosis of ankylosing spondylitis?

Diagnosis is typically delayed by 5–7 years which has implications for disease progression. Making the diagnosis early is difficult because the onset of ankylosing spondylitis is insidious, with symptoms developing over several years, and there is no definitive diagnostic test. Early diagnosis therefore requires a high index of suspicion.

Suspect ankylosing spondylitis in anyone with chronic or recurrent low back pain, fatigue and stiffness, especially if:

They are a teenager, or adult aged less than 45 years.

The back pain has been present for more than 3 months.

Stiffness is inflammatory (rather than mechanical) and worse in the morning.

They have current or previous:

Buttock pain, sometimes on one side and sometimes on the other — distinguish from sciatica which usually radiates down one leg and is associated with neurological symptoms and signs.

Arthritis predominately asymmetric and in the lower limbs.

Enthesitis, costochondritis or epicondylitis.

Anterior uveitis (iritis) — this presents as an acutely painful red eye with severe photophobia; if untreated, it can lead to loss of vision.

Psoriasis or inflammatory bowel disease, or recent infective diarrhoea or sexually transmitted disease (especially Chlamydia).

Symptoms wake them in the night.

Symptoms respond to a course of nonsteroidal anti-inflammatory drugs (NSAIDs) within 48 hours.

Around three-quarters of people with ankylosing spondylitis have a good response to NSAIDs within 48 hours of treatment. In contrast, only around 15% of people with mechanical back pain will respond well.

There is a family history of ankylosing spondylitis or spondyloarthropathy.

Other conditions with similar presentations have been excluded, see Differential diagnosis.

Refer to a rheumatologist for confirmation of the diagnosis as this can be difficult. There are a number of different classification criteria available to aid the diagnosis of ankylosing spondylitis. Certain investigations can be arranged from primary care prior to referral.

Diagnostic criteria

Diagnostic criteria

These are examples of diagnostic criteria which may be used by rheumatologists to help to confirm a diagnosis of ankylosing spondylitis.

For the 'modified New York criteria' for diagnosing ankylosing spondylitis, see Table 1.

For the Assessment of Spondylitis international Society (ASAS) classification criteria for axial spondyloarthritis, see Table 2.

Table 1 . Modified New York criteria for diagnosing ankylosing spondylitis.
Modified New York criteria
Clinical criteria: Low back pain; present for more than 3 months; improved by exercise but not relieved by rest. Limitation of lumbar spine motion in both the sagittal and frontal planes. Limitation of chest expansion relative to normal values for age and sex.
Radiological criterion: Sacroiliitis on X-ray.
Diagnose: Definite ankylosing spondylitis if the radiological criterion is present plus at least one clinical criterion. Probable ankylosing spondylitis if three clinical criteria are present alone, or if the radiological criterion is present but no clinical criteria are present.
Data from: [van der Linden et al, 1984]
Table 2 . ASAS classification criteria for axial spondyloarthritis
ASAS classification criteria (for people with back pain for 3 months or longer who were < 45 years old at onset of back pain)
Sacroilitis on imaging* plus 1 or more spondyloarthritis features†
or
HLA-B27 plus 2 or more other spondyloarthritis features†
* Sacroiliitis on imaging: active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with spondyloarthritis, or definite radiographic sacroiliitis according to the modified New York critieria † Spondyloarthritis features: inflammatory back pain; arthritis; enthesitis (heel); uveitis; dactylitis; psoriasis; Crohn's disease/ulcerative colitis; good response to NSAIDs; family history of spondyloarthritis; HLA-B27; elevated C-reactive protein
Data from: [Rudwaleit et al, 2009]

Basis for recommendation

Basis for recommendation

When to suspect

These recommendations are based on published expert opinion [Elyan and Khan, 2006; McVeigh and Cairns, 2006; Kain et al, 2008], a prospective case ascertainment trial looking at identifying people with axial spondyloarthritis in primary care [Braun et al, 2011b], literature reviews of clinical criteria used to diagnose ankylosing spondylitis and undifferentiated axial spondyloarthopathy [Rudwaleit et al, 2004; Sieper, 2012], and expert opinion from reviewers of this CKS topic.

One review found that, assuming that the background prevalence of axial spondyloarthritis was 5% [Rudwaleit et al, 2004]:

If there were features of inflammatory back pain, the probability of axial spondyloarthritis was 14%.

If two or three features of axial spondyloarthritis were present, the probability of axial spondyloarthritis was 90%.

Response to treatment with an NSAID had a sensitivity of 61–77%, a specificity of 75–85%, and a likelihood ratio of 2.8–5.1 (ranges of findings in five studies).

Making the diagnosis early is difficult because the onset of ankylosing spondylitis is insidious, with symptoms developing over several years, and there is no definitive diagnostic test. The average delay in diagnosis ranges from 3–11 years, depending on the type of symptoms and the skill of the physician [Elyan and Khan, 2006]. Early diagnosis therefore requires a high index of suspicion.

Diagnostic criteria

The British Society for Rheumatology recommended that the 'modified New York criteria' be used to diagnose ankylosing spondylitis (see Table 1) [BSR, 2004].

These criteria are important for standardizing entry into genetic studies and therapeutic trials, but are less useful for making an early diagnosis [O'Shea et al, 2007].

More recently, the Assessment of SpondyloArthritis international Society (ASAS) has developed classification criteria for early and established cases of axial spondyloarthritis (see Table 2). These include magnetic resonance imaging as an important tool for early diagnosis [Sieper et al, 2009] and are aimed at helping rheumatologists diagnose axial spondyloarthritis in people with chronic back pain [Rudwaleit et al, 2009].

Investigations

What investigations should I arrange when ankylosing spondylitis is suspected?

Confirm inflammation with erythrocyte sedimentation rate (ESR), and/or C-reactive protein (CRP), and full blood count (FBC) test.

ESR and CRP provide evidence of inflammation if they are elevated. But they may be within normal limits or only mildly elevated in people with ankylosing spondylitis.

FBC — a mild normochromic normocytic anaemia also provides evidence of inflammation.

Follow local referral protocols on imaging the sacroiliac joints and spine, or seek specialist advice on imaging before referral.

X-rays. In well established cases, radiographs of the sacroiliac joints and spine are diagnostic, showing extensive sclerosis and erosions in the sacroiliac joints, bony bridging between vertebrae, ligamentous calcification joining posterior spinous processes, and erosions and sclerosis in the vertebrae. However, these changes may take several years to show radiographically.

Magnetic resonance imaging (MRI). Although at first presentation there is often no radiographic abnormality, MRI can detect early changes in sacroiliac joints.

Ultrasound scanning can confirm a clinical impression of enthesitis. It has been used to image the sacroiliac joints during research, but is not helpful in clinical practice.

Rheumatoid factor and anti-nuclear antibodies — neither a positive test nor a negative test are useful in diagnosing ankylosing spondylitis.

HLA-B27 — if testing is to be done this will be in secondary care.

Sensitivity and specificity for ankylosing spondylitis were about 90% in one study. However, for a condition with low prevalence (e.g. about 5% of people presenting with back pain) the HLA-B27 test is not thought to be accurate enough to be helpful in primary care settings.

Screening unaffected or asymptomatic relatives for HLA-B27 status is not justified as there is no preventive or curative therapy.

IgA — IgA levels can be raised in people with ankylosing spondylitis, but the test is not useful for diagnosis.

Basis for recommendation

Basis for recommendation

Recommendations for investigating ankylosing spondylitis are based on expert opinion from review articles [Khan, 2002; Rudwaleit et al, 2004; Sieper and Rudwaleit, 2005; McVeigh and Cairns, 2006; Kain et al, 2008].

Differential diagnosis

What else might it be?

Mechanical back pain (such as prolapsed disc, spondylolisthesis, sciatica)

Mechanical back pain is not aggravated by rest, and rest does not lead to stiffness lasting more than a few minutes. Buttock pain due to sciatica or other mechanical cause does not alternate between the left and right sides, usually radiates in a dermatomal distribution, and is associated with neurological symptoms and signs.

Inflammatory back pain, a key feature of ankylosing spondylitis, tends to become worse with rest. People with ankylosing spondylitis may wake in the night and have to move around to obtain relief. Stiffness after resting is prolonged (e.g. lasts for more than 30 minutes) and is relieved by activity. In ankylosing spondylitis buttock pain may alternate between the left and right sides.

Other spondyloarthropathies (such as psoriatic arthritis, reactive arthritis, Reiter's syndrome, inflammatory bowel disease)

Psoriasis is characterized by typical skin and nail lesions.

In reactive arthritis and Reiter's syndrome the onset is rapid and there may be a history of urethritis, gastroenteritis, or other infection, or a history of conjunctivitis or inflammatory bowel disease.

However, some people with psoriatic arthritis, reactive arthritis, Reiter's syndrome, or inflammatory bowel disease do meet the criteria for ankylosing spondylitis.

Rheumatoid arthritis

In rheumatoid arthritis, back pain is a rare presenting feature, and peripheral arthritis is common and symmetric (affecting similar joints on the left and right sides).

In contrast, in ankylosing spondylitis, back pain and buttock pain are typical, and peripheral arthritis tends to be uncommon and asymmetric.

Polymyalgia rheumatica

Polymyalgia rheumatica tends to affect older women and men, while ankylosing spondylitis tends to affect younger men.

The onset of polymyalgia rheumatica is often rapid, and symptoms tend to affect the neck and shoulder before the hips and lower back.

Infections (such as sepsis; tuberculous, fungal, or viral infection; infectious spondylitis)

Infections that present with back pain or arthritis can be diagnosed or excluded with blood cultures, tuberculin skin tests, or blood tests for antigens. The person is unwell, unless immunosuppressed. Spondylitis and septic discitis can be diagnosed with spinal imaging.

Cancer (metastatic or primary)

Cancer rarely presents similarly to ankylosing spondylitis, but it should be specifically excluded if there is a history of cancer, or if there is unexplained weight loss.

Basis for recommendation

Basis for recommendation

This information is pragmatic and is based on the clinical experience of CKS authors and expert opinion from reviewers of this CKS topic.

Management

Management

Scenario: Suspected ankylosing spondylitis : covers the initial management of ankylosing spondylitis in primary care, when to refer, and what advice to give.

Scenario: Confirmed ankylosing spondylitis : covers the assessment, treatment and referral of someone with confirmed ankylosing spondylitis.

Scenario: Suspected ankylosing spondylitis

Scenario: Suspected ankylosing spondylitis

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Advice

What advice should I give a person with suspected ankylosing spondylitis?

Advise the person with suspected ankylosing spondylitis that:

Diagnosis of ankylosing spondylitis can be difficult and referral to a rheumatologist is required for confirmation — clinical features and diagnostic tests for ankylosing spondylitis can help make the diagnosis, but may not be definitive. The rheumatologist may arrange blood tests and X-rays (for more information, see Investigations in the section on Diagnosis).

Ankylosing spondylitis is a chronic condition and there is no cure. However, for most people the prognosis is relatively good. Modern treatment can control symptoms and significantly slow the progressive stiffening of the spine and damage to the joints that can occur if the disease is not treated.

There is wide variation in the ways that ankylosing spondylitis affects different people. In most people the major problem is pain and stiffness in the spine. Some people have arthritis in the hips or shoulders, and some have arthritis in peripheral joints. Many people have enthesitis — painful inflammation where tendons or ligaments attach to bone; common places for enthesitis are the back of the heel and the heel pad. Some people have costochondritis (painful inflammation of the rib cartilage).

There is one complication in particular that they should be aware of — anterior uveitis (also known as iritis). Uveitis is inflammation of the eye. It should be suspected and medical attention sought immediately if one eye suddenly becomes painful and red. If not treated quickly there can be permanent (partial or complete) loss of vision in the eye. Treatment of anterior uveitis is usually very successful.

Initial treatment for ankylosing spondylitis will include something to control symptoms, for example a nonsteroidal anti-inflammatory drug (NSAID). When the specialist confirms the diagnosis, they will arrange physiotherapy (stretching, exercise, advice on maintaining the best posture), and may initiate treatment to prevent osteoporosis. Exercise is important for managing the back pain and for reducing the risk of cardiovascular disease.

An important goal of treatment is to help the person stay in employment.

The National Ankylosing Spondylitis Society (NASS) has useful information and advice on their website: www.nass.co.uk.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion and are in line with British and international recommendations [McVeigh and Cairns, 2006; Sidiropoulos et al, 2008; Braun et al, 2011a].

Initial treatment

What treatment should I start for someone with ankylosing spondylitis while waiting for referral?

Consider prescribing a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen or naproxen while waiting for referral. Take account of the person's risk of serious adverse effects, the safety profiles of individual standard NSAIDs or coxibs, the person's ability to tolerate individual NSAIDs, their other medications, and their preferences.

If NSAIDs are contraindicated, prescribe a standard analgesic (paracetamol with or without codeine).

If the person is at increased risk of gastrointestinal (GI) adverse effects, or is unable to tolerate NSAIDs because of GI adverse effects, prescribing options are:

A standard NSAID together with a proton pump inhibitor (PPI).

A coxib with a PPI.

A standard analgesic (paracetamol with or without codeine).

If the person is at increased risk of cardiovascular or renal adverse effects, choice of NSAID will depend on the type of cardiovascular disease or degree of renal impairment. For more information on prescribing options, see the section on Preventing and managing cardiovascular and renal adverse effects in the CKS topic on NSAIDs - prescribing issues.

For more information on prescribing NSAIDs, gastroprotection, and analgesics, see the CKS topics on NSAIDs - prescribing issues and Analgesia - mild-to-moderate pain.

Manage modifiable cardiovascular risk factors if present (smoking, overweight, raised cholesterol, sedentary lifestyle, comorbidities). For more information on assessing and managing cardiovascular risk factors, see the CKS topics on:

CVD risk assessment and management .

Hypertension - not diabetic and Diabetes - type 2.

Lipid modification - CVD prevention .

Obesity .

Smoking cessation .

Basis for recommendation

Basis for recommendation

Nonsteroidal anti-inflammatory drugs (NSAIDs)

There is consistent evidence from systematic reviews of RCTs of treatments for ankylosing spondylitis [Boulos et al, 2005; Zochling et al, 2006b] and subsequently published RCTs [Wanders et al, 2005; Barkhuizen et al, 2006; Sieper et al, 2008] that NSAIDs improve spinal pain, peripheral joint pain, and functional ability in the short term.

Evidence from one RCT suggests that NSAIDs are more effective in modifying radiological progression when used continuously, than when used as required [Wanders et al, 2005].

The systematic reviews found no good evidence that any one NSAID is more effective than any other when they are used at appropriate doses.

For discussion of the gastrointestinal and cardiovascular adverse effects of standard NSAIDs and coxibs, see the CKS topic on NSAIDs - prescribing issues.

Paracetamol and other analgesics

There is no direct evidence from clinical trials to support the use of paracetamol or other analgesics for ankylosing spondylitis, but this practice is commonly recommended by British and international experts [McVeigh and Cairns, 2006; Braun et al, 2011a].

Cardiovascular risk

Experts recommend that clinicians should take particular care to identify and treat modifiable cardiovascular risk factors in people with ankylosing spondylitis because ankylosing spondylitis is associated with increased rates of cardiovascular morbidity and mortality [McVeigh and Cairns, 2006].

A systematic review found evidence from observational studies that people with ankylosing spondylitis may be at increased risk for cardiovascular disease [Peters et al, 2004].

Referral

When should I refer a person with suspected ankylosing spondylitis?

Refer urgently (same day) to ophthalmology if anterior uveitis (iritis) is suspected.

Suspect uveitis when an eye suddenly becomes red and acutely painful — uveitis is especially likely if there is also photophobia.

Refer to rheumatology all new or suspected cases of ankylosing spondylitis. The rheumatologist will:

Confirm the diagnosis.

Review current treatment including any need for anti-TNF agents.

Assess whether treatment with bisphosphonates is indicated.

Refer to physiotherapy for assessment, education and a regular home exercise programme.

Refer to occupational therapy or physiotherapy if aids for activities of daily living are required.

Make arrangements for follow up and monitoring, which may be a shared care arrangement.

Basis for recommendation

Basis for recommendation

These recommendations are based on the opinions of British and international experts [McVeigh and Cairns, 2006; Kain et al, 2008; Sidiropoulos et al, 2008; Braun et al, 2011a].

International guidelines state that the management of people with ankylosing spondylitis should be led by a rheumatologist [Braun et al, 2011a].

Scenario: Confirmed ankylosing spondylitis

Scenario: Confirmed ankylosing spondylitis

192months3060monthsBoth

Assessment

How should I assess a person with confirmed ankylosing spondylitis?

Assess disease activity and progression in terms of:

Neck, chest, and lower back symptoms.

Hip arthritis.

Inflammatory arthritis in other joints.

Enthesitis (inflammation causing pain/tenderness where tendon or ligament attaches to bone, for example at the back of the heel or in the heel pad).

Costochondritis (inflammation where cartilage joins the ribs).

Assess the impact of the disease on:

Activities of daily life at work and at home: dressing, feeding, personal hygiene.

Threat to ability to work ('work instability').

Quality of life: pain, sleep disturbance, fatigue, mood.

Flexibility of the ribcage — monitor by measuring maximal chest expansion.

Flexibility of the lumbar and cervical spine — measure lumbar forward flexion with Schober's test.

With the person standing upright, mark the points in the midline 5 cm below and 10 cm above the lumbosacral junction. Have the person bend as far forward as possible while keeping the knees straight, and re-measure the distance between the two marked points. An increase of less than 5 cm indicates loss of lumbar flexibility.

Check if there are symptoms or signs of the complications of ankylosing spondylitis, for example:

Anterior uveitis (iritis) — an acutely painful red eye, photophobia.

Fracture of spinal vertebrae — suspect this if there is sudden onset of pain in the spine.

Assess the risk factors for cardiovascular disease and osteoporosis.

Basis for recommendation

Basis for recommendation

These recommendations are based on the opinions of British and international experts [Elyan and Khan, 2006; McVeigh and Cairns, 2006; Braun et al, 2011a].

Treatment

How should I manage uncontrolled symptoms?

Check compliance with, and tolerance to, exercise/stretching and current drug treatments.

If the current nonsteroidal anti-inflammatory drug (NSAID) is ineffective, options to consider include:

Seeking specialist advice.

Changing to another NSAID.

Changing to a slow-release NSAID preparation (if night pain and morning stiffness are a problem).

Adding additional analgesia. For example, paracetamol and/or codeine.

Intra-articular injection of corticosteroid for an inflamed accessible joint — only if there is an appropriate level of expertise. Refer if requisite skills are unavailable.

If the current NSAID is poorly tolerated:

Check that gastroprotection with a proton pump inhibitor (PPI) is being used (even if the current NSAID is a coxib).

Consider using an analgesic such as paracetamol or codeine.

If symptoms are poorly controlled despite appropriate treatment, referral for specialist rheumatology assessment is usually indicated. Interventions that rheumatologists can use to control symptoms include:

For sacroiliitis: injection of corticosteroids.

For enthesitis (inflammation where bone joins tendon or ligament): injection of corticosteroids.

For uncontrolled disease in general: tumour necrosis factor (TNF)-alpha inhibitors such as etanercept, adalimumab, and golimumab.

Oral or intravenous bisphosphonates.

Basis for recommendation

Basis for recommendation

These recommendations are in line with British and international recommendations [McVeigh and Cairns, 2006; Sidiropoulos et al, 2008; Braun et al, 2011a], and are supported by systematic reviews of clinical trials [Boulos et al, 2005; Zochling et al, 2006b; Lavie et al, 2007], and subsequently published randomized controlled trials (RCTs).

Analgesia

There is no direct evidence that paracetamol and codeine are effective for pain in ankylosing spondylitis, but they are widely recommended by experts [McVeigh and Cairns, 2006; Braun et al, 2011a; Sidiropoulos et al, 2008].

A Cochrane systematic review of combination therapy with two or more drugs (including nonsteroidal anti-inflammatory drugs, paracetamol, and opioids) for pain management in inflammatory arthritis (including ankylosing spondylitis) found 23 trials, but concluded that there is insufficient evidence to evaluate the effectiveness of combining treatments [Ramiro et al, 2011].

CKS found no clinical trials comparing slow-release preparations of NSAIDs with standard preparations. Slow-release NSAIDs for morning stiffness are recommended by some experts on the basis of plausibility and clinical experience.

Tumour necrosis factor (TNF)-alpha inhibitors

There is good evidence that TNF-alpha inhibitors are effective in ankylosing spondylitis that is poorly controlled with NSAIDs [Zochling et al, 2006b]. A TNF-alpha inhibitor may be started and should be monitored by a rheumatologist [BSR, 2004].

The three TNF-alpha inhibitors that are approved by the National Institute for Health and Care Excellence (NICE) for the treatment of ankylosing spondylitis are adalimumab, etanercept, and golimumab [NICE, 2010; NICE, 2011].

Corticosteroid injections

There is evidence from two small RCTs that corticosteroid injections are effective for sacroiliitis. Although there is no evidence from clinical trials that corticosteroid injections are effective for arthritis of peripheral joints and enthesitis (inflammation where bone joins tendon or ligament), their use is recommended by British and international experts [McVeigh and Cairns, 2006; Zochling et al, 2006b; Sidiropoulos et al, 2008; Braun et al, 2011a].

Bisphosphonates

Although bisphosphonates possess anti-inflammatory properties [Toussirot and Wendling, 2007], a systematic literature review found insufficient data to support their use for the treatment of active ankylosing spondylitis. However, a Delphi procedure between experts concluded that bisphosphonates may be useful for the management of osteoporosis in ankylosing spondylitis [Sidiropoulos et al, 2008].

Follow up

How should I follow-up a person with ankylosing spondylitis?

Follow up is usually a shared care arrangement with the rheumatology service; local practices vary.

The frequency of monitoring should be decided by the rheumatologist in charge of management.

Follow up should monitor disease progression and response to treatment.

Disease progression is monitored by measuring spinal movements and chest expansion.

Response to treatment is monitored by assessing:

Control of symptoms (pain, fatigue, morning stiffness).

Adverse effects of drugs.

Extra-articular manifestations and complications, particularly uveitis.

The impact of the condition on activities of daily living.

If chest wall movement is restricted, arrange influenza and pneumococcal immunizations.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion and are in line with British and international recommendations [McVeigh and Cairns, 2006; Sidiropoulos et al, 2008; Braun et al, 2011a].

Referral

When should I refer a person with ankylosing spondylitis?

Refer urgently (same day) to ophthalmology if anterior uveitis (iritis) is suspected.

Suspect uveitis when an eye suddenly becomes red and acutely painful; uveitis is especially likely if there is photophobia. For more information, see the CKS topic on Uveitis.

Refer (with urgency appropriate to the clinical situation) to orthopaedics if:

Vertebral fracture is suspected.

Suspect a vertebral fracture when there is sudden onset of new spinal pain.

There is refractory hip pain or disability in association with structural damage on X-ray — hip arthroplasty may be considered.

The person has severe disabling deformity of the spine — spinal corrective osteotomy may be considered.

For people treated with a tumour necrosis factor (TNF) alpha inhibitor, urgently refer to, or consult with, rheumatology if a serious adverse effect is suspected (for example, infection, immunosuppression, malignancy, or a lymphoproliferative disorder).

Seek advice from the person's rheumatologist if symptoms are uncontrolled despite appropriate treatment.

If not already arranged by secondary care:

Refer all people to physiotherapy for assessment, education, development of a home exercise programme, and physical treatments such as hydrotherapy.

Refer to occupational therapy or physiotherapy or a Disability Equipment Assessment Centre for aids for activities of daily living such as walking sticks.

Suggest joining the local support group run by the National Ankylosing Spondylitis Society (NASS; www.nass.co.uk).

Basis for recommendation

Basis for recommendation

These recommendations are based on the opinions of British and international experts [McVeigh and Cairns, 2006; Sidiropoulos et al, 2008; Braun et al, 2011a].

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Oral NSAIDs

Oral nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAID prescribing issues

What issues should I consider before prescribing a standard or coxib nonsteroidal anti-inflammatory drug?

For more information on prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs, see the CKS topic on NSAIDs - prescribing issues.

Proton pump inhibitors (PPIs)

Proton pump inhibitors (PPIs) for gastroprotection

PPI prescribing issues

What issues should I consider before prescribing a proton pump inhibitor?

For more information on prescribing proton pump inhibitors in association with a nonsteroidal anti-inflammatory drug, see the CKS topic on NSAIDs - prescribing issues.

Paracetamol and codeine

Paracetamol and codeine

Paracetamol and codeine prescribing issues

What issues should I consider before prescribing paracetamol and codeine?

For more information on prescribing analgesia such as paracetamol and codeine, see the CKS topic on Analgesia - mild-to-moderate pain.

Evidence

Evidence

Supporting evidence

NSAIDs

Evidence on NSAIDs

There is consistent evidence from systematic reviews of randomized controlled trials (RCTs) of treatments for ankylosing spondylitis that nonsteroidal anti-inflammatory drugs (NSAIDs) improve spinal pain, peripheral joint pain, and functional ability over the short term. Data from anRCT suggest that NSAIDs are more effective in modifying radiological progression when used continuously than when used as required. There is no good evidence that any one NSAID is more effective than any other when they are used at appropriate doses. CKS found no trials of slow-release NSAIDs compared with standard preparations.

A systematic review assessed the use of NSAIDs (and other management strategies) for ankylosing spondylitis [Zochling et al, 2006b].

The systematic review found eight RCTs that compared NSAIDs with placebo: results from four of these studies could be pooled for meta-analysis. The study also found 26 RCTs that compared different NSAIDs.

To allow results from different studies to be compared and aggregated, the systematic review converted outcome measures in the included studies to effect sizes (ES). ES is the mean change in outcome measure divided by the standard deviation of the change. An effect size greater than zero means that the intervention is more effective than the comparison; and vice versa for effect sizes less than zero. However, interpretation of the results is difficult because it is not clear what effect size is clinically meaningful — effect size is a relative, not absolute, measure.

Compared with placebo, standard NSAIDs and coxibs improve spinal and peripheral joint pain, and, over the short term (6 weeks), can improve the level of functioning. Standard NSAIDs and coxibs were equally effective.

Spinal pain was significantly improved:

All eight RCTs found that NSAIDs improve spinal pain.

ES 1.11 (95% CI 0.96 to 1.26) — meta-analysis of four studies.

Peripheral joint pain was significantly improved:

ES 0.62 (95% CI 0.26 to 0.97) — one study.

Function improved over 6 weeks:

ES 0.62 (95% CI 0.47 to 0.76) — meta-analysis of four studies.

Coxibs were as effective as standard NSAIDs:

Spinal pain: ES 1.05 (95% CI 0.88 to 1.22) — meta-analysis of three studies.

Peripheral joint pain: not specifically investigated.

Function: ES 0.63 (95% CI 0.47 to 0.80) — meta-analysis of three studies.

There was no good evidence that any one NSAID was more effective than any other — review of 26 RCTs.

An earlier systematic review [Boulos et al, 2005] had essentially the same findings and conclusions as the meta-analysis summarized above [Zochling et al, 2006b].

CKS found two relevant RCTs which were published after the systematic reviews. The results of the RCTs support and extend the conclusions of the two systematic reviews.

In the first RCT, celecoxib and naproxen were significantly more effective over 12 weeks than placebo, in relieving pain, reducing disease activity, and improving function [Barkhuizen et al, 2006]. Celecoxib 400 mg daily was as effective as naproxen 500 mg twice daily, which was more effective than celecoxib 200 mg daily.

In the second RCT, celecoxib and diclofenac were similarly effective [Sieper et al, 2008]. Celecoxib 200 mg twice a day was as effective as diclofenac standard release (SR) 75 mg twice a day for all outcome measures, including measures of pain and function. Celecoxib 200 mg twice a day and diclofenac reduced some parameters associated with inflammation more effectively than celecoxib 200 mg once a day.

In terms of reducing radiological progression:

An RCT (n = 215) assessed outcomes over 2 years and found that continuous treatment of AS with an NSAID was more effective than as-required treatment in delaying or preventing structural changes shown by X-rays of the lumbar and cervical spine [Wanders et al, 2005].

More recently, the German Spondyloarthritis Inception Cohort (GESPIC) study investigated the effect of NSAIDs on radiographic spinal progression over 2 years in people with AS (n = 88) and non-axial spondyloarthritis (n = 76), although the study was not specifically designed and powered for this purpose. In people with AS, when compared with a low NSAID intake, a high NSAID intake was associated with lower chance of significant radiographic progression (OR 0.15, 95% CI 0.02 to 0.96, p = 0.045). This effect was less evident in people with non-radiographic axial spondyloarthritis [Poddubnyy et al, 2013].

In another RCT, participants were randomized to either continuous (n = 76) or on-demand (n = 74) treatment. In people in the continuous treatment group, slowing of radiological progression was greater in those with elevated acute phase reactants such as ta-CRP and ta-ESR [Kroon et al, 2012].

Paracetamol and other analgesics

Evidence on paracetamol and other analgesics

CKS and one systematic review found no evidence from clinical trials of paracetamol or other analgesics (alternatives to nonsteroidal anti-inflammatory drugs) used to treat ankylosing spondylitis [Zochling et al, 2006b].

Physiotherapy

Evidence on physiotherapy

Individual home-based or supervised exercise programmes may be better than no intervention. Supervised group physiotherapy may be better than home exercise, and combined inpatient spa-exercise therapy followed by group physiotherapy may be better than group physiotherapy alone.

Systematic reviews, including a Cochrane systematic review, found six controlled clinical trials of physiotherapy treatments, including stretching (passive and active), exercise, education, transcutaneous electrical nerve stimulation (TENS), pulsed magnetic fields, and various types of balneotherapy (including hydrotherapy, heat therapy, and cryotherapy). Treatment settings were in the clinic, at home, or at a spa, and treatments were given to groups or to individuals. Given the number and complexity of the interventions, the small numbers of trials, and the short durations of follow up, no strong conclusions can be drawn from the evidence [Zochling et al, 2006b; Dagfinrud et al, 2008].

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of ankylosing spondylitis.

Search dates

July 2008 — December 2012

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Spondylitis, Ankylosing/ or ankylosing spondylitis.tw. or spondyloarthr$.tw. or ankylos$.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

World Health Organization

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

NHS Scotland National Patient Pathways

New Zealand Guidelines Group

Agency for Healthcare Research and Quality

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Singapore Ministry of Health

National Resource for Infection Control

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - Patient Journeys

Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

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