Managing ankylosing spondylitis
Identify knowledge gaps
The Royal Pharmaceutical Society’s areas of competence for pharmacists are listed in “Plan and record”. This article relates to “common disease states” (see appendix 4 of “Plan and record”).
The term “ankylosing spondylitis” (AS) comes from Greek; angkylos meaning bent and spondylos meaning spinal vertebrae. The disease is characterised by prominent inflammation of spinal joints and adjacent structures.
Persistent inflammation leads to progressive and ascending bony fusion of the spine as the body tries to repair tissue damage — the spine is affected with characteristic bony spurs (syndesmophytes), which eventually fuse with the vertebral bone above (ankylosis). The hips and shoulders can be involved in up to a third of cases and inflammatory lesions of extra-articular organs, such as the eyes and the heart, can occur, although this is less common.
Clinically, radiographically, epidemiologically and genetically, AS is related to a family of arthritic diseases termed the seronegative spondyloarthropathies (ie, they test negative for rheumatoid factor, the antibody found in rheumatoid arthritis). Other diseases in this group include juvenile ankylosing spondylitis, Reiter’s syndrome (reactive arthritis), psoriatic arthritis and arthropathies associated with inflammatory bowel diseases.
The features that unite these conditions are their tendency to affect the spinal joints (causing sacroiliitis and spondylitis), and that patients also tend to suffer peripheral arthritis (typically affecting a few joints) and asymmetric inflammation where tendon and ligaments attach to bone (enthesitis).
|X-ray showing fused vertebrae ("bamboo spine") (Alfred Pasieka/SciencePhoto Library)|
The course of the disease can vary. In advanced stages the calcified ligaments along with the fused joint (sometimes called a “bamboo spine”) can be seen on X-rays and spinal mobility is reduced. In a few patients there is progression to kyphosis, neck hyperextension (“question mark posture”), and spinocranial ankylosis.1
Prevalence and causes
In Britain, ankylosing spondylitis affects about one in 250 males and about one in 500 females. It usually has a young age of onset, presenting between the ages of 15 and 35 years.
There are two peak onsets: at 30 years of age, twice as many men present with the condition than women, but at 16 years of age, an even larger proportion of men (6:1) present with the disease.1
The cause of AS is unknown but a family predisposition and a strong association with a genetic polymorphism of the major histocompatibility complex encoding for human leukocyte antigen B27 (HLA B27), which is present on the surface of white blood cells, has been noted.
In fact, more than 95 per cent of patients with AS will exhibit the genetic marker HLA B27 but it is important to recognise that not all those with HLA B27 will develop the condition — 7 per cent of the general population carry this genetic marker and only 5 per cent of these people will develop AS.2
It is possible that pathogens can interface with HLA B27, triggering the inflammatory cascade. This might explain why some patients who develop gastroenteritis will see an acute exacerbation of their AS. There are also reports that patients become more aware of their symptoms during periods of extended bed rest following illness. This suggests that illness can accelerate an otherwise underlying mild condition, although lack of motion could lead to muscle atrophy, which could also exacerbate symptoms.
|The first symptoms to be reported are typically chronic lower back pain and stiffness (Tiero/Dreamstime.com)|
Signs and symptoms
The first symptoms to be reported by patients with AS are typically chronic lower back pain and stiffness. Because of the general nature of these symptoms and the insidious nature of the disease it is not uncommon to find patients who struggle to date when the symptoms first began or to pinpoint the affected sites.
Alternating pain from one buttock to that of the other, with occasional radiation down the back of the thigh, which can reflect involvement of the sacroiliac joints (see Figure 1), can be elicited from some patients but these symptoms are often incorrectly ascribed to hip problems (eg, arthritis) or sciatica.
Characteristically, inflammatory back pain is suggested by prominent stiffness and pain in the morning or following other periods of inactivity. Symptoms of AS improve with exercise and pain reduces towards the end of the day, particularly in patients under the age of 40 years.
|Figure 1: Anatomy of pelvis and spine (Anatomical Travelogue/Science Photo Library)|
Although these symptoms are useful indicators of AS, it should be noted that there is a subset of patients who report non-specific symptoms or no symptoms at all despite radiographic changes. Less commonly, patients can present with peripheral arthritis (typically affecting one or a few joints — often one or both knees).
The condition also tends to manifest differently between the sexes. In men, the spine and pelvis are commonly affected (although other joints may become involved, namely chest wall, shoulders, hip and feet). In women, the involvement of the spine is less severe and the hips, pelvis, knees, ankles and wrists are more commonly affected.
It is rare for children under the age 12 years to develop AS but in those who are affected the first joints to become involved are the wrists, hips, knees and ankles — back pain is rarely reported.
Diagnosis requires a physical examination. The earliest abnormality that is usually detected is tenderness in the sacroiliac joints or pain in that area elicited by hip hyperextension (where the patient is asked to lie face down and raise his leg from its resting place). The straight leg raise test, often used to detect sciatic nerve irritation by a ruptured disc, is negative in most cases, and tendon reflexes in the lower limbs are normal. Reduced expansion of the thoracic spine when the patient bends side to side, backwards and forwards indicates the progressively reduced movement that the condition can cause.
Although diagnosis is clinical, investigations can include radiography and a full blood count to establish the presence of anaemia and raised surrogate markers evidencing active inflammation (eg, erythrocyte sedimentation rate and C-reactive protein). Sacroiliitis is the earliest feature to be picked up by magnetic resonance imaging (when an X-ray can appear normal).
At present, there is no cure for AS and the available treatments are used to provide symptomatic relief and to increase periods of remission, aiming to slow disease progression.
Conservative treatment starts with the patient doing plenty of exercise and sustaining a good posture, and physiotherapy support can be important. The aim is to increase the range of motion and to strengthen muscles around the affected joints. Reduced activity can lead to muscle atrophy such that patients would then need to engage in stretching these muscles again. As a general exercise, swimming can can help strengthen muscles without putting weight on the affected joints.
Drug therapy includes non-steroidal anti-inflammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDs) and tumour necrosis factor alpha (TNF-a) inhibitors.
NSAIDs are usually prescribed first-line to patients with AS. However, those who are susceptible to the side effects of NSAIDs, such as peptic ulceration, increased risk of bleeding, bronchospasm and renal impairment, may be prescribed paracetamol instead. A large subset of those affected by AS take NSAIDs with other analgesics to reduce inflammation, stiffness and pain.
The DMARDs are reserved for patients with AS who also have peripheral arthritis unresponsive to NSAIDs or inflammatory bowel disease. These agents can slow down and, perhaps, stop the progress of inflammation in some people, but it can take four to six months for a desirable outcome to be achieved. It has been reported that the benefits of methotrexate and sulfasalazine are variable, showing greatest benefit in those with peripheral joint involvement and not just spinal symptoms.
Sulfasalazine is started at 500mg od and increased by 500mg weekly to a maximum of 2–3g per day in divided doses. Approximately 20 per cent of patients stop taking the drug because of side effects, which include nausea, gastrointestinal disturbances, headaches, skin rashes and mouth ulcers. Enteric coated tablets decrease the chance of peptic reactions.
Methotrexate is reserved for patients who do not respond to NSAIDs or sulfasalazine. Like other immunosuppressants it is frequently used in the treatment of chronic inflammatory arthritic diseases. Methotrexate is administered weekly and is a relatively slow-acting antirheumatic, so patients should be advised not to expect swift results. The drug is usually well tolerated but can cause nausea, diarrhoea and reduced anorexia.
Both these DMARDs are not painkillers, but will help to relieve the pain by controlling underlying inflammation. Most importantly, both sulfasalazine and methotrexate carry a risk of haematological and hepatic toxicity so increased monitoring is needed.
For sulfasalazine, blood counts should be performed initially and monthly for the first three months of treatment and liver function tests monthly for the first three months; and for methotrexate, blood counts, liver function tests and renal function tests should be performed initially and then weekly until treatment is stabilised and then every two or three months.
In addition, patients should be advised to report any signs of an infection, such as a sore throat, fever or difficulty in breathing, or signs of liver toxicity, such as nausea and vomiting and dark urine.
Corticosteroids have no therapeutic value in the long-term management of musculoskeletal aspects in AS because of their serious side effects, and because they do not stop disease progression. A local corticosteroid injection may, however, help to control persistent joint inflammation and enthesitis.
Tumour necrosis factor is a cytokine produced by inflammatory cells, which acts as a messenger protein, playing a vital role in the body’s immune response by controlling the production of other mediators involved in inflammation.
The effect of TNF is to promote inflammation and to orchestrate an environment that allows cells to heal or repair themselves. It works by attaching to TNF receptors found on cells involved in mounting the immune response.
Once circulating TNF interfaces with a receptor, the complex draws the factor into the cell to exert its effect. Surplus TNF receptors are released into the blood stream to mop up any excess TNF in the systemic circulation or in tissues. If too much free TNF is produced, it can go on to damage healthy tissues and contribute to a variety of conditions, such as toxic shock.
The TNF-a inhibitors licensed for use in AS are adalimumab, etanercept and
The human-sequence antibody adalimumab binds specifically to the TNF-a subtype. This complex allows for the neutralisation of TNF-a — its biological function is turned off because it cannot interact with cell-surface receptors. Adalimumab has full UK marketing authorisation for the treatment of severe active ankylosing spondylitis in adults who have failed to respond adequately to more conventional therapies.
Common adverse effects reported during adalimumab therapy include infections and injection site reactions. More uncommon side effects include non-serious allergic reactions. Because of the risk of infection due to immune system modulation, all patients must be assessed for both active and inactive tuberculosis.
Adalimumab is contraindicated in patients who have moderate to severe heart failure and in those with active infections. It is administered subcutaneously every two weeks and a clinical response is expected within 12 weeks. The summary of product characteristics for Humira states that continuing therapy should be carefully considered in a patient not responding within 12 weeks. The annual cost of adalimumab is approximately £9,300 for 26 doses at 40mg every two weeks.
Etanercept is a recombinant human TNF receptor fusion protein that blocks the activity of TNF-a. It is licensed as an immunomodulator and works by acting as a decoy TNF receptor that snags and neutralises excess TNF, preventing it from binding to the TNF receptors. The adverse effects with this preparation are much the same as those with adalimumab so patients need to be evaluated before treatment is started — etanercept is contraindicated in people with an active infection.
Patients should be advised to be aware of symptoms that may suggest a blood disorder, such as a sore throat, fever, bruising and bleeding, and to seek medical attention if these are experienced. Caution with use should be exercised in individuals with heart failure, conditions such as multiple sclerosis or a blood disorder because there is a risk of exacerbation. Etanercept is administered subcutaneously either 50mg once or 25mg twice weekly. The annual cost is approximately £9,300.
Infliximab Infliximab is a chimeric monoclonal antibody that binds with a high affinity to TNF-a, rendering it inactive. It is licensed for the treatment of AS in individuals with severe spinal symptoms and raised serological markers reflecting inflammatory activity, and in those who have not had an adequate
response to conventional therapy.
The most common adverse reactions reported during therapy include infections, acute infusion-related reactions, delayed hypersensitivity reactions and, in some instances, anaphylaxis. The SPC for Remicade states that it is contraindicated in patients with moderate to severe heart failure or active tuberculosis so patients must be screened before treatment. A number of uncommon side effects are also listed in the SPC and are related to the drug’s immunomodulatory activity.
Infliximab is administered by intravenous infusion at weeks 0, 2 and 6, and then every six to eight weeks. Continued therapy is not advised if there is no response by the sixth week of treatment. The first three loading doses cost about £5,035 in total and this is followed by annual cost of approximately £11,700 to £15,100, depending on whether the infusions are repeated every six or eight weeks.
Specialist use only
All of these preparations should only be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of AS. In May this year the National Institute for Health and Clinical Excellence released guidance on the use of TNF-a inhibitors in AS.3 The appraising committee acknowledged that there were statistically significant improvements in measures of disease activity, functional disability and composite outcomes, observed at 12 weeks and in some studies at 24 weeks.
The committee reported hearing from expert patients, where those with AS who had received TNF-a inhibitors experienced dramatic improvements both in their functional ability and symptoms. It concluded that there is clear evidence for the clinical effectiveness of TNF-a inhibitors in patients with severe active AS compared with placebo in the short-term.
NICE laid out the following criteria for initiating therapy with TNF-a inhibitors in adults with AS:
- Particular criteria for diagnosis (the modified New York criteria) must be satisfied
- Sustained active spinal disease is demonstrated by a score of at least four units on the Bath ankylosing spondylitis disease activity index (BASDAI) and by at least 4cm on the 0–10cm spinal pain on the visual analogue scale tool, on two occasions at least 12 weeks apart without any change or treatment (The BASDAI assesses signs and symptoms of disease activity, such as the duration and severity of morning stiffness and several aspects of pain and fatigue. The visual analogue scale is used to confirm sustained active spinal disease.)4
- Conventional treatment with two or more NSAIDs taken sequentially at the maximum tolerated and recommended doses for four weeks has failed to alleviate the symptoms
According to NICE, infliximab is not recommended for people with ankylosing spondylitis, however, it said that healthcare professionals should not stop prescribing infliximab for patients who were already taking it when the guidance was issued and that these people should be able to continue with infliximab until they and their healthcare professionals decide it is right to stop treatment.
NICE also said that patients who developed an intolerance or had contraindications to either adalimumab or etanercept could be prescribed the other of this pair of TNF-a inhibitors as an alternative treatment if
intolerance was evident before the first clinical effectiveness assessment 12 weeks from the start of therapy.
Other treatments for AS include surgery (eg, hip replacement to
ease pain and improve mobility and spinal osteotomy, although this is rare). Bisphosphonates may be prescribed because of the increased risk of osteoporotic spinal fractures in patients with AS.
Apart from talking to patients with AS about their medicines, pharmacists can also advise on simple measures that can be taken to manage AS more easily (see Panel). Patients should be reassured that although the course of AS is variable, most people with the disease do well and continue to live normal and productive lives even though they may have to modify their lifestyles or their work environments.
Advice for patients with ankylosing spondylitis
|Navjot Singh Nannar, MB ChB, MRPharmS, is a foundation year doctor at South Staffordshire and Shropshire NHS Trust|
- National Ankylosing Spondylitis Society Tel 020 8948 9117; website
- Arthritis Research Campaign Tel 0870 850 5000; website
Action: practice points
Reading is only one way to undertake CPD and the Society will expect to see various approaches in a pharmacist’s CPD portfolio.
For your work to be presented as CPD, you need to evaluate your reading and any other activities. Answer the following questions: What have you learnt? How has it added value to your practice? (Have you applied this learning or had any feedback?) What will you do now and how will this be achieved?
References1. Longmore M, Wilkinson I, Turmezei T, Cheung CK. Oxford handbook of clinical medicine. 7th Ed. Oxford: Oxford University Press; 2007.
2. Weisman MH, Reville JD, Heijde DVD. Ankylosing spondylitis and the spondyloarthropathies. London: Mosby Elsevier; 2006.
3. National Institute for Health and Clinical Excellence. Ankylosing spondylitis - adalimumab, etanercept and inflixima. Technology appraisal 143. Available at www.nice.org.uk (accessed on 12 September 2008).
4. Dougados M, Heijde DVD. Ankylosing Spondylitis. Oxford: Health Press; 2004.
Citation: The Pharmaceutical Journal URI: 10032121