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Ankylosing Spondylitis (AS) Causes and Treatment

This case shows a 45 year old male patient with severe ankylosing spondylitis. Ankylosing spondylitis is a form of arthritis that occurs at the lower back of the body. It is a chronic inflammatory disease that affects the spine and also the sacroiliac joints, which can be located between the sacrum and iliac bones. The sacrum bone is located right above the tailbone whereas the iliac bones are the bones that can be found on the either side of the upper buttocks. The term ankylosing is defined as the fusion of joints and spondylitis is the inflammation of the spinal bones, also known as the vertebrae. This condition causes the tendons that are being attached to the bones and also the joints between the spinal bones to be inflamed. When inflammation occurs, the body will produce new bones to repair the damage, which will eventually fuse together, causing the spine to have permanent damage such as losing spinal mobility and also the development of a “question mark posture” called neck hyperextension. Ankylosing spondylitis does not just affect the spinal bones but it is also a systemic disease which will spread to other parts of body and joints such as neck, eyes, heart and lungs and sometimes the kidney. Around 70% of patients complained of having neck pain while 10-40% of patients suffered from AS will develop cardiovascular disease during the course of the disease. During the later stage of the disease progression, up to 40% of patients with AS will develop uveitis, which is the inflammation of the eye that can lead to scarring and blurring of vision and even blindness if not treated carefully.
The prevalence of AS is around 0.25%-1% in the general population. So it is roughly estimated that around one in 200 men and one in 500 women in UK develop AS. The mortality rate is significantly high; with patients having 1.5 to 4 times likelihood to die from this disease especially since AS may increase the risk of developing cardiovascular diseases. AS usually affects young people and patients will present symptoms of the disease around the age of 30. Men are twice as more likely to develop AS than women and their symptoms are also more pronounced compared to women whereby some men will have structural changes such as a “bamboo spine” whereas women might not have such obvious symptoms.
Symptoms of AS can be as mild as none which occurred in 10% of the patients during the early stages and can also be as severe as losing spinal mobility due to irreversible structural damage. The common symptoms for AS patients are lower back pain that radiates to the hips with alternating buttock pain which is made worse by rest. Patients are often awake at night due to unbearable back pain and they also experience spinal morning stiffness for more than 30 minutes that can be relieved through exercise. The other common symptoms would be fatigue, and certain patients developed enthesitis, whereby there’s an inflammation at the insertion site of tendon or ligaments into the bone especially on the heels such as Archilles tendonitis and also inflammation of the finger known as “sausage digit”. Other extra articular symptoms includes aortitis, ulcerative colitis and also acute anterior uveitis (AAU), as the prevalence rate of AS with AAU for antigen HLA-B27 positive is 0.4% in the population and 0.02% in HLA-B27 negative population.
For a patient who suffers from a chronic condition such as ankylosing spondylitis, their life expectancy would be 1.5 times lower than normal people and their quality of life would be greatly affected by it as the onset of the disease occurs at an earlier stage of life. This affects mostly the working class individuals. About one third of individuals with AS would quit their job prematurely due to fatigue, impaired physical functioning, and low self esteem. The reduction in labour force can seriously damage the economy. AS also affects patients in a social context due to increased concern about their medical condition and lesser time spent for leisure. Besides, they had to attend for routine medical checkups which will reduce the time spent with their friends and family. Besides, drugs to relieve inflammation such as NSAIDs create more pain for the patient because of it undesirable gastro-intestinal side effects. AS also affects patients’ quality of life because it causes pain and disables them to a different extend, with certain patients having to undergo surgeries to replace joints and hips or even spinal surgery for patients with severely deformed spine.
Patients with suspected AS are commonly diagnosed based on physical examination, clinical features and radiology evidence. The Modified New York criteria 1984 for ankylosing spondylitis is the most widely used diagnostic tool for AS4. They must fit the clinical criteria of having more than 3 months of lower back pain and morning stiffness which can be relieved through exercising, a reduction of spinal mobility and also a restricted chest expansion. MRI scan is also useful to detect any structural changes to the spine and to detect if any inflammation is present.
Aetiology (Cause) of disease
The cause of the disease is still unknown. However, there was a strong association between AS and the human leukocyte antigen B27 (HLA-B27), which is said could trigger inflammatory response towards infectious agents. The relationship between HLA-B27 and AS is more common among the Caucasian population. A study done by the University of Leeds showed that 90.2% of their AS patients with HLA-B27 positive gene had a significantly longer duration of disease compared to AS patients with HLA-B27 negative gene even though their age is similar8. Over 90% of Caucasian AS patient are positive for HLA-B27 antigen but only 6-8% of the general population that are HLA-B27 positive will develop AS. Therefore, the HLA-B27 antigen is only responsible for 20-50% of patients that developed AS and most people with HLA-B27 positive antigen still remains healthy and free from AS3,13. A recent study shows that AS is not only caused by one gene, but it’s a polygenic disease. The other genetic markers that are also linked to AS includes interleukin-1 (IL-1) gene cluster, aminopeptidase regulator of TNFR1 shedding (ARTS1), and the interleukin-23 receptor gene (IL-23R). Despite having theories regarding environmental and genetic predisposition that leads to AS, there are still no concrete evidence to what causes this disease and what is the mode of action for it.
Treatment options
The main aim for treatment and management of AS is to relieve the disease symptoms, which is morning stiffness and also to reduce lower back pain, improving patient’s quality of life and slow down disease progression15,16. So far, there are no specific literature guidelines for treatment of AS. However, the International Assessment in AS (ASAS) society and the European League against Rheumatism (EULAR) came out with evidence based recommendations for treatment of AS that involves 3 main types of drug treatments4. The first line drug treatment for AS would be the use of NSAIDs to minimise inflammation and to relieve pain and stiffness. If the patient couldn’t tolerate NSAIDs or pain is not managed, adjuvant therapy with low dose corticosteroids, analgesics and muscle relaxants are given15. The second line treatment comprised of disease modifying antirheumatic drugs (DMARDs) treats only peripheral arthritis and not for the treatment of axial manisfestations17. Lastly, the use of anti tumour necrosis factor (TNF-α) such as infliximab and etanercept had been approved by the food and drug administration (FDA) and European countries to treat severe active ankylosing spondylitis only if certain criteria had been fulfilled15. Other non pharmacology treatment options include frequent exercising to reduce morning stiffness, physiotherapy and patient education about the disease14,15.
Side Effects, Costs, Advantages and Disadvantages compared with other drugs
NSAID has been the most commonly prescribed treatment option for ankylosing spondylitis because of its ability to relieve pain and stiffness and one can even slow radiographic progression of the disease and inhibits new bone formation16. Studies showed that up to 68% of patients in UK received NSAIDs as part of their treatment for AS17. It had been the primary treatment option for over 5 decades because it is a useful treatment for rheumatoid arthritis (RA) and there was no extensive research done for the treatment of AS18. However it should be noted that while some of the treatments such as DMARDs may work on RA, it may have limited effect on reducing radiographic progression in AS19. NSAID inhibits cyclo-oxygenase (COX) enzyme, hence reducing the production of prostaglandins released during inflammation11. There are 2 types of COX enzyme namely COX-1 and COX-2. COX-1 inhibitor will cause side effects such as gastro-intestinal discomfort and even bleeding because COX-1 is being induced to release mediators with gastro protective function whereas COX-2 is only being induced to secrete prostaglandins during inflammation12. Therefore, extensive research had been carried out for selective COX-2 inhibitors (coxibs). Other unwanted side effects of NSAIDs are renal impairment, headaches and confusion, and haematological side effects such as agranulocytosis12.
There are a lot of NSAIDs choices out there with different duration of action and clinical efficacy but the most common drug that AS patients had been prescribed is phenylbutazone15. In European Union, phenylbutazone is only been allowed a maximum of 600mg daily for short term treatment only for arthritis and this dosage had been approved for treatment of AS17. However, 32 randomised controlled trials which tested the efficacy of NSAIDs showed that none of the NSAIDs are better than another of the same drug class20. Out of 5 randomised controlled trials, only 2 concluded that phenylbutazone showed a better result than the comparator drug20. The main drawback of phenylbutazone is that it causes aplastic anaemia and hepatic injury which is life threatening and therefore it is not wise to use it for long term treatment22. Patients with high risk of cardiovascular diseases are contra-indicated for treatment using NSAIDs and those with previous episodes of gastro-intestinal bleeding are advised to continue treatment alongside with proton pump inhibitor such as lansoprazole, histamine H2-receptor antagonist such as ranitidine or prostaglandin analogues such as misoprostol as protective agents11,12. Since phenylbutazone is the first generation NSAID and it’s not been used as widely nowadays as indomethacin, the estimated cost of phenylbutazone per week if patients take 300mg daily would be around £20 which is reasonably cheap as it is requires a long duration of treatment.
Clinical Outcome (% of success rate)
NSAIDs had anti-inflammatory properties to control pain and stiffness but not much evidence to support that it can slow down the disease progression. A trial concluded that up to 80% of patients acknowledged that NSAIDs are excellent against in controlling their symptoms but only about 15% of AS patients with non-inflammatory caused lower back pain gave similar responses17. However, a study was done and showed that treatment with celecoxib continuously for 2 years could slow down the disease progression compared with another group which only receives treatment during flare-ups17,21. Celecoxib is being indicated for AS and the dosage in BNF is 200mg daily in divided doses and increased to maximum 400mg daily if necessary. They’ve also advice to discontinue treatment if no improvement was shown after 2 weeks on maximum dosage11. Coxibs might be safer to the gastrointestinal tract but it causes patients to have a higher cardiovascular risk. A cancer study showed that celecoxib had dose dependant increase in cardiovascular risk compared to placebo22. Another study shown that 9% of AS patients on continuous celecoxib treatment with maximum 400mg daily will develop hypertension which can lead to 2.8 fold risk for cardiovascular events16,17. The cost of celecoxib weekly would be around £5 if patient is on 200mg daily dose11.
NSAIDs are fast acting drugs which effects can be seen within 2 days of drug intake. However, this leads to rapid relapse of AS once the treatment had been discontinued. Therefore, it is debatable whether NSAIDs should be given continuously as it is a chronic condition but at the same time contemplating the fact that this drug could cause damage to the gastrointestinal tract and cardiac toxicity6.
Clinical Evidence of efficacy (Journals)
There was no concrete evidence to support that analgesics such as paracetamol could be beneficial in AS. In a questionnaire involving 15 people, 87% said that analgesics are not as effective as NSAID but no further analysis of the questionnaires had been carried out23. The second line for treatment of AS would be DMARDs such as sulfasalazine (SSZ) and methotrexate. So far no DMARDs had been approved as treatment for AS unless patients couldn’t tolerate NSAIDs19. Both the drugs showed no effect in treating axial manifestations of AS and only effective during early disease and peripheral arthritis19,23. A randomised trial involving 85 patients with active AS showed that SSZ is more pronounced for its effectiveness in reducing morning stiffness and inflammatory markers such as erythrocyte sedimentation rate (ESR) for patients with peripheral arthritis compared to those with axial manifestations compared with placebo24. A randomised controlled study involving 242 patients with early AS was given SSZ or placebo and the group with only inflammatory back pain and less spinal structure damage responded better24. There is also a 6 months trial whereby patients had been given a maximum of 3g daily SSZ and results showed that there’s significant reduction in ESR and improvement in patient’s overall assessment but not on pain nor morning stiffness and 16% of patients quit the trial due to adverse effects23. There were 2 meta analyses done involving SSZ, one with limited amount of studies and the second with 11 randomised controlled trials. The first analysis showed that SSZ improved pain, morning stiffness, overall physical assessment and reduce ESR while the second recent analysis showed SSZ only reduces ESR and improves spinal stiffness, which is sign of inflammation significantly but showing no superiority to placebo in other aspects16,24. The common side effects of SSZ are nausea, vomiting, loss of appetite and sperm abnormalities which can lead to infertility and also hypersensitivity reactions that occur rarely. SSZ of a maximum 3g daily would cost a patient roughly £8, which is more expensive than NSAIDs with lesser efficacy11. Trials involving methotrexate failed to show its efficacy for this disease therefore would not be discussed further23.
Recently, they’ve made a breakthrough by identifying anti tumour necrosis factor (TNF-α) drugs as a probable treatment option. 2 of the drugs which are infliximab and etanercept had gone through randomised controlled trial and the results were tremendous4. Both drugs had been approved by FDA and recommendations given by ASAS must be followed for the treatment to be started4. So far, there were no trials done to compare infliximab, etanercept and adalimumab. A 3 month randomised controlled trial involving infliximab concluded that it is better than placebo in terms of improving spinal activity and function, peripheral arthritis proves that infliximab is efficacious for short term treatment25. Another 6 weeks randomised controlled trial involving patients with active AS receiving 5mg/kg every 2 weeks showed 53% of them had significant improvement in terms of reduction in ESR, overall health assessment and quality of life23. A 3 year ongoing study to prove the safety and efficacy of infliximab was done to 70 patients with severe or active AS. They received 5mg/kg every 6 weeks for 3 years and 70% managed to complete while 30% dropped out due to adverse reactions. Only 40% managed to achieve 50% improvement in BASDAI value24. BASDAI value is an index to assess axial and peripheral pain, fatigue and spinal stiffness25. Before commencing treatment with anti TNF-α, it is a requirement to screen for Tuberculosis(TB) as continuous infusion could cause systemic infection. Other adverse reactions include hypersensitivity reactions11. Infliximab is given 5mg/kg at week 2 and 6 intially and every 6-8 weeks after that. That’ll cost a 50kg patient £60 per infusion which is very costly11.
Etanercept is another anti TNF being approved by FDA and European countries as treatment for AS. A dose with 25mg twice weekly or 50mg subcutaneous injection is the standard regimen of treatment. A randomised controlled trial showed both regimens are as effective as the other. Another randomised controlled trial with placebo involving 277 patients with active AS showed that after 24 weeks, 59% of patients had ASAS 20 improvement, which means that they had 20% improvement in terms of pain, inflammation, spinal function and overall well-being in at least 3 of the criterias without any significant deterioration of the 4th element. 9% of them showed signs of flare-ups and was restarted with the regimen and follow up till week 102 and showed more than 50% achieved BASDAI 50, with improvement of 2 elements or 50% improvement of 3 criterias. A similar trial was done with 257 patients for 192 weeks and showed 81% achieved ASAS 2024. Etanercept carries similar adverse effect as other anti TNF drugs but it’s slightly better in terms of patient susceptibility to TB compared to infliximab and adalimumab20,23. Etanercept 25mg twice weekly would cost £178.75.
Adalimumab is also approved as treatment for AS. The standard dose is 40mg subcutaneous injection on alternate weeks and discontinue if no improvement for 12 weeks. In a large randomised controlled trial with placebo, 58% of patient achieved ASAS 20 with significant improvement in ASAS 40 and BASDAI 50 in week 12 and 1423. 2 open label study using 40mg subcutaneous injection in alternate weeks with 15 and 20 AS patient each showed 47% and 53% respectively achieved ASAS 40 and BASDAI 50 with improvement in spinal inflammation24. Cost of 40mg vial is £357.5011.
In conclusion, NSAIDs are still the first line recommendation for treatment for AS as they’re able to control inflammation and also slow radiographic progression. Only when patients failed to tolerate NSAIDs and they are still in early stages of the disease are they been advised to commence treatment using DMARDs as they are only effective against peripheral but not axial symptoms of AS. When more than 2 NSAIDs failed as treatment then patients are advised to be started on anti TNF agents. Only when there is a long term efficacy established by anti TNF agents should they be used as first line treatment because anti TNF agents are really costly. Hopefully early detection of disease progress using MRI with appropriate treatment plus frequent exercise could help to slow down the disease progress as the mode of action for this disease is still unknown.

Effect of Increased CO2 on Plants

There is an increase in CO2 emissions caused by the industrial revolution and increasing number of factories. The high amount of emission causes a rise in free CO2 concentration ([CO2]) in air. The effect of this increase on the ecosystem and plants is a subject of curiosity which has led to scientists trying to understand the effect of elevated [CO2]. The first experiment was made by Wittwer (1964) et. al. They investigated horticultural plants under elevated [CO2] in greenhouses (Wittwer and Robb 1964). Then, scientists used open-top chambers to determine the effect of elevated [CO2]. However, the problem was that inside the open-top chamber, the air was more humid, shaded, warmer, and the air movement was changing (Kimball, Pinter et al. 1997). Because of this reason, the Free-Air CO2 Enhancement (FACE) system was developed. In this system, there are vertical and horizontal pipes arranged to make a circle of different diameters. These pipes provide CO2 emission to the circle, to bring it to the desired [CO2]. The FACE system is more reliable than the open-top chamber system, so researchers have preferred to use the FACE system. They have used this system to observe the effect of elevated [CO2] on the ecosystem and plants, which will be the topic that is discussed in this essay.
Firstly, we will investigate the effect of elevated [CO2] on plants’ stomatal conductance (gs), Rubisco response, and photosynthesis response. Initially, when plants are exposed to high [CO2], there is a similar decrease in gs for both C3 and C4 plants (Ainsworth and Long 2005). Stomata give a short-term and a long-term response to make decrease in gs, which depends on duration of high [CO2] exposure. In the short term response, stomatal aperture decreases to decrease gs (Wand, Midgley et al. 1999). In the long term response, stomatal density decreases as well as stomatal aperture, to decrease gs. There is a gene called the HIC (High Carbon Dioxide) gene which is a negative regulator of stomatal development. To prove the decrease in stomatal density, Gray (2000) et al., used mutant HIC plants and control plants. When the control plants were exposed to an elevated [CO2], the decrease in stomatal development was observed . However, in mutant HIC plants the stomatal initiation increased because of disruption in the signal pathway. Another issue about stomatal conductance is its acclimation. Scientists tried to figure this out and they used an equation to determine whether or not there is an acclimation. The equation was developed by Ball et al. (1987). The equation is:

If there is any acclimation about gs, the values of the constants g0 and m must change in the equation. However, according to Medlyn et al. (2001), there wasn’t any change in these values. So, they concluded that gs didn’t show any acclimation to elevated [CO2].
Secondly, the most important issue with plants is the Rubisco response to elevated [CO2]. Almost all of the assimilated carbon passes the Rubisco active site. In the active site of Rubisco, we observe two different reactions. In one reaction, RubP (Ribulose -1,5-bisphosphate) is combined with CO2 to produce 2 molecules of 3-phosphoglyceric acid (3PGA) at the active site of Rubisco. And in other reaction, Rubisco reacts with O2 to yield one molecule of 3PGA and one molecule of 2-phosphoglycollate (2PG). The 3PGA produced by the oxygenase reaction enters the Calvin Benson Cycle, and 2PG enters the photorespiratory pathway where CO2 is released.

This pathway is observed mostly in C3 plants; conversely C4 plants prevent photorespiration by concentrating CO2 at the active site of Rubisco (Sage 2004). CO2 is converted to HCO3– to increase the concentration of CO2 at the active site of Rubisco. Thus, in C4 plants the concentration of CO2 is 15 times higher than C3 plants. This is why C3 plants use N less efficiently even though they invest a higher amount of N in Rubisco. C3 plants use a high amount of N in Rubisco and this results in a much more higher concentration of Rubisco than its substrate, CO2. This condition makes reaction substrate limited, CO2, instead of enzyme limited, Rubisco. By the end of this century, the [CO2] in the atmosphere will be between 500 and 1000 ppm. Therefore, the [CO2] will increase at the active site of Rubisco and, the rising [CO2] will increase the rate and efficiency of photosynthesis in C3 plants because of two reasons:
Rubisco is substrate limited today, so an increase in [CO2] will increase the carboxylation reaction
Oxygenation and carboxylation reactions show competitive behaviour. Therefore, elevated CO2 concentration will inhibit the oxygenation reaction and this will cause the reduction in CO2 releasing (Long, Ainsworth et al. 2004).
On the other hand, the effect of [CO2] rising on C4 plants is not forecasted easily because they are already CO2 saturated and they don’t have a photorespiratory effect at the current [CO2]. For this reason, it is predicted that C4 plants will lose their metabolic advantage with respect to C3 plants at elevated [CO2] (Long, Ainsworth et al. 2004).
Until now, we mentioned how Rubisco will behave at the elevated [CO2], but there is also a molecular control mechanism of Rubisco. Now, we will talk about this mechanism. To function properly, Rubisco must be activated by carbamylation of a lysine residue and by the binding of Mg2 . Rubisco activation needs the catalytic chaperone, Rubisco activase enzyme which is ATP dependent. Rubisco is sensitive to the ATP:ADP ratio because of the redox regulation of Rubisco activase. Rubisco is usually fully active under high light conditions at current [CO2]. As [CO2] increases, carbon fixation increases. So plants will need more ATP for RubP regeneration. This will make photosynthesis limited by RubP regeneration instead of being limited by Rubisco.

Thirdly, the elevated [CO2] will affect the photosynthesis response in plants. It is obvious that, elevated [CO2] stimulates photosynthesis rate (A) in C3 plants. There is a significant response of light saturated CO2 uptake (Asat) in C3 plants but it shows differences between C3 species. For example, trees show higher stimulation than legume and shrub (Ainsworth and Rogers 2007). Surprisingly in the research, an increase in photosynthesis rate of C4 plants, at elevated [CO2] was observed. To understand the reason of this increase, Leakey et al. (2006) applied water stress to maize, which is a C4 plant. They found that there isn’t any increase in A value, if there isn’t any water stress (Leakey, Uribelarrea et al. 2006). It shows that the C4 plants are stimulated by drought-stress rather than elevated [CO2]. In C3 plants, the maximum carboxylation rate (Vc,max) and the maximum rate of electron transport (Jmax) are also significantly reduced at elevated [CO2]. But the reduction in Vc,max is approximately double the reduction in Jmax (Ainsworth and Rogers 2007).
Secondly, the effect of elevated [CO2] on ecology is another important issue. According to research, it is predicted that at the end of this century the [CO2] will be between 500-1000 ppm. So the effect of this rise on photosynthetic acclimation thus, nitrogen uptake and carbohydrates accumulation, is the subject of curiosity. According to research, the photosynthetic acclimation is achieved through the accumulation of carbohydrates, and decrease in N concentration ([N]) (Nowak, Ellsworth et al. 2004). The decrease in [N] will cause the reduction of protein content. This reduction in protein content is not observed generally in the proteins in the leaf, however there is a significant decrease in the Rubisco content. (Spreitzer and Salvucci 2002). Additionally, because of the carbohydrate accumulation there will be huge increase in the amount of sugar and starch. Thus, we will obtain high energetic plants. Another issue about the elevated [CO2] is the growth and yield of plants. It is said that elevated [CO2] will result in taller plants which have bigger stems ,and more leaves and branches; however the crop yield increase is not as much as estimated (Ainsworth and Long 2005). Furthermore, the effect of elevated O3 concentration ([O3]) with elevated [CO2] is also a field of interest in ecology. It is known that elevated [O3] causes significant decrease in growth and yield of many crops, and it is predicted that elevated [CO2] will diminish the negative effect of elevated [O3] (Ainsworth 2008). However, all of these results depend on the functional groups and where the experiments took place. They show many differences according to differences in conditions and species. Therefore there needs to be more research on FACE experiments to better understand the response of different plants to different conditions.
As a result, FACE experiments are very important to learn the effect of elevated [CO2] on plants and the ecosystem but the experiments are not enough. There needs to be more specific experiments to understand the impacts of the increase of free-air [CO2].
References
Ainsworth, E. A. (2008). “Rice production in a changing climate: a meta‐analysis of responses to elevated carbon dioxide and elevated ozone concentration.” Global Change Biology 14(7): 1642-1650.
Ainsworth, E. A. and S. P. Long (2005). “What have we learned from 15 years of free-air CO2 enrichment (FACE)? A meta-analytic review of the responses of photosynthesis, canopy properties and plant production to rising CO2.” New Phytologist 165(2): 351-372.
Ainsworth, E. A. and A. Rogers (2007). “The response of photosynthesis and stomatal conductance to rising [CO2]: mechanisms and environmental interactions.” Plant, cell

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