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Should exercise be prescribed for breast cancer survivors?

Being physically active has many health benefits and it may have profound effect in women who had breast cancer. Living an active life seems to protect women from getting breast cancer; similarly it also seems to stop it from coming back in survivors of cancer. Levels of activity go down in women who have had breast cancer or other cancers.

For many of those who have had breast cancer exercise is extremely difficult to do. Even thinking about activity for many fatigued survivors is a challenge. Yet some evidence seems to suggest that it does not have to be strenuous. It may not be necessary to regularly exercise in the gym or play sport. The normal activity of daily living may have protective benefit. So the key may be to be active in some way, as much as can be tolerated, and light exercise such as daily walks may be beneficial.

Being overweight has been implicated in breast cancer incidence and recurrence. A higher blood insulin level in overweight women has been linked to breast cancer.

However, not everyone who is overweight is at increased risk. It depends on when the extra pounds are put on and where the fat accumulates on the body.

Women who are overweight before breast cancer are more at risk of getting it and if you lose weight the risk goes down. Women who undergo weight reduction surgery are less at risk. The Nurses’ health study found that maintaining weight loss for at least 4 years lower the risk of getting breast cancer by 40%. Not only are you more at risk of getting it if you are overweight, but the prognosis is also worse if you get breast cancer as it is associated with decreased overall survival.

The association between weight and breast cancer is not clear cut. If you are overweight as a child and continue to be as an adult then you seem to be less likely to get it than if you gain weight as an adult especially after the menopause. The amount of hormones in fat has been implicated. If you gain weight before the menopause the fat will contain lower concentrations of estrogen. After the menopause, the fat in breasts is more likely to have higher estrogen levels, which means higher risk of breast cancer.

Also where you put on the weight seems to play a role. If you gain weight in the tummy area then the risk is higher than if the weight is gained in the hips or thighs. The type of fat that accumulates in the tummy tends to be more active and dividing; two factors that may be related to an increased risk of cancers.

Being overweight after breast cancer is an important risk factor for recurrence, especially in terms of reducing the risk of it coming back over many years. This is an important health issue as most women with breast cancers get a cure for their cancer – as many as 80% survivor their breast cancer. This means that prevention of the breast cancer recurring is an extremely important health promotion issues. Women survivors of breast cancer need to remain free of recurrence. And weight reduction is an extremely important aspect of this prevention strategy.

Physical activity reduces the risk of breast cancer and the risk of recurrence over and above the simple benefits of weight reduction. However, it is unclear how much is required. Some evidence suggests that if the cancer doctor prescribes exercise that it is of benefit and reduces the risks of relapse. However, it is unclear whether it is the level of the physical exercise or whether the cancer doctor’s encouragement simply gets the patient to move. A study from the Women’s Health Initiative found that walking briskly for 1-3 hours per day reduced the risk of recurrence by 16%. However there is no evidence that walking for 5 hours per day will reduce the risk more.  So the benefit may not correlate with the amount of exercise done and simply doing some activity may reap a good deal of the benefit and reduce the risk of breast cancer recurrence.

Weight loss is extremely important in breast cancer survivors to prevent the cancer from coming back. Physical activity, or perhaps just moving around during the day, is equally if not more important than just losing the pounds.


Targeted Therapies for Cancer

Personalised medicine has become the goal for modern cancer therapy. The chemotoxicity of many cancer drugs is down to their systemic effects and finding more targeted therapies will help in theory reduce toxicity and improve patient tolerance of medicines.

Chemotherapeutic drugs that are targeted do not kill all cells but are specifically designed for tumor cells and can be personalized to specific cancers and to each patient’s individual genetic makeup.

Many of these drugs function by stopping cancers from growing and dividing, spreading or by using or immune response to attack the cancer, or may even trigger the cancer cell to die itself by harnessing natural mechanisms that we use ourselves to recycle cells.

One specific type of new drugs are called monoclonal antibodies. When our body responds to infection it will create a range of these special molecules that are targeted at the specific infection. By cloning one of them it is possible to create a special colony of cancer attackers. They can be used to carry drug specifically to cancers by attaching onto cancer cells or may trigger the immune response to attack.

Vaccines have also been used to protect against cancer – a kind of immune memory is triggered – and they can also stimulate our immune system to tackle the cancer if it develops. They can prevent cancer by protecting us against specific infections implicated as cancer triggers, such as the human papilloma virus linked with cervical cancer.

Toxicity of Targeted Therapy

Great strides have been made in reducing the toxicity of cancer drugs. The systemic nature of much chemotherapy resulted in a range of general unwanted effects with variable severity, duration and type.

Targeted cancer therapy is more elusive but it does offer improved patient tolerability. Yet even targeted therapy is not without unwanted side-effects, and although they are frequently much milder they can last longer and greatly impede patient quality of life. This is particularly relevant if they are not treated as more than just bothersome.

Chemotherapy although often life-saving has effects that are too general and way too toxic. For chemotherapy the toxicity tends to last for a short time immediately after administration of treatment. If you get chemotherapy it is usual that you feel very badly for a few days to 1 week and then you start to feel better.

In the case of targeted therapy there tends to be more prolonged toxicity and you are often told to live with it and it is often not pleasant and not easy to do this. The toxicity is everyday and the problems can be infections, such as thrush, diarrhoea and fatigue.

In many cases, chemotherapy and targeted therapy are given together. Then the side-effects are additive and in particular in the case of fatigue this can be a serious problem. It is not just a tiredness and a lack of energy, but an inability to do anything and many can’t even stand up or function at all normally.

Staying in bed is not a solution for this kind of fatigue, especially in the case of targeted therapy as it is given long-term, and this is a prolonged period of suffering and there is little quality of life. Chemotherapy and targeted therapy will prolong survivals but attention needs to be paid to what kind of survival and to address problems like fatigue.

Targeted therapy was initially considered to be the ultimate goal as in theory this reduces toxicity generalized side-effects. However, even though the target is identified it does not always work. In some cases, the tumour may express the target but the tumour is resistant to the target therapy. So it is vital to identify those who will benefit from a specific target therapy so that are none on target therapy and getting the side-effects that lower the quality of life without any benefit.

Living with severe fatigue is difficult for anyone, especially in active people who no longer can work, have social activity or play sports like they did before. If targeted therapy does not work for them, then they will have reduced quality of life for no reason.

Side-effects related to targeted therapies should not be ignored. Assessing how the cancer sufferer feels about the impairment of their quality of life, toxicity and most importantly ensuring target therapy works before administration will limit those suffering from more than bothersome side-effects.

Pain in the CancerBone


Neurobiology investigations are leading to the development of new bone pain therapies that may help fight cancers.

Using neurobiology to derive models of bone cancer pain helps to identify the biological mechanisms that drive the bone pain. The aim is to enable the development of new drugs not just for bone cancer, but for other types of cancer as well.

Tumour growth slows down in the bone, and this may be a way tumours evade targeted treatments. So finding the mechanisms involved in tumor-related bone pain will help tackle bone cancers, and provide clues of how to prevent metastasis or spread of other types of cancers as well.

Bone pain occurs in up to 84% of all major cancers. Bone is a common tissue of cancer spread, and primary bone cancer is rare, particularly breast cancer and prostate cancers.

Red cells are made in bone and a number of factors are present in bone that speed up and slow down cell growth. In bone, many cancer cells slow down their growth, and they do not divide as fast.  This has the benefit that it slows down cancer progression and may prolong survivals. However, it also may mean that the cancer evade treatments for this reason. So when the cancer eventually spreads through the bone, and then recurs it can become widespread in the body.

So how do cancers cause bone pain? Some cancers produce chemicals that weakens and cracks bone and this leads to pain. However other cancers can also produce chemicals that harden bone, which thus can lose its functional elasticity and this also leads to pain. Also as tumor cells grow, nerve endings also go into the bone and this can cause pain.

Pain in the bone can often be the first sign of cancer and in prostate cancer bone pain manifesting as low back pain may be the presenting sign.

The way that an individual type of cancer impacts on bone and causes pain is variable. For example, prostate cancer generally leads to abnormal bone growth, whereas breast cancer is more likely to cause more bone destruction.

Spread of cancer from the bone tends to be to multiple organs. Understanding the interactions between tumor and bone may help to identify potential targets for chemotherapeutic intervention to halt tumor growth.

If the vertebrae are riddled with tumour cells, treatment is very difficult and irradiating the whole body or half the body if often required. Many patients already have bone marrow suppression making this an not a viable treatment option.

Breakthrough cancer pain is one of the most difficult types of pains to manage. It is not tumour breaking through the bone, but pain is breaking through the analgesic regime that the patient is on to manage their pain. For patients it is a very difficult pain to deal with because it feels as if the bone is breaking. It is a key pain to  target to improve quality of life and functional status.

As pain increases, the patient quality of life deteriorates. Stepwise pain control involves going from a non-opiate adjuvant to mild opiates and then on to strong opiates plus a NSAID  depending on increasing pain severity.

Despite escalating medication  most patients experience some breakthrough pain or end-of-dose pain. Opiates are very useful drugs but have significant side-effects that are more prevalent in the elderly.

 The cancer affects the areas of mechanical stress where there is greatest bone destruction from the tumour. Growth factors embedded in the bone stimulate tumour cells and further destroy the bone.

One of the reasons it is so difficult to treat cancer pain is that there is simply not one type of pain and there may be combinations of tumorigenic, neuropathic and inflammatory pain. In tumorigenic pain, tumour cells are secreting factors which excite the sensory fibres that radiate to the bone and other parts of the body. Much of a tumour mass is composed of inflammatory cells that potentially cause pain. Neuropathic pain occurs as the tumour is driving through the tissue that it is invading and it causes nerves to sprout.

The pain experienced by many cancer patients is probably all three of these types occurring simultaneously. So a therapy is being given to treat neuropathic pain and at the same time the inflammatory or neuropathic pain, as there is probably multiple mechanisms driving the pain.


Opioids or Pain?

Medical advances keep us alive longer, but for some it is just living longer in pain. Opioids are the major drugs given to those with long-term chronic pain, but have limited usefulness because of tolerance and side-effects, and, of course, the underlying risks of addiction.

The risks of addiction with opioid treatments are real and a valid concern. For long-term use, the balance between potential addiction and relief from chronic pain determines the appropriateness of their use.

The choice to take opioids also depends on the type of pain experienced, and underlying causative disease, quality of life, and prognosis.

Opioids are powerful medications and significantly reduce pain – they decrease the perception of and reaction to pain, and increase tolerance to pain. However, they don’t work in everyone. Individual responses vary complicating their use, and the same dose can elicit variable levels of therapeutic effect in different individuals.

Dosing Opioids

Opioids exert their effects through receptors in the central and peripheral nervous system and in the GI tract. How an individual responds to a specific opioid therapy depends on the nature of the receptor it binds and affinity.

Long-term opioids reach a dose ceiling due to rapid onset of analgesic tolerance coupled with gradual tolerance to the side-effects of respiratory depression, nausea and decreased gastrointestinal motility.

Side-effects of Opioids

The patient who can tolerate the side-effects of an opioid drug gains more pain relief.

Opioids mediate variable unwanted central and peripheral side-effects – respiratory depression, nausea, sedation, euphoria/dysphoria, decreased gastrointestinal motility and itching.

Opioids can cause cough suppression, which can be both an indication for opioid administration or an unintended side effect.

How Tolerance Develops

Various factors influence a patient’s physiologic response to opioids, including the individual’s genetic makeup, concomitant medications, gut microflora, and how the individual opioid is metabolized.

Understanding tolerance mechanisms helps improve pain management and will help develop new drugs so opioids can be used more effectively.

Tolerance has two aspects: reduced efficacy of the drug at reducing pain and the patient’s ability to tolerate adverse effects. Both of these factors impact opiate-mediated pain relief.

If the patient on opioids becomes tolerant they no longer gain benefit in terms of pain relief as the drug has a reduced pharmacological effect with a higher dose needed for similar benefit

Conversely, tolerance can offer benefit as adverse effects decline with increased use.

The best opiate medicine provides sufficient pain relief and the patient can tolerate it in high doses.

If tolerance to the side-effects develops, treating pain is easier. If the rarer tolerance to pain relief occurs – failure to provide sufficient pain relief – this makes pain relief difficult.

Tolerance to pain relief occurs either because opioid receptors are reduced or act less effectively.

Opioids for Cancer Pain

Opioids are vital medicines for the palliative care of cancer patients. Cancer induced pain is separated into three types: acute, chronic and breakthrough pain. The mechanisms of cancer pain also influences the response to opioids – such as inflammatory pain, nociceptive pain, or neuropathic or mixed pain.

Even patients with similar types of cancer pain may require variable doses for pain control. Thus it is not just the pain itself, but other factors also influence the individual’s  response to opioids. These include the patient’s psychosocial status, concurrent medications they are taking, gender or genetic factors, and whether the patient is opioid naive or has previously been opioid tolerant.

Most cancer patients gain good relief from pain while on opioids. Tolerance to the analgesic effects of opioids does not develop as quickly as in those with other types of pain.

The reason to raise the dose of an opioid in a cancer patient is most likely to be due to the progression of disease generating further pain. Analgesic tolerance is rarely a limiting factor to the use of opioid

Breakthrough pain is managed using a  powerful fast-acting opioid such as intravenous morphine or transmucosyl fentanyl.

Patients with cancer pain may require higher doses of opioids to attain analgesia – tolerance develops – for a number of reasons: disease progression, metastasis, neuropathic pain or psychological factors such as anxiety.

Thin cancer patients respond worse to opioids than those with a normal body mass index.

Oxycodone is increasingly used in cancer pain because its main metabolic pathway is the inducible cyp3A4. Tolerance to oxycodone can develop with concomitant medications. Patients on stable doses of oxycodone with stable analgesia can suddenly develop increasing pain.

If the concomitant drug induces the cyp3a4 pathway, then it functions more efficiently and oxycodone is metabolised to moroxycodone, which is a less inactive metabolite. Then pain relief that the patient has will be less from the same drug.

Oxycodone is actively taken up into the brain so the brain concentration of oxycodone is a few times higher than in the plasma; the reverse is true for morphine. Because it is transported more efficiently analgesia is often better with oxycodone than morphine. So measuring plasma concentrations does not help determine efficacy.

Transporter systems regulate opioid transport across the blood brain barrier and dictate opioid efficacy and the development of tolerance. Genetic studies show a p-glycoprotein gene mutation causes a malfunction in the transporter and improves morphine analgesia.

Tolerance to Side-Effects

Choosing an appropriate opioid involves balancing how much pain relief the patient experiences and how they tolerate any side-effects related to the medication.

Boosting patient tolerance to unwanted side-effects improves their compliance as well as opiate efficacy. Lack of tolerance minimizes drug efficacy and impedes dose escalation.

Administering add-on treatments or choosing the most appropriate analgesic in a personalised medicine approach reduces the impact of unwanted side-effects of opioids.

Psychological Factors

Anxiety plays a role through the cholecystokinin receptor in all types of pain; it contributes more to pain intensity than depression. Administering repeated opioids induces tolerance as it chronically stimulating cholecystokinin receptors and induces tolerance. So cholecystokinin receptor antagonists may counteract this effect and improve opiate efficacy.

Increased tolerance is seen after adrenalectomy and hypophysectomy – it is reversed with ACTH – so some researchers suggest the HPA axis plays a role in opioid tolerance.

Chronic pain itself counteracts opioid tolerance and pain generates excitatory input that balances opioid effects.


Reducing Tolerance

Many different mechanisms influence tolerance. Some suggest candidate interventions for example if morphine binds the opioid receptor, then it does not enter the cell.

Chronic opioid exposure activates the glia and this is one mechanism that explains both hyperalgesia and tolerance. Glial inhibitors – minocycline, ibudiplast and pentoxifylline – can be used to limit tolerance, but don’t seem to prevent it.

Anti-opioid peptides counteract the opioid analgesic effects. Low doses of these opioid antagonists may reduce side-effects and tolerance to opioids.

Some studies indicate that opioid antagonists can reduce both opioid central effects – e.g. respiratory depression – and peripheral effects – constipation – depending on how they are administered. If naloxone is given with oxycodone then it blocks the opioid mu receptor in the gut, but when it gets to the liver it is metabolized. So there is no naloxone effect on naloxone on opioid effects on the brain and it does not inhibit the central effects of the opioid. But if  methylnaltrexone is given as well, the methyl group prevents the drug from getting into the brain, so the side-effects remain peripheral.

Naloxone prevents binding of the excitatory G-protein coupling to epinephrine and has non-opioid mediated effects.

NMDA receptor antagonists are the most promising drugs for fighting tolerance and some of them are already available.

Ketamine improves opioid analgesia for some patients when tolerance develops, but has very low bioavailability and a narrow therapeutic window.

The need for effective-long term analgesia remains. In order to develop new therapeutics and more novel strategies for use of current analgesics, the processes that mediate tolerance must be understood, including the potential pharmacokinetic (changes in metabolite production, metabolizing enzyme expression, and transporter function) and pharmacodynamic (receptor type, location and functionality; alterations in signaling pathways and cross-tolerance) aspects of opioid tolerance development.


Pharmacogenomics – Hope for Cancer Pain?

Controlling pain – a complex and subjective experience – is critical to care of cancer patients. Managing cancer pain with analgesics is complicated by inter-individual variability in efficacy, side-effects and adverse drug reactions

Pharmacogenomics – how genetic inheritance affects response to medications – may help explain why some of us respond differently to pain treatments. Subjective responses govern cancer pain perception and there is some genetic contribution to variability. Other influences include biological variations (ethnicity, age and gender); environmental factors (smoking status and perhaps the gut microflora); co-morbidity and concomitant medications (potential for drug-drug interactions).

Opiates remain the major treatment choice for cancer pain, but in some patients they fail or side-effects are intolerable. Dosing traditionally involves carefully escalating and adjusting it based on the clinical response and any side effects or adverse drug reactions. Success is getting enough analgesia, while minimizing adverse effects of taking the drug.

Opiate drugs can cause unpleasant side-effects, such as nausea, vomiting, constipation and sedation. But they can also cause some serious side-effects including strong sedation, respiratory depression and even death if the patient is unable or has reduced ability to metabolize opiates.

Morphine is the most common opiate given. At a population level, morphine has a similar safety profile and efficacy to the other opiates. However, individuals vary in morphine response. Non-responders get little pain control despite increasing the dose. So far only two factors predict non-response to morphine – renal impairment and sepsis.

Giving catecholines enhances opiate efficacy. Catechol-0-methyltransferase inactivates catecholamines (dopamine, adrenaline and norepinephrine); variability in the enzyme’s gene causes differences in pain sensitivity and response.

Identifying known variant alleles that affect the pharmacology of opiates will help tailor treatment and select the best dose.  Codeine – the most researched opiate – exerts analgesia when converted to morphine via the action of cytochrome P450 2D6. The enzyme’s marked genetic variability controls the response to codeine. Some patients produce only a little enzyme, so when given codeine, they don’t make much morphine – up to 10% of Caucasians. Others are very fast or extensive metabolizers have increased enzyme activity but get worse side-effects.

Many genes are likely to play a role; each with just a modest association with pain. So we need sample sizes in the thousands to identify genes involved with any certainty. Most studies performed to date were underpowered to detect modest effects, but will detect strong effects. If we measured all the factors influencing the opiate response, we could perhaps model inter-individual variation to morphine response. Also we could stratify patients according to age, disease process and psychological profile.

Using pharmacogenomics to predict pain management in the clinic is for the future. First we need to define a good clinical response to opioids. Perhaps then we will develop a simple blood test to predict the best opiate and dose for individual patients.

Pharmacogenomic approaches in pain management could lead to individualized therapy to best select the appropriate analgesic from the onset to provide sustained efficacy with the lowest side effect profile.

Harnessing the Metabolome

Spotting individual differences is the key to personalised medicine. In the future, identifying individuality using the metabolome – a personal metabolic snapshot at a particular instant – we may categorise patients into intervention responders and non-responders. By determining susceptibility to future disease and intervening early we may prevent disease from occurring.

We usually target specific metabolites when developing drugs. Using metabolomics offers a different approach as it generates a hypothesis, whereas we usually test a hypothesis. But once we generate the hypothesis it can then be tested.

Imaging technology – nuclear magnetic resonance or mass spectrometry – can generate unique signatures based on each individual’s environment and their genome at a particular time. These metabolomic signatures tend to cluster together – rats cluster with rats and humans with other humans. We, humans, eat different types of food and have different environments so we tend to have wider clusters than inbred rats that tend to have similar lifestyles.

By analysing different biofluids the aim is to look for the differences between for example disease and healthy individuals. For example using urine metabolic signatures a difference was found between osteoarthritis patients and controls, and between those with more severe and less severe disease.

In a study of cardiovascular disease, those with diseased arteries clustered in a signature different from those whose arteries were normal. In the future, metabolomic signatures may be more useful to traditional biomarkers such as cholesterol used to target patients for intervention. Perhaps it will help use blood and biofluid measurements in more informed way and predict outliers in disease and treatment response.

Interpreting data is complex and difficult. Signatures generate vast amounts of data and all of the metabolites in a pathway – some of them not yet identified. Looking at specific important molecules in a pathway simplifies the approach and helps separate signal from noise.

Examining the gut microflora offers an opportunity. We might identify specific microflora associated with gastrointestinal diseases, such as irritable bowel disease, and investigate how they affect metabolite profiles.

In population studies, it may be possible to investigate clusters of healthy people and diseased people with similar phenotypes to see if there are differences in their metabolome.

The way to harness the true potential of the metabolome is to predict healthy people who are likely to get ill and to intervene to protect them.


Treating Advanced Parkinson’s Disease

In advanced Parkinson’s disease, major motor and non-motor fluctuations increase and reduce quality of life. Long-term oral levodopa worsens involuntary movements – dyskinesia – and wearing off – off time or ‘untreated’ period of time between dose activity when motor fluctuations present.

Disabling motor fluctuations occur in 80% of patients with advanced disease. As Parkinson’s disease progresses the challenge is to stimulate dopamine receptors continuously but avoid unwanted involuntary movements.

Oral Levodopa Treatment Fails

Traditional treatments lose effectiveness later in disease course. Oral levodopa only stimulates dopamine receptors intermittently because of its short plasma half life (1.5-2 hours), and the erratic stomach emptying- seen in Parkinson’s patients –  slows absorption in the intestine.

Treatment induced dyskinesia results from the intermittent and pulsatile supply of levodopa, with variable plasma concentration and insufficient stimulating of dopamine receptors. Frequent reduced, divided dosing of oral levodopa given with catechol-O-methyltransferase inhibitors increases the plasma half life, but does not stabilise fluctuating plasma levels completely. Longer-acting dopamine agonists – eg slow release levodopa/carbidopa combinations – stimulate dopamine receptors continuously with less dyskinesia, but affect symptoms suboptimally.

Treatment Options

Three main choices exist for treating advanced Parkinson’s Disease: enteral infusions of levodopa/carbidopa (duodopa), subcutaneous infusions of apomorphine, and deep brain stimulation (DBS).

Duodopa Treatment

Duodopa is delivered continuously via a portable pump and provides smoother plasma levels than oral levodopa. Less motor fluctuations occur with off time reduced by 70-90%. Infusing duodopa into the duodenum  improves global functioning, walking, and lessens off time and motor fluctuations. It reduces the daily dose of levodopa required and eliminates delay due to gastric or absorbing the drug in the intestine. Keeping levodopa plasma levels constant limits severe fluctuations between extreme stiffness and involuntary movements. Most problems encountered occur when inserting the device. Contraindications include patients unfit for abdominal surgery, pronounced dementia, and inadequate patient compliance or support.

Apomorphine Pumps

Infusing apomorphine continuously into the skin via a pump reduces off time and is a viable alternative for some patients with advanced disease. Apomorphine contraindications include presence of dementia, hallucinations and the lack of compliance or support.

Deep Brain Stimulation

Stimulating specific regions of the brain electrically – deep brain stimulation – reduces symptoms in many patients. For deep brain stimulation, a surgeon places the stimulating device under the skin and attaches electrodes to the areas of the brain that control motor function. The device stimulates these areas and blocks the abnormal signals for tremor. Contraindications include patients over 70 years of age or unfit for brain surgery, presence of dementia, depression or anxiety.

Pump treatments and deep brain stimulation are best for motor and non-motor symptoms in advanced disease. In the future, the aim is to developing more physiological dopaminergic agents and even better forms of brain stimulation.

Managing Severe Psoriasis

Psoriasis is a common inflammatory and proliferative skin disorder with marked tender plaques topped with a silvery scale. Psoriasis is common, with a prevalence of 1.5-3% in most ethnicities; it is a chronic, persistent condition of variable severity with a relapsing-remitting course. The exact cause of psoriasis is unknown, but it may be a T-cell mediated autoimmune disease.

Assessing severity involves measuring the physical extent of the disease and level of disability – both practical and psychological suffered. Discordance often exists between the patient’s clinical symptoms and level of distress. Psoriasis patients report decreased quality of life similar to cancer and other chronic diseases.

No psoriasis cure exists; treatments include phototherapy; photosensitive drugs plus phototherapy; and systemic treatments – including biologics. Tailoring treatment depends on individual symptoms and level of disability, and aims to improve quality of life.

Phototherapy – ultraviolet B or photochemotherapy using ultraviolet A – alters the immune response. The main adverse effect of ultraviolet B irradiation is redness of the skin; reports remain unproven of an increased incidence of skin cancers. PUVA – a photosensitising agent (psoralens) plus ultraviolet A irradiation- induces complete or partial control of symptoms in 70% or more patients. Two methoxy-psoralen compounds are given – 8-MOP and 5-MOP – either taken orally or by bathing the plaques. 8-MOP is used more often; it the patient suffers nausea it is substituted by 5-MOP.

PUVA is not given long-term because of an associated increased risk of skin cancer; only ten courses of treatment are recommended. Protective glasses are worn for a day after taking psoralen treatment to prevent eye damage.

Low-dose methotrexate is a cheap and effective treatment for sever psoriasis. Nausea is the most common adverse event, but this can be prevented by also giving folic acid. Liver and bone marrow damage can occur, so careful monitoring of the patient’s blood profile is required. If the patient is taking certain antibiotics or has kidney damage while on methotrexate, then bone marrow damage can be acute. Women taking methotrexate should not conceive because of the risk of foetal damage.

Ciclosporin is a fast and effective treatment, but it can cause hypertension and kidney damage.Ciclosporin suppresses the immune response and may increase risk of cancer. Women on ciclosporin should undergo regular cervical smears. Limiting UV exposure is recommended; as are regular dental checks for gingival hyperplasia.

Low doses of acitretin – a second-generation retinoid – is a esafe, effective treatment for psoriasis and well tolerated. Damage to the skin and mucous membranes is common, including conjunctivitis, hair loss and inflammation of the lips. Retinoids affect liver enzymes and blood lipids; toxic reactions are rare. Pregnant women should not take retinoids and women advised not to conceive until two years after stopping treatment.

Retinoids and PUVA act in concert, and are given together to reduce the dose of ultraviolet A irradiation required.

Hydroxyurea inhibits DNA synthesis in proliferating cells and is reported to be effective in treating psoriasis. It is very slow to act and given as a trial for at least 8 weeks.

Immunosuppression occurs as bone marrow cells are suppressed and immune cells in the blood are depleted. Anaemia is uncommon. Blood cell counts are monitored and if levels fall too low the treatment changed. Advise women to wait until six weeks after stopping treatment to conceive.

Half of patients taking fumaric acid esters achieve a 75% improvement in psoriasis in four months. Over 60% of treated patients experience gastrointestinal problems, including abdominal pain, nausea and diarrhoea. Flushing occurs in one-third and can last from minutes to hours. Monitoring blood cell counts, renal function and liver chemistry is recommended.

Two classes of biologic agent are currently in use for treating psoriasis – those that alter cytokine production – TNFα inhibitors – and those that target T cells – efalizumab.

TNFα plays a key pro-inflammatory role in psoriasis. Membrane bound receptors – p55 and p75 – mediate TNFα activity. When released into the circulation,they bind excess TNFα and limit the inflammatory response.

Etanercept – a fusion protein of human immunoglobulin and two soluble p75 receptors – binds circulating TNFα. Given etanercept, 49% of patients achieve a 75% improvement in twelve weeks. Injection site reactions, occur in one third of patients, are usually mild, occur early in treatment and resolve with repeated injections.

Infliximab – a monoclonal antibody (a chimera of human constant and mouse variable regions) – forms stable complexes with soluble and membrane-bound TNFα.Infliximab is rapid-acting and highly effective; 87% of patients get a 75% improvement at 10 weeks. The presence of murine sequences can provoke antibodies causing infusion reactions and reduced efficacy.

Adalimumab – a fully humanised monoclonal antibody – binds  to both soluble and membrane-bound TNFα. On adalimumab, 80% of patients achieve a 75% improvement in 12 weeks.

All three anti-TNFs increased risk of infection (especially TB), exacerbate heart failure, and worsen multiple sclerosis and hepatitis. Antinuclear antibodies and a lupus-like syndrome can develop.

Efalizumab – a recombinant human monoclonal to lymphocyte function associated antigen-1 –  blocks T cell activation, trafficking and adhesion. Efalizumab is less effective than anti-TNFs. Headaches, flu-like symptoms, skin rashes and thrombocytopenia can occur. Disease can flare when treatment is withdrawn. Efalizumab does not increase the risk of infection or malignancy.

Treating severe psoriasis effectively involves choosing the best treatment for individual patients,. In the future, improved understanding of the processes involved in psoriasis may result in new medicines.

Social Phobia – Under the Spotlight

Social phobia is a common mental disorder; yet most sufferers feel isolated and alone.  They often fear seeking help from friends or health professionals because they feel their condition is not taken seriously or that they will be ridiculed. Ironically, this is the root of their problem.

Feeling shy is normal; fear is a normal response. Most of us find first dates, meeting new people and speaking in public daunting. But for some people their butterflies become unmanageable and chronic.

Social phobics can’t put a brake on extreme feelings – even normal events trigger them. They feel nervous and extreme anxiety. Their pulse races and they go puce; they feel extreme nausea and physically ill when in public. Others label them as too timid or quiet. Far from just excessive shyness, social phobia is a chronic, disabling disorder of extreme anxiety and stress. It carries considerable personal burden.

Social phobics feel they are under a constant spotlight and scrutinised by others, so they avoid social situations. They underachieve academically, are usually unemployed, have difficulty starting and maintaining relationships, and become socially isolated with impaired quality of life. Many social phobics have problems with doing simple things when in public. They can’t shop or go to the bank, and may shake uncontrollably when even just asked to sign their name.

An overactive amygdala triggers the difficulties experienced by social phobics. The fear response protects us in times of attack; the brain prepares us to respond either to flee or to fight. 

Social phobia initiates in childhood or in the teens with a slight bias towards presentation in females. It triggers after a single traumatic event or results from a series of setbacks eroding self-esteem. 

Taking a family history can help make a differential diagnosis as it has a genetic component.  Selective mutism presenting in a child may indicate underlying social phobia. Comorbidity can mask diagnosis, but social phobia usually manifests first.  Anxiety disorders occur in up to one third of those with social phobia; two thirds have a history of depression and one quarter of alcohol abuse. They have a heightened suicide risk.

Selecting the best treatment depends on the presence of comorbidity, eg anxiety disorder, or depression, or suicide risk. Non-pharmocological approaches such as CBT can change patterns of thinking and improve coping skills.

Benzodiazepines may alleviate anxiety associated with social phobia in the short-term, but side-effects limit usefulness. MAOIs help some patients, but concomitant interactions and the ‘cheese effect‘ with patients needing to avoid dietary tyramine is cumbersome. Using RIMAs reduces this dietary risk and offers similar benefit to MAOIs.

SSRIs help social phobics, especially if depression is present. In one study, long-term paroxetine reduced relapses, which occur in 50% of patients when medication is discontinued.

Social phobia needs addressing and is a public health issue. Assessing the effectiveness of various combination therapies and evaluating the benefit of SSRI long-term use require further investigation.

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