Dr Colin Michie, FRCPCH FRSA FLS RNutr, London; Dr Beatrice Kenol, MD, Columbus, Ohio, USA
Wont You Celebrate With Me
Won't you celebrate with me what i have shaped into a kind of life? i had no model. born in babylon both nonwhite and woman what did i see to be except myself? i made it up here on this bridge between starshine and clay one hand holding tight my other hand; come celebrate with me that everyday something has tried to kill me and has failed. Lucille Clifton 1960s
Three years ago one of my colleagues from the Dominican Republic became tired during her first pregnancy. She felt increasingly anxious and had heart palpitations in the final weeks. After her healthy baby arrived, her legs became swollen – She took some time off and recovered. Her second pregnancy followed a similar course but she developed pains in her wrists, knees and fingers, muscle pains in her legs and some rashes around her cheeks. Her baby had some curious rashes too, but they disappeared. That winter, although it was not very cold, these pains returned; they were worse in the mornings and her hands became cold and pale. She developed mouth ulcers, hair loss some redness on her face and some breathing problems. She was seen by several doctors; after three months she told us a diagnosis of systemic lupus erythematosus had been made, and she had started a treatment. She has not complained about her joints since and was glad of the diagnosis. However, she felt her life had changed forever and she has not returned to work.
What is systemic lupus erythematosus?
This disorder deserves exploration. SLE is complex. It is rare. It is relapsing, so that it comes and goes, but it is unlikely to disappear altogether. SLE often reduces the quality of a patient’s life until good treatments are established. SLE is nine times more frequent in women and is more frequent in those with African ethnic backgrounds. It most frequently manifests in women of childbearing age. It is sometimes in childhood or adolescence. SLE in men although rare tends to be more severe. SLE varies and differs a great deal between patients. SLE will often have appeared in the family tree before and so there may be clusters of patients in some communities. New treatment strategies have been developed in the last 10 years.
There are different types of lupus, the most common being systemic lupus erythematosus (SLE) that affects many organs. Other forms cause more problems in the skin and mucous membranes (for instance the mouth, respiratory tract or gut). A mild type may involve the new-born of a mother with SLE. An uncommon variant of lupus can develop following exposure to some medications.
A disordered Immune system
One of the hallmarks of SLE is the unusually wide spectrum of antibodies in the patient’s blood that attack the patient’s own cells. Why these develop is not known. The new autoantibodies can cause a large increase in the total level of protein in the blood. Lupus is an autoimmune disease because the body’s immune system leads an attack on the patient. It is a patient’s immune system that causes the harms in SLE. Immune systems normally form your powerful protective shield against infection and cancer. Checks and balances usually prevent personal attacks by your immune system. Normally immunological aggression is directed against invading pathogens or perhaps malignant cells.
Antibodies are made by mature bursa or B cells. B cells are found in the spleen, lymph nodes and bone marrow. Antibodies are made against invaders that find their way into your respiratory spaces, gut or skin. These might include viruses such as influenza or rotavirus. They will be made after vaccines in yourself, your pets or domestic animals, for instance against tetanus, polio, whooping cough, measles or papillomavirus. Antibodies are protective, which is why vaccines prevent disease. Concentrated antibodies from blood donors, known as intravenous gamma globulins, may be used in a range of hospital treatments.
In SLE B cells make unhelpful auto-antibodies. ‘Auto’ means they bind to different parts of the patient’s own tissues. In particular, in SLE they bind to nuclei in cells. A cell nucleus contains molecules including the genetic code, deoxyribose nucleic acid, or DNA, and its blanket of proteins, the histones. So to diagnose SLE, a doctor has to search for autoantibodies to DNA, histones and other nuclear molecules. By the time a patient has pains in their joints, it is likely that they will also have some damage to the lining of their blood vessels, such as those in the kidneys, brain and sometimes skin and brain too.
Other autoimmune diseases you may have read about are mostly more ‘focused’. Type 1 diabetes, for instance, develops when the immune system attacks just those cells that make insulin. In vitiligo, autoimmunity targets cells in the skin that make melanin, destroying them and causing patches of skin to lose their pigment.
One of the puzzles of SLE is its variation in activity. Sometimes it causes rashes, join pain and fatigue, inflaming tissues. At other times it is not very noticeable. This activity is driven by the SLE autoantibodies Active disease will often show many signs of immunological mahem, with inflammation in the blood, blood vessels and tissues. One inflammatory system, complement, is a set of proteins activated by autoantibodies. Normally there are large amounts of complement protein in the blood. If SLE becomes active, complement levels fall.
How is SLE diagnosed? The importance of a family tree
Because of the wide variations in this illness, SLE can be difficult to diagnose. No two cases are exactly the same. A family tree can be valuable in helping make a diagnosis. For instance, did an aunt or cousin, or possibly a more close relative suffer with an illness involving their joints? Their skin? Their kidneys? This information is really useful to an investigating doctor. If someone in the family has had a diagnosis of SLE, what were the best medications for them? Did they have any complications, for instance with their lungs or heart? This type of approach will help find a diagnosis more quickly. Although many genes have been identified by scientists, the direct value of these to personalising a diagnosis or treatment is not practicable, so using that great treasure, the family tree, remains helpful.
In order to make the diagnosis of SLE, elements of a patient’s history, family tree, physical findings and a blood sample results will be listed. The blood check will be for various autoantibodies, complement levels and the function of the kidneys, liver and bone marrow. A scoring system has been tested in many countries to allow SLE to be diagnosed on the basis of such coding. The same system may be adapted to check on treatments.
Sometimes imaging with X-rays or ultrasound is useful to assess lupus inflammation, that can show up as fluid around organs such as the lungs or the heart. Biopsies of affected organs such as the kidney or the skin may help make a diagnosis and to guide treatments too. For example, if there are clues from urine tests, a kidney biopsy becomes invaluable to classify the type and extent of damage there.
What do autoantibodies do?
SLE can show itself in different ways in different people. It is known as an imitator because of this. Because it is uncommon in men, sex hormones must play a part. Those who contract the disease in childhood or adolescence tend to have more severe problems. Some women start with a rash, others with joint problems, yet others with fatigue and fever. Some can have heart conduction issues, some are diagnosed because their new-born baby has an unusual heart rhythm. The course of the illness will depend on the types of autoantibodies produced as well as the other genes a patient has inherited (that family tree). For instance, some individuals who have inherited certain types of blood fat (types of the apolipoprotein L1) are more likely to suffer with blood vessel damage in their kidneys if they develop SLE. This particular problem is more common in those with west African ancestries, as it represents a genetic adaptation that was once useful in protecting against sleeping sickness (Trypanosoma brucei rhodesiense)
How is SLE treated?
As SLE is driven by dangerous autoantibodies, it would make sense to stop these being made by B cells in the first place. In the last 20 years such ‘biologic’ treatments have become available. However a more practical strategy is to start treatment with more established medication, reserving the more powerful biologics for more severe illness. Treatment goals are directed at improving long-term survival with as little damage from SLE as possible, while improving the quality of a patient’s life. There should be limitation of side-effects from medications too. Patients may be asked to monitor their condition and sometimes adjust medication for any ‘flare-ups’.
First-line treatments usually include anti-inflammatory medicines together with lifestyle modifications. These keep blood vessels, particularly those in the heart, healthy. So non-steroidal anti-inflammatory medicines (including aspirin) may be prescribed together with a low salt, low fat diet, and regular exercise. It is important to reduce any effects of obesity, smoking or inactivity as all these will increase damage from the SLE or the treatments worse. Careful consideration of mental health is useful from the start of treatments too, as patients may have effects of SLE on their brain. Counselling and the value of local community groups is invaluable in developing this type of reassurance, hope and support.
The importance of hydroxychloroquine and chloroquine
All patients with lupus are treated with hydroxychloroquine unless it is contraindicated.
This medication is not only beneficial in controlling the joint pains and skin manifestations, but also prevents flare-ups. If tolerated, this is the most important drug used for lupus and should be continued even if there are no symptoms of lupus.
In general corticosteroids, such as prednisolone, are reserved for use during times when the SLE is acutely ‘flaring’, causing more pain or reducing mobility. Though these steroids are usually effective in acting quickly to reduce inflammation, long term use may be associated with many adverse effects. A goal for most patients is therefore to reduce the severity and frequency of flareups.
Stronger immunosuppressive agents can be prescribed to reduce B cell activity and inflammation. These include methotrexate, azathioprine, mycophenolate, cyclophosphamide and cyclosporin. Two new biologics have been used by specialists for SLE. The older, rituximab, reduces mature B cell activity. A new agent belimumab blocks the activation of B cells to stop them producing antibodies. This last ‘biological’ agent has not been tested extensively in patients of all ethnicities. An underlying problem with such treatments too is that to turn off this SLE driven auto-immune problem, treatments can turn off the normal activities of a patient’s immune system. Care has to be taken therefore to avoid patients developing infections or cancers.
Some therapies are not employed in all Hospitals. For instance, some doctors prescribe a statin medication to improve blood vessel health. Another treatment that is less toxic but not widely used is the use of ultraviolet A radiation, part of the rays normally found in sunshine. This has given benefit to some patients. Many new treatments or treatment combinations, are being tested to improve the care of patients with SLE. For instance some skin problems with lupus respond to treatment with colchicine, a drug isolated from the root of the flame lily, the national flower of Zimbabwe.
Last year several new treatments for SLE were found useful in good clinical trials. There is a new anti-inflammatory medication (anifroluman) and an immunosuppressant particularly helpful in kidney disease (voclosporin). Other agents are still being tested, so please think about joining in a trial of treatment. The combination of pharmacological ingenuity and trial design is becoming more effective and will benefit patients.
Talk to others, other patients, your healthcare team
Managing your SLE is often a slow and challenging process. It is a chronic disease, so it will not disappear and its course is not predictable. There are often issues relating to medications too, most of which can have adverse effects. It can become a challenge to decide whether a problem – such as a headache, or anxiety – is related to the lupus or to the treatments. For instance, although hydroxychloroquine can reduce joint pain and the risks of many problems from SLE, it can cause fatigue, headaches and stomach problems. Steroids can aggravate the stomach too; they often cause weight gain, mood changes and bone damage. On the other hand problems such as headache or anxiety might be due to SLE or to the stresses of being unwell.
Patients find support from fellow patients especially useful. Support groups, particularly local ones, are valuable. They provide an audience, aid, kindness, hope and ideas when needed – from familiar people. Within these support groups patients share experiences, give encouragement, talk about different treatments, discuss health goals or just have a laugh. Support groups have been particularly helpful in contributing to trials of new treatments. Online and social media resources, as well as national groups are becoming more effective in their delivery of different resources and discussions. In America the Lupus Foundation, the Centres for Disease Control and the American Rheumatology Association have helpful websites and guides.
The future
Care for those with SLE is improving and becoming safer in many centres. There are encouraging prospects of new treatments and new combinations of treatments. However there are wide differences between the treatments used in different centres. Making diagnoses earlier, improving therapies and lifestyles will benefit particularly from the engagement of patient support groups. Families and communities can join in supporting these; benefits from this type of bridgebuilding, between Clifton’s starshine and clay, will be rapid.