How much harm are reaction treatments doing and how can we change that?

Dr Indra Napit

Research Director, TLM Nepal

How much harm are reaction treatments doing and how can we change that?

Around one in every three leprosy patients may develop leprosy reactions and for many, these reactions will recur over a number of years. These reactions are inflammations caused by the body's immune response to leprosy bacteria, whether that bacteria is dead or alive.

Some will experience type 1 reactions, when the inflammation is localised only where the bacteria is found. Type 2 reactions can affect the whole body (systemic), with worse symptoms and involvement of multiple organs over a longer period. It can be an incredibly painful experience leading to long-term sickness.

Most of the time, reaction patients are treated with corticosteroids, thalidomide, clofazimine, methotrexate etc. Corticosteroids remain the most effective first line drug of choice and

widely available treatment for acute nerve inflammation in leprosy reactions and have prevented disability in countless patients. However, when reactions become chronic or recurrent, prolonged steroid use exposes patients to substantial adverse effects.

Some of the consequences listed on the next page are direct side effects of prolonged steroid use and some are indirect consequences like long-term disability and socio-economic impact. They can be life-limiting and even life threatening.

Potential consequences of prolonged steroid treatment

Weight gain and moon face (Cushingoid appearance)
Osteoporosis and fractures
Diabetes mellitus
Hypertension
Increased susceptibility to infections
causing deaths
Cataracts and Glaucoma

Poor mental health with mood changes and psychiatric disturbances like:

Insomnia
Irritability
Anxiety and depression, including suicidal thoughts

Cardiovascular risks

Risk of arterial blocks and Stroke
Kidney failure risk in some patients

Some other commonly used drugs like thalidomide can cause major side effects like birth defects of limbs in newborn babies if used during pregnancy, blocking of arteries (embolism) and peripheral neuropathy in all population. Similarly, clofazimine can cause skin discoloration (black pigmentation of skin) which is reversible after stopping it.

Oral steroids are very cheap and many leprosy endemic countries like India and Nepal, where patient can buy it over the counter, so many patients take high dose steroids irregularly for longer periods which leads to severe side effects and very difficult for further management.

Over the coming pages, we will consider what each of these consequences looks like and how common it is.

These are the realities that doctors walk through with patients all the time.

Hypertension (high blood pressure)

Steroids cause sodium and water retention, which in turn causes hypertension. This increases risk of heart disease, heart attack, stroke, heart failure, kidney disease, and vascular dementia.

Like diabetes, hypertension requires lifelong medication and lifestyle changes for patients, and it is a common side effect of long-term steroid use.

Eye health

Glaucoma and cataracts can both be consequences of long-term steroid use. Steroid-induced cataracts often occur in relatively young patients with chronic leprosy reactions and may be worsened by steroid-induced diabetes. Cataract surgery may be delayed because some patients cannot be weaned off corticosteroids, making ophthalmologists hesitant about operating. Steroid-induced glaucoma can cause eye pain and irreversible vision loss and may not always be satisfactorily controlled despite treatment.

Untreated, these can lead to blindness and treatment can be costly and hard to access for people living in remote areas.

Early surgery of cataract prevents blindness, whereas glaucoma requires lifetime medicines like in diabetes and hypertension.

Diabetes

Diabetes is a disease that can cause lifelong and life-limiting consequences due to nerve damage like in leprosy. That leprosy treatment with a prolonged use of steroids can lead to diabetes is a double-blow for patients. 

Direct or indirect? This is a direct consequence of prolonged steroid treatment, which causes high levels of glucose in the body.Corticosteroids increase blood glucose levels by making the body less responsive to insulin and by increasing glucose production in the liver. In some people—particularly those with underlying risk factors—this can lead to steroid-induced diabetes.

How common is this? This is one of the more common consequences of steroid treatment but requires prolonged use before it occurs.

Prednisolone is taken at least for 12 weeks (3 months) and as long as two years, or perhaps even longer

Life-long medication: Steroid-induced diabetes may persist after steroids are stopped in some patients, particularly those with underlying risk factors, while others recover normal glucose control. This means taking medicine for the rest of their life, a new expense for patients to worry about. This is on top of lifestyle changes such as exercise and healthy eating.

Chronic Kidney disease: In patients with type 2 leprosy reaction with high blood glucose and blood pressure increases pressure on the kidney's filters, which can damage them and lead to chronic kidney disease, and occasionally kidney failure. This would require a kidney transplant, something that is very expensive and difficult to access. Because this would only happen to patients later in life, it is hard to know how frequently this happens for reaction patients, but it is a known risk.

Nerve damage: Like leprosy, diabetes affects the nerves, leading to loss of sensation and ulcers. This means an increased risk of needing ongoing treatment and ulcer care as well as long-term disabilities that make employment harder to access.

Increased risk of stroke and heart disease: Blood vessels are damaged when a build up of sugar forces the sugar to stick to red blood cells, making them harder and more likely to become blocked, leading to blood clots and then to strokes and heart disease.

What are the knock-on effects

of a diabetes diagnosis?

Osteoporosis

(loss of bone density)

Osteoporosis is a condition that leads to bones being weakened due to reduced bone density. Even a small bump or fall can lead to fractures and for a person already sick with reactions, this can take a long time to heal.

Direct or indirect? This is another direct consequence of long-term steroid use. Steroids affect the cells that both break down and build up our bones, as well as reducing the body's ability to absorb calcium. This weakens bones over longer periods.

How common is this? Doctors warn patients that this is one of the most common side effects of long-term steroid treatment.

What would osteoporosis look like in practice?

Kyphosis

This is an excessive rounding of the upper back - a hunch. This can happen after a spinal fracture caused by osteoporosis because the spine becomes compressed and will not return to how it was before.

Increased susceptibility to

infections leading to death

Infections are common as the patients are immunosuppressed due to prolonged steroid intake. The symptoms are not classical hence difficult for clinicians to recognize and treat early. When detected late, these infections could become life threatening occasionally leading to death.

Perhaps the most shocking consequence of prolonged steroid treatment is death. Since the dawn of Multi Drug Therapy in the 1980s, we very rarely think about leprosy as a disease linked to fatalities, but this can be a consequence of long-term steroid use.

Direct or indirect? This is an indirect consequence of steroid treatment. Steroid treatment over extended periods causes the immune system to be compromised. In these situations, a secondary infection such as pneumonia can easily prove fatal.

How common is this? The Leprosy Mission's disability task force conducted a review of 117 papers on leprosy reactions which revealed a total of 24 deaths in reaction patients who were immunocompromised by long-term steroid treatment. The mortality rate attributable directly to steroids is extremely low, with most deaths being infection-related. These are only the cases that have been reported in journals, but there likely have been more deaths that have not been recorded.

Photo credit: Tom Bradley

Economic impact

Many reaction patients are away from their income for long periods because of illness. In informal economies, it is likely that a person will lose their job in this situation. Returning home with impairments, diabetes, ulcers, hypertension, and osteoperosis means it is very unlikely that a patient would find work in manual labour. They may need to retrain or find another type of job or rely on government social protection, which may prove insufficient or hard to access. TLM researchers will look further into the economic impact of reactions.

The toll this takes on a person

Leprosy reactions are very unpleasant periods of extended pain and ill-health. This would be a challenge for anyone. But when you consider all of the further damage that can be caused by the currently available treatments, it is no surprise that the consequences are psychological, social, and economic, and may even result in death.

Social consequences

Anyone who has experienced long-term sickness can tell you this is an isolating experience, as leaving the home - or even the hospital - can be a challenge. For many reaction patients, this is undoubtedly true. In-patients can expect to be away from home for many months at a time and the distance between home and hospital might make it very difficult for friends and family to visit. Isolation sets in easily.

Mental health and suicidal thoughts

Dr. Indra Napit (TLM Nepal) says there is not a lot of data available on suicidal thoughts among reaction patients, but he sees the link.

“We see this link often. Many reaction patients we speak to have thought of suicide and some of them have attempted it. We are planning a small quantitative study among patients to understand the mental health implications of such prolonged and challenging treatment."

A word on thalidomide

Thalidomide is a medication with an infamous reputation, having caused as many as 10,000 babies to be born with birth defects after their mothers had been given this medication.

Thalidomide is still used to treat leprosy reactions in some countries, although it is never given to women of child-bearing age. Still, even among other people, thalidomide can cause nausea and vomiting, as well as arthritis and blocked arteries, which can be fatal. It can also cause peripheral sensory neuropathy which will be a double blow in already existing leprosy neuropathy. It is administered strictly under supervised admission in hospitals, though some countries recommend it for OPD based use.

What efforts are being made to find better treatments for patients?

Any patient faced with the set of potential consequences that have been laid out on the previous pages would have reason to feel that they are not being given good options. We are in urgent need of finding better reaction treatments, and The Leprosy Mission is addressing this through clinical trials of alternative reaction drugs.

There are two medications that derive from Thalidomide, Dovramilast and Apremilast, previous studies have shown fewer side effects and appear to be safe and promising.

Dovramilast is still under investigation for use in leprosy reactions. Anandaban Hospital is conducting a phase 2 study to see the safety and efficiency of Dovramilast in leprosy reactions. Apremilast is readily and cheaply available in leprosy endemic countries worldwide and have been shown to be safe and effective for treating other diseases like psoriasis. TLM's dermatologists in Nepal are trialling them to treat leprosy reactions, and the early results are promising. The Leprosy Mission is currently looking for funding to implement a Randomised Control Trial on these medications with the hope that their efficacy and safety can be proved in a few years' time. 

If this happened, reaction patients would finally be given treatment options that did not cause life changing consequences. For people struggling with serious ill-health, stigma, disability, and economic uncertainty, this would be a very welcome relief.