Being treated for ENL can be a dangerous process, these researchers are looking to change that

What is ENL and why is the current treatment a problem?

ENL happens when the body’s immune system causes an inflammatory response to leprosy bacteria in the body. While Type 1 Reactions can happen if you have low or high levels of leprosy bacteria, ENL only occurs if you have high levels of bacteria. In fact, 50 percent of those with the highest levels of bacteria develop ENL. This can happen before, during, or after treatment, as the reaction can be to dead and alive leprosy bacteria.

The current treatment for ENL is steroids, particularly prednisolone, which is effective at reducing inflammation. This current treatment is not without its problems, however. Steroids are not intended for long-term use, but ENL patients often require long-term treatment.

Long-term treatment with steroids has a series of potentially serious side effects. This includes diabetes, hypertension, acne, the development of brittle bones that break easily, muscle pain and weakness, cataracts that leads to blindness. Steroids can also cause weight gain and redistribution of fat in the body; patients become disfigured, with pot bell and hunched back, and rounded ‘moon’ face.

Steroids are an immunosuppressant, which is why they work to treat ENL inflammation. However, reducing immunity can also place patients at risk for flare of a hidden TB infection – which is more common in low-resource settings, where leprosy is found.

With such a range of potentially devastating side effects, current treatments for ENL are far from ideal and ENL patients deserve a better alternative.

A team of scientists on the ENLIST study group are currently using Leprosy Research Initiative funding to look at ways to treat ENL without being reliant on long-term steroid treatment. This is the MaPs project (Methotrexate and Prednisolone study).

ENL Reaction causes inflammations across the whole body. Patients typically experience fever and inflamed skin lesions all over the body. They can be in severe pain in their skin, bones, muscles, eyes, and, testicles.

What is the alternative to steroid treatment?

Methotrexate is an immunosuppressant drug that has been used in other skin and joint conditions. It has undergone limited trials for treating leprosy, and those initial results suggest that it works. Methotrexate could be a “steroid-sparing” treatment that reduces the need for long-term steroid use.

The ENLIST team are starting a full-scale, double blind, randomised control trial of Methotrexate in centres in India, Bangladesh, Nepal, Ethiopia, Philippines, and Indonesia with The London School of Hygiene and Tropical Medicine playing the central coordinating role.

A randomised control trial (RCT) randomly assigns the test drug(s) or placebo to different patients enrolled. This helps to “double blind” the doctor and patient as to which medication is being taken – which means observations are based on evidence rather than subjective expectations from knowing the drugs. Of course, if any serious adverse events develop in an individual patient, the doctor can “unblind” the study treatment in order to best take care of the individual’s needs.

How will the trial work?

There are three types of ENL patients: acute, recurrent, and chronic.

An acute patient will arrive at the medical centre with their first case of ENL, with nodules and pain, and will receive steroid treatment to calm the inflammation. A recurrent patient is someone who comes back for further steroid treatment because they have had a recurrence of ENL. A chronic patient is someone that doctors cannot bring off steroid treatment without them experiencing another inflammation.

The MaPs project will split these three types of patients into two groups. The first group will be acute and recurrent patients and the second group will be chronic patients. Across all the countries, the study teams aim to recruit 150 patients from the acute and recurrent group and 400 from the chronic group.

Each group will then be split into two further groups. One will receive the standard 20-week prednisolone treatment alongside Methotrexate followed by Methotrexate for the rest of 1 year, whilst the second group will receive only prednisolone followed by a placebo instead.

The MaPs team anticipate that it will take four years to enrol their target number of patients and each patient will receive 1 year treatment with 1 year follow-up.

Over the course of the year of treatment, the patients will reduce their dosage of steroid treatment whilst they initially maintain their dosage of Methotrexate. Eventually, the steroid treatment and Methotrexate treatment will both be tapered off.

Standard prednisolone treatment for ENL is 20 weeks of tapered doses from 40-5mg; but if the ENL flares at any point, more prednisolone may be Standard prednisolone treatment for ENL is 20 weeks of tapered doses from 40-5mg; but if the ENL flares at any point, more prednisolone may be needed to control symptoms. To test the effectiveness of Methotrexate, it will be taken alongside the standard prednisolone treatment and then tapered to reduced maintenance doses of 10-5mg for the rest of 1-year total treatment.

If ENL flares or recurs during the study, doctors may need to add prednisolone on top of the study treatment to reduce ENL symptoms again. The hope, however, is that Methotrexate will reduce need for further prednisolone treatment.

What is the expected outcome of the trial?

The MaPs team hope to see that maintaining the Methotrexate dosage will allow the steroid dosage to be reduced gradually while the ENL inflammation stays under control. They hope this will lead to less dependency on prednisolone, fewer side effects for patients, fewer recurrences of ENL, and more time in between any recurrences. This would be a huge victory for ENL patients, whose lives are so often devastated by recurrent and chronic inflammations.

The success of the trial will be measured through the ENLIST ENL Severity Scale and the SF36 Quality of Life survey instrument.

The trial length means that results may not be seen until 2028, but they could be worth the wait. Patients who experience the worst consequences of leprosy would no longer have to also suffer the painful consequences of long-term steroid treatment.

This would mean a better quality of life, fewer hospital stays, and more time at work, earning money, and being with family and friends.