BEN NAAFS

IJsselmeerziekenhuizen Emmeloord/Lelystad and Leiden University

Medical Centre (LUMC), The Netherlands
Instituto Lauro de Souza Lima (ILSL), Bauru, SP, Brazil
Regional Dermatology Training Centre (RDTC), Moshi, Tanzania
Accepted for publication 9 September 2003
Summary In this paper, earlier data on the length of prednisolone treatment are
re-examined. Based on those data and supported by the literature and the author's
own observations, it can be concluded that type I leprosy reaction should be treated
with prednisolone for a longer period than the 12 weeks, advised by the WHO. The
paper also warns against silent nerve damage that may occur when prednisolone is
discontinued early.
Introduction
The 7th WHO Expert Committee on Leprosy stated in June 1997
1
that `the crucial elements
in the management of leprosy reactions and thereby the prevention of disabilities, are early
diagnosis of reactions together with prompt and adequate treatment'. The committee also
stated that `most reactions and neuritis can be treated successfully under eld conditions by a
standard 12 weeks course of prednisolone'. The former statement on the importance of early
diagnosis cannot be overestimated. However the latter statement that most reactions and
neuritis can be successfully treated in 12 weeks is most likely to be incorrect.
Nerve damaging reactions are the cell-mediated type I leprosy reaction (reversal reaction,
RR) and the type II leprosy reaction (erythema nodosum leprosum, ENL), which seems to be
immune-complex driven (see Table 1 for criteria). Very little is known on the duration of
these reactions. It is assumed that a type I reaction lasts for months and a type II reaction for
weeks. The duration of the type II leprosy reaction; less than 1 week 187%, up to 2 weeks
324%, up to 3 weeks 186% and up to 1 month 293% was noted by Lara in 1924 at Cullion
leprosarium in the Philippines as described by de Souza-Araujo.
2
However, ENL may reoccur
and become chronic, lasting for years.
3,4
During the 15th World Leprosy Congress in Beijing in 1998,
5
it became apparent that
no evidence-based treatment schedules were available for the treatment of these reactions.
Lepr Rev (2003) 74, 328336
Treatment duration of reversal reaction:
a reappraisal. Back to the past
Correspondence to: B. Naafs, Gracht 15, 8485 KN Munnekeburen, The Netherlands (e-mail: [email protected])
328 0305-7518/03/064053+09 $1.00 q Lepra
Evidence based at that time meant, `double-blind, placebo controlled studies'. However, the
understanding of `evidence-based' has changed during the past few years, giving more credit
to careful monitoring of individual patients and retrospective studies.
Type I leprosy reaction (reversal reaction): treatment
Steroid treatment (prednisolone) is still considered the treatment of choice for the RR,
6
and
the starting dose of 3040 mg also leads to little discussion.
7
However, the length of
treatment does.
6,7
In 1950, Chaussinand
8
in his textbook `La Lepre' commented that, a 47 day course of
injections with cortisol or ACTH has been used successfully, but the reactions usually
re-appeared once the treatment was stopped. Treatment with steroids was also a matter of
discussion during the 6th World Leprosy Congress in Madrid (1953). It was considered
effective but `rebounds' were feared.
Cochrane
9
cited Cap Oliver in his textbook on leprosy, `Acute forms of neuritis
associated with dimorphous or tuberculoid reactions are best treated with corticosteroid
drugs, prednisolone 2040 mg daily depending on the severity, and gradually decreasing the
dose corresponding to the stage of clinical resolution. Treatment given for 1 week to 1 month,
or occasionally longer is usually sufcient to deal with the pain'. This treatment schedule
based on clinical observation was used by most leprologists, afraid as they were to use
steroids for prolonged periods. However, for some the cost was also an inhibitory factor.
Nevertheless, at the end of the 1950s, some leprologists tended to treat for longer treatment
periods.
10
Treatment duration of reversal reaction 329
Table 1. Criteria for reactions to be used for research or in the eld (proposed by B. Naafs, P. K. Das, W.
R. Faber and D. V. A. Opromolla)
A patient has a type I (reversal) reaction when he has the major criterion or at least two minor criteria
(without signs of ENL).
Major Pre-existing and/or new skin lesions become inamed, red and swollen.
Minor 1. One or more nerves become tender and may be swollen.
2. Crops of new (painless) lesions appear.
3. Sudden oedema of face and extremities.
4. Recent loss of sensation in hands and feet or signs of recent nerve damage
(loss of sweating, sensation, muscle strength) in an area supplied by a particular nerve.
A patient has a type II (ENL) reaction when he has the major criterion or at least three minor criteria.
Major A sudden eruption of tender (red) papules, nodules or plaques, which may ulcerate.
Minor 1. Mild fever, the patient is unwell.
2. Tender enlarged nerves.
3. Increased loss of sensation or strength.
4. Arthritis.
5. Lymphadenitis.
6. Epididimo-orchitis.
7. Iridocyclitis or episcleritis.
8. Oedema of extremities or face.
9. Positive Ryrie or Ellis test.
In 1968, Goodwin published the voluntary muscle test (VMT) adapted for leprosy
patients.
11
From that time onwards, it became possible to objectively assess motor nerve
function during treatment. Not long afterwards, Pearson introduced Weddell's graded bristle
test to assess sensory nerve function.
12
Between 1968 and 1974, researchers at the All Africa Leprosy and Rehabilitation
Training Centre (ALERT) in Addis Ababa used two different regimens for treating RR.
13
One regimen comprised 4560 mg prednisolone daily tapered off over 1 month to 5 mg and
then continued with 5 mg for another month. The other regimen started with 15 mg and
tapered off to 5 mg in 1 month and continued at the same dose for another month. This
regimen was repeated once or twice when patients showed increased activity. Patients were
monitored carefully using the VMT. Retrospective analyses comparing the two regimens did
not reveal any difference in the outcome of treatment (Naafs, unpublished observations).
Pearson was one of the rst to adjust treatment to an objective change in the nerve
function parameters and consequently he gradually lengthened the treatment period. With
the introduction of EMG equipment at ALERT in 1974 by Baar, motor nerve conduction
velocity could be used in addition to VMT and sensory testing as a parameter of nerve
involvement.
14,15
From 1974 onward, patients at ALERT with an RR were started on 3040 mg
prednisolone once daily, which was then after 1 month reduced over a 23 month period
to 2025 mg. Thereafter, the prednisolone dose was reduced by 5 mg once monthly.
13
The
dose was increased again to the previous dose when nerve function parameters deteriorated.
In a few instances, the increase was 10 mg instead of 5 mg. This was also done when
improvement came to a halt after reducing the dose. It was observed that 1520 mg
(6030035 mg/kg) was the critical dose of prednisolone to control an RR after the initial
period. The total duration of treatment was 49 months for BT patients, 414 months for BB
patients and 620 months for BL patients.
13
These treatment durations are in accordance with
the experience of Rose and Waters
16
and with recently reported data on the length of RR by
Li Huan-Ying
17
(Table 2).
The ALERT prednisolone treatment used before 1974 was compared with the predniso-
lone treatment used after 1974 using the VMT as parameter. Patients were followed-up for 3
years. Anti-leprosy treatment was 200300 mg dapsone once weekly before 1974. In the rst
2 weeks of anti-reaction treatment dapsone was discontinued, thereafter restarted and
increased slowly again. After 1974, patients received 5, 50 or 100 mg dapsone daily and
the treatment was not interrupted, only one BL patient received clofazimine (Naafs,
unpublished observations).
In Table 3, it can be seen that the number of patients that deteriorated after the rst months
despite the treatment was much higher during 19681974 than it was during 19741978.
13
It
B. Naafs 330
Table 2. Length of RR of patients on MDT reported by Li Huan-Ying
17
Duration in months
<3 46 712 1324 2548
BT 8 5 2 3 0
BB 2 2 1 0 1
BL 21 9 30 1 1
is obvious that the process of nerve damage in most patients was not arrested by the short
period of prednisolone treatment. When a longer period of prednisolone treatment was used,
very few patients deteriorated once the treatment was initiated and none after 3 months.
The average of the VMT decits during and after prednisolone treatment is shown in
Figure 1.
13
During severe reactions (initial VMT decit > 12) during 19681974, there was
no improvement in the average value during the rst half year, though there was a gradual
improvement thereafter. This could be explained by assuming that the reaction had settled,
the natural course during anti-leprosy treatment as conrmed by Li Huan-Ying.
17
During
19741978, there was a continuous improvement from the start of prednisolone treatment
and that continued for at least 2 years. The average duration of anti-reaction treatment was
69 months, which is slightly longer than the period described by Concigli et al.
10
However
they especially studied BT patients.
It is unlikely that the type of anti-leprosy treatment had a major inuence on the course of
the reaction in patients with severe nerve involvement except by eliminating the bacilli and
therewith the antigens, a major trigger for reaction. Among patients with a mild reaction,
there was the impression that the ones who received the higher dose of dapsone did better than
the ones on the lower dose. However, the dose of dapsone did not inuence the main outcome
of that study (Naafs, unpublished observations). The message of the study was that the
treatment must be prolonged and preferably personalized.
13
It was clear that in the eld individually tailored anti-reaction treatment was not feasible.
Therefore, xed and semi-xed, schedules were recommended and implemented.
1820
The
results in general were good, although no long-term follow-up was performed at that time.
WHO advised a shorter treatment regimen,
1
in which the prednisolone dose stayed above
the crucial dose of 1520 mg only during the rst 23 months. The results at the end of the
treatment seemed to be good.
21
However, there was no proper follow-up of the patients
during the post-treatment period. Becx-Bleumink et al. using a similar treatment regime
found that during follow-up at least one-third of the BL patients deteriorated after the
prednisolone treatment.
22
Based on the paper by Naafs et al.,
13
the editorial of Rose and Waters
16
and the data
supplied by Li Huan-Ying
17
it was unlikely that such a short treatment could be effective
in the long run. Therefore patients who had been treated with the WHO advised regimen
and had been followed-up with VMT were reassessed 38 months after treatment with
prednisolone was stopped.
23
Data of 16 evaluable patients are shown in Figure 2
6,23
and in
Table 3.
23
Treatment duration of reversal reaction 331
Table 3. Comparison of treatment results for the periods 19681974,
13
19741978
13
and
19941995
23
Time at which maximum
nerve damage was
observed ALERT
13
ALERT
13
WHO
23
25 patients 23 patients 16 patients treated
19681974 19741978 19941995
Start or after 1 month 8 19 8
At 3 months 6 4 1
At 612 months 11 0 7
The graph in Figure 2 shows that although the VMT decit improved markedly during the
prednisolone treatment in 15 of the 16 patients; nine of them deteriorated subsequently to
values not much different from the pretreatment values. The average result in VMT decit
before and 6 months after treatment was about the same.
In Table 3, the result of the WHO treatment (19941995)
23
is compared with the result of
the treatment preferred at ALERT before 1974 and with those of the patient tailored-
treatment in the period 19741978.
13
It can be seen that seven of the patients on WHO
treatment had a higher VMT decit 912 months after treatment than before treatment. These
results were better than those obtained with the short 12 months treatment with prednisolone
before 1974 at ALERT, but fell far short of those obtained by the longer duration patient-
tailored one. This small study showed clearly that at least half of the patients in type I leprosy
reaction would benet from prolonged prednisolone treatment.
There are more data available to support this statement. Nicholls remarked at the Asian
Leprosy Congress in Agra, India (2000) in a workshop on nerve damage that recurrent
reactions were frequent. Most of the participants at that session concurred with him. The
author of this paper was one of the exceptions. He has personally treated (patient-tailored)
and followed-up between 1974 and 2003 an estimated 400 patients with type I leprosy
reaction over a period of at least 3 years using VMT and graded sensory bristles; moreover,
electrophysiological parameters in about 200 of them. Less then 2% of the patients who
B. Naafs 332
Figure 1. Improvement in borderline patients with neuritis during a 3-year follow-up period. Short-term steroid
treatment compared with prolonged steroid treatment (reprinted from
13
).
Treatment duration of reversal reaction 333
Figure 2. The course of nerve function during reversal reaction treated by prednisolone, measured in arbitrary units.
The larger the value, the more damaged the nerves. Each line represents a single patient; *One patient assessed 3
months after completing prednisolone treatment (reprinted from
6
and
23
).
followed the recommended treatment had a recurrent reaction (Naafs, unpublished observa-
tions). His prednisolone treatment, however, often exceeded the 6 months, whereas the
treatment the other participants referred to were shorter.
Recurrent RR was seen before the introduction of WHO/MDT in patients who developed
dapsone resistance (Naafs, unpublished observation). Some of the patients developed a
recurrent reaction after the introduction of MDT, indicating that probably they had been
resistant to dapsone before. A recurrent RR was frequently noted in patients who had
prematurely stopped their prednisolone treatment, similar to the present-day situation with
WHO advised steroid treatment. After the introduction of MDT, recurrent RR was
occasionally seen in MB patients released from anti-leprosy treatment. This was probably
due to the disappearance of the protective effect of dapsone.
24,25
Recently it has also been
seen in patients infected with HIV who received HAART (Highly Active Anti-Retroviral
Treatment) (Naafs, unpublished observation).
Thacker et al.
26
studied leprosy patients electrophysiologically during and after reactions.
The patients were treated with prednisolone over a 6-week period. They observed signicant
improvement during treatment, but deterioration after prednisolone was stopped. Li Huan-
Ying
17
reporting on the duration of a RR found that only 396% subsided in less than 3
months and 621% within 6 months. In 222% of the BL patients it was found that the RR
lasted at least 712 months. These data conrm the data of Naafs et al.
13
Other evidence supporting prolonged treatment with prednisolone was reported recently
by Little et al.,
27
who observed that there was a continuing Th1 cytokine activity even 180
days after the start of prednisolone in some of the patients at follow-up. They used
immunohistochemistry. At the 16th International Leprosy Congress in Salvador, Bahia,
Brasil, P. S. Rao presented a controlled trial of different prednisolone dosages and durations
in type I reactions, based on a protocol written by Lienhardt, which showed clearly that the
longer duration was statistically better than the shorter duration, but that the initial dose
(60 mg compared to 30 mg) was not signicant.
7
Based on this and on recent data from Nepal
(Tripod 1): `a 34 month prophylactic treatment with steroids in MB patents starting on MDT
does prevent nerve function impairment (NFI) only at 4 and 6 months but the effect is not
sustained at 12 months',
28
together with information from Ethiopia and Nepal
29,30
also
reported and discussed during the congress, Lockwood remarked that it may be that the
treatment of RR has to be prolonged.
Public health oriented leprologists recommend that patients should be instructed about the
signs and symptoms of reactions and when to return for assessment. This has become a
general WHO policy. However, the investigation of Otters and Gieteling
23
showed that
hardly any of the patients who had deteriorated after the treatment with prednisolone had
been discontinued, would have reported back on their own account. Because they had not
noticed any pain and because the deterioration had been very gradual (silent nerve damage)
and did not bear resemblance with the `disease' they had been treated for in the past. Hence
there was no reason for them to report. Silent nerve damage is considered to be a major
problem,
31,32
especially how to detect and treat it. However, a number of clinicians reported
at the World Leprosy Congress in Salvador that improvement in function may occur after
prolonged treatment with steroids.
32
Acknowledgement
Dr Bob Tank advised on the use of the English language.
B. Naafs 334
Addendum
Treatment proposal for type 1 leprosy reactions, prednisolone once daily in the morning:
Paucibacillary Multibacillary
40 mg 2 weeks 30 mg 1 month
30 mg 2 weeks 25 mg 2 months
25 mg 1 month 20 mg 3 months
20 mg 2 months 15 mg 2 months
15 mg 1 month 10 mg 2 weeks
10 mg 2 weeks 5 mg 2 weeks
5 mg 2 weeks
Total 6 months Total 9 months
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