the development of a severity scale for erythema nodosum ... · 332 0305-7518/16/064053+15 $1.00 q...

The development of a severity scale for

Erythema Nodosum Leprosum – the

ENLIST ENL severity scale

STEPHEN L. WALKER*, KIRSTY L. KNIGHT**,

VIVEK V. PAI***, PETER G. NICHOLLS****,

MEDHI ALINDA*****, C. RUTH BUTLIN******,

JOYDEEPA DARLONG*******, DEANNA A.

HAGGE********, SABA M. LAMBERT*,*********,

M. YULIANTO LISTIAWAN*****,

ARMI MAGHANOY**********, JOSE A.C.

NERY***********, KAPIL D. NEUPANE********,

PITCHAIMANI*******, ANASTASIA POLYCARPOU*,

ANNA M. SALES***********, MAHESH

SHAH******** & DIANA N.J. LOCKWOOD*

on behalf of the Erythema Nodosum Leprosum International STudy

Group^

*Faculty of Infectious and Tropical Diseases, London School of

Hygiene and Tropical Medicine, London, United Kingdom

** Royal United Hospitals Bath NHS Foundation Trust, Bath,

United Kingdom

*** Bombay Leprosy Project, Mumbai, India

**** Faculty of Health Sciences, University of Southampton,

Southampton, United Kingdom

***** Dr Soetomo General Hospital, Surabaya, Indonesia

****** The Leprosy Mission International, Bangladesh

******* The Leprosy Mission Hospital, Purulia, India

******** Anandaban Hospital, Kathmandu, Nepal

********* ALERT Center, Addis Ababa, Ethiopia

********** Leonard Wood Memorial Center for TB and Leprosy

Research, Cebu, Philippines

*********** FIOCRUZ, Rio de Janeiro, Brazil

Accepted for publication 8 June 2016

^ The other members of the Erythema Nodosum Leprosum International STudy (ENLIST) Group at the time ofthe meeting referred to in this manuscript are listed in the acknowledgements.

Correspondence to: Steve Walker, Faculty of Infectious and Tropical Diseases, London School of Hygiene andTropical Medicine, Keppel Street, London WC1E 7HT (e-mail: [email protected])

Lepr Rev (2016) 87, 332–346

332 0305-7518/16/064053+15 $1.00 q Lepra

Summary

Introduction: Erythema nodosum leprosum (ENL) is a severe, multi-system

complication of leprosy which is difficult to manage. The evidence for effective

treatment is limited and defining outcome measures for clinical trials is difficult.

There are no validated measures of disease severity and so we wished to develop a

clinical severity scale.

Methods: Three published scales that had been used in ENL research were applied

to patients with ENL at six leprosy referral centres. An analysis of the clinical features

associated with ENL severity was performed on data obtained from the ENLIST 1

study. A meeting of experienced leprosy researchers was held to incorporate the

findings from the scale testing and data analysis into a clinical severity scale for ENL

Results: None of the three scales used were found to be ideal but some features of

each were incorporated into a new scale along with novel items felt to be appropriate.

A final 16 item scale – the ENLIST ENL Severity Scale was agreed by the meeting

participants and detailed notes and definitions developed.

Conclusions: We have developed a new severity measure for ENL which we

propose to subject to formal validation.

Introduction

Erythema nodosum leprosum (ENL) is a severe, inflammatory, painful, multisystem

complication of lepromatous leprosy. ENL causes significant morbidity. Patients are treated

with immunomodulatory drugs, particularly corticosteroids, which are used for prolonged

periods of many months or years. Many patients require high doses of corticosteroids to

control their disease and this leads to complications and deaths associated with long-term use

of these drugs.1 Thalidomide is very effective but is not available in many countries or is

severely restricted because of the risk of teratogenicity. Affordability may also limit the use

of thalidomide in some countries. The identification of other agents for controlling ENL is a

priority.2

The Erythema Nodosum Leprosum International STudy (ENLIST) Group aims to improve

the understanding of the mechanisms which cause ENL, improve the evidence to guide

treatment decisions of individuals with ENL and improve access to effective treatments.3

The development of a quantitative measure to assess the severity of ENL has been

highlighted as a priority research area.3 A tool which enables clinicians to accurately assess

the severity of ENL would be useful in defining outcomes for clinical trials. It would facilitate

the even distribution of patients with similar disease severity between the arms of clinical

trials. A measure of ENL severity could also be used in treatment guidelines to indicate the

need for therapy. A quantitative measure of ENL severity may be a useful prognostic tool.

Our objective was to critique existing scales and if necessary develop a clinical severity

scale for ENL which could be subjected to formal validation.

Methods

A meeting of leprosy experts from eight leprosy endemic countries was organised by the

ENLIST Group and hosted by the Bombay Leprosy Project in Mumbai, India form 7–9th

ENLIST ENL Severity Scale 333

April 2015.4 The aims of the meeting with respect to developing a severity scale for ENL

included: reviewing the results of the ENLIST 1 study of the clinical features of ENL,

reviewing published severity scales of ENL and agreeing on the scale items to be tested in the

validation of a severity scale of ENL. The 13 clinical leprosy workers who participated in the

scale development at the meeting had a total of 218·5 years (Range 3-30) experience of

working with patients with ENL.

In the 4 weeks prior to the meeting three published severity scales for ENL (see Appendix 3),

none of which had been validated, were applied to patients at leprosy referral centres in five

leprosy endemic countries (Brazil, Ethiopia, India, Nepal and the Philippines). The scales were

chosen because they resulted in a quantitative measure and had featured in publications of

original research of ENL within 10 years of the meeting.

The case definition of ENL employed was a patient diagnosed with leprosy has ENL if

he/she had crops of tender cutaneous or subcutaneous lesions. In the absence of cutaneous

signs ENL could also be diagnosed if a patient with leprosy had fever or malaise and

histological features consistent with ENL in a tissue biopsy.

Each patient with ENL to whom the scales were applied was categorised by another

assessor, an experienced physician who examined them, as having mild, moderate or severe

ENL. No attempt was made to standardise severity assessments between assessors. The

nature of ENL was defined as:

. acute for a single episode lasting less than 24 weeks,

. recurrent if a patient experienced a second or subsequent episode of ENL occurring

28 days or more after stopping treatment for ENL

. chronic if occurring for 24 weeks or more during which a patient has required ENL

treatment either continuously or where any treatment free period had been 27 days or less.1

The assessor who determined the severity of ENL in an individual was blinded to the scores

that had been determined by the other assessor using the three scales. At the meeting, the face

and content validity and ease of application of each scale was discussed. The scales chosen

were: the prototype of the “Reaction Severity Assessment”5 developed as part of the ILEP

Nerve Function Impairment and Reaction (INFIR) Cohort Study,6 the ‘modified Ramu’

scoring system reported in a controlled trial of thalidomide in Chandigarh, India7 and a scale

described by Haslett et al. in a study of the effects of thalidomide in Nepali patients with

ENL.8 In each scale the higher the score the more severe the ENL.

The prototype of the ‘Reaction Severity Assessment’ was used because it had more items

relating to ENL than the final published version.5 We simplified the prototype by removing

two items which referred to the ‘maximum motor impairment’ and the ‘maximum sensory

impairment’. This scale, which we shall refer to as the ‘modified van Brakel’ scale, had 14

items and the range of possible scores was 0 to 64 for males and 0 to 59 for females. Each item

scored 0, 1, 3 or 5 though for three items the maximum score possible was three and for one

item 0, 1 or 5 were the possible scores. Two minor changes were made to the ‘modified

Ramu’ scale. The assessment of temperature was changed from Fahrenheit to Celsius and the

number of affected joints in the ‘arthritis’ item was clarified. The range of scores possible was

0 to 18 in males and 0 to 17 in females. The possible scores for each item are not uniform in

this scale with ranges of possible scores of 0 or 1, 0–2, 0–3 and 0 or 3. The ‘Haslett’ scale

which uses cutaneous signs was not changed and the range of scores possible was 0 to 31.

This scale scored each of seven anatomical regions 0-3 depending on the extent of the

S.L. Walker et al.334

cutaneous lesions of ENL (in terms of the proportion of each region involved). The score was

increased by a further 10 if an individual had ‘blistered, pustular, or ulcerated’ ENL skin

lesions at any site.

We did not attempt to calculate the item to total score correlation of the three scales, their

internal consistency nor reliability.

Data from the cross-sectional ENLIST 1 study were analysed to identify clinical features

of ENL that were significantly associated with severity.9

A new severity scale was then devised incorporating the best of each of the three

published scales and other items the group deemed important. A round table expert discussion

of each component item and the scoring system was conducted and the scale modified until a

consensus was reached. The proposed scale was called the ENLIST ENL Severity Scale.

Detailed notes were taken during this discussion which enabled explanatory notes and

definitions for the scale to be developed.

A pilot exercise in which the draft version of the ENLIST ENL Severity Scale was

applied to patients with ENL in the clinic of the Bombay Leprosy Project from April 18th to

July 2nd 2015 with the objective of ensuring that the scale could be used easily and any areas

of uncertainty clarified prior to a formal validation exercise. The same methodology was

employed as in the earlier work with the three published scales.

The anonymised data were entered into an Excel database and analysed using Stata 14

(StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP).

The differences between groups was assessed using odds ratios, the Mann Whitney test, Chi

squared test or ANOVA. The level for statistical significance was set at P # 0·05. A

univariate ordered logistic regression analysis of clinical features of ENL in the ENLIST 1

study was followed by a multilevel ordered logistic (MOL) regression analysis using

purposeful selection of those features that achieved P , 0·25 in the univariate analysis.10

The study was routine. The data collected pertained to the standard of care at each centre

and no ethical approval was necessary.

Results

TESTING THE THREE PUBLISHED SCALES

Forty-three patients with a median age of 32 years were examined. There were almost four

times as many men as women studied. The type of ENL and physician determined severity is

recorded in Table 1.

All three scales showed an increase in score as ENL became more severe (Figures 1a, 1b

and 1c). The differences in the scores of patients with mild and moderate disease were

significantly different for each of the three scales (modified van Brakel P ¼ 0·008, modified

Ramu P ¼ 0·018 and Haslett P ¼ 0·01). However only the modified van Brakel scale

demonstrated a statistically significant difference between the scores of patients classified as

having moderately severe ENL and those with severe ENL (P ¼ 0·017).

CRITIQUE OF THE THREE PUBLISHED SCALES BY ENLIST MEETING ATTENDEES

During the group discussion it was felt that some of items used in the ‘modified van Brakel’

were vague such as the distinction between ‘Chronic’, ‘Mild, acute’ and ‘Definite’ for some

items relating to extracutaneous involvement. It was also felt that there was too great a


weighting in favour of neurological features. The ‘modified Ramu’ scale was felt to have

good face and content validity but again suffered from imprecise language in the description

of items particularly of the skin. The Haslett scale was felt to lack content validity because it

only included the cutaneous features of ENL. The items in the Haslett scale were felt to be

clear although it was argued by some that attempting to determine the proportion of the area

of a region involved may not be easy (Table 2).

ORDERED LOGISTIC REGRESSION ANALYSIS OF ENLIST 1 DATA

A univariate analysis of the association between ENL severity and the presence of feelings of

depression, new nerve function impairment, any nerve function impairment, fever (greater

than 37·58C), presence of vesicles or bullae or pustules, ulcerated skin lesions, more than 20

ENL skin lesions, the presence of oedema, the presence of oedema at two or more sites,

dactylitis, arthritis, dactylitis and arthritis, orchitis, lymphadenitis, rhinitis, any extra-

cutaneous involvement and severe pain (a score of four or five on the Wong-Baker Pain

Rating Scale11) was performed and presented to the group (Table 3).

Three variables reached statistical significance in the MOL regression analysis: fever,

ENL skin lesions with a vesicular, bullous or pustular morphology and severe pain.

THE ENLIST ENL SEVERITY SCALE

From the discussion a new 14 item scale was drafted which incorporated items and features

from all three scales as well as novel items. The features of ENL that were deemed important

to include in a new scale were: an assessment of pain associated with ENL and a measure of

wellbeing. The new items that were incorporated to reflect these features were a Visual

Analogue Scale (VAS) of pain12 and the Arizona Integrative Outcomes Scale (AIOS) which

is also a VAS.13 The scoring of the responses to the pain VAS were based on published

values14 and for convenience the same system was used for the AIOS although no such values

exist for this tool. Both instruments were to be translated into the relevant languages.

Table 1. Description of patients with ENL and outcome of the three published scales. IQR ¼ interquartile range

Number (n=43) (%)

Modified van Brakel (Median

Score [IQR])

Modified Ramu (Median Score

[IQR])

Haslett (Median Score [IQR])

Male:Female 3·8:1 ------ ------- ------

Median age (years [Range]) 32 [18–75] ------ ------ ------

Physician determined severity

Mild 11 (25·6) 8 [10] 1 [3] 4 [4]

Moderate 11 (25·6) 15 [8] 4 [5] 10 [11]

Severe 21 (48·8) 25 [14] 7 [4] 12 [17]

Type of ENL Acute 11 (25·6) 17 [11] 4 [5] 6 [15]

Recurrent 9 (20·9) 12 [4] 3 [3] 8 [7]

Chronic 23 (53·5) 20 [19] 6 [5] 12 [15]


0

10

20

30

40

Mod

ified

van

Bra

kel S

core

MILD MODERATE SEVERE

0

5

10

15

Mod

ified

Ram

u Sc

ore


0

10

20

30

Has

lett

Scor

e


(a)

(b)

(c)

Figure 1. a, b, c Scores across severity groups for (a) Modified van Brakel scale, (b) Modified Ramu scale and (c)Haslett scale.


The new scale was circulated to all participants and on the final day a consensus meeting

was held where each of the 14 items in the draft scale were discussed in detail including the

scores that should be applied. The outcome was a 16 item scale. An additional item,

urinalysis, was included to reflect renal involvement. Two items representing new motor and

new sensory impairment replaced a single item relating to nerve function impairment (NFI) in

general. ‘New’ for this purpose was defined as NFI occurring since the start of the current

episode of ENL. An ‘episode’ of ENL is the onset of new or deterioration in established ENL

symptoms.

The item for fever was the subject of much discussion. It was accepted that it was an

important item to include. Many patients complain of fever but often no elevation in

temperature is demonstrable at the time of examination. This was an important finding of the

ENLIST 1 study.9 It was agreed that the item should include a score for patient reported

history of fever as well as a documented elevated temperature at the time of the examination.

PILOT STUDY OF THE ENLIST ENL SEVERITY SCALE

The 22 individuals who were included in this part of the study are described below in Table 4.

The scale was deemed to be easy to use in the clinical setting albeit more time consuming

than the three used in the previous exercise.

Table 2. Critique of three published ENL severity scales

Feature of scale Modified van Brakel Modified Ramu Haslett

Face validity Good Good Good

Content validity Good Good Limited

Number of unclear items/Total number of items

5/14 3/8 0/8

Ease of use Simple Simple Very simple

Table 3. Results of multivariate analysis of the clinical features of ENL in the univariate analysis with P , 0·25

ENL severity (Mild-Moderate-Severe

UnivariateOdds Ratio 95% CI P

Proportional Odds Ratio 95% CI P

New nerve function impairment

1·91 0·89–4·09 0·096 1·14 0·6–2·14 0·693

Any nerve function impairment

0·34 0·15–0·81 0·014 0·75 0·4–1·41 0·371

Fever >37·5ºC 6·87 3·15–14·96 <0·001 5·69 2·82–11·46 <0·001

Vesicles/Bullae/Pustules 3·84 1·40–10·56 0·009 3·52 1·59–7·8 0·002

Oedema 0·57 0·29–1·11 0·098 0·76 0·43–1·35 0·344

Oedema at two or more sites

2·32 1·09–4·91 0·028 1·62 0·84–3·14 0·152

Orchitis 2·67 0·85–8·37 0·092 1·98 0·8–4·88 0·139

Any extracutaneous involvement

4·84 1·7–13·79 0·003 2·10 0·99–4·45 0·052

Severe pain 3·09 1·74–5·49 <0·001 3·42 2·07–5·66 <0·001


The median scores of individuals increased as ENL was judged more severe (Figure 2).

There was no statistically significant difference between the scores of those with mild and

moderate ENL (P ¼ 0·088) nor those with moderate and severe disease (P ¼ 0·129).

However there was a significant difference (P ¼ 0·028) when three severity groups were

analysed together.

The only change to the scale following the pilot process was to reverse the AIOS so that

the positive outcome was on the left hand side rather than the right. This was to reduce any

confusion with measuring and scoring the outcomes of the two VASs.

Discussion

We have developed and piloted a new scale for measuring the severity of ENL which builds

on previously published scales to which we are indebted. We acknowledge that the number of

Table 4. Description of patients with ENL and outcome of ENLIST ENL Severity Scale. IQR ¼ interquartile range

Number in pilot study (n=22) (%)

ENLIST ENL Severity Scale (Median Score

[IQR]) (n=21)

Male:Female 6·3:1 ------

Median age (years [Range]) 28 [18–51] ------

Ridley Jopling Borderline lepromatous leprosy

12 (54·5) ------

Lepromatous leprosy 10 (45·5) ------

Physician determined severity

Mild 4 (18·2) 9·5 [4]

Moderate 10 (45·5) 14 [8]

Severe 8 (36·4) 20 [5]

Type of ENL Acute 10 (45·5) 13 [10]

Recurrent 8 (36·4) 18 [5]

Chronic 4 (18·2) 10·5 [5·5]

5

10

15

20

25

ENLI

ST E

NL

Seve

rity

Scal

e Sc

ore

Mild Moderate SevereFigure 2. Scores across severity groups for the prototype ENLIST ENL Severity Scale.


individuals in the scale assessment exercise (n ¼ 43) and the pilot exercise (n ¼ 22) is small

and that male patients are over represented compared with our large, previous study,9

however useful information was obtained from both.

During the development of the ENLIST ENL Severity Scale we assessed the utility of

three previously published scales and incorporated elements of them we felt were successful.

The analysis of the ENLIST 1 data also helped inform the scale by demonstrating the

importance of pain as a potential marker of ENL severity. We also took a novel approach by

incorporating a history of fever into the scale in addition to demonstrable fever at the time of

examination.

The 16 item ENLIST ENL Severity Scale is a prototype (see Appendix 1.) and may

change following formal validation when some items may prove to be redundant. The scale is

easy to use but we accept that incorporating two VASs into this severity measure make it

more time consuming. One of the main reasons for piloting the scale was to ensure that there

were no problems with respect to translation and interpretation of the VASs, particularly the

AIOS which has not been validated outside of the United States. One of the advantages of

including a validated measure such as the pain VAS is that it may also serve as an ‘anchor

scale’ along with another gold standard such as expert opinion during a formal validation

study.15

The ENLIST ENL Severity Scale is not currently gender neutral because one item,

‘Orchitis due to ENL’, relates solely to males. During the validation of the scale it will be

important to determine whether this item is useful or not. This will require the analysis to be

conducted for men and women separately in the first instance. Should the item prove to

be indispensable then a male and female version of the scale will be produced. The results of

separate scales will need to be interpreted in light of this. The alternative would be to use a

conversion factor.

We have developed a User Guide of detailed accompanying notes (see Appendix 2.) to

facilitate application of the scale and we will continue to scrutinise and improve these where

necessary.

The ENLIST ENL Severity Scale is now being formally tested to assess validity,

reliability and minimal clinically important difference in six centres affiliated with the

ENLIST Group. We hope that the final scale will prove useful in both laboratory and clinical

research and in the assessment of patients in routine clinical settings.

Acknowledgements

The membership of the ENLIST Group also includes: Marivic Balagon, Shimelis N. Doni,

Annamma John, David Khan, Milton Moraes, Pawan Parajuli, Euzenir Sarno, Digafe

Tsegaye.

Funding

The workshop was funded by the Novartis Foundation with additional support from Cipla.

Dr Walker is supported in part by a grant from the Hospital and Homes of St. Giles.

The funders had no role in study design, data collection and analysis, decision to publish,

or preparation of the manuscript.


References

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3 Walker SL, Saunderson P, Kahawita IP, Lockwood DN. International workshop on erythema nodosum leprosum(ENL) - consensus report; the formation of ENLIST, the ENL international study group. Lepr Rev, 2012; 83:396–407.

4 Walker S, Lockwood D. Erythema Nodosum Leprosum International Study Group: 3rd ENLIST Meeting Report,Mumbai, 7th-9th April 2015. Lepr Rev, 2015; 86: 407–411.

5 Feuth M, Brandsma JW, Faber WR et al. Erythema nodosum leprosum in Nepal: a retrospective study of clinicalfeatures and response to treatment with prednisolone or thalidomide. Lepr Rev, 2008; 79: 254–269.

6 van Brakel WH, Nicholls PG, Lockwood DN et al. A scale to assess the severity of leprosy reactions. Lepr Rev,2007; 78: 161–164.

7 Kaur I, Dogra S, Narang T, De D. Comparative efficacy of thalidomide and prednisolone in the treatment ofmoderate to severe erythema nodosum leprosum: a randomized study. Australas J Dermatol, 2009; 50: 181–185.

8 Haslett PA, Roche P, Butlin CR et al. Effective treatment of erythema nodosum leprosum with thalidomide isassociated with immune stimulation. J Infect Dis, 2005; 192: 2045–2053.

9 Walker SL, Balagon M, Darlong J et al. ENLIST 1: An International Multi-centre Cross-sectional Study of theClinical Features of Erythema Nodosum Leprosum. PLoS Negl Trop Dis, 2015; 9: e0004065.

10 Bursac Z, Gauss CH, Williams DK, Hosmer DW. Purposeful selection of variables in logistic regression. SourceCode Biol Med, 2008; 3: 17.

11 Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs, 1988; 14: 9–17.12 Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain),

Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill PainQuestionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), andMeasure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken), 2011; 63(Suppl11): S240–252.

13 Bell IR, Cunningham V, Caspi O et al. Development and validation of a new global well-being outcomes ratingscale for integrative medicine research. BMC Complement Altern Med, 2004; 4: 1.

14 Jensen MP, Chen C, Brugger AM. Interpretation of visual analog scale ratings and change scores: a reanalysis oftwo clinical trials of postoperative pain. J Pain, 2003; 4: 407–414.

15 Clark LA, Watson D. Constructing validity: basic issues in objective scale development. PsychologicalAssessment, 1995; 7: 309–319.


Appendix 1. ENLIST ENL Severity Scale

ITEM

SCORES

0 1 2 3 SCORE

1 VAS – Pain (mm)

0 1–39 40–69 70–100

2 VAS Wellbeing (mm)

0 1–39 40–69 70–100

3 Fever None (37·5 or less)

No fever now but history of fever in last 7 days

37·6–38·5 38·6 or higher

4 Number of ENL skin lesions

None 1–10 11–20 21 or more

5 Inflammation of ENL skin lesions

Non tender

Redness Painful Complex

6 Extent of ENL skin lesions

0 1–2 regions 3–4 regions 5–7 regions

7 Peripheral oedema

None 1 site of Hands or Feet or Face

2 sites All three sites (Hands and Feet and Face)

8 Bone pain None Present on examina-tion but does not limit activity

Sleep or activitydisturbed

Incapacitating

9 Inflammation of Joints and/or digits due to ENL

None Present on examina-tion but does not limit activity

Sleep or activitydisturbed

Incapacitating

10 Eye inflamma-tion due to ENL

None redness or pain redness and pain

Blurring and/or reduced vision

11 Orchitis due to ENL

None Tenderness Pain on walking or movement

Pain at rest

12 Lymphadeno-pathy due to ENL

None Enlarged Pain or tenderness

Pain or tender-ness in 2 or more groups

13 Nerve tender-ness due to ENL

None Absent if attention distracted

Present even if attention distracted

Patient with-draws limb on examination

14 Number of nerves with NEW sensory NFI due to ENL

None 1 2 3 or more

15 Number of nerves with NEW motor NFI due to ENL

None 1 2 3 or more

16 Urinalysis for protein

None Trace 1 or 2+ 3+

TOTAL


Appendix 2. User Guide for the ENLIST ENL Severity Scale

SCALE ITEM NOTES

1. VAS Pain Instruct the patient to point to the position on the line to indicate how much pain they are currently feeling. The far left end indicates ‘No pain’ and the far right end indicates ‘Worst possible pain’.Take the measurement (in mm) using a ruler from the LEFT end of the line to the centre of the cross.

2. VAS Modified AIOS Instruct the patient to point to the position on the line to indicate their sense of well-being. The far left end indicates the ‘Best’ they have ever been and the far right end indicates the ‘Worst’. Take the measurement (in mm) using a ruler from the LEFT end of the line to the centre of the cross.

3. Fever Take temperature (in °C) using a thermometer. If the temperature is GREATER than 37·5°C the patient has a fever. If it is less than or equal to 37·5°C the patient scores 0 for this item UNLESS they give a history of having had a fever in the last 7 days in which case they score 1. The cause of the fever does not need to be established.

4. Number of ENL skin lesions

Note: only skin lesions due to ENL are to be considered for this item.

5. Inflammation of ENL skin lesions

Note: only skin lesions due to ENL are to be considered for this item. The term complex refers to the following skin lesions: vesicular, bullous, pustular, erythema multiforme-like, panniculitis, necrotic, ulcerated.If the participant fulfils criteria for more than one score then the highest scoring criteria should be used. For example if there are red ENL skin lesions and some are ulcerated or vesicular or pustular then the patient scores 3 because “complex” lesions are present.

6. Extent of ENL skin lesions

Note: only skin lesions due to ENL are to be considered for this item.The separate regions are: a) Head and neck b) Left upper limb c) Right upper limb d) Torso –front (including genitals) e) Torso back (including buttocks) f) Left lower limb g) Right lower limb

7. Peripheral oedema due to ENL

The three sites to be considered are the face, hands and feet. Oedema thought to be due to treatment such as corticosteroids or thalidomide should not be counted.

8. Bone pain Bone pain is distinct from pain or tenderness of the joints. It is most usually elicited by palpation of the subcutaneous border of the tibia.

9. Inflammation of Joints and/or digits due to ENL

Note: only joint inflammation due to ENL is to be considered for this item. Inflammation of the joint will be present if there is any of the following: pain or tenderness, redness, swelling or heat. It them must be determined if any of these are sufficiently severe to meet the criteria of the scores. If more than one joint is affected the most severely affected joint is used to determine the score.

10. Eye inflammation due to ENL

Only eye symptoms due to ENL are to be considered. For example blurred vision due to cataract caused by previous steroid use would not count. If the participant fulfils criteria for more than one score then the highest scoring criteria should be used. For example: a patient with a red eye and blurred vision would score 3.

11. Orchitis due to ENL The testes must be examined.

12. Lymphadenopathy due to ENL

The lymph node groups to be examined are: a) Head and neck (including the supraclavicular fossae) b) Axillary c) InguinalNote: Lymph node groups on the different sides of the body are separate for example: left axillary and right axillary. Therefore there are 6 lymph node groups for the purposes of the scale.

13. Nerve tenderness due to ENL

Any peripheral or cutaneous nerve tenderness due to ENL is to be considered. If the participant fulfils criteria for more than one score then the highest scoring criteria should be used. The most severely affected nerve should be used.

14. Number of nerves with NEW sensory NFI due to ENL

NEW nerve function impairment (NFI) is defined as NFI occurring since the start of the current episode of ENL. An “episode” of ENL is the onset of new or deterioration in established ENL symptoms.NFI of the hands is an inability to feel the 2 g monofilament at two sites for a given sensory nerve.NFI of the feet is an inability to feel the 10 g monofilament at two (of the four) sites for the posterior tibia nerve.Nerves on different sides of the body are separate for example left and right ulnar nerves.

15. Number of nerves with NEW motor NFI due to ENL

NEW nerve function impairment (NFI) is defined as NFI occurring since the start of the current episode of ENL. An “episode” of ENL is the onset of new or deterioration in established ENL symptoms.Motor impairment is defined as Muscle power MRC Grade 4 or less in a muscle/muscle group innervated by a given nerve.)Nerves on different sides of the body are separate for example left and right ulnar nerves.

16. Urinalysis for protein A simple bedside test using a dipstick is adequate.


For patients with newly diagnosed ENL, recurrent ENL or those on treatment for ENL

whose symptoms require an increase in current or additional treatment

Acute ENL is a single episode of ENL of less than 24 weeks duration

Recurrent ENL: is a second or subsequent episode of ENL occurring 28 days or more after

stopping treatment for ENL

Chronic ENL: is ENL occurring for 24 weeks or more during which a patient has required

ENL treatment either continuously or where any treatment free period has been 27 days or

less.

Appendix 3. Data collection tool used for the assessment of the three published scales

Details

Gender (Male/Female)

Age (years)

Physician determined Severity (Mild/Moderate/Severe)

Type of ENL (Acute/Recurrent/Chronic)


‘modified’ van Brakel et al. Leprosy Review 2007;78:161-4 (Range Males 0-59, Females 0-54)

ITEM 0 1 3 5 SCORE

Degree of inflammation of nodules

None Tender nodule (s) Painful nodule (s) Ulceration

Number of nodules

None ≤10 >10 >50/uncountable

Inflammation of lymph nodes due to current reaction

None Chronic Mild, acute Definite

Inflammation of joints due to current reaction


Inflammation of eye due to currentreaction


Inflammation of testis due to current reaction


Bone pain due to current reaction


Fever due to reaction (°C)

<37·5 37·5–38·9 >39 ---------

Peripheral oedema due to reaction

None Oedema not affecting function

Oedema affecting function

---------

Number of limbs with peripheral oedema

None 1 2 or more ----------

Nerve pain None Mild, does not limit activity

Sleep or activity disturbed

Incapacitating

Nerve tender-ness on gentle palpation

None Mild tenderness or paraesthesia, absent if attention distracted

Present, even if attention distracted

Severe, patient withdraws limb forcibly

Degree of new nerve enlarge-ment, in nerves previously known to be normal)

No new nerve enlargement or borderline

Definite new enlargement

----------- Nerve abscess

Number of nerves showing recent sensory or motor function impairment

None 1 2 or 3 4 or more

TOTAL


“modified Ramu”. Kaur et al. Australasian Journal of Dermatology 2009;51:181-5 (Range Males 0-18, Females 17)

ITEM 0 1 2 3 SCORE

Fever (°C) --------------- 36·9–37·7 37·8–38·8 ≥38·9

Extent of inflammatory skin lesions, that is, exacerbation of lesions, erythema nodosum leprosum etc

--------------- Scattered lesions involv-ing the upper arms/thighs, face or part of the trunk

More extensive lesions affect-ing two limbs (upper/lower limbs), trunk with occasional pustulation

Widespread extensive lesions with postulation and ulceration

Neuritis Absent Neuritis of single nerve

Neuritis of more than one nerve trunk

-----------------

Arthritis Absent ≤2 joints 3–4 joints 5 or more joints

Orchitis Absent Involved --------------- -----------------

Scleritis Absent Involved --------------- -----------------

Lymphadenitis Absent Single node ≤2 cm

More than one node, ≥2·5 cm

-----------------

Internal organ involve-ment (liver/kidney/any other)

Absent ----------------- ----------------- Present

TOTAL

Haslett et al. Journal of Infectious Diseases 2005;192:2045-53 (Range 0-31)

Location of skin lesions Extent of lesions on region involved SCORE

0 1 2 3

HEAD None <25% 25–75% >75%

TORSO – FRONT None <25% 25–75% >75%

TORSO – BACK None <25% 25–75% >75%

LEFT UPPER LIMB None <25% 25–75% >75%

RIGHT UPPER LIMB None <25% 25–75% >75%

LEFT LOWER LIMB None <25% 25–75% >75%

RIGHT LOWER LIMB None <25% 25–75% >75%

SUBTOTAL

Any ulcerated or blistered or pustular skin lesion/s at ANY site?

IF YES ADD 10 POINTS

TOTAL


the development of a severity scale for erythema nodosum ... · 332 0305-7518/16/064053+15 $1.00 q...

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