Thalidomide and steroid in the management of erythema nodosum leprosum.

OBJECTIVE: The objective of the study was to assess the efficacy and safety profiles of combined treatment of prednisolone with thalidomide (Gr-A) and prednisolone with clofazimine (Gr. B) in patients with erythema nodosum leprosum (ENL) or type 2 lepra reactions.
MATERIALS AND METHODS: Efficacy of both regimens was assessed on the basis of clinical recovery of recurrent ENL measured by reaction severity score (RSS), Visual Analog Scale (VAS), and recurrence of type 2 lepra reaction. The causality assessment of adverse drug reactions was done using the WHO UMC causality assessment scale.
RESULTS: The average age of patients with recurrent ENL was 42.8 years (male) and 51.8yrs (female) and had mean duration of leprosy and recurrent ENL 2.4 years and 2.09 years, respectively. 80% of nonrecurrence was observed in Gr-A versus 66% in Gr-B. Significant (P < 0.05) lower RSS and VAS was found in both the treatment groups as compared to pretreatment value. The reduction in RSS and VAS was statistically significant (P < 0.05) in Gr-A compared to Gr-B treatment.
CONCLUSION: Thalidomide combination with steroid was found to be more efficacious than clofazimine combination with steroid in the treatment of ENL both the treatment regimens showed few tolerable side effects. Improved strategies for the treatment and management of these reactions need to be developed.

Introduction

Leprosy (Hansen's disease) is a public health problem. Erythema nodosum leprosum (ENL) is an immune-mediated complication that occur before, during, and after multiple drug therapy (MDT) for lepromatous leprosy (LL) and Borderline LL.[1] Its pathogenesis is not fully understood; however, it is characterized by immune complex deposition and T-cell activation with high levels of tumor necrosis factor α, interleukin (IL)-6 and IL-1, whose presence has been confirmed by some reports (Sampaio et al. 1991, Pannikar 2003). ENL can manifest as crops of tender erythematous, subcutaneous nodules located on apparently normal looking skin. It may or may not be accompanied with fever, neuritis, orchitis, and bone pain. The incidence of ENL varies in cohorts worldwide from 5% to 49%.[2] The management of this serious, relapsing, and remitting complication is challenging.[1] The extended duration of ENL has both social and medical implications. The WHO has recommended the anti-inflammatory agent, clofazimine, for chronic severe ENL that does not respond well to corticosteroid or for those, the risk of steroid toxicity is high.[12] Clofazimine alone is not sufficient for symptomatic control and it takes for weeks to work.[3] Although steroid (prednisolone) rapidly provides symptomatic relief, it has risk of complications on long-term use.[3] Thalidomide as a potent immunomodulating agent has been reintroduced for the treatment of ENL in 1998 and multiple myeloma in 2006.[45] It appears to be highly effective in treating the acute inflammation as well as maintaining long-term immunosuppression in patients with ENL and also having few side effects due to its steroid-sparing effect.[6] For recurrent or chronic ENL, there is the lack of use of evidence-based standard drug combination regimen, when the individual drug with less side effects fails to control the ENL reaction. Therefore, the present study has been conducted to assess the efficacy and safety of combined treatment regimen of thalidomide plus steroid and clofazimine plus steroid in patients of chronic and recurrent ENL.

Aim and objectives

Aim

To study the effect of steroid and thalidomide in the management of patients with ENL.

Objectives:

To compare the efficacy and safety profiles between thalidomide plus steroid and clofazimine plus steroid treatment regimens

To evaluate and compare the recurrence rate of ENL between the two groups.

Materials and Methods

This open label, prospective, observational study was conducted in eligible consented patients of both gender aged 18 yrs and above attending the dermatology outpatient department/inpatient department for the treatment of recurrent ENL, from June 2018 to November 2018. Our study protocol was approved by the Institutional Ethics Committee of SCB MCH Cuttack.

Recurrent ENL is defined as having four to seven episodes per year, with or without treatment. All clinically diagnosed (by the dermatologist) recurrent ENL cases had completed the treatment for leprosy with MDT and also treated with steroid to which they were found to be not responding.

Pregnant and lactating women or women planning for conception and not using effective contraceptive measures and men who were planning to start a family were excluded. Patients with history of allergy, contraindication for steroid use (diabetes, tuberculosis, gastritis, etc., existing peripheral neuropathy (by SNAP study), hypothyroidism (thyroid profile study), and critically ill patients were excluded. A total of 30 patients were included in the study out of which 15 were in Gr-A (thalidomide plus steroid) and 15 were in Gr-B (clofazimine plus steroid). All the patients had already been treated with steroid and were found to be nonresponders to it. All patients were examined for ENL lesions based on the reaction severity score (RSS).[2] The episodes of recurrence of ENL were also determined by using the RSS. The pain severity was assessed using the Visual Analog Scale (VAS).[7] Adverse drug reactions (ADR) were assessed by using the WHO UMC causality assessment scale.

Data were expressed as mean ± standard deviation and analyzed by using unpaired t-test and by percentage (%) calculation.

Group A: Capsule thalidomide 300 mg and tablet prednisolone 40 mg were administered for a duration of 3 months. Then gradual tapering of thalidomide dose to 200 mg for 1st month, 100 mg for next month and 100 mg on alternate day in the last month along with prednisolone 30 mg for 2 weeks, 20 mg for next 2 weeks, 15 mg for next 2 weeks and 10 mg for next 2 weeks then were weaned off completely. Treatment was continued with thalidomide 100 mg every alternate day for 1 month.

Group B: Capsule clofazimine 300 mg and tablet prednisolone 40 mg were administered for a duration of 3 months, tapered dose of clofazimine 200 mg for 2 months and 100 mg for 1 month along with prednisolone 30 mg for 2 weeks, 20 mg for 2 weeks, 15 mg for 2 weeks, 10 mg for 2 weeks then weaned off completely and continued the treatment with only clofazimine 100 mg every day for 1 month.

The baseline and follow-up parameters were recorded in a predesigned case record form [Figure 1: Case Record Form)], which included the demographic profile, duration of leprosy, and ENL. The clinical assessment in all patients was made before and after treatment by using RSS [Figure 2: RSS], and VAS) [Figure 3: VAS]. The ADRs were assessed by using the WHO UMC causality assessment scale [Figure 4: WHO UMC causality assessment scale].

Figure 1

Case study from

Figure 2

Observations

Figure 3

Visual analogue scale

Figure 4

WHO-UMC ADR Assessment sacle

The patients were followed up on day 0, day 7, and day 30 of 1st month and at monthly interval for the rest 5 months. The follow-up parameters such as RSS (determined by crops of nodules and erythema) were studied. The incidence of recurrence (RSS), pain by VAS, and ADRs were assessed by using WHO-UMC scale and were analyzed.

Results

In our study, a total of 30 patients (25 male/5 female) were included, out of which 15 patients (13 male/2 female) received thalidomide and steroid (Gr-A), rest 15 patients (12 male/3 female) received clofazimine and steroid (Gr-B). The mean age of the males was 42.81 ± 11.04 years and that of the females was 51.8 ± 3.63 years, [as shown in Table 1, Graph 1]. The mean duration of leprosy was 2.4 ± 0.621yrs and mean duration of ENL was 2.09 ± 0.79 years [as shown in Table 2, Graph 2].

Table 1

Age & Gender Distribution of Study Subjects

Gender	Mean age in years
Male	42.81±11.04
Female	51.8±3.63

Graph 1

Age and Gender distribution of study subjects (It is the graphical representation of Table 1)

Table 2

Mean Duration of Leprosy and Mean Duration of ENL

Parameter	Duration in years
Mean duration of leprosy	2.4±0.621
Mean duration of enl	2.09±0.79

Graph 2

Mean duration of leprosy and duration of Erythema nodosum leprosum (graph representation of Table 2)

The mean RSS of Gr-A and Gr-B before treatment was 5.46 ± 0.516 and 5.2 ± 0.414, respectively, as shown in Table 3.

Table 3

Comparison of Mean RSS Score between 2 Groups

Groups	Mean RSS Score±SEM at Different Time Intervals
	Day 0	Day 7	Day 30	2 M	3 M	4 M	5 M	6 M
Group A	5.46±0.516	1.86±0.743	0.2±0.414	0.066±0.258	0*	0.2* ± 0.560	0.066* ± 0.25	0.066* ± 0.25
T+S
Group B	5.2±0.414	1.86±1.06	0.4±0.632	0.26±1.03	0.26±0.59	0.4±1.12	0.33±0.89	0.13±0.35
C+S
P	0.064	0.5	0.157	0.23	0.046	0.046	0.013	0.038

*Significantly Lower RSS was observed in Group A (T + S) at 3M to 6M of observation in Comparison to Group B (C + S).

This study showed significant lower RSS in both the treatment groups from the 3rd month to 6th month of the study in comparison to pretreatment value. When compared between two treatment groups, significant reduction was observed in RSS in Gr-A treatment in comparision to Gr-B treatment (P < 0.05) from the 3rd month to 6th month of study as depicted in [as shown in Table 3].

The percentage episodes of recurrence of ENL determined by using the RSS were found to be lower in Gr-A in comparison to Gr-B (20% vs. 34%) as depicted in [as shown in Table 4, Graph 3].

Table 4

Comparison of Recurrence in Two Groups at end of 6 months using Reaction Severity Score

Category of Patient	Group A Thalidomide		Group B Clofazimine
	Number	%	Number	%
Recurrent	3	20	5	34
Non-Recurrent (Weaned Off Steroids)	12	80	10	66
Total Number of Patients	15	100	15	100

Graph 3

Comparison of recurrence in two groups at end of 6 months using Reaction severity score (graph representation of Table 4)

Table 5 depicted the mean VAS (pain) in Gr-A and Gr-B before treatment as 6.8 ± 1.01 and 7.2 ± 1.01, respectively, and gradual reduction in VAS started from the 2nd month onward of treatment in both the groups compared to pretreatment value (percentage wise). Significant reduction in mean VAS was observed in Gr A treatment as compared to Gr B treatment (P < 0.05) from the 2nd month onward, as shown in Table 5.

Table 5

Comparison of Pain (VAS) between Two Groups

Time Interval	T + S (Group A)		C + S (Group B)		P
	Mean VAS Score	% Improvement	Mean VAS Score	% Improvement
Day 0	6.8±1.01	-	7.2±1.01	-	0.1462
Day 7	3.4±1.5	50	3.4±0.9	51	0.51
Day 30	2.8±1.01	58	3.3±1.39	53	0.1207
Month 2	2.06±0.7	69	3.13±1.55	56	0.01103*
Month 3	1.73±0.45	74	2.66±1.39	62	0.0102*
Month 4	1.46±0.51	78	2.46±1.68	65	0.0181*
Month 5	1.3±0.48	80	2.13±0.83	70	0.001*
Month 6	1.2±0.41	82	1.53±0.51	78	0.03*

*The reduction in the mean VAS Score was significant for both the treatment groups when calculated at 6 months in comparison to baseline.

The mean VAS (pain) in Gr-A & Gr-B before treatment were 6.8 ± 1.01 and 7.2 ±1.01 respectively and gradual reduction in VAS started from 2nd month onwards of treatment in both the groups compared to pretreatment value (percentage wise). Significant reduction in mean VAS was observed in gr A treatment as compared to gr B treatment (P<0.05) from 2nd month onwards [as shown in Table 5]. As depicted in Figures 5-7, definite clinical improvement was observed after treatment with both regimens. Adverse drug reactions occurred in four patients in each group. In Gr-A (thalidomide + steroid), two patients (13.3%) had dizziness & two patients ((13.3%) had fatigue. In Gr-B (clofazimine+steroid), three patients (20%) had hyperpigmentation & one patient (6.6%) had nausea and vomiting [as shown in Table 6]. According to WHO UMC causality assessment system 25% ADRs were probable and 75% were possible [as shown in Table 7, Graph 4]. Adverse drug reactions were self-limiting and did not lead to drop outs. No death was found during the total study period.

Figure 5

Before treatment by Thalidomide

Figure 7

Before and after Clofazimine treatment

Table 6

ADRs Observed in Two Groups

ADR Type	Group A		Group B
	Number of Patients	%	Number of Patients	%
Dizziness	2	13.3	-	0
Fatigue	2	13.3	-	0
Hyperpigmentation of Skin	-	0	3	20
Nausea and Vomiting	-	0	1	6.6

Table 7

WHO-UMC ADR Assessment Scale

Causality Term	(n)	%
Possible	6	75
Probable	2	25

Graph 4

Adverse drug reactions observed according to WHO UMC Causality assessment Scale (graph representation of Table 7)

After treatment of Thalidomide

Discussion

Recently, there has been a rising interest in the treatment schedule of ENL which is a severe, chronic and recurrent reaction. There are variable opinions about the treatment of this severe reaction. Steroids have been extensively used for the management of ENL including prevention and treatment of nerve function impairment.[8]

Most of the times, it is difficult to control many cases of ENL with prescribed dose of steroid (prednisolone 40 mg/day). Many patients develop new ENL lesions and there is the chance of steroid dependency in some situations when the steroids are tapered. It is often not realized that addition of an alternative drug; thalidomide or clofazimine may reduce the need for steroids.[9] Further, to reduce the long-term side effects of cumulative dose of steroid, researchers are searching for better steroid based regimen.

In our study population, the mean duration of ENL was 2.09 years which was found to be shorter in contrast to the study done by Nabarro et al.[10] Further our study showed that the mean duration of leprosy was 2.4 years. This suggests the early diagnosis and treatment of leprosy and its reaction in our study population. Steroid nonresponder patients (Gr-A and Gr-B) received the treatment as described earlier. Significant clinical improvement was found in both the treatment groups, but it was found to be significantly better in Group A in comparison to Group B. The RSS value was found to be significantly reduced (P < 0.05) in Gr-A in comparison to Gr-B. The significant reduction in VAS was observed in Gr-A treatment in comparison to Gr-B treatment (P < 0.05), which is in accordance with a study by Kar and Gupta.[11]

In this study, the patients treated with thalidomide had fewer recurrence than those receiving clofazimine which was similar to a study by Kar and Gupta where the recurrence were 17.65%, and 40%, respectively. Similar to our study, patients of a study by Kar and Gupta were weaned off from steroids for a period of 1 month.[11] Both thalidomide and clofazimine when combined with steroid proved to be very effective drug in the management of recurrent/chronic ENL. Clofazimine being a slow acting drug may take a year or even more to make the patient steroid free.[11]

Our study of only 6 month duration may not be sufficient to give opinion about whether treatment with clofazimine and steroids can be a good combination in chronic and recurrent ENL, because of its anti-inflammatory effect and in cases where thalidomide cannot be given. Our study proved that thalidomide is a very effective drug but cannot completely replace steroid in the management of ENL.

The better tolerability to treatment might be due to steroid sparing effect of thalidomide. Further we did not get any neurological side effects of thalidomide which might be due to additional use of steroid or due to short study duration. In the study done by Nabarro et al., there were ten ADRs reported in each group which could be due to longer study period, in contrast to ours.[10] Compared to others, there were no deaths found during our study period. Walker et al. found a mortality rate of 7.9% in patients hospitalized for ENL in Ethiopia, where thalidomide is not available. The shorter study period and small sample size of our study might not be able to conclude about the role of thalidomide for zero mortality.

Conclusion

Steroid-based combination therapy with thalidomide and clofazimine was found to be effective in the treatment of steroid nonresponder recurrent ENL patients with few tolerable side effects. The recurrence rate of ENL was also less in thalidomide combination than clofazimine combination treatment.

Further work is needed to better define the clinical aspect of the condition and refine the response to treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.