Alitretinoin 30mg compared to placebo for patients with moderate to severe chronic hand eczema refractory to potent topical corticosteroids

Patient or population: patients with moderate to severe chronic hand eczema refractory to potent topical corticosteroids

Setting:

Intervention: alitretinoin 30mg

Comparison: placebo

Outcomes

Anticipated absolute effects^* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with alitretinoin 30mg

Disease severity according to patients
assessed with: PaGA of clear or almost clear (responders)
follow up: range 12 weeks to 24 weeks

143 per 1.000

392 per 1.000
(311 to 497)

RR 2.74
(2.17 to 3.47)

1210
(2 RCTs) ^a

⨁⨁⨁◯
MODERATE ^b

Alitretinoin 30 mg probably results in a large improvement of disease severity according to the patients.

Disease severity according to physician
assessed with: PGA of clear or almost clear (responders)
follow up: range 12 weeks to 24 weeks

155 per 1.000

430 per 1.000
(344 to 537)

RR 2.77
(2.22 to 3.46)

1210
(2 RCTs) ^a

⨁⨁⨁◯
MODERATE ^b

Alitretinoin 30 mg probably results in a large improvement of disease severity according to the physicians.

Change from baseline in health related quality of life
assessed with: Skindex-29
follow up: 24 weeks

The decrease from baseline at EOT in total Skindex-29 scores was significantly greater in alitretinoin- vs placebo treated patients (-33 vs -15; p<0.001).

596
(1 RCT) ^c

⨁⨁⨁◯
MODERATE ^d

Alitretinoin 30mg probably improves quality of life according to patients.

Proportion of patients that dropped out due to adverse events
follow up: range 24 weeks to 28 weeks

In Fowler et al. the number of patients with AE during treatment up to 7 days after EOT was for the intervention group N=216 73% and in the control group N=155 52%. Most common were headache, nausea, upper respiratory tract infection and flushing in the alitretinoin group. In Ruzicka et al. it was unclear how many people reported at least one adverse event. Headache was the most frequently reported AE (more in 30mg group than in the other two groups, N=20, 5%) and most frequent for withdrawal. No other AE led to more than two withdrawals in any group (data not published). Withdrawal because of headache: Alitretinoin N=17 , 4% and control group N=1, 1%. Most common were headache, erythema, nasopharyngitis and flushing.

1210
(2 RCTs) ^a

⨁⨁◯◯
LOW ^b,e

The evidence suggests that alitretinoin 30mg causes more adverse events than placebo.

Number of patients that relapsed at any time point
follow up: range 24 weeks to 72 weeks

3 per 1.000

10 per 1.000
(1 to 177)

RR 3.22
(0.18 to 58.27)

127
(1 RCT) ^c

⨁◯◯◯
VERY LOW ^d,f

We are uncertain about the effect of alitretinoin 30 mg on the number of patients that relapse.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Alitretinoin 20mg compared to placebo for patients with moderate to severe chronic hand eczema refractory to potent topical corticosteroids

Patient or population: patients with moderate to severe chronic hand eczema refractory to potent topical corticosteroids

Setting:

Intervention: alitretinoin 20mg

Comparison: placebo

Outcomes

Anticipated absolute effects^* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with alitretinoin 20mg

Disease severity according to patients
assessed with: PaGA of clear or almost clear (responders)
follow up: range 12 weeks to 24 weeks

115 per 1.000

313 per 1.000
(156 to 627)

RR 2.71
(1.35 to 5.43)

158
(1 RCT) ^a

⨁⨁◯◯
LOW ^b,c

Alitretinoin 20mg appears to improve disease severity according to patients.

Disease severity according to physician
assessed with: PGA of clear or almost clear (responders)
follow up: range 12 weeks to 24 weeks

269 per 1.000

401 per 1.000
(253 to 630)

RR 1.49
(0.94 to 2.34)

158
(1 RCT) ^a

⨁⨁◯◯
LOW ^b,c

Alitretinoin 20mg appears to improve disease severity according to physician.

Change from baseline in health related quality of life according to patient
assessed with: DLQI
follow up: 24 weeks

Ruzicka et al. (2004) stated that DLQI improved during treatment with a general trend to more positive effects with higher drug doses without reaching the α level of statistical significance of p=0.05.

158
(1 RCT) ^a

⨁◯◯◯
VERY LOW ^b,c,d

We are uncertain about the effect of alitretinoin 20 mg on the improvement of quality of life compared to placebo.

Proportion of patients that dropped out due to adverse events
follow up: range 12 weeks to 24 weeks

51 per 1.000

63 per 1.000
(17 to 224)

RR 1.22
(0.34 to 4.37)

158
(1 RCT) ^a

⨁◯◯◯
VERY LOW ^b,e

We are uncertain about the effect of alitretinoin 20mg on withdrawal due to adverse events.

Number of patients that relapsed at any time point - not measured

No study addressed this outcome.

-

-

We are very uncertain about the effect of alitretinoin 20mg on the number of patients that relapsed at any time point during the study.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Alitretinoin 10mg compared to placebo for patients with moderate to severe chronic hand eczema refractory to potent topical corticosteroids

Patient or population: patients with moderate to severe chronic hand eczema refractory to potent topical corticosteroids

Setting:

Intervention: alitretinoin 10mg

Comparison: placebo

Outcomes

Anticipated absolute effects^* (95% CI)

Relative effect
(95% CI)

№ of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Risk with placebo

Risk with alitretinoin 10mg

Disease severity according to patients
assessed with: PaGA of clear or almost clear (responders)
follow up: range 12 weeks to 24 weeks

141 per 1.000

240 per 1.000
(174 to 334)

RR 1.70
(1.23 to 2.36)

781
(2 RCTs) ^a

⨁⨁⨁◯
MODERATE ^b

Alitretinoin 10mg probably improves disease severity according to patients slightly.

Disease severity according to physician
assessed with: PGA of clear or almost clear (responders)
follow up: range 12 weeks to 24 weeks

194 per 1.000

309 per 1.000
(233 to 408)

RR 1.59
(1.20 to 2.10)

781
(2 RCTs) ^a

⨁⨁⨁◯
MODERATE ^b

Alitretinoin 10mg probably improves disease severity according to physicians slitghly.

Change from baseline in health related quality of life
assessed with: DLQI
follow up: 24 weeks

Ruzicka et al. (2004) stated that DLQI improved during treatment with a general trend to more positive effects with higher drug doses without reaching the α level of statistical significance of p=0.05.

158
(1 RCT) ^c

⨁◯◯◯
VERY LOW ^b,d,e

We are uncertain about the effect of alitretinoin 10 mg on the improvement of quality of life compared to placebo.

Proportion of patients that dropped out due to adverse events
follow up: 24 weeks

In Ruzicka et al. (2008) it was unclear how many people dropped out because of adverse events. Headache was the most frequently reported AE and most frequent for withdrawal (N=6 vs. N=1 in control group, both 1%). No other AE led to more than two withdrawals in any group (data not published). In Ruzicka et al. (2004) withdrawal because of headache was N=1 (1%) and unknown for control group.

158
(1 RCT) ^c

⨁◯◯◯
VERY LOW ^b,f

We are uncertain about the effect of alitretinoin 10mg on drop out due to adverse events.

Number of patients that relapsed at any time point - not measured

No study addressed this outcome.

-

-

We are very uncertain about the effect of alitretinoin 10mg on the number of patients that relapsed at any time point.

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High certainty: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different
Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect

Author (year of publication)

Study design

Patients (N)

Inclusion criteria

Follow-up

Outcome measures

Results

Lost to follow-up

Comments

Diepgen 2012

Efficacy and Tolerability of Alitretinoin for Chronic Hand Eczema Under Daily Practice Conditions: Results of the TOCCATA Open Study Comprising 680 Patients

Non-interventional observational open study

(TOCCATA)

Intervention: oral alitretinoin (Toctino®, 30 or 10 mg daily)

680 patients

Patients with severe chronic hand eczema (CHE) unresponsive to potent topical corticosteroids during routine medical practice*

Stratification at baseline morphology: Vesicular/pompholyx, hyperkeratotic rhagadiform and fingertip.

Max 24 weeks

Investigation of effectiveness and tolerability of alitretinoin, and collection of structured data under daily dermatological practice conditions.

Subtypes of hand eczema defined according to the German guidelines “Guideline on the management of hand eczema” after the PGA for definition of severity of HE, helped by a validated photographic guide.

Overall assessment of effectiveness and tolerability by patient

333 (49%) patients completed treatment ahead of schedule (45% stated “clearance of hand eczema”). 57% of patients achieved a PGA rating of “clear” or “almost clear” hands with a continuous increase in response observed during the treatment course.

Slightly higher response rates (61%) were observed for patients rated PGA-moderate at the beginning and slightly lower rates (53%) for patients rated PGA-severe at baseline.

Total of 298 ADR were recorded in 23% of the 680 patients with headache as the most frequent one (7.5%) followed by increased blood triglycerides (4.9%) and increased blood cholesterol (3.8%). Serious adverse drug reactions were documented in only four (0.6%) patients (lymphatic oedema, paranoia, recto-sigmoiditis and soft-tissue swelling).

NS

272 patients completed treatment ahead of schedule other than clearance of HE

(Reasons: patient decision, Insufficient efficacy, AE /ADR (n=42), lab. value change, patient did not return, other)

*inclusion criteria:
- Disease duration ≥ 3 months or > 2 flares within the last 12months
- pretreatment with topical corticosteroids
- no long-lasting healing under adequate topical treatment
- no other active severe skin diseases or acute skin infections dominating the clinical picture

From visit T3 onwards (week 12), treatment could be stopped if patient showed total clearance.

Level B because of large study group, clear inclusion criteria, long follow up. Comparative in dose, but no placebo.

Dirschka 2010

An open-label study assessing the safety and efficacy of alitretinoin in patients with severe chronic hand eczema unresponsive to topical corticosteroids

Open-label study

Intervention: oral alitretinoin 30mg 1dd for up to 24 weeks

249 patients

CHE ≥ 6 months, aged 18–75 years old and unresponsive to standard treatment including topical corticosteroids.

24 weeks

NS

They evaluated safety and efficacy of alitretinoin: adverse events, Physician’s Global Assessment (response defined as a rating of ‘clear’ or ‘almost clear’, and partial response defined as ‘clear’ almost clear’ or ‘mild disease’), modified Total Lesion Symptom Score (mTLSS), Patient’s Global Assessment, extent of disease, intensity of pain and pruritus as determined by visual analogue scale (VAS) and a categorical scale for pruritus.

Alitretinoin was well tolerated when given for up to 24 weeks. Dose reduction occurred in 16.5% of patients. Dose interruption was required for 15.7% of patients, most commonly for headache. AEs and laboratory changes comprised effects typical of the retinoid class. A PGA response of ‘clear’ or ‘almost clear’ was reported for 46.6% of patients. Results of VAS and categorical assessments of pruritus provided supporting evidence of efficacy, and treatment was assessed as providing meaningful benefits to patients.

190 (76.3%) completed the full 24 weeks

59 (23.7%) were prematurely withdrawn from the study

Dua 2013

Our experience with alitretinoin in the management of patients with chronic, severe hand eczema

Prospective study

Intervention: alitretinoin 30mg or 10mg for 4 to 36 weeks

28 patients

Adults with severe, chronic hand eczema unresponsive to potent topical corticosteroids.

4-36 weeks

PGA ‘clear’ or ‘almost clear’, time to relapse, adverse events.

A satisfactory response (PGA score ‘clear’ or ‘almost clear’ hands): 20 patients (71%) within 24 weeks. 12 patients relapsed (60%) with an average time to relapse of 12 weeks (range1 week–9 months). 6 patients started a second course of alitretinoin. Side-effects were reported by 18 (64%); most common was headache (16 patients, 57%). 2 patients dis-continued treatment due to side-effects (neck pain; rash) and one patient died of unrelated causes.

?

Poster only

Khoury 2016

Alitretinoin for the treatment of patients with severe refractory chronic hand eczema

Prospective study

Intervention: alitretinoin

(dosage and treatment time unknown)

28 patients

Unresponsive patients with CHE.

-

Not specified.

They evaluated disease severity (reported by the patient) and the Dermatology Life Quality Index (DLQI).

68% of the patients reported symptoms alleviation after alitretinoin treatment (11% complete remission, 25% pronounced improvement and 32% moderate improvement). Adverse events were tolerated and self-reported adherence was satisfactory.

-

Poster only

Kumari 2016

Impact of systemic alitretinoin treatment on skin barrier gene and protein expression in patients with chronic hand eczema*

Prospective study

Intervention: alitretinoin 30 mg daily up to 27 weeks

15 patients

Patients with CHE who are refractory to topical corticosteroids.

Up to 27 weeks

Not specified.

They evaluated disease severity (assessed using the clinical score ‘Manuscore’ and the transepidermal water loss (TEWL))

Patients showed a significant reduction in the clinical score (P = 0.0068) after therapy with alitretinoin whereas the TEWL values before and after treatment remained stable. Analysis of skin biopsies before treatment showed a significant increase in Ki-67-positive cells in the suprabasal layer and a dysregulated expression of various skin barrier genes, such as claudin 1, loricrin, filaggrin and cytokeratin 10, which were normalized after treatment. TSLP was significantly upregulated in patients with CHE and also normalized after alitretinoin treatment and negatively correlated with filaggrin.

?

Lynde 2012

Extended treatment with oral alitretinoin for patients with chronic hand eczema not fully responding to initial treatment

Open-label trial

Intervention: alitretinoin 30 mg once daily

243 patients

3 groups:
-alitretinoin 30/30 (n=69)

-alitretinoin 10/30 (n=117)

-placebo/30 (n=57)

Patients with severe chronic hand eczema (CHE) who did not fully respond to initial treatment in the BACH study: rated as ‘mild’, ‘moderate’ or ‘severe’ eczema according to the Physician’s Global Assessment (PGA).

12-24 weeks.

The primary endpoint was the PGA (using a five-point, predefined scale to rate CHE severity from ‘clear’ to ‘severe’).

Secondary endpoints included the Patient’s Global Assessment (PaGA), Modified Total Lesion Symptom Score (mTLSS), extent of disease and time to response.

By the end of the follow-on study, the PGA response rate to the subsequent course of alitretinoin 30 mg was 50% and 39% in patients treated previously in BACH with 10 or 30 mg per day, respectively, and 51% in patients who previously received placebo in BACH. Alitretinoin was well tolerated, and no significant late-arising toxicities were seen.

?

Politiek 2016a

Alitretinoin and acitretin in severe chronic hand eczema; results from a retrospective daily practice study

Retrospective study

Intervention: Alitretinoin 30 mg/day and acitretin 20–30 mg daily

Treatment period is 12–24 weeks depending on the response.

204 patients

Adult patients having a clinical diagnosis of chronic hand eczema (≥3 months), treated with acitretin between 01-01-1994 and 01-08-2015 and/or alitretinoin between 01-09-2013 and 01-08- 2015.

-

Effectiveness of treatment according to the clustered physician’s global assessment (PGA) score (PGA1: good effect of treatment, PGA2: moderate effect, PGA3: failure of treatment), median time to relapse (time until retreatment or time until severe signs and symptoms of hand eczema reoccurred).

95 patients were treated with alitretinoin and 109 patients with acitretin. The main reasons for discontinuation were adverse events and cleared hand eczema, 29.5 and 27.4% in alitretinoin versus 43.1 and 23.9% in acitretin. Patients with hyperkeratotic hand eczema had most often a good effect of treatment: 68.3% in alitretinoin and 50.7% in acitretin treatment. The drug survival rates of alitretinoin and acitretin after 12, 24, 36, and 52 weeks were 69.3, 45.1, 19.6, 7.0% and 74.3, 45.5, 33.8, 23.2%, respectively.

-

Thaci 2016

Effectiveness of alitretinoin in severe chronic hand eczema: PASSION, a real-world observational study

Prospective study

Intervention: alitretinoin 30mg once-daily alitretinoin for 24 weeks under standard daily practise conditions

631 patients

Diagnosis of severe CHE with no limit to the duration of disease, scheduled for treatment with alitretinoin.

Up to 24 weeks

Effectiveness assessed by Physician Global Assessment (PGA), QoL Assessment (EQ-5D) and work impairment. Tolerability and safety were assessed by adverse event (AE) monitoring.

Of the 631 patients enrolled, 29.8% achieved a PGA rating of clear/almost clear at week 24. Mean (standard deviation) EQ-5D utility and EQ-5D visual analogue scale scores at baseline were 0.76 (0.25) and 53.6 (23.55), respectively, and increased to 0.94 (0.12) and 80.8 (19.23) at Week 24, indicating improved QoL. At baseline, 49.4%/29.1% of patients reported strong/very strong workplace impairment, respectively, and decreased to 8.5%/1.4%, respectively, at Week 24. AEs were reported in 116 (18.4%) patients. No new safety signals were observed.

In total, 279 (44.2%) patients dropped out before Week 24.

Artikel

Reden van exclusie

Al Dhubaibi 2018

Review

Bissonnette 2009

Zelfde populatie gebruikt als Ruzicka 2008, studie naar herbehandeling met alitretinoïne

Garritsen 2017

Geen geschikte uitkomstmaten

Granlund 1998

Pseudo-gerandomiseerd