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Tacrólimus tópico para la dermatitis atópica

Appendices

Appendix 1. Validated scores and classification criteria

Validated scores, scales, and diagnosis and severity criteria (Charman 2000; Rehal 2011)

‐ Hanifin and Rajka criteria

"The diagnosis of atopic dermatitis using the Hanifin and Rajka criteria requires that patients have at least 3 of the 4 major criteria and 3 of the 23 minor criteria.

Major criteria:

  • Pruritus

  • Dermatitis affecting flexural surfaces in adults and the face and extensors in infants

  • Chronic or relapsing dermatitis

  • Personal or family history of cutaneous or respiratory atopy

Minor criteria can be divided into four categories:

  • Facial features: facial pallor, facial erythema, hypopigmented patches, infraorbital darkening, infraorbital folds (Dennie‐Morgan folds), cheilitis, recurrent conjunctivitis, anterior neck folds

  • Triggers: foods, emotional factors, environmental factors, skin irritants

  • Complications: susceptibility to cutaneous infections, impaired cell‐mediated immunity, immediate skin‐test reactivity, elevated IgE, keratoconus, anterior subcapsular cataracts

  • Other: early age of onset, dry skin, ichthyosis, hyperlinear palms, keratosis pilaris, hand and foot dermatitis, nipple eczema, white dermatographism, perifollicular accentuation" (Hanifin 1980).

‐ The Rajka and Langeland Scoring System

"It is a simple scale measuring clinical course, intensity, and extent of atopic eczema. It is probably most suitable for baseline categorization of patients rather than to monitor severity changes in trials. The scale involves an assessment of body surface area involvement, albeit into 1 of 3 categories only" (Rajka 1989).

‐ Severity Scoring of Atopic Dermatitis (SCORAD)

On this score, the disease extent is assessed by the rule of nines* and disease severity is evaluated based on five clinical characteristics: one ‐ erythema, two ‐ edema, three ‐ oozing/crusts, four ‐ excoriation, and five ‐ lichenification. It still evaluates pruritus and sleep loss (subjective symptoms) with Visual Analogue Scales. The combination of the points given to those 3 aspects (extention and severity of disease and subjective symptoms) give a maximum score of 103.

*The rule of 9 is used to calculate the affected area: head and neck representing 9%; each upper limb representing 9%; each lower limb representing 18%; anterior trunk representing 18%; the back representing 18%; genitals, each palm, and the back of each hand representing 1% each.

‐ Eczema Area and Severity Index (EASI) and modified EASI (mEASI)

On this score, four clinical characteristics (erythema, induration, excoriation, and lichenification) are evaluated on a scale of zero (absent) to three (severe), together with disease extension measured at four body sites (head and neck, upper limbs, trunk, lower limbs). EASI give a maximum score of 72.

mEASI represents a variation of EASI, with the inclusion of the assessment of pruritus, not included on the EASI score (Hanifin 2001b).

‐ Investigator's Global Assessment (IGA)

"This score uses a 6‐point severity scale from clear to very severe disease (0 = clear, 1 = almost clear, 2 = mild disease, 3 = moderate disease, 4 = severe disease, and 5 = very severe disease). IGA uses clinical characteristics of erythema, infiltration, papulation, oozing and crusting as guidelines for the overall severity assessment" (Rehal 2011).

Appendix 2. CENTRAL (Cochrane Library) search strategy

#1 (eczema or neurodermatitis or dermatitis):ti,ab,kw
#2 MeSH descriptor Eczema explode all trees
#3 MeSH descriptor Dermatitis explode all trees
#4 MeSH descriptor Neurodermatitis explode all trees
#5 MeSH descriptor Dermatitis, Atopic explode all trees
#6 (#1 OR #2 OR #3 OR #4 OR #5)
#7 (tacrolimus or protopic or fk506 or "fk 506"):ti,ab,kw
#8 MeSH descriptor Tacrolimus explode all trees
#9 (#7 OR #8)
#10 (#6 AND #9)

Appendix 3. MEDLINE (Ovid) search strategy

1. exp Eczema/ or eczema.mp.
2. exp Dermatitis, Atopic/
3. neurodermatitis.mp. or exp Neurodermatitis/
4. exp Dermatitis/ or dermatitis.mp.
5. or/1‐4
6. exp Tacrolimus/
7. topical tacrolimus.mp.
8. Protopic.mp.
9. (tacrolimus adj3 topical$).mp.
10. (tacrolimus adj3 ointment).mp.
11. (fk 506 or fk506).mp.
12. or/6‐11
13. randomized controlled trial.pt.
14. controlled clinical trial.pt.
15. randomized.ab.
16. placebo.ab.
17. clinical trials as topic.sh.
18. randomly.ab.
19. trial.ti.
20. 13 or 14 or 15 or 16 or 17 or 18 or 19
21. (animals not (humans and animals)).sh.
22. 20 not 21
23. 5 and 12 and 22

[13‐22: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision)].

Appendix 4. EMBASE (Ovid) search strategy

1. eczema.mp. or exp ECZEMA/
2. exp DERMATITIS/ or dermatitis.mp.
3. exp atopic dermatitis/
4. neurodermatitis.mp. or exp NEURODERMATITIS/
5. or/1‐4
6. exp tacrolimus/
7. topical tacrolimus.ti,ab.
8. Protopic.ti,ab.
9. (tacrolimus adj3 ointment).ti,ab.
10. (tacrolimus adj3 topical).ti,ab.
11. (fk506 or fk 506).ti,ab.
12. or/6‐11
13. random$.mp.
14. factorial$.mp.
15. (crossover$ or cross‐over$).mp.
16. placebo$.mp. or PLACEBO/
17. (doubl$ adj blind$).mp.
18. (singl$ adj blind$).mp.
19. (assign$ or allocat$).mp.
20. volunteer$.mp. or VOLUNTEER/
21. Crossover Procedure/
22. Double Blind Procedure/
23. Randomized Controlled Trial/
24. Single Blind Procedure/
25. 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24
26. 5 and 12 and 25

Appendix 5. LILACS search strategy

(eczema or eccema or dermatitis or neurodermatitis) and (tacrolimus or protopic or fk506 or "fk 506")

[Searched using the Controlled clinical trials topic‐specific query filter].

Appendix 6. MEDLINE (Ovid) adverse effects search strategy

1. exp product surveillance, postmarketing/ or exp adverse drug reaction reporting systems/ or exp clinical trials, phase iv/
2. ((adverse or undesirable or harm$ or serious or toxic) adj3 (effect$ or reaction$ or event$ or outcome$)).ti,ab.
3. exp hypersensitivity/ or exp drug hypersensitivity/ or exp drug eruptions/ or exp hypersensitivity, delayed/ or exp hypersensitivity, immediate/
4. exp anaphylaxis/ or exp conjunctivitis, allergic/ or exp dermatitis, atopic/ or exp food hypersensitivity/ or exp respiratory hypersensitivity/ or exp urticaria/
5. side effect$.ti,ab.
6. exp Poisoning/
7. exp hepatitis, toxic/ or exp hepatitis, chronic, drug‐induced/
8. exp Substance‐Related Disorders/
9. exp Drug Toxicity/
10. exp Abnormalities, Drug‐Induced/
11. exp Teratogens/
12. exp Mutagens/
13. exp Carcinogens/
14. metabolite$.ti,ab.
15. exp dermatitis, contact/ or exp dermatitis, allergic contact/ or exp dermatitis, irritant/ or exp dermatitis, phototoxic/
16. photoallergic reaction$.ti,ab.
17. exp dermatitis, allergic contact/ or exp dermatitis, photoallergic/
18. phototoxicit$.ti,ab.
19. (sensitization or sensitisation).ti,ab.
20. exp Burning Mouth Syndrome/
21. stinging.ti,ab.
22. burning.ti,ab.
23. fetal abnormalit$.ti,ab.
24. exp Drug Monitoring/
25. drug effect$.ti,ab.
26. Sleep Apnea, Obstructive/
27. ARRHYTHMIA/
28. (safe or safety).ti,ab.
29. toxicity.ti,ab.
30. noxious.ti,ab.
31. complication$.ti,ab.
32. treatment emergent.ti,ab.
33. tolerability.ti,ab.
34. rebound.ti,ab.
35. Hypercalcemia/ci [Chemically Induced]
36. Urinary Calculi/ci [Chemically Induced]
37. Tachyphylaxis/ci, de [Chemically Induced, Drug Effects]
38. Substance Withdrawal Syndrome/ci, de [Chemically Induced, Drug Effects]
39. ATROPHY/ci [Chemically Induced]
40. TELANGIECTASIS/ci [Chemically Induced]
41. skin thinning.ti,ab.
42. Liver Diseases/ci [Chemically Induced]
43. Kidney Diseases/ci [Chemically Induced]
44. Disseminated Intravascular Coagulation/ci [Chemically Induced]
45. Multiple Organ Failure/ci [Chemically Induced]
46. Stevens‐Johnson Syndrome/ci [Chemically Induced]
47. Epidermal Necrolysis, Toxic/ci [Chemically Induced]
48. Heart Block/ci [Chemically Induced]
49. COMA/ci [Chemically Induced]
50. PARALYSIS/ci [Chemically Induced]
51. exp Nausea/
52. exp Vomiting/
53. benign intracranial hypertension.ti,ab. or exp Pseudotumor Cerebri/
54. exp Pigmentation Disorders/ or pigmentation.ti,ab. or exp Pigmentation/
55. lupus induced hepatitis.ti,ab.
56. or/1‐55
57. ae.fs.
58. to.fs.
59. co.fs.
60. po.fs.
61. or/57‐60
62. exp Tacrolimus/
63. tacrolimus.ti,ab.
64. protopic.ti,ab.
65. (fk506 or fk 506).ti,ab.
66. 62 or 63 or 64 or 65
67. exp Ointments/
68. ointment$.ti,ab.
69. exp Skin Cream/
70. (cream or creams).ti,ab.
71. (lotion or lotions).ti,ab.
72. topical$.ti,ab.
73. epicutaneous.ti,ab.
74. skin.ti,ab.
75. 67 or 68 or 69 or 70 or 71 or 72 or 73 or 74
76. 66 and 75
77. 56 and 76
78. 61 and 76
79. 77 or 78

Appendix 7. EMBASE (Ovid) adverse effects search strategy

1. side effect$.ti,ab.
2. metabolite$.ti,ab.
3. photoallergic reaction$.ti,ab.
4. phototoxicit$.ti,ab.
5. (sensitization or sensitisation).ti,ab.
6. stinging.ti,ab.
7. burning.ti,ab.
8. fetal abnormalit$.ti,ab.
9. (toxic effect$ or drug effect$).ti,ab.
10. (safe or safety).ti,ab.
11. toxicity.ti,ab.
12. noxious.ti,ab.
13. complication$.ti,ab.
14. tolerability.ti,ab.
15. treatment emergent.ti,ab.
16. tolerability.ti,ab.
17. ((adverse or undesirable or harm$ or serious or toxic) adj3 (effect$ or reaction$ or event$ or outcome$)).ti,ab.
18. rebound.ti,ab.
19. skin thinning.ti,ab.
20. lupus induced hepatitis.ti,ab.
21. exp postmarketing surveillance/
22. exp drug surveillance program/
23. exp drug hypersensitivity/ or exp hypersensitivity reaction/ or exp delayed hypersensitivity/ or exp hypersensitivity/ or exp immediate type hypersensitivity/
24. exp drug eruption/
25. exp anaphylaxis/
26. exp allergic conjunctivitis/
27. exp atopic dermatitis/
28. exp food allergy/
29. exp respiratory tract allergy/
30. exp urticaria/
31. exp intoxication/
32. exp toxic hepatitis/
33. exp addiction/
34. exp drug toxicity/
35. exp teratogenic agent/
36. exp mutagenic agent/
37. exp carcinogen/
38. exp contact dermatitis/
39. exp skin allergy/
40. exp irritant dermatitis/
41. exp phototoxicity/
42. exp photodermatosis/ or exp photoallergy/
43. exp burning mouth syndrome/
44. exp drug monitoring/
45. exp sleep apnea syndrome/
46. exp heart arrhythmia/
47. hypercalcemia/
48. urolithiasis/
49. tachyphylaxis/
50. withdrawal syndrome/
51. atrophy/
52. telangiectasia/
53. liver disease/
54. kidney disease/
55. disseminated intravascular clotting/
56. multiple organ failure/
57. Stevens Johnson syndrome/
58. toxic epidermal necrolysis/
59. heart block/
60. coma/
61. paralysis/
62. nausea/
63. vomiting/
64. benign intracranial hypertension.ti,ab. or exp brain pseudotumor/
65. exp pigment disorder/
66. exp pigmentation/
67. pigmentation.ti,ab.
68. exp adverse drug reaction/
69. exp drug safety/
70. exp phase 4 clinical trial/
71. (ae or to).fs.
72. or/1‐70
73. exp tacrolimus/
74. tacrolimus.ti,ab.
75. protopic.ti,ab.
76. (fk506 or fk 506).ti,ab.
77. or/73‐76
78. exp ointment/
79. ointment$.ti,ab.
80. exp skin cream/
81. (cream or creams).ti,ab.
82. exp lotion/
83. (lotion or lotions).ti,ab.
84. exp topical drug administration/
85. topical$.ti,ab.
86. epicutaneous.ti,ab.
87. skin.ti,ab.
88. or/78‐87
89. 77 and 88
90. 72 and 89
91. 71 and 89
92. 90 or 91

Appendix 8. Study selection form

Study eligibility ‐ topical tacrolimus for atopic dermatitis

First author

Journal/Conference proceedings, etc.

Year

RCT

Relevant participants

People with atopic dermatitis who have been diagnosed by a physician

Relevant interventions

Topical tacrolimus

Relevant outcomes

Physician's overall evaluation; patient's self‐assessment; rates of improvement as defined in the trial report; improvement in atopic dermatitis severity grade; incidence and severity of adverse effects; dropout rates

Yes/No/Unclear

Yes/No/Unclear

Yes/No/Unclear

Yes/No*/Unclear 

*Do not proceed if any of the above answers are 'No'. If the study is to be included in the 'Excluded studies' section of the review, record below the information to be inserted into the 'Characteristics of excluded studies' tables

 

References to trial

Check other references identified in the searches. If there are further references to this trial, link the papers now and list them below. All references to a trial should be linked under one Study ID in Review Manager. 

Code each paper

Author(s)

Journal/Conference proceedings, etc.

Year

A

The paper listed above

 

 

B

Further papers

 

 

Study flow diagram
Figures and Tables -
Figure 1

Study flow diagram

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies
Figures and Tables -
Figure 2

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study
Figures and Tables -
Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study

Forest plot of comparison: 2 Tacrolimus 0.1% versus pimecrolimus 1%, outcome: 2.1 Physician's assessment of global response of improvement, clear or excellent
Figures and Tables -
Figure 4

Forest plot of comparison: 2 Tacrolimus 0.1% versus pimecrolimus 1%, outcome: 2.1 Physician's assessment of global response of improvement, clear or excellent

Forest plot of comparison: 3 Tacrolimus 0.03% versus corticosteroids, outcome: 3.1 Physician's assessment of global response of improvement, clear or excellent
Figures and Tables -
Figure 5

Forest plot of comparison: 3 Tacrolimus 0.03% versus corticosteroids, outcome: 3.1 Physician's assessment of global response of improvement, clear or excellent

Forest plot of comparison: 4 Tacrolimus 0.03% versus tacrolimus 0.1%, outcome: 4.1 Physician's assessment of global response of improvement, clear or excellent
Figures and Tables -
Figure 6

Forest plot of comparison: 4 Tacrolimus 0.03% versus tacrolimus 0.1%, outcome: 4.1 Physician's assessment of global response of improvement, clear or excellent

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 1 Physician's assessment of global response of improvement, clear or excellent.
Figures and Tables -
Analysis 1.1

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 1 Physician's assessment of global response of improvement, clear or excellent.

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 2 Adverse effects: burning.
Figures and Tables -
Analysis 1.2

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 2 Adverse effects: burning.

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 3 Adverse effects: pruritus.
Figures and Tables -
Analysis 1.3

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 3 Adverse effects: pruritus.

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 4 Adverse effects: skin infection.
Figures and Tables -
Analysis 1.4

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 4 Adverse effects: skin infection.

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 5 SCORAD: 3 weeks.
Figures and Tables -
Analysis 1.5

Comparison 1 Tacrolimus 0.1% versus steroids, Outcome 5 SCORAD: 3 weeks.

Comparison 2 Tacrolimus 0.1% versus pimecrolimus 1%, Outcome 1 Physician's assessment of global response of improvement, clear or excellent.
Figures and Tables -
Analysis 2.1

Comparison 2 Tacrolimus 0.1% versus pimecrolimus 1%, Outcome 1 Physician's assessment of global response of improvement, clear or excellent.

Comparison 2 Tacrolimus 0.1% versus pimecrolimus 1%, Outcome 2 Adverse effects ‐ 6 weeks.
Figures and Tables -
Analysis 2.2

Comparison 2 Tacrolimus 0.1% versus pimecrolimus 1%, Outcome 2 Adverse effects ‐ 6 weeks.

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 1 Physician's assessment of global response of improvement, clear or excellent.
Figures and Tables -
Analysis 3.1

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 1 Physician's assessment of global response of improvement, clear or excellent.

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 2 Participants's assessment of global response of improvement better or much better.
Figures and Tables -
Analysis 3.2

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 2 Participants's assessment of global response of improvement better or much better.

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 3 Adverse effects: burning.
Figures and Tables -
Analysis 3.3

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 3 Adverse effects: burning.

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 4 Adverse effects: pruritus.
Figures and Tables -
Analysis 3.4

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 4 Adverse effects: pruritus.

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 5 Adverse effects: skin infection.
Figures and Tables -
Analysis 3.5

Comparison 3 Tacrolimus 0.03% versus steroids, Outcome 5 Adverse effects: skin infection.

Comparison 4 Tacrolimus 0.03% versus tacrolimus 0.1%, Outcome 1 Physician's assessment of global response of improvement, clear or excellent.
Figures and Tables -
Analysis 4.1

Comparison 4 Tacrolimus 0.03% versus tacrolimus 0.1%, Outcome 1 Physician's assessment of global response of improvement, clear or excellent.

Comparison 4 Tacrolimus 0.03% versus tacrolimus 0.1%, Outcome 2 Adverse effects.
Figures and Tables -
Analysis 4.2

Comparison 4 Tacrolimus 0.03% versus tacrolimus 0.1%, Outcome 2 Adverse effects.

Comparison 5 Tacrolimus 0.03% versus pimecrolimus 1%, Outcome 1 Physician's assessment of global response of improvement.
Figures and Tables -
Analysis 5.1

Comparison 5 Tacrolimus 0.03% versus pimecrolimus 1%, Outcome 1 Physician's assessment of global response of improvement.

Comparison 5 Tacrolimus 0.03% versus pimecrolimus 1%, Outcome 2 Adverse effects.
Figures and Tables -
Analysis 5.2

Comparison 5 Tacrolimus 0.03% versus pimecrolimus 1%, Outcome 2 Adverse effects.

Comparison 6 Tacrolimus 0.1% versus ciclosporin, Outcome 1 Adverse effects.
Figures and Tables -
Analysis 6.1

Comparison 6 Tacrolimus 0.1% versus ciclosporin, Outcome 1 Adverse effects.

Comparison 6 Tacrolimus 0.1% versus ciclosporin, Outcome 2 SCORAD.
Figures and Tables -
Analysis 6.2

Comparison 6 Tacrolimus 0.1% versus ciclosporin, Outcome 2 SCORAD.

Summary of findings for the main comparison. Tacrolimus 0.1% compared with corticosteroids for atopic dermatitis

Tacrolimus 0.1% compared with corticosteroids for atopic dermatitis

Patient or population: people with atopic dermatitis
Settings: outpatients, Europe and Canada

Intervention: tacrolimus 0.1%
Comparison: corticosteroids

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Corticosteroids

Tacrolimus 0.1%

Physician's assessment of global response of improvement, clear or excellent ‐ tacrolimus 0.1% versus hydrocortisone acetate 0.1%: 3 weeks
Follow‐up: mean 3 weeks

Study population

RR 3.09
(2.14 to 4.45)

371
(1 study)

⊕⊕⊕⊝
moderate¹

157 per 1000

484 per 1000
(335 to 698)

Moderate

157 per 1000

485 per 1000
(336 to 699)

Physician's assessment of global response of improvement, clear or excellent ‐ tacrolimus 0.1% versus hydrocortisone butyrate: 3 weeks
Follow‐up: mean 3 weeks

Study population

RR 0.95
(0.78 to 1.16)

377
(1 study)

⊕⊕⊝⊝
low¹, ²

516 per 1000

490 per 1000
(403 to 599)

Moderate

516 per 1000

490 per 1000
(402 to 599)

Physician's assessment of global response of improvement, clear or excellent ‐ tacrolimus 0.1% versus hydrocortisone acetate and butyrate 0.1%: short term (6 months)
Follow‐up: 6 months

Study population

RR 1.32
(1.17 to 1.49)

972
(1 study)

⊕⊕⊝⊝
moderate¹

464 per 1000

612 per 1000
(543 to 691)

Moderate

464 per 1000

612 per 1000
(543 to 691)

Adverse effects: burning ‐ tacrolimus 0.1% versus hydrocortisone acetate 0.1%: 3 weeks
Follow‐up: mean 3 weeks

Study population

RR 2.91
(1.6 to 5.28)

371
(1 study)

⊕⊕⊕⊝
moderate¹

70 per 1000

204 per 1000
(112 to 371)

Moderate

70 per 1000

204 per 1000
(112 to 370)

Adverse effects: burning ‐ tacrolimus 0.1% versus hydrocortisone butyrate: 3 weeks
Follow‐up: mean 3 weeks

Study population

RR 4.59
(3.1 to 6.78)

377
(1 study)

⊕⊕⊕⊝
moderate¹

129 per 1000

592 per 1000
(400 to 875)

Moderate

129 per 1000

592 per 1000
(400 to 875)

Adverse effects: burning ‐ tacrolimus 0.1% versus hydrocortisone acetate and butyrate 0.1%: 6 months

Follow‐up: 6 months

Study population

RR 3.79

(2.99 to 4.81)

972

(1 study)

⊕⊕⊕⊝
moderate¹

138 per 1000

524 per 1000

(413 to 664)

Moderate

138 per 1000

524 per 1000

(413 to 664)

Participant's self‐assessment of global response of improvement

Follow‐up: mean 6 months

Study population

RR 1.21

(1.13 to 1.29)

974

(1 study)

⊕⊕⊝⊝
low¹, ³

718 per 1000

868 per 1000

(811 to 926)

Moderate

718 per 1000

869 per 1000

(811 to 926)

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (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 quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

¹Downgraded one level due to publication bias because only one study was identified and publication bias was strongly suspected.
²Downgraded one level due to Imprecision: sample size falls below the optimal information size; 95% CI of the estimated effect includes both no effect and appreciable benefit.
³Downgraded one level due to Imprecision: sample size falls below the optimal information size.

Figures and Tables -
Summary of findings for the main comparison. Tacrolimus 0.1% compared with corticosteroids for atopic dermatitis
Summary of findings 2. Tacrolimus 0.1% compared with pimecrolimus 1% for atopic dermatitis

Tacrolimus 0.1% compared with pimecrolimus 1% for atopic dermatitis

Patient or population: people with atopic dermatitis
Settings: outpatients, USA
Intervention: tacrolimus 0.1%
Comparison: pimecrolimus 1%

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Pimecrolimus 1%

Tacrolimus 0.1%

Physician's assessment of global response of improvement, clear or excellent ‐ 6 weeks
Follow‐up: mean 6 weeks

Study population

RR 1.8
(1.34 to 2.42)

506
(2 studies)

⊕⊕⊕⊝
moderate¹

202 per 1000

363 per 1000
(270 to 488)

Moderate

199 per 1000

358 per 1000
(267 to 482)

Adverse effects ‐ 6 weeks
Follow‐up: mean 6 weeks

Study population

RR 0.89
(0.47 to 1.71)

506
(2 studies)

⊕⊝⊝⊝
very low¹, ², ³

229 per 1000

204 per 1000
(108 to 392)

Moderate

227 per 1000

202 per 1000
(107 to 388)

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (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 quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

¹Downgraded one level due to publication bias because only one study was identified and publication bias was strongly suspected.
²Downgraded one level due to inconsistency: there is moderate level of heterogeneity between studies: I² value of 69%.
³Downgraded one level due to imprecision: 95% CI of the estimate of summary effect includes both no effect and appreciable harm.

Figures and Tables -
Summary of findings 2. Tacrolimus 0.1% compared with pimecrolimus 1% for atopic dermatitis
Summary of findings 3. Tacrolimus 0.03% compared with corticosteroids for atopic dermatitis

Tacrolimus 0.03% compared with corticosteroids for atopic dermatitis

Patient or population: people with atopic dermatitis
Settings: outpatients, Europe, Tunisia, Pakistan, Morocco, Taiwan
Intervention: tacrolimus 0.03%
Comparison: corticosteroids

Outcomes

Ilustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Corticosteroids

Tacrolimus 0.03%

Physician's assessment of global response of improvement, clear or excellent ‐ tacrolimus 0.03% 1x/day versus hydrocortisone acetate 1% 2x/day
Follow‐up: mean 3 weeks

Study population

RR 2.05
(1.36 to 3.08)

411
(1 study)

⊕⊕⊕⊝
moderate¹

136 per 1000

279 per 1000
(185 to 419)

Moderate

136 per 1000

279 per 1000
(185 to 419)

Physician's assessment of global response of improvement, clear or excellent ‐ tacrolimus 0.03% 2x/day versus hydrocortisone acetate 1% 2x/day
Follow‐up: mean 3 weeks

Study population

RR 2.58
(1.96 to 3.38)

790
(2 studies)

⊕⊕⊕⊝
moderate¹

146 per 1000

376 per 1000
(286 to 493)

Moderate

146 per 1000

377 per 1000
(286 to 493)

Physician's assessment of global response of improvement, clear or excellent ‐ tacrolimus 0.03% 2x/day versus corticosteroids moderate‐potency 2x/day
Follow‐up: 3 to 4 weeks

Study population

RR 0.45
(0.13 to 1.57)

409
(2 studies)

⊕⊝⊝⊝
very low¹, ², ³

527 per 1000

237 per 1000
(69 to 828)

Moderate

591 per 1000

266 per 1000
(77 to 928)

Physician's assessment of global response of improvement, clear or excellent ‐ tacrolimus 0.03% 2x/day versus methylprednisolone 0.03% 1x/day
Follow‐up: mean 3 weeks

Study population

RR 1
(0.85 to 1.19)

265
(1 study)

⊕⊕⊝⊝
low¹, ³

667 per 1000

667 per 1000
(567 to 793)

Moderate

667 per 1000

667 per 1000
(567 to 794)

Adverse effects: burning ‐ tacrolimus 0.03% versus steroids

Study population

RR2.48
(1.96 to 3.14)

1883
(5 studies)

⊕⊕⊕⊕
high

89 per 1000

221 per 1000
(174 to 279)

Moderate

70 per 1000

174 per 1000
(137 to 220)

Participant's self‐assessment of global response of improvement: tacrolimus 0.03% 2x/day versus hydrocortisone acetate 1% 2x/day

Follow‐up: 3 weeks

Study population

RR 1.64

(1.41 to 1.90)

416

(1 study)

⊕⊕⊕⊝
moderate¹

505 per 1000

828 per 1000

(712 to 959)

Moderate

505 per 1000

828 per 1000

(712 to 959)

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (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 quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

¹Downgraded one level due to publication bias because only very small number of studies were identified and publication bias was strongly suspected.
²Downgraded one level due to inconsistency: there is moderate level of heterogeneity between studies: I² value of 79%.
³Downgraded one level due to imprecision: 95% CI of estimated summary effect includes both no effect and appreciable harm.

Figures and Tables -
Summary of findings 3. Tacrolimus 0.03% compared with corticosteroids for atopic dermatitis
Summary of findings 4. Tacrolimus 0.03% compared with tacrolimus 0.1% for atopic dermatitis

Tacrolimus 0.03% compared with tacrolimus 0.1% for atopic dermatitis

Patient or population: people with atopic dermatitis
Settings: outpatients, USA, Japan, China
Intervention: tacrolimus 0.03%
Comparison: tacrolimus 0.1%

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Tacrolimus 0.1%

Tacrolimus 0.03%

Physician's assessment of global response of improvement, clear or excellent
Follow‐up: 3 to 12 weeks

Study population

RR 0.82
(0.72 to 0.92)

1640
(6 studies)

⊕⊕⊕⊕
high

430 per 1000

353 per 1000
(310 to 396)

Moderate

445 per 1000

365 per 1000
(320 to 409)

Adverse effects
Follow‐up: mean 3 weeks

Study population

RR 0.95
(0.86 to 1.06)

986
(4 studies)

⊕⊕⊕⊝
moderate¹

573 per 1000

544 per 1000
(492 to 607)

Moderate

448 per 1000

426 per 1000
(385 to 475)

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (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 quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

¹Downgraded one level due to imprecision: sample size is below the optimal information size.

Figures and Tables -
Summary of findings 4. Tacrolimus 0.03% compared with tacrolimus 0.1% for atopic dermatitis
Summary of findings 5. Tacrolimus 0.03% versus pimecrolimus 1% for atopic dermatitis

Tacrolimus 0.03% versus pimecrolimus 1% for atopic dermatitis

Patient or population: people with atopic dermatitis
Settings: outpatients, USA
Intervention: tacrolimus 0.03% versus pimecrolimus 1%

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Tacrolimus 0.03% versus pimecrolimus 1%

Physician's assessment of global response of improvement
Follow‐up: mean 6 weeks

Study population

RR 1.42
(1.02 to 1.98)

139
(1 study)

⊕⊕⊝⊝
low¹, ²

429 per 1000

609 per 1000
(437 to 849)

Moderate

429 per 1000

609 per 1000
(438 to 849)

Adverse effects ‐ application site reaction
Follow‐up: mean 6 weeks

Study population

RR 1.07
(0.6 to 1.91)

141
(1 study)

⊕⊕⊝⊝
low², ³

239 per 1000

256 per 1000
(144 to 457)

Moderate

239 per 1000

256 per 1000
(143 to 456)

Adverse effects ‐ burning
Follow‐up: mean 6 weeks

Study population

RR 0.87
(0.43 to 1.75)

141
(1 study)

⊕⊕⊝⊝
low², ³

197 per 1000

172 per 1000
(85 to 345)

Moderate

197 per 1000

171 per 1000
(85 to 345)

Adverse effects ‐ itching
Follow‐up: mean 6 weeks

Study population

RR 2.37
(0.96 to 5.81)

141
(1 study)

⊕⊕⊝⊝
low², ³

85 per 1000

200 per 1000
(81 to 491)

Moderate

85 per 1000

201 per 1000
(82 to 494)

Adverse effects ‐ erythema
Follow‐up: mean 6 weeks

Study population

RR 2.2
(0.89 to 5.46)

141
(1 study)

⊕⊕⊝⊝
low², ³

85 per 1000

186 per 1000
(75 to 461)

Moderate

85 per 1000

187 per 1000
(76 to 464)

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (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 quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

¹Downgraded one level due to imprecision: sample size is smaller than the optimal information size.
²Downgraded one level due to publication bias because only one study was identified and publication bias was strongly suspected.
³Downgraded one level due to imprecision: 95% CI of the estimate of summary effect includes both no effect and appreciable harm.

Figures and Tables -
Summary of findings 5. Tacrolimus 0.03% versus pimecrolimus 1% for atopic dermatitis
Summary of findings 6. Tacrolimus 0.1% versus ciclosporin for atopic dermatitis

Tacrolimus 0.1% versus ciclosporin for atopic dermatitis

Patient or population: people with atopic dermatitis
Settings: outpatients, Italy
Intervention: tacrolimus 0.1% versus ciclosporin

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Tacrolimus 0.1% versus ciclosporin

Adverse effects
Follow‐up: mean 6 weeks

Study population

RR 1
(0.31 to 3.28)

30
(1 study)

⊕⊝⊝⊝
very low¹, ², ³

267 per 1000

267 per 1000
(83 to 875)

Moderate

267 per 1000

267 per 1000
(83 to 876)

*The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (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 quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

¹Downgraded one level due to risk of bias: randomisation and allocation concealment procedures were unclear.
²Downgraded one level due to imprecision: sample size is smaller than optimal information size; 95% CI of the estimate of summary effect includes both no effect and appreciable benefit and harm.
³Downgraded one level due to publication bias because only one study was identified and publication bias was strongly suspected.

Figures and Tables -
Summary of findings 6. Tacrolimus 0.1% versus ciclosporin for atopic dermatitis
Table 1. Characteristics of treatment and participants in included studies

Study

Number of participants

(n = 5885)

Age

Intervention

Follow up

Classification of AD

Antiga 2010

24

Adults (21 to 65 years)

Tacrolimus 0.1% ointment vs hydrocortisone butyrate 0.1% ointment (BID)

3 weeks

Moderate to severe (SCORAD)

Bieber 2007

265

Children

(2 to 15 years)

Tacrolimus 0.03% ointment (BID) vs methylprednisolone aceponate 0.1% ointment (evening) and vehicle ointment (morning)

2 to 3 weeks

Severe flare (IGA > 4) history of moderate to severe AD

Boguniewicz 1998

169

Older children

(7 to 16 years)

Tacrolimus 0.03% ointment vs tacrolimus 0.1% ointment vs tacrolimus 0.3% ointment vs vehicle ointment (BID)

3 weeks

Moderate to severe (Rajka and Langeland (Rajka 1989))

Caproni 2007

16

Adults

Tacrolimus 0.1% ointment vs hydrocortisone butyrate 0.1% ointment (BID)

3 weeks

Moderate to severe (SCORAD)

Doss 2010

473

Children

(2 to 15 years)

Tacrolimus 0.03% ointment vs fluticasone 0.005% ointment (BID)

3 weeks

Moderate to severe (Rajka and Langeland (Rajka 1989)) and with prior inadequate response to topical corticosteroids

Dou 2006

202

Adults (> 18 years)

Tacrolimus 0.03% ointment vs tacrolimus 0.1% ointment vs vehicle ointment (BID)

3 weeks

Moderate to severe

Draelos 2005

37

Adults

Tacrolimus 0.1% ointment vs pimecrolimus 1% cream (BID)

2 weeks

Moderate to severe (IGA)

Fleischer 2007

281

Adults (> = 16 years)

Tacrolimus 0.1% ointment vs pimecrolimus 1% cream (BID)

6 weeks

Moderate to severe (IGA)

Hanifin 2001

632

Adults (> = 16 years)

Tacrolimus 0.1% ointment vs tacrolimus 0.03% ointment vs vehicle ointment (BID)

3 months

Moderate to severe (Rajka and Langeland (Rajka 1989))

Hung 2007

60

Adults and

children

(9 months to 33 years)

Tacrolimus 0.03% ointment (BID) alone or with fusidic acid 2% cream vs fluticasone propionate 0.05% cream (BID) alone or with fusidic acid 2% cream

6 months

Moderate to severe (Rajka and Langeland (Rajka 1989))

Kempers 2004

141 (for safety)

139 (for efficacy)

Children (2 to 17 years)

Tacrolimus 0.03% ointment vs pimecrolimus 1% cream (BID)

6 weeks

Moderate (IGA)

Otsuki 2003

213

Children (2 to 15 years)

Tacrolimus 0.03% ointment vs tacrolimus 0.1% ointment vs vehicle ointment (BID)

3 weeks

Moderate to severe (Rajka and Langeland (Rajka 1989))

Pacor 2004

30

Adults and

children (13 to 45 years)

Tacrolimus 0.1% ointment (BID) vs ciclosporin 3 mg/kg orally

6 weeks

Moderate to severe (Rajka and Langeland (Rajka 1989))

Paller 2001

351

Children (2 to 15 years)

Tacrolimus 0.03% ointment vs tacrolimus 0.1% ointment vs vehicle ointment (BID)

3 months

Moderate to severe (Rajka and Langeland (Rajka 1989))

Paller 2005

225

Children (2 to 15 years)

Tacrolimus 0.1% ointment vs pimecrolimus 1% cream (BID)

6 weeks

Moderate to severe (IGA)

Reitamo 2002a

570

Adults (16 to 70 years)

Tacrolimus 0.1% ointment vs tacrolimus 0.03% ointment vs hydrocortisone butyrate 0.1% ointment (BID)

3 weeks

Moderate to severe (Rajka and Langeland (Rajka 1989))

Reitamo 2002b

560

Children (2 to 15 years)

Tacrolimus 0.1% ointment vs tacrolimus 0.03% ointment vs hydrocortisone acetate 1% ointment (BID)

3 weeks

Moderate to severe (Rajka and Langeland (Rajka 1989))

Reitamo 2004

621

Children (2 to 15 years)

Tacrolimus 0.03% ointment (OD) vs tacrolimus 0.03% ointment (BID) vs hydrocortisone acetate 1% ointment (BID)

3 weeks

Moderate to severe (Rajka and Langeland (Rajka 1989))

Reitamo 2005

972

Adults (> = 18 years)

Tacrolimus 0.1% ointment vs hydrocortisone butyrate 0.1% ointment (on trunk and extremities) and hydrocortisone acetate 1% ointment (on face and neck) (BID)

Up to 6 months

Moderate to severe (Rajka and Langeland (Rajka 1989))

Sikder 2005

45

Older children (7 to 15 years)

Tacrolimus 0.03% ointment (BID) vs clobetasone butyrate 0.05% cream (BID) vs clobetasone butyrate 0.05% cream (morning) and tacrolimus 0.03% ointment (evening)

4 weeks

Moderate to severe (Rajka and Langeland (Rajka 1989))

AD: atopic dermatitis.
BID: twice a day.
IGA: Investigators' Global Assessment.
OD: once daily.
SCORAD: SCORing Atopic Dermatitis.
vs: versus.

Figures and Tables -
Table 1. Characteristics of treatment and participants in included studies
Table 2. Spontaneous reported malignancies in association with topical tacrolimus use

Malignancy

Age (years)

Application site

Occurence site

Comment

Exposure to onset (days)

B‐cell lymphoma, EBV‐associated, and primary lung carcinoma

49

Face

Kidney

730

Cutaneous Kaposi sarcoma

28

Axilla, groin

Axilla, groin

HIV patient on HAART, treated for inverse psoriasis, developed KS at these sites, which metastasised, and the patient died

30

Hepatoblastoma

5

Liver

Considered unrelated

455

Lymphadenopathy – possible
lymphoma

40

Application site

Application site

Pre‐existing lymphoma lesions 'looked like' lymphoma and resolved spontaneously*

Lymphoma or Sézary syndrome

16

Face

Lymph nodes

Participant also had been on systemic ciclosporin

730

Metastatic angiosarcoma

16

Face/neck

Clavicle

Present before treatment but increased rapidly in size

105

Metastatic melanoma

39

Generalised

Metastatic disease newly detected from primary 3 years early

21 to 28

Metastatic sweat gland carcinoma

43

Not axilla

Axilla

4 years

Nodular follicular lymphoma

60

Lower limbs, face

May be associated with EBV

504

Non‐Hodgkin lymphoma

52

Used tacrolimus for 6 months. Insufficient evidence

365

Non‐Hodgkin lymphoma

54

Used tacrolimus on extensive areas: 50% of body. Died from lymphoma. Insufficient evidence

Oesophageal cancer with metastases

49

Oesophagus

122

Panniculitis‐like T‐cell lymphoma

53

Trunk, limbs

Trunk, limbs

Also used pimecrolimus

240

Squamous cell carcinoma

34

Face

Face

UV therapy, outdoor sports

Squamous cell carcinoma

57

Penis

Penis

Treated for balanitis considered to be lichen sclerosus et atrophicus; non‐specific biopsy

70

Squamous cell carcinoma

51

Mouth

Long history of pipe smoking

Squamous cell carcinoma recurrence

75

Vulva

Vulva

Treated for lichen sclerosus et atrophicus

42

T‐cell lymphoma, anaplastic large cell

50

Right hip

Right hip

Insufficient evidence

EBV: Epstein–Barr virus.
HIV: human immunodeficiency virus.
HAART: highly active antiretroviral therapy.
KS: Kaposi sarcoma.
UV: ultraviolet.
*Questionable if this should be classed as malignant.
Data shown in Ormerod 2005.

Figures and Tables -
Table 2. Spontaneous reported malignancies in association with topical tacrolimus use
Table 3. Lymphoma risk

Study

Study population

Follow‐up

Comparisons

Results related to lymphoma risks

Arellano 2007

294 cases/293,000 controls

TCIs and TCS in participants with AD

‐ Increased risk in AD participants (related to severity)

‐ No evidence of increased risk with any of the topical treatments

Arellano 2009

> 3,000,000 (cohort)

1992 to 2006

AD, treatment with topical immunosuppressants, or both

‐ Increase risk in AD participants (related to severity)

‐ Increased risk with topical corticosteroids (related to potency)

‐ Insufficient data to assess TCI‐related risks

Hui 2009

953,064 (cohort) (96% unexposed, 4% exposed)

Median 2.4 years

AD or eczema participants exposed or not to TCI

‐ Increased risk in the exposed group**

Schneeweiss 2009

‐ 118,863 for pimecrolimus

‐ 38,757 for tacrolimus

‐ 1,043,025 mid to potent corticosteroid

‐ 118,825 untreated dermatitis

‐ 118,863 for general population

2002 to 2006

(median 1.3 years)

See study population

‐ Increased risk compared with general population*

‐ No risk differences between the 3 treatments

*pre‐existing lymphomas misdiagnosed as AD.
**proportion of people who had diagnosis of AD was 2 times higher in the exposed group (i.e., there was a higher prevalence of AD than eczema in the exposed group). See Summary of main results (Risk of malignancies).
AD: atopic dermatitis.
TCI: topical calcineurin inhibitor.
TCS: topical corticosteroids.

Figures and Tables -
Table 3. Lymphoma risk
Table 4. Non‐melanoma skin cancer (NMSC) and melanoma (MM) skin cancer risk

Study

Study population

Follow up

Comparisons

Results related to skin cancer risks

Hui 2009

953,064 (cohort) (96% unexposed, 4% exposed)

Median 2.4 years

AD participants exposed or not to TCI

‐ Similar risks for NMSC

‐ Lower risks for MM

Margolis 2007

875 cases

1946 controls

Dermatitis participants (AD, seborrhoeic dermatitis, rosacea, other dermatitis) with or without use of TCI

‐ No increased risk of NMSC in TCI‐treated participants

‐ MM risk not evaluated

Naylor 2005

9813 tacrolimus‐treated participants

3 months to 4 years

AD participants with tacrolimus use compared with an aged cohort in the US

‐ No increased risk of NMSC in tacrolimus treated participants

‐ MM risk not evaluated

AD: atopic dermatitis.
TCI: topical calcineurin inhibitor.
MM: melanoma.
NMSC: non‐melanoma skin cancer.

Figures and Tables -
Table 4. Non‐melanoma skin cancer (NMSC) and melanoma (MM) skin cancer risk
Table 5. Observational non‐comparative studies

Study

1. Population

2. Age group

3. Follow‐up

Tacrolimus formulation

Common local effects

Systemic effects

Laboratory values

Malignancies

Others (number of events)

Detectable blood concentration

Gontijo 2008

1. n = 174

2. Paediatric
3. 6 weeks

0.03%

‐ Burning

‐ Pruritus

‐ Asthma (2)

‐ Pneumonia (2)

‐ Pyodermitis (1)

Koo 2005

1. n = 7923

2. Adult/paediatric

3. Median: 210 days

0.1% (92.7%)

0.03% (7.3%)

‐ Burning

‐ Pruritus

‐ Flu‐like symptoms

‐ Headache

(frequency similar to that expected of the general population)

‐ 13 cases of NMSC (no risk with calculated incidence)

‐ Alcohol intolerance 3.7%

Mandelin 2012

1. n = 50

2. Paediatric (< 2 years)

3. 2 years

0.03%

‐ Pruritus

‐ Local infection

‐ Non‐serious respiratory

infection and

gastroenteritis

< 1 ng/ml (in 98%)

Reitamo 2000

1. n = 316

2. Adults

3. 6 to 12 months

0.1%

‐ Burning

‐ Pruritus

‐ Erythema

Normal

(only 1 transient

increase in

liver enzymes)

‐ Alcohol intolerance

5 serious events:

‐ Eczema herpeticum (1)

‐ Cellulitis (1)

‐ Varicella (1)

‐ AD flare‐up (1)

Staphylococcus aureus

superinfection (1)

Minimal < 1 ng/dl in 76% of participants

Reitamo 2007

1. n = 672

2. Adults

3. 2 years

0.1%

‐ Burning

‐ Pruritus

‐ 2 cases (Bowen and prostate carcinoma) not related

‐ Benign neoplasm (7)

‐ Herpes (7%) (expected in AD participants)

‐ Eczema herpeticum (1)

‐ Erythroderma (1)

‐ AD exacerbation (1)

Reitamo 2008

1. n = 782

2. Adult/paediatric

3. 4 years (median: 1422 days)

0.1%

‐ Burning

‐ Pruritus

‐ Skin infection

‐ Flu‐like symptoms

(more in children)

6 cases

‐ Cervical carcinoma (1)

‐ Acute leukaemia (1)

‐ Chronic leukaemia (1)

‐ Basal cell carcinoma (2 to 3 on the same participant)

‐ 34 benign neoplasms

Remitz 2007

1. n = 466

2. Paediatric

3. 29.5 months (mean: 16.3 months)

0.03%

0.1%

‐ Burning

‐ Pruritus

‐ Seasonal infection

(flu‐syndrome)

‐ No growth

retardation

Normal

‐ Leukopenia (1)*

‐ Herpes (4.9%)/eczema herpeticum (0.9%)

‐ Molluscum 3%)

‐ Warts (3.6%)

Saple 2003

1. n = 125

2. 12 to 69 years

3. 5 weeks

0.03%

‐ Burning

‐ Pruritus

‐ Erythema

Normal

Won 2004

1. n = 18

2. Adult/paediatric

3. 4 weeks

0.03%

‐ Burning

‐ Pruritus

Normal

Serious events (3):

‐ Flu‐syndrome (1)

‐ Severe skin rash (1)

‐ Eczema herpeticum (1)

Wong 2003

1. n = 30

2. Adult/paediatric

3. 4 weeks

0.1% adults

0.03% paediatric

‐ Burning

‐ Pruritus

Normal

2 participants

< 5 ng/ml

* 6‐year‐old participant, at month 6, resolution after withdrawn.
AD: atopic dermatitis.
NMSC: non‐melanoma skin cancer.

Figures and Tables -
Table 5. Observational non‐comparative studies
Comparison 1. Tacrolimus 0.1% versus steroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Physician's assessment of global response of improvement, clear or excellent Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.1 Tacrolimus 0.1% versus hydrocortisone acetate 0.1%: 3 weeks

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 Tacrolimus 0.1% versus hydrocortisone butyrate: 3 weeks

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.3 Tacrolimus 0.1% versus hydrocortisone acetate and butyrate 0.1%: short‐term (6 months)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

1.4 Tacrolimus 0.1% versus hydrocortisone acetate and butyrate 0.1%: long‐term (12 months)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Adverse effects: burning Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Tacrolimus 0.1% versus hydrocortisone acetate 0.1%: 3 weeks

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Tacrolimus 0.1% versus hydrocortisone butyrate: 3 weeks

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 Tacrolimus 0.1% versus hydrocortisone acetate and butyrate 0.1%: short‐term (6 months)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 Tacrolimus 0.1% versus hydrocortisone acetate and butyrate 0.1%: long‐term (12 months)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Adverse effects: pruritus Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.1 Tacrolimus 0.1% versus hydrocortisone acetate 0.1%: 3 weeks

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.2 Tacrolimus 0.1% versus hydrocortisone butyrate: 3 weeks

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3.3 Tacrolimus 0.1% versus hydrocortisone acetate and butyrate 0.1%: short‐term (6 months)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4 Adverse effects: skin infection Show forest plot

3

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.1 Tacrolimus 0.1% versus hydrocortisone acetate 0.1%: 3 weeks

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.2 Tacrolimus 0.1% versus hydrocortisone butyrate: 3 weeks

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

4.3 Tacrolimus 0.1% versus hydrocortisone acetate and butyrate 0.1%: short‐term (6 months)

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

5 SCORAD: 3 weeks Show forest plot

2

37

Mean Difference (IV, Fixed, 95% CI)

‐8.82 [‐15.36, ‐2.27]

Figures and Tables -
Comparison 1. Tacrolimus 0.1% versus steroids
Comparison 2. Tacrolimus 0.1% versus pimecrolimus 1%

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Physician's assessment of global response of improvement, clear or excellent Show forest plot

3

543

Risk Ratio (M‐H, Fixed, 95% CI)

1.80 [1.35, 2.42]

1.1 13 days

1

37

Risk Ratio (M‐H, Fixed, 95% CI)

1.89 [0.19, 19.13]

1.2 6 weeks

2

506

Risk Ratio (M‐H, Fixed, 95% CI)

1.80 [1.34, 2.42]

2 Adverse effects ‐ 6 weeks Show forest plot

2

506

Risk Ratio (M‐H, Random, 95% CI)

0.89 [0.47, 1.71]

Figures and Tables -
Comparison 2. Tacrolimus 0.1% versus pimecrolimus 1%
Comparison 3. Tacrolimus 0.03% versus steroids

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Physician's assessment of global response of improvement, clear or excellent Show forest plot

5

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Tacrolimus 0.03% 1x/day versus hydrocortisone acetate 1% 2x/day

1

411

Risk Ratio (M‐H, Random, 95% CI)

2.05 [1.36, 3.08]

1.2 Tacrolimus 0.03% 2x/day versus hydrocortisone acetate 1% 2x/day

2

790

Risk Ratio (M‐H, Random, 95% CI)

2.58 [1.96, 3.38]

1.3 Tacrolimus 0.03% 2x/day versus steroids moderate potency 2x/day

2

409

Risk Ratio (M‐H, Random, 95% CI)

0.45 [0.13, 1.57]

1.4 Tacrolimus 0.03% 2x/day versus methylprednisolone 0.03% 1x/day

1

265

Risk Ratio (M‐H, Random, 95% CI)

1.00 [0.85, 1.19]

2 Participants's assessment of global response of improvement better or much better Show forest plot

2

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Tacrolimus 0.03 1x/day versus hydrocortisone acetate 1% 2x/day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Tacrolimus 0.03% 2x/day versus hydrocortisone acetate 1% 2x/day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 Tacrolimus 0.03% 2x/day versus fluticasone 0.005% 2x/day

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Adverse effects: burning Show forest plot

5

1883

Risk Ratio (M‐H, Fixed, 95% CI)

2.48 [1.96, 3.14]

3.1 Tacrolimus 0.03% versus hydrocortisone acetate 1%

2

998

Risk Ratio (M‐H, Fixed, 95% CI)

1.87 [1.36, 2.57]

3.2 Tacrolimus 0.03% versus steroids moderate potency

3

885

Risk Ratio (M‐H, Fixed, 95% CI)

3.52 [2.45, 5.06]

4 Adverse effects: pruritus Show forest plot

5

1883

Risk Ratio (M‐H, Fixed, 95% CI)

1.51 [1.17, 1.95]

4.1 Tacrolimus 0.03% versus hydrocortisone acetate 1%

2

998

Risk Ratio (M‐H, Fixed, 95% CI)

1.37 [1.00, 1.88]

4.2 Tacrolimus 0.03% versus steroids of moderate potency

3

885

Risk Ratio (M‐H, Fixed, 95% CI)

1.81 [1.18, 2.80]

5 Adverse effects: skin infection Show forest plot

4

1643

Risk Ratio (M‐H, Fixed, 95% CI)

1.07 [0.69, 1.66]

5.1 Tacrolimus 0.03% versus hydrocortisone acetate 1%

2

788

Risk Ratio (M‐H, Fixed, 95% CI)

0.94 [0.49, 1.79]

5.2 Tacrolimus 0.03% versus steroids of moderate potency

2

855

Risk Ratio (M‐H, Fixed, 95% CI)

1.19 [0.65, 2.18]

Figures and Tables -
Comparison 3. Tacrolimus 0.03% versus steroids
Comparison 4. Tacrolimus 0.03% versus tacrolimus 0.1%

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Physician's assessment of global response of improvement, clear or excellent Show forest plot

6

1640

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.72, 0.92]

1.1 3 weeks

4

985

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.71, 0.96]

1.2 12 weeks

2

655

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.64, 0.99]

2 Adverse effects Show forest plot

4

986

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.86, 1.06]

Figures and Tables -
Comparison 4. Tacrolimus 0.03% versus tacrolimus 0.1%
Comparison 5. Tacrolimus 0.03% versus pimecrolimus 1%

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Physician's assessment of global response of improvement Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.1 Application site reaction

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 Burning

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 Itching

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 Erythema

1

Risk Ratio (M‐H, Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 5. Tacrolimus 0.03% versus pimecrolimus 1%
Comparison 6. Tacrolimus 0.1% versus ciclosporin

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Adverse effects Show forest plot

1

Risk Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2 SCORAD Show forest plot

1

Mean Difference (Fixed, 95% CI)

Totals not selected

2.1 14 days

1

Mean Difference (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 21 days

1

Mean Difference (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 28 days

1

Mean Difference (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 35 days

1

Mean Difference (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.5 42 days

1

Mean Difference (Fixed, 95% CI)

0.0 [0.0, 0.0]

Figures and Tables -
Comparison 6. Tacrolimus 0.1% versus ciclosporin