Appendix 1. Outcomes adapted from Pirmohamed 2011

Primary outcome:

• Drug‐induced skin reaction (yes, no) Figure 7

Figure 7

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Drug‐induced skin rash: top panel = maculopapular exanthema, bottom panel = Steven Johnson Syndrome (blistering skin rash with skin detachment)

Secondary outcomes:

• SJS/TEN (Stevens‐Johnson syndrome, toxic epidermal necrolysis)

• • Skin detachment 1% to 10% (SJS), 10% to 30% (overlap syndrome), and > 30% (TEN)

  • Severe, often hemorrhagic, erosions of mucous membranes

  • Other manifestations indicating systemic involvement (e.g. fever, liver chemistry elevations, intestinal and pulmonary manifestations, or the presence of lymphopenia)

  • Severe pain and tenderness in the skin

  • Target lesions, representing the degree of epidermal necrosis

• AGEP (acute generalised exanthematous pustulosis)

• • Acute widespread edematous erythema followed by a sterile pustular eruption. Often the pustules are first localised in the neck, groin, and axillae, and later become widely disseminated

  • Fever (temperature > 38 °C)

  • Neutrophilia with or without a mild eosinophilia

• HSS (Hypersensitivity syndrome)

• • Additional terminology includes Drug‐induced hypersensitivity syndrome (DIHS), Drug reaction with eosinophilia and systemic symptoms (DRESS), Drug‐induced delayed multiorgan hypersensitivity syndrome

  • Variable skin manifestations; exanthema are most common

  • Increased liver function tests, hepatitis, cholestasis

  • Colitis

  • Nephritis

  • Pneumonitis

  • Aseptic meningitis, encephalitis, inappropriate antidiuretic hormone syndrome

  • Myocarditis

  • Myositis

  • Lymphocytic thyroiditis

  • Eosinophilia, atypical lymphocytes, agranulocytosis, thrombocytopenia, haemolytic anaemia, aplastic anaemia

  • Lymphadenopathy, pseudolymphoma

Appendix 2. CRSW/Skin Specialised Register search strategy

(Exanthema or rash or rashes or “drug induced skin injur*” or “drug hypersensitiv*” or “hypersensitiv* reaction*” or “hypersensitiv* syndrome*” or “drug eruption*” or “drug toxicity” or “adverse drug reaction*” or “toxic epidermal necrolysis” or ten or “stevens johnson syndrome” or “Acute Generalized Exanthematous Pustulosis” or “erythema multiforme” or “dress syndrome” or “Drug Reaction with Eosinophilia and Systemic Symptoms” or “Drug Rash with Eosinophilia and Systemic Symptoms”) and (“genetic test*” or pharmacogenomic* or pharmacogenetic* or screening or “patch test*” or “HLA Antigen*” or “hla allele*” or “genetic polymorphism*” or “genetic variation*” or “genetic variant*" or "genetic variabilit*”)

Appendix 3. CENTRAL (Cochrane Library) search strategy

#1 exanthema:ti,ab
#2 MeSH descriptor: [Exanthema] explode all trees
#3 (rash or rashes):ti,ab
#4 drug induced skin injur*:ti,ab
#5 MeSH descriptor: [Drug Hypersensitivity] explode all trees and with qualifier(s): [Genetics ‐ GE, Prevention & control ‐ PC]
#6 drug near/2 hypersensitiv*:ti,ab
#7 hypersensitiv* reaction*:ti,ab
#8 hypersensitivity syndrome*:ti,ab
#9 drug eruption*:ti,ab
#10 MeSH descriptor: [Drug‐Related Side Effects and Adverse Reactions] explode all trees and with qualifier(s): [Genetics ‐ GE, Prevention & control ‐ PC]
#11 drug toxic*:ti,ab
#12 adverse drug reaction*:ti,ab
#13 toxic epidermal necrolysis:ti,ab
#14 MeSH descriptor: [Stevens‐Johnson Syndrome] explode all trees
#15 stevens johnson syndrome:ti,ab
#16 Acute Generalized Exanthematous Pustulosis:ti,ab
#17 MeSH descriptor: [Acute Generalized Exanthematous Pustulosis] explode all trees
#18 erythema multiforme:ti,ab
#19 MeSH descriptor: [Erythema Multiforme] explode all trees
#20 dress syndrome:ti,ab
#21 Drug Reaction with Eosinophilia and Systemic Symptoms:ti,ab
#22 Drug Rash with Eosinophilia and Systemic Symptoms:ti,ab
#23 {or #1‐#22}
#24 MeSH descriptor: [Genetic Testing] explode all trees
#25 genetic test*:ti,ab
#26 MeSH descriptor: [Pharmacogenetics] explode all trees
#27 (pharmacogenomic* or pharmacogenetic*):ti,ab
#28 screening:ti,ab
#29 patch test*:ti,ab
#30 MeSH descriptor: [Patch Tests] explode all trees
#31 MeSH descriptor: [HLA Antigens] explode all trees
#32 hla allele*:ti,ab
#33 MeSH descriptor: [Polymorphism, Genetic] explode all trees
#34 genetic polymorphism*:ti,ab
#35 (genetic variant* or genetic variation* or genetic variabilit*):ti,ab
#36 MeSH descriptor: [Genetic Variation] explode all trees
#37 {or #24‐#36}
#38 #23 and #37

Appendix 4. MEDLINE (Ovid) search strategy

1. exp Exanthema/
2. exanthema.ti,ab.
3. (rash or rashes).ti,ab.
4. drug induced skin injur$.ti,ab.
5. exp Drug Hypersensitivity/ge, pc [Genetics, Prevention & Control]
6. (drug adj2 hypersensitiv$).ti,ab.
7. hypersensitiv$ reaction$.ti,ab.
8. hypersensitivity syndrome$.ti,ab.
9. drug eruption$.ti,ab.
10. exp Drug Toxicity/ge, pc [Genetics, Prevention & Control]
11. drug toxic$.ti,ab.
12. adverse drug reaction$.ti,ab.
13. toxic epidermal necrolysis.ti,ab. or exp Epidermal Necrolysis, Toxic/
14. stevens johnson syndrome.ti,ab. or exp Stevens‐Johnson Syndrome/
15. exp Acute Generalized Exanthematous Pustulosis/
16. Acute Generalized Exanthematous Pustulosis.ti,ab.
17. erythema multiforme.ti,ab. or exp Erythema Multiforme/
18. dress syndrome.ti,ab.
19. "Drug Reaction with Eosinophilia and Systemic Symptoms".ti,ab.
20. "Drug Rash with Eosinophilia and Systemic Symptoms".ti,ab.
21. or/1‐20
22. exp Genetic Testing/
23. genetic test$.ti,ab.
24. exp Pharmacogenetics/
25. (pharmacogenomic$ or pharmacogenetic$).ti,ab.
26. screening.ti,ab.
27. patch test$.ti,ab.
28. exp Patch Tests/
29. exp HLA Antigens/
30. hla allele$.ti,ab.
31. exp Polymorphism, Genetic/
32. genetic polymorphism$.ti,ab.
33. exp Genetic Variation/
34. (genetic variant$ or genetic variation$ or genetic variabilit$).ti,ab.
35. or/22‐34
36. randomized controlled trial.pt.
37. controlled clinical trial.pt.
38. randomized.ab.
39. placebo.ab.
40. clinical trials as topic.sh.
41. randomly.ab.
42. trial.ti.
43. 36 or 37 or 38 or 39 or 40 or 41 or 42
44. exp animals/ not humans.sh.
45. 43 not 44
46. 21 and 35 and 45

[Lines 36‐45: Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity‐ and precision‐maximizing version (2008 revision)]

Appendix 5. Embase (Ovid) search strategy

1. exp rash/
2. exanthema.ti,ab.
3. (rash or rashes).ti,ab.
4. drug induced skin injur$.ti,ab.
5. exp drug hypersensitivity/pc [Prevention]
6. (drug adj2 hypersensitiv$).ti,ab.
7. hypersensitiv$ reaction$.ti,ab.
8. hypersensitivity syndrome$.ti,ab.
9. drug eruption$.ti,ab.
10. exp drug toxicity/pc [Prevention]
11. drug toxic$.ti,ab.
12. adverse drug reaction$.ti,ab.
13. toxic epidermal necrolysis.ti,ab.
14. toxic epidermal necrolysis/
15. Stevens Johnson syndrome/
16. stevens johnson syndrome.ti,ab.
17. acute generalized exanthematous pustulosis/
18. Acute Generalized Exanthematous Pustulosis.ti,ab.
19. erythema multiforme/
20. erythema multiforme.ti,ab.
21. DRESS syndrome/
22. dress syndrome.ti,ab.
23. "Drug Reaction with Eosinophilia and Systemic Symptoms".ti,ab.
24. "Drug Rash with Eosinophilia and Systemic Symptoms".ti,ab.
25. or/1‐24
26. genetic screening/
27. genetic test$.ti,ab.
28. exp pharmacogenetics/
29. (pharmacogenomic$ or pharmacogenetic$).ti,ab.
30. screening.ti,ab.
31. patch test$.ti,ab.
32. patch test/
33. exp HLA antigen/
34. hla allele$.ti,ab.
35. exp genetic polymorphism/
36. genetic polymorphism$.ti,ab.
37. genetic variability/
38. (genetic variant$ or genetic variation$ or genetic variabilit$).ti,ab.
39. or/26‐38
40. crossover procedure.sh.
41. double‐blind procedure.sh.
42. single‐blind procedure.sh.
43. (crossover$ or cross over$).tw.
44. placebo$.tw.
45. (doubl$ adj blind$).tw.
46. allocat$.tw.
47. trial.ti.
48. randomized controlled trial.sh.
49. random$.tw.
50. or/40‐49
51. exp animal/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/
52. human/ or normal human/
53. 51 and 52
54. 51 not 53
55. 50 not 54
56. 25 and 39 and 55

Appendix 6. LILACS search strategy

tw:((exanthema OR exantema OR rash OR rashes OR "toxic epidermal necrolysis" OR "stevens johnson syndrome" OR "erythema multiforme" OR "dress syndrome") AND ("genetic test" OR "genetic testing" OR screening OR "patch test" OR "patch testing"))

In LILACS we searched using the above terms and the Controlled clinical trials topic‐specific query filter.

Appendix 7. Contacted authors