Adverse drug reactions of the skinL27.0

Drugs are chemical compounds of small molecular size (usually <1 kD) that are administered to treat, prevent or diagnose a disease. In addition to the desired effects, they can also trigger numerous undesirable, unpredictable reactions (the Greek word Pharmakon means both remedy and poison).

Adverse drug reactions (ADRs) are therefore defined as:

unpredictable (unexpected), undesirable and harmful effect of a drug administered in a prescribed dose, of varying aetiology and clinical presentation, which may affect the skin and/or mucous membranes and internal organs (see pharmacogenetics; see also cytochrome P450 enzymes). The possibility of adverse drug reactions should always be considered within the framework of a risk-benefit assessment before the start of therapy.

Time factor:

An adverse drug reaction can:

• immediate (immediate type drug reaction of the immediate type "immediate": urticaria, asthma, anaphylaxis)

or

• days/weeks after the start of treatment (delayed type - ADR of the delayed type "non-immediate": maculopapular drug exanthema, AGEP, Stevens-Johnson syndrome/TEN)

or less frequently

• only occur several weeks/months (late typeADRs) after the start of treatment of the triggering drug(DRESS)

Pathogenesis:

A cutaneous ADR can be immunological (IgE- or non-IgE-mediated) or non-immunological (non-allergic drug hypersensitivity - mechanism mostly unknown-, often predictable pharmacological side effects, toxic, cumulative toxic effects, etc.).

Clinical (morphological criteria):

A cutaneous ADR may be visible or non-visible, exanthematous (urticarial, maculopapular - special form lichenoid-, vesiculo-bullous, pustular) or non exanthematous (fixed toxic drug reaction, dyschromia, angioedema, pruritus, etc.) de novo. Non-visible cutaneous drug reactions are characterized by pruritus, burning or stinging of the skin.

Clinic (Enhancement):

A cutaneous ADR can trigger or aggravate pre-existing skin symptoms (see below e.g. psoriasis vulgaris, acne vulgaris, lichen planus).

A cutaneous drug reaction can trigger solar or radiation-induced recall reactions.

System participations:

A cutaneous ADR can be associated with different organ diseases (haematological, nephrological, hepatological, etc.)

Interactions:

A cutaneous ADR can be caused by undesirable interactions, which in principle can occur between all drugs, but also between drugs and other substances such as alcohol, nicotine, environmental toxins or food.

Co-factors:

• Co-factor - Infections:
  • A cutaneous ADR occurs (only) in connection with infectious co-factors (e.g. viral infections - type Epstein-Barr virus infection and intake of antibiotics, especially aminopenicillins).
• Co-factor vaccinations: AEFI (adverse events following immunisation) can occur in connection with the intake of drugs.
• Co-factor - physical noxae:
  • Electromagnetic radiation: A special form of cutaneous ADRs concerns phototoxic or photoallergic reactions. Its diagnosis is simple, as a heliotropic macro pattern of the skin is formed (see below phototoxic dermatitis; photoallergic eczema).
  • Pressure: Cutaneous ADRs occur only in areas exposed to pressure(Koebner phenomenon, pressure urticaria).
  • Other: Water(Urticaria aquagene), Exertion ( among others )

Side effects of cytostatic drugs are recorded using standardized criteria (see below Common toxicity criteria).

From the etiopathogenetic point of view one can basically be divided into:

• ADRtype A: Non-immunological (augmented - pharmacological-toxic) drug reactions, 70-80% of ADRs (predictable)
  • overdose
  • Known or unknown toxicity
  • Interactions
  • Teratogenicity;
• ADR Type B: "Bizarre" hypersensitivity reaction to medicinal products; unexplained due to its pharmacological property; (unpredictable or unexpected) adverse drug reaction Such reactions occur only in specially predisposed patients. There are 2 different forms:
  • drug allergy (hypersensitivity is based on an immunological reaction (type I - type VI - extended according to Coombs and Gell; the T-cellular type IV drug reactions are additionally subdivided into types IVa-d; see below Immunological drug allergy)
  • Non-immunological drug hypersensitivity (an immunological - allergic - mechanism is not detectable:
    • Drug intolerance: typical symptoms of pharmacological action (toxicity) develop even at low doses that are usually tolerated.
    • Drug adiosyncrasy: the symptoms differ from the pharmacological effect of the substance. Reactions with symptoms corresponding to allergic diseases are also called pseudoallergies.

Depending on the clinically formative leading efflorescences one differentiates between:

• De novo (exanthematic and non-exanthematic) drug reactions:
  • Macular drug exanthema
  • Papular drug exanthema
  • Urticarial drug exanthema (see below urticaria)
  • Angioedema
  • Vesicular/bullous drug exanthema
  • Acneiform drug exanthema
  • Lichenoid drug exanthema
  • Lymphomatoid (lymphocytic) drug reaction
  • Light-provoked exanthema (see below light dermatoses; see also UV reactivation reaction)
  • Pseudolymphomas
  • Neutrophil papular exanthema (e.g. Sweet syndrome)
  • Pustular dermatoses(pustuloses)
  • Shape circle of the Purpura pigmentosa progressiva
  • Multiforme exanthema(erythema multiforme, Stevens-Johnson syndrome; toxic epidermal necrolysis)
  • Vasculitic drug exanthema
  • Dyschromia caused by drugs
  • Skin symptoms with cytostatic therapy
  • Skin symptoms with tyrosine kinase inhibitors
  • Skin necrosis with anticoagulation (see also heparin necrosis, coumarin necrosis)
  • Drug reaction, fixed: Mostly singular or limited to a few foci, roundish, blue-red, sharply defined, livid red succulent erythema or plaques. Bullous transformation possible in the centre.
  • Pruritus (e.g. pruritus after HAES infusions or ACE inhibitors)
  • Tissue hyperplasia (e.g. gingival hyperplasia, scleroderma-like drug reactions)
  • Nail alterations(Beau-Reils transverse furrows, photoonycholysis, paronychia, etc.)
  • Hair growth changes (effluvium, alopecia, hypertrichosis)
• Triggering, deterioration or resistance to therapy of defined skin diseases, e.g.:
  • acne vulgaris
  • Alopecia
  • Dermatosis, acute febrile neutrophils (Sweet syndrome)
  • Dermatomyositis
  • Erythema nodosum
  • Hirsutism
  • Hypertrichosis
  • lichen planus
  • lupus erythematosus
  • Nail dystrophies (see below nail diseases)
  • Pemphigoid, bullous
  • Pemphigus
  • Photoallergic and phototoxic diseases (see below light dermatoses)
  • Porphyria
  • psoriasis vulgaris
  • Urticaria
  • Vasculitis
  • Vitiligo

Remark: see also classification under histology

In addition to skin ADRs, other ADRs can be distinguished according to organ manifestation (system organ class):

• Infections and parasitic diseases
• Benign, malignant and unspecific neoplasms (including cysts and polyps)
• Diseases of the blood and lymphatic system
• Diseases of the immune system
• Endocrine diseases
• Metabolic and nutritional disorders
• Psychiatric diseases
• diseases of the nervous system
• Eye diseases
• Diseases of the ear and the labyrinth
• Heart diseases
• Vascular diseases
• Diseases of the respiratory tract, chest and mediastinum
• diseases of the gastrointestinal tract
• Diseases of the skin and subcutaneous cell tissue
• Skeletal musculature, connective tissue and bone diseases
• diseases of the kidneys and urinary tract
• Diseases of the reproductive organs and the mammary gland
• General illnesses and complaints at the place of administration
• Injury, poisoning and complications caused by surgery

Reliable epidemiological data on ADRs are not available. On average, a patient receives 10 different drugs during an inpatient hospital stay. The rate of side effects increases proportionally to the frequency of use. The number of ADRs is < 5% for the administration of < 6 drugs. With the administration of > 15 medications the rate is > 40%.

Remember! Approx. 3-5% of inpatient admissions are caused by drug side effects.

Frequencies: ADRs are classified according to their frequency in:

• very often >1:10
• frequent (> 1:100 <1:10)
• occasionally (>1:1,000<1:100)
• rare (>1:10,000 <1:1,000)
• very rare (<1:10,000 including individual reports).

In principle, any drug can cause any adverse drug reaction, although certain priorities can be observed depending on the clinical appearance. A few widely used drugs are responsible for 90% of all adverse drug reactions, e.g. acetylsalicylic acid, digoxin, anticoagulants, diuretics, antibiotics, glucocorticoids, cytostatics, antidiabetics.

A prerequisite for cutaneous drug hypersensitivity is a stable association of a drug with a protein so that hapten-protein conjugates can be produced. A typical route could be the formation of such conjugation by keratinocytes (analogous mechanism for contact allergic reaction). However, not all drugs in their native form are the actual allergen. Occasionally, metabolites are more reactive than the original substance (bioactivation).

There is no "simple" method to safely identify a UAW as such. The following types of ADRs can be identified by their trigger mechanism:

• Classical allergic reactions: Specific immune reaction against the drug if it is a protein, oligopeptide or polysaccharide.
• Autoimmune reactions: Triggered e.g. by penicillamine or vaccinations (see AEFI below).
• Immunomodulatory effects: Activation of immunocompetent cells by the medicinal product (TNF-alfa induction - i.e. drug reactions by biomodulators - and occurrence of pseudoscleroderma by bleomycin).
• Genetic enzyme abnormalities with disturbance of drug degradation: e.g. glucose-6-phosphate dehydrogenase deficiency; defects of N-acetyltransferase, slow acetylation, etc.
• Intolerance reactions: Non-allergic reactions with partly unknown mechanism, e.g. by:
  • Mediator release from mast cells: (tartrazine (?), antibiotics, muscle relaxants, opioids).
  • Influencing the metabolism of arachidonic acid: X-ray contrast agent, analgesics, anti-inflammatory drugs, food dyes (?), benzoates (?).
  • Complement activation (immunoglobulin aggregates, X-ray contrast media, protamine).
  • Kinin activation (local anaesthetics, ACE inhibitors).
  • Lymphocyte activation (ampicillin, hydantoin, release of neurotransmitters, erythrosine, glutamate)
  • Excitation of receptors of the autonomic nervous system (sulphites, glutamate, local anaesthetics).

Notice! The method of application of the drug plays an essential role in the frequency of sensitization! The risk of a drug reaction increases in the following order: peroral > intravenous > intramuscular > subcutaneous > topical!

Danger-Hypothesis: The discrepancy between suspected and actually proven drug (mostly antibiotic) exanthema, which can be observed especially in children, is often caused by bacterial or viral immune reactions. The "Danger-Hypothesis" is the explanation for this: systemic infections with best-known diseases. Viruses or bacteria or autoimmune diseases can lower the reaction threshold of the immune system. The consequence are passagere, infection-associated, drug-induced autoimmune phenomena (e.g. exanthema in the context of infectious mononucleosis and ampicillin intake), which cannot be triggered again after the immunological activation has subsided even if the suspected drug is taken again. Infections act as cofactors in this process.

The mean age of the patients in larger studies is 65 years (27-96 years). They occur 2-3 times more frequently in geriatric patients than in patients < 30 years. In geriatric patients, ADRs affect significantly more than 10% of this population group.

Ubiquitous, skin and/or mucous membrane

Appears as:

• monotopic (e.g. fixed toxic drug exanthema see below) drug exanthema, fixed, toxic) or
• polytopic (disseminated, generalized or universal) reaction.

Various drug reactions are influenced by orthostatic moments (e.g. lower extremity, contact points).

Photo-induced or photo-engraved exanthema occur in exposed areas.

Varied clinical course, depending on the drug that triggers it. The severity of the clinical course ranges from harmless to life-threatening, its course from protracted to highly acute, so that emergency measures may be necessary. Development either de novo or through exacerbation of a pre-existing disease. The skin organ is one of the frequently affected organs. In most cases, generalized, symmetrical, often itchy lesions of different morphologies are impressive. Depending on the clinically formative leading efflorescences, a distinction is made, for example, between macular, urticarial, papular, vesicular or pustular exanthema with or without a hemorrhagic component or even just pruritus. Often clinic of erythema multiforme, purpura pigmentosa progressiva, urticaria, angioedema or lichen planus.

Other symptoms may be: fever (often the only symptom, but usually occurring together with other allergic manifestations) and changes in blood count (all blood cell lines may be affected, e.g. leukocytosis, eosinophilia, leukopenia, left-shifting, absolute lymphopenia, thrombopenia).

No landmark histological phenomena. Depending on the clinical appearance (macular, papular, urticarial, EEM) an analogous histological pattern can be expected. Histoeosinophilia is to be expected in a larger proportion of cases. Otherwise lymphocytes predominate, more rarely neutrophil granulocytes.

The following basic histological patterns can be found in cases of adverse cutaneous drug effects (var. n. K. Kerl et al. 2016):

Superficial and deep dermal infiltrates (with/without epidermal involvement)

• maculopapular exanthema
• Urticaria
• Pseudolymphomas of the skin
• DRESS
• Lupus erythematosus drug-induced

Cytotoxic/lichenoid (epidermal) drug action

• Erythema multiforme/Stevens-Johnson syndrome/toxicepidermal necrolysis/fixeddrug reaction
• Lichen planus (drug-induced)
• Fixed drug reaction
• Phototoxic dermatitis
• "Epidermal dysmaturation"
• Hand-foot syndrome
• "Radiation recall dermatitis
• UV-Recall Dermatitis
• lupus erythematosus

Spongiotic drug reaction

• Pityriasis rosea-like drug response
• Eczematous drug reaction
• SDRIFE/Baboon syndrome

Granulomatous drug reaction

• Vaccination granulomas
• Sarcoidosis
• Interstitial granulomatous dermatitis

Leucocytoclastic vasculitis

Psoriasiform drug reaction

• Drug-induced psoriasis
• Acute generalized exanthematous pustulosis (AGEP)

Neutrophilic drug reactions

• Sweet Syndrome
• Neutrophil eccrineHidradenitis

Vesiculous-bullous drug reaction

• Linear IgA dermatosis
• drug-induced pemphigus
• Pemphigoid
• Pseudoporphyria

drug-induced panniculitis

• Erythema nodosum
• Panniculitis after chemotherapy
• Panniculitis after injection of a drug

Folliculitis

• Eosinophil pustular folliculitis
• Folliculitis(acne) after blockage of the epidermal growth factor receptor (EGF)
• acne medicamentosa
• Bromoderma tuberosum

Sclerodermiform drug reactions

Hyper/and depigmentations

• Vitiligo (drug-induced)
• Hyperpigmentations(Chloasma)

General medical history:

• Basic biographical data (gender, age, occupation)?
• Known hypersensitivities (is there an allergy passport; have allergological tests been carried out before; are there IgE determinations/RAST results; was an inpatient stay for provocation testing already necessary; has the patient participated in pharmacological studies or follow-up observations)?
• Atopic diseases, food allergy (also family history)
• Predisposing diseases (e.g. bronchial asthma, polyposis nasi, chronic urticaria, mastocytosis, EBV or HIV infection, metabolic diseases)?
• Other past or present diseases?
• Current use of medication?
• Recent vaccinations (see also influenza vaccinations, skin changes)?

Medication used in time with the reaction:

• Trade names?
• Single active substance or combination preparation?
• Form of application (topical, tablets, drops, sprays, p.o., i.v., i.m., s.c., rectal)?
• Ingredients (possibly active substances/auxiliary agents)?
• Duration of application?
• Dosage?
• Tolerability for previous or renewed application?
• Are there still residues of the accused drug (batch numbers [are there any evidence available])?

Classification of the clinical reaction:

• Timing in relation to the use of the drug (time of intake; how often?; when did symptoms appear after intake: acute = 0-60 min., subacute = 1-24 hrs., delayed or accelerated = more than 24 hrs. post applikationem)?
• Symptomatology/diagnostic classification?
• Laboratory findings (e.g. eosinophilia, transaminase elevation, blood count changes, serumtryptase concentration)?
• Therapy and clinical course of the disease?
• Were there similar reactions without drug application in the medical history?

Circumstances of the reaction:

• Date, time of occurrence?
• Original indication for drug use?
• Illnesses at the time of the reaction (e.g. intercurrent viral infection; flu symptoms)?
• Location and activity (in particular physical or mental stress, UV exposure)?
• Food intake, alcohol intake, drug abuse?

Allergological tests:

Remember! Skin tests should be carried out at the earliest 2-3 weeks after the reaction symptoms have subsided or after systemic glucocorticoid therapy and/or antihistamine therapy and not later than 3 months afterwards!

• Test material: Drug preparations, active ingredients, excipients; positive and negative controls depending on the test procedure; appropriate test concentrations to avoid toxic or pharmacological reactions (e.g. to morphine derivatives) or false negative test results (threshold test, if necessary). Preparation of the material suitable for skin testing.
• Prick test or intradermal painting test (IDT)
• Epicutaneous testing: depending on the drug in question, different (non-irritant) skin test concentrations are required.
• RAST (specific IgE): Validated tests for the detection of specific IgE antibodies in serum are only available for a few drugs (mainly betalactam antibiotics). Otherwise, no standardized and evaluated in vitro methods are available.
• Other immunological laboratory methods (e.g. basophil histamine release test, basophil activation test, leukotriene release test (CAST-ELISA [sulfidoleukotrienes from peripheral leukocytes after stimulation with a specific antigen], lymphocyte transformation test) are only applicable for clinical diagnosis in certain selected cases. In case of positive reactions, sufficient control tests are necessary.
• In case of appropriate clinical symptoms, determination of drug-metabolizing enzymes to detect metabolic disorders associated with hypersensitivity to certain drugs (e.g. glucose-6-phosphate dehydrogenase, dihydropyrimidine dehydrogenase, thiopurine S-methyltransferase).
• If necessary, pharmacogenetic investigations (e.g. acetylation status in case of sulfonamide allergy).
• Provocation or evasion tests (usually the only safe method for the diagnosis of drug intolerances). Provocation tests are necessary if the trigger of drug hypersensitivity cannot be identified with certainty by anamnesis, skin test and in vitro examinations. This is often the case, especially in suspected reactions to substances of indispensable or permanently unavoidable pharmaceutical groups (e.g. analgesics, local anaesthetics). Provocation tests also serve to identify tolerated preparations (alternative preparations, especially in the run-up to intended pharmacotherapy or preoperatively; in the case of risk of cross-reactions to drugs).

The final evaluation of the findings must take into account the failure of skin, in vitro and provocation tests and in particular the history of the clinical reaction. A definite exclusion of hypersensitivity to a drug is not always possible, even if all available test procedures are applied. The result of the overall assessment must be recorded in detail in the allergy passport. The type of reaction and the substances/preparations that were not tolerated must be documented with reference to possible cross-reactions. Possible (tested) alternative substances/preparations should be documented with the exact dose tested and tolerated/not tolerated (e.g. acetylsalicylic acid tolerated up to a single dose of 500 mg with oral provocation). It should be explained that the future tolerability of alternative substances/preparations cannot be guaranteed with certainty, as the result of the provocation test only allows an assessment of the risk in the case of re-exposure. Information on possible pharmacoprophylaxis of hypersensitivity reactions (e.g. premedication with the administration of X-ray contrast media or during surgical interventions under general anaesthesia) and on the induction of tolerance should also be documented in writing if necessary.

A warning passport must always be issued in the case of systemic reactions.

• Detection and elimination of the triggering drugs. Discontinuation or conversion of all drugs under consideration.
• Depending on the severity of the disease, glucocorticoids in medium (60-80 mg prednisolone equivalent/day) or higher (80-200 mg prednisolone equivalent/day) doses, or several times as needed. Later, gradual dose reduction and change to oral medication, then also stomach protection (e.g. Riopan Gel). Antihistamines for severe itching such as dimetinden (e.g. Fenistil) 2 times/day 1 amp. i.v. or desloratadine (e.g. Aerius) 1 time / day 1 tbl. p.o.
• Intravenous access, circulation monitoring, balancing, intensive monitoring if necessary.
• Otherwise the therapeutic measures depend on the respective clinical appearance, see there.

Most frequent triggers of adverse drug reactions (ADRs) according to clinic

clinical questions about ADRs

• Is there a convincing temporal relationship between the application of the substance and the occurrence of the symptoms?

• Is the symptom consistent with a known pharmacological effect or a known NW of the substance (e.g. cheilitis after taking acitretin; drowsiness with antihistamines)?

• Was the preparation taken at all?

• Is the disease of the patient itself or a non-pharmacological therapy as explanation for the symptom (e.g. infectious exanthema as DD for an ampicillin exanthema)?

• Does the symptom disappear after discontinuation?

• Did the ADR reappear after repeated administration?

• Are there relevant laboratory parameters that indicate a drug reaction (e.g. hematological values such as eosinophilia, neutrophilia, neutropenia, agranulocytosis)?

The Bfarm (Federal Institute for Drugs and Medical Devices) documents all side effects of a drug since 1995 in a database accessible to all patients (see below(http://www.bfarm.de)

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