Anatoli Chkaroubo

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Chemically Induced AutoimmunityIdiosyncratic
Drug Reactions

• Anatoli Chkaroubo
• Jessica Fitzgerald
• Alison Hulme
• Naomi Steenhof

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Idiosyncratic Drug Reactions
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Clinical Characteristics

• Incidence predicted that out of all ADRs 20 are
  idiosyncratic
• Time to onset in almost all cases there is a
  delay between starting the drug and the onset of
  the adverse reaction
• Dose dependence Drugs given at low doses are
  less likely to cause an IDR.
• Adaptation In many cases the initial reaction
  will resolve despite continued treatment.
• Clinical Features highly variable being
  dependent on both the drug and the patient. There
  are non-specific manifestations such as fever,
  rash, arthralgia and eosinophilia.

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Immunology simplified

• Both Signal 1 and Signal 2 are required for an
  immune response
• Signal 1 - recognition of drug-modified peptide
  fragments presented in the MHC groove of the APCs
  by T cells
• Signal 2 co-stimulation of T-cells by APCs

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Mechanism Hypotheses

• Hapten Hypothesis
• PI Hypothesis
• Danger Hypothesis

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The Hapten Hypothesis

• Studies by Landstiner (1935) small molecules
  cannot induce immune response unless they are
  chemically reactive, and bound to protein.
• Led to Hapten Hypothesis a small molecule
  (called hapten) binds to cellular protein, this
  modified protein is what induces an immune
  response
• Drug-modified protein is seen as foreign
  immune response

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Hapten Pathway

• 1.Reactive drug/metabolites bind to protein
• 2. Taken up by APC
• 3. Processsed
• 4. Presented in MHC groove to T cells
• 5. Gives immune response

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• Evidence for Hapten
• Penicillin-induced anaphylaxis

• Penicillin chemically reactive because of
  beta-lactam ring
• Reacts irreversibly with free amino and
  sulfhydryl groups on proteins
• Generates immune response against
  penicillin-protein adduct
• If sufficient IgE antibodies produced severe
  allergic reaction can result (anaphylaxis)
• Studies in support Most antibodies associated
  with penicillin allergies are directed against
  penicillin-modified proteins

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Pharmacological Interaction Hypothesis

• Studies by Pichler (2002) T cell clones from
  patients with IDR history proliferated in the
  presence of drug, in the absence of metabolism
• Led to PI Hypothesis Drugs bind reversibly to
  MHC complex, induces immune response can lead
  to IDR
• Drug binds to MHC immune response

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PI Pathway

• 1.Drug binds reversibly to MHC complex
• 2. Presented in MHC groove to T cells
• 3. Gives immune response

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Evidence for PI

• Sulfamethoxazole
• major drug in original studies
• primary aromatic amine
• associated with significant IDR incidence (if
  given 10mg/day)
• Undergoes oxidation to reactive metabolites
• controversy What is binding and causing immune
  response? Is it the parent drug, or reactive
  metabolites??

• Ximegalatran
• does not form reactive metabolites
• structurally similar to a small peptide
• evidence that it binds directly and reversibly to
  MHC

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The Danger Hypothesis

• Proposed by Polly Matzinger (1994)
• challenges the classical self-nonself hypothesis
  of immunology
• responding to something unless it was causing
  injury or was dangerous to an organism is
  inefficient
• in general, foreign proteins do not generate a
  significant immune response, unless an adjuvant
  stimulates APCs
• Damage to cells causes them to release danger
  signals
• The danger signals up-regulate Signal 2 and cause
  the immune response.
• No Signal 2 is immune tolerance

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Danger Pathway

• In IDRs, it may be that some reactive metabolites
  cause cell damage, which generates a danger
  signal
• The metabolites themselves could act as danger
  signals rather than as haptens
• Or they could do both
• Some drugs may form reactive metabolites but do
  not cause IDRs because the metabolites dont
  cause/dont signal danger

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Evidence for Danger Hypothesis

• Therefore, other types of injuries or infections
  could increase the incidence of IDRs.
• In fact, some viral infections do increase the
  risk of IDRs, as do episodes of inflammation.

A. Roth et al. JPET 307 (2003) 1-8
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• danger signals are not all known but are likely
  different for different types of cell stress and
  different types of cells.

M. Pirmohamed et al. / Toxicology 181182 (2002)
5563
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Drug Induced Lupus Erythematosus

• A classic IDR

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Drug Induced Lupus Erythematosus (DILE)

• an autoimmune disease that can affect skin,
  joints, heart, lungs, kidneys and brain.
• presents with similar symptoms to idiopathic
  systemic lupus erythematosus (SLE) but resolves
  when causative drug removed
• as many as 10 of SLE cases could actually be
  DILE
• DILE is equally probable in males and females
  while SLE is more common in women than in men
  (ratio of 91)
• must be cautious during diagnosis to confirm that
  it is DILE and not a drug-associated exacerbation
  of SLE or another underlying autoimmune disease.

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DILE - Causes

• Generally caused by continuous drug exposure
  ranging from one month to as long as a decade and
  can begin anytime from 3 weeks to 2 years after
  exposure.
• Physical and clinical problems resolve within
  days to months of withdrawing the causative drug
• Drugs that can cause DILE hydralazine,
  procainamide, quinidine, isoniazid, diltiazem
  (over 80 confirmed medications that can cause
  DILE)
• 20 incidence of DILE in procainamide patients at
  normal doses for one year.
• People who have deficiencies of the
  N-acetyltranserase enzyme are predisposed to
  experiencing DILE

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DILE - Diagnosis and Treatment

• no standard diagnostic criteria but generally
  patients have arthritis, serositis, anti-nuclear
  and antihistone antibodies .
• patients frequently present with arthalgia (often
  the only symptom). Can also have myalgia, fever
  and pericarditis.
• changes of the skin are less common with DILE
  than SLE
• NSAIDS to control the symptoms.
• Corticosteroids and immunosuppressive agents
  should
• be reserved for patients with organ damage.
• should not rechallenge because will result in
  recurrence.

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Strategies to decrease the risk of ADRs

• Decreasing Reactive Metabolites
• Developing biomarkers to Predict IDR risk
• Personalized drug therapy
• Developing a better understanding of IDR
  mechanism

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References

• Kauffman, C. Lisa Lupus Erythematosus,
  Drug-Induced, 2007. http//emedicine.medscape.com
  /article/1065086-overview
• Matzinger, P. Annu. Rev. lmmunol. 12 (1994)
  991-1045
• Pirmohamed, M. et al. Toxicology 181182 (2002)
  5563
• Roth, A. et al. JPET 307 (2003) 1-8
• Uetrecht , J., Annu. Rev. Pharmacol. Toxicol. 47
  (2007) 51339
• Uetrecht, J. Autoimmunity Reviews 4 (2005)
  309314
• Vedove CD. Archives of Dermatological Research,
  Drug Induced lupus erythematosus
• 2009 Jan 301 (1) 99-105
• Images (accessed March 3 2009)
• http//www.eorthopod.com/public/patient_education/
  6590/systemic_lupus_erythematosus.html
• http//www.flickr.com/photos/listsanddiagrams/2389
  358590/
• http//users.rcn.com/jkimball.ma.ultranet/BiologyP
  ages/T/Tolerance.html