Patofisiologi

VIII

Alergi, Pseudoalergi, Rhematoid

Arthritis, Ghout
 Allergy
• is an immune response, which is accompanied
damage of own tissues.
• The cause of allergic disease is an allergen.
• Allergens have all properties of antigen
(macromolecularity, mainly protein nature,
foreign for particular organism).
 Allergy
• However allergic reactions can be caused by
substances not only antigen nature, but also
substances, not possessing these properties.

• To this group belong many bacterial products,

polysaccharides, simple chemical substances
(bromine, iodine, chrome, nickel).
• These substances are called haptens. They
become antigens (allergens) only after binding
with tissues proteins.
 Allergy
• Exogenous allergens: penetrate the organism
from outside
• Endoallergens: are formed in the organism

• Infectious: Bacteria, Virus

• Non-Infectious: Haptens, Chemicals, Antigen.
General Mechanism
Typical “mild” Allergic Reactions

• Sneezing
• Irritation
• Red Eye
• Itchy
• Swelling
Typical “Severe”Allergic Reactions: Exanthems

Maculopapular exanthem
(MPE) Acute generalized
Bullous
Exanthem exanthematous
pustulosis (AGEP)
Exanthems: infiltration of T cells in
dermis and epidermis
CD4+ CD8 +
SKIN TEST
 Four Classifications
• Type I (Immediate) Hypersensitivity
• Type II (cytotoxic) hypersensitivity
• Type III (immune complex mediated)
hypersensitivity
• Type IV (delayed) hypersensitivity
 Type I (Immediate) Hypersensitivity

• When IgE meets its specific allergen it causes the

mast cell to discharge its contents of vasoactive
substances into the circulation.
• This release leads to symptoms of:
– sneezing,
– runny noses,
– red watery eyes and
– wheezing.
• Symptoms subside when allergen is gone.
• The most common immunological abnormality seen
in medical practice.
Type I (Immediate) Hypersensitivity
 Type I (Immediate) Hypersensitivity

• Anaphylactic shock is the most serious and

fortunately the rarest form of this Type I
hypersensitivity.

• Symptoms are directly related to the massive

release of vasoactive substances leading to
fall in blood pressure, shock, difficulty in
breathing and even death.
Anaphylaxis
 Adverse drug reactions
Park et al., Chem.Res.Toxicol., 1998
• Type A: predictable; strictly dose dependent /INTRINSIC
- 80% of all side effects
– Pharmacological side effects: ex. Β-blocker (Heartblock),
Aspirin (bleeding)

• Type B: not predictable; usually not dose dependent, and

sometimes reactions to very small
amounts/IDIOSYNCRATIC
– 15-20% of all side effects
– Immunologic/allergic or Non-immune mediated,
“pseudoallergic”
– Ex. Halothane, Phenytoin (Anticonvulsant)
 Adverse drug reactions
Park et al., Chem.Res.Toxicol., 1998
• Type C: Chemical reactions
Adverse reactions occurs, but Pharmacological effects of drugs
based on chemical structure cannot be predicted.
Ex.: Paracetamol: hepato- and pulmotoxicity.

• Type D: Delayed reactions

– Adverse reaction occurs after years of treatment
Ex. Chemotherapeutic agents: Sec. Tumour
Phenytoin : Teratogenic effect in children / Fetal Hydantoin
Syndrome

• Type E: end-of-treatment reactions

– Adverse reaction occurs on drugs withdrawal.
– Phenytoin and Paroxetine
DRUG „PSEUDOALERGY“

IgE Antibody
IgE-Fc Receptors
Mast Cells
Mediator
(Histamin…)
Body-Reactions
 Drug Allergy
Drug hypersensitivity

Drug allergy Non-allergic hypersensitivity

eg: Non-specific histamine release,
Arachidonic acid pathway activation,
Bradykinin pathway alteration,
Complement activation
IgE-mediated Non IgE mediated
drug allergy drug allergy

Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised
nomenclature
for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy
 Drug-related Pseudoallergy risk factors
• Nature of the drug: Metabolism/processing
dependent/independent
– Hapten concept
– Pro-hapten concept
– P-I-concept
• Degree of exposure
– Dose, duration, frequency, intermittent repeated administration
• Route
– Topical, oral, parenteral
• Cross-sensitization
– Reactivity either to drugs with a close structural chemical
relationship or to immunochemically similar metabolites.
Drug reactions with immune systems:
Processing/metabolism
dependent/independent
 Hapten, prohapten and
p-i concept
• Hapten
– chemically reactive drug
– able to bind covalently to proteins Antigen
– Examples: Penicillin

• Prohapten
– chemically non reactive drug
– becomes reactive upon metabolism (transformation of prohapten 
hapten)
– Examples: Sulfamethoxazole

• p-i concept
– Pharmacologic interaction with immune complexes
– Drugs binds T-Cells, interact with MHC-Molecules, and activates T-Cells
– Examples: Lidocain, Ciprofloixacin, Sulfamethoxazole
HAPTEN CONCEPT
HAPTEN CONCEPT
Clinical manifestation of drug allergy
Clinical manifestation of drug allergy
 Gout
• The most common cause of inflammatory
arthritis in US adults (3.9% of Americans;
approx. 8.3 million people; 2007-2008)
• Prevalence is greater in men (5.9%; 6.1
million) than women (2.0%; 2.2 million)

 Inflammatory Arthritis
 Gout Pathophysiology
• Caused by the deposition of monosodium urate
crystals in tissues (high level Uric Acid)
• High Purine Diet

Purineshypoxanthinexanthineuric acid
Catalyzed by xanthine oxidase, found in the liver
• When balance disrupted, caused: hyperuricemia:
– Overproduction (10%) of Uric Acid
– Underexcretion (90%) of Uric Acid
Pathophysiology

Rees, F. et al. (2014) Optimizing current treatment of gout

Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2014.32
 Risk Factors
• High Purine Diet (Red Meat, Fatty Poultry, High Fat Dairy, Seafood)
• Alcohol Consumption
• Trauma
• Osteoarthritis
• Surgery
• Starvation
• Dehydration
• Obesity
• Drugs (Allopurinol, uricosuric agents, thiazides, loop diuretics, low dose
aspirin)
• Renal Impairment
• Genetic Mutations (SLC22A9, SLC22A12, ABCG2)
 Diagnosis
• Arthrocentesis (Synovial Fluids)

Labs: cell count with differential, gram stain,

culture, examination for crystals under
polarized light microscopy.
Gout Treatment
 Rheumatoid Arthritis
• Joint Inflammation, Morning Stiffness

• In the initial stages of each joint involvement,

there is warmth, pain, and redness, with
corresponding decrease of range of motion of
the affected joint

• Progression of the disease results in reducible

and later fixed deformities  Fibroblast-like
Synoviocytes

• Muscle weakness and atrophy develop early in

the course of the disease in many people
 Treatment
• NSAIDS - Usually, only one such NSAID should be given at a
time. Can be titrated every two weeks until max dosage or
response is obtained. Should try for at least 2 to 3 wk
before assuming inefficacy.
• Slow acting - Generally, if pain and swelling persist after 2 to
4 mo of disease despite treatment with aspirin or other
NSAIDs, can add a slow-acting or potentially disease-
modifying drug (eg, gold, hydroxychloroquine, sulfasalazine,
penicillamine) Methotrexate, an immunosuppressive drug
is now increasingly also used very early as one of the
second-line potentially disease-modifying drugs.
 Medications
• Corticosteroids – offer the most effective short-term relief as
an anti-inflammatory drugs. Long-term though improvement
diminishes. Corticosteroids do not predictably prevent the
progression of joint destruction, although a recent report
suggested that they may slow erosions. Severe rebound
follows the withdrawal of corticosteroids in active disease.

• Immunosuppressive drugs These drugs (eg, methotrexate,

azathioprine, cyclosporine) are increasingly used in
management of severe, active RA. They can suppress
inflammation and may allow reduction of corticosteroid
doses. Major side effects can occur, including liver disease,
pneumonitis, bone marrow suppression, and, after long-term
use of azathioprine, malignancy.