Drug Hypersensitivity, autoimmune diseases (SLE)

Question 1

Overview of drug hypersensitivity reaction (DHR) (types, trigger molecules, clinical manifestations)

Answer 1

*DHR: activation of IMMUNE/ INFLAMMATORY cells -> A/E to drug
- accounts for 10-15% of ALL ADR

Types
1. Immune (allergy):
- Immunologically mediated hypersensitivity reaction to a drug in a sensitised person; immune response to the antigenic substance -> host tissue damage (MANIFESTS as ORGAN-SPECIFIC/ GENERALISED SYSTEMIC REACTION)
[type 1: (IgE) mast cell/ cytokine-related | type 2: (IgM/IgG) Fc receptor/ complement mediated | type 3: immune complexes | type 4: T cell]
-> immediate (IgE mediated) -> atopy
-> Delayed (IgM, IgG, T cell mediated)

2. Nonimmune “pseudoallergy”
   - accounts for ~77% of hypersensitivity reactions
   *drugs: release of MEDIATORS (histamine, prostaglandians, kinins: often mast cell/ basophil derived) by PHARMACOLOGIC/ PHYSICAL effect rather than IgE
   -> Vancomycin “Red man syndrome”: direct release of HISTAMINE
   -> ACE/ Sacubitril -> Angioedema: INHIBITION of breakdown of BRADYKININ
   -> NSAIDS induced asthma: ALTERED metabolism of PROSTAGLANDINS

Effectors of DHR:
- major components of innate & adaptive immune systems: cellular elements (T/B cells etc), IgE, complements, cytokines
- Pharmacologically active CHEMICAL MEDIATORS: histamines, platelet-activating factor (PAF), prostaglandins (PG), thromboxanes, leukotrienes

Clinical manifestations
1. ANAPHYLAXIS: acute, life-threatening recation that involves multiple organ systems
^risk of FATAL anaphylaxis GREATEST within FIRST FEW HOURS
- notable drugs: penicillins, NSAIDs, insulin

2. Serum sickness/ drug fever: circulating immune complexes -> systemic symptoms (fever, malaise, rash)
   - antibiotics
3. Drug induced autoimmunity *common: SLE
   - methyldopa (-> hemolytic anemia), phenytoin (-> hepatitis)
4. Vasculitis: INFLAMMATION & NECROSIS of blood vessel walls; limited to skin OR may involve multiple organs
   - allupurinol, thiazide
5. Respiratory
   - NSAIDs (asthma); nitrofurantoin, bleomycin (acute infiltrative & chronic fibrotic pulmonary reactions)
6. Hematologic: eosinophillia (COMMON MANIFESTATION OF DHR)
   > hemolytic anemia, thrombocytopenia, argranulocytosis (low WBC pdtn)

Question 2

Serious Cutaneous Adverse Reactions (SCAR) types, treatment

Answer 2

1. Drug Rash with EOSINOPHILIA & Systemic Symptoms (DRESS)
   *allopurinol, anticonvulsants
   > Triad of RASH, EOSINOPHILIA, INTERNAL ORGAN INVOLVEMENT
   > mortality rate ~10%
2. Mucotaneous disorders:
   - Steven Johnson Syndrome (SJS)
   - Toxic Epidermal Necrolysis (TEN)
   *antibiotics (esp. sulfonamides)
   > Progressive bullous or “blistering” disorders that constitute DERMATOLOGIC EMERGENCIES
   > progress to include MUCOUS MEMBRANE EROSION & EPIDERMAL DETACHMENT (SJS: <10% body surface area; TEN >30%)
   > Mortality rates (SJS 1-5%, TEN 10-70%)

Treatment: LESS DEFINED/ STANDARDISED
-> similar to burn pts: SUPPORTIVE CARE (wound care, nutritional support/ fluids/ temp regulation/ pain management & prevention of infection); Intravenous Immunoglobulin (IVIG) and cyclosporine may be used
*steroids use CONTROVERSIAL

Question 3

Involvement of genetic disposition towards drug allergies/ hypersensitivity

Answer 3

*HUMAN LEUKOCYTE ANTIGEN (HLA) alleles: INCREASES susceptibility to several drug hypersensitivity syndromes

eg. Abacavir: HLA-B701 -> hypersensitivity reactions
Carbamazepine / Phenytoin: HLA-B1502 -> SJS/TEN (TESTING REQUIRED)

Genetic factors CAN influence METABOLIC DEACTIVATION of drugs via phase 1 & 2 metabolism

Question 4

Treatment of anaphylaxis

Answer 4

GOAL: restore respiratory & CV function
*vasodilation (hypotension), bronchial smooth muscle contraction

Drug of choice: Epinephrine (Adrenaline)
-> counteracts bronchoconstriction & vasodilation

*if managed to reach ambulance/ hospital:
> IV fluids: restore volume/ BP
> intubation if necessary to save airway
> Norepinephrine (noradrenaline) if SHOCK
> others: steroids, glucagon, diphenhydramine (H1) + ranitidine (H2)

Question 5

Overview of autoimmune disease, prevalence, management

Answer 5

• body attacked by its own immune system
• GENETIC BACKGROUND AND ENVIRONMENTAL STIMULI (smoking, infection): INCREASES risk for developing autoimmune disorder
  eg. psoriasis, graves disease, T1DM, rheumatoid arthritis, multiple sclerosis, Sjogren’s syndrome, SLE, Scleroderma, Systemic vasculitis

SG: ~11% of population

Etiology: probably multifactorial (accumulation of multiple minor genetic variants, each of them incapable of producing autoimmune disease PLUS environmental factors)

*Targets in use/ under investigation of autoimmune diseases: Cytokines, Cells (T & B), Kinases

DIFFICULT TO TREAT:
- large proportion DO NOT RESPOND to treatment/ LOSE RESPONSE to treatment/ DO NOT TOLERATE/ HAVE ADVERSE REACTIONS to treatment (a lot/ serious)
- poor indication of drugs for autoimmune diseases (most off-label) -> great variability of treatment among centres & specialists
- costly
- social stigma -> less likely to seek medical attention

Question 6

Overview of Systemic Lupus Erythematosus (SLE) [pathophysiology, risk factors, complications, treatment, monitoring]

Answer 6

• associated with AUTO-ANTIBODY PRODUCTION -> IMMUNE COMPLEX FORMATION
  *multisystem disease

Risk factors:
- Females (F:M prevalence 10 to 1)
- Non-white > white (African descent appears highest)
- Genetic disposition (1st degree relatives 20x more likely)
- Environmental factors: smoking, infection, certain drugs; *UV light, Epstein-Barr virus etc implicated

Mortality risk: 2.6-3x higher than general population
*CV, RENAL, INFECTIONS

Clinical Presentation:
*FLUCTUATIONS with periods of REMISSION, FLARES, PROGRESSION (70% of pts)

1. Lupus nephritis (various stages; class I to VI)
2. Neuropsychiatric Lupus: cerebrovascular disease (STROKE), anxiety, seizures, cognitive dysfunction, confusion, peripheral neuropathy, psychosis etc
3. Cardiovascular: Pericarditis, myocarditis; Accelerated atherosclerosis

[Labs]
Full Blood Count: hemolytic anemiaa (LOW RBC), LOW WBC/ lymphocytes, LOW platelet count
Immunologic: Antinuclear antibody (ANA), Antidouble-stranded DNA (dsDNA), Anti-Smith antibody (anti-Sm), antinuclear ribonucleoprotein (anti-RNP), LOW complement (C3, C4, CH50)

Treatment
(General principles): GOAL should be REMISSION BUT achieving low disease activity might be more realistic
- PREVENT flares & other organ involvement, SLOW disease activity, REDUCE use of steroids, IMPROVE QoL, MINIMISE A/E
**evaluate & treat for ANY OTHER COMORBIDITIES

Pharmacological: aspirin, prednisone, hydroxychloroquine, belimumab (rest off-label)

Monitoring:
ADR
Comorbidities
Measures of disease activity
Regular labs q1-3months (ACTIVE); 6-12months (STABLE)
- Urinalysis/ renal function
- anti-dsDNA antibodies
- **Complement C3, C4
- C-reactive protein
- Full Blood Count
- LFT

*ANA, anti-Sm, anti-RNP do not need to be repeated: levels do not fluctuate with disease activity

Question 7

Pharmacological agents for SLE

Answer 7

1. Hydroxychloroquine
   *indicated for ALL SLE patients INCLUDING PREGNANT WOMEN
   - helps prevent flare, improves long term survival: anti-inflammatory, immunomodulatory, anti-thrombotic effects
   - minimal A/E but RETINAL TOXICITY >10% prevalence after 20yrs use
   - Onset: 4-8weeks
2. NSAIDs eg. aspirin
   *1st line for ACUTE symptoms
   **CAUTION in WORSENING lupus nephritis, INCREASED cardiac risk, GI bleed
3. Steroids eg. prednisone
   - Monotherapy OR adjunctive to CONTROL FLARES & maintain low disease activity
   - RAPID onset
   **high dose, long-term use concerning (AE: osteoporosis, hyperglycemia/ diabetes, HTN, preeclampsia)
4. Biologics eg. belimumab, rituximab
   - Targets & disrupts functioning of B cells
5. Immunosuppressants
   > IV/PO Cyclosporine (for severe disease w severe organ involvement) for INDUCTION therapy (AE: cystitis, bladder malignancy, infertility)
   > Mycophenolate: INDUCTION AND MAINTENANCE therapy (GI S/E)
   > Azathioprine: ALTERNATIVE to mycophenolate for MAINTENANCE (test thiopurine methyltransferase TPMT before starting)
   ** helps reduce steroid dose

Question 8

Drug-induced lupus (MOA, treatment)

Answer 8

10-15% of SLE, up to 30% of subacute cutaneous LE
- Mostly IDIOSYNCRATIC REACTIONS precipitated by interplay of genetics & environment

MOA: drugs -> small molecules that can induce an immune response by BINDING TO LARGER MOLECULES (eg. proteins)

*highest risks: procainamide, hydralazine, quinidine
others: minocycline, isoniazid, methyldopa, carbamazepine etc

**TNF-alpha inhibitors induce TNF-alpha ANTAGONIST INDUCED LUPUS-LIKE SYNDROME (TAILS)

Primary treatment: STOP drugs, consider symptomatic treatment

Question 9

Antiphospholipid Syndrome (APS) in SLE

Answer 9

Antiphospholipid antibody +ve
- lupus anticoagulant, anticardiolipin, anti-beta2 glycoprotein I
*found in 40% of SLE pts BUT <40% experienced thrombotic events

• HIGH RISK of CLOTTING
• HIGH RISK of PREGNANCY MORBIDITY (can be diagnostic criteria)

General treatment (non-pregnant):
- Primary thromboprophylaxis: ASPIRIN
- SECONDARY thromboprophylaxis: WARFARIN
> Hydroxychloroquine (protective)

Question 10

Overview of immunosuppression (indications, targets, agents, complications )

Answer 10

Indication:
autoimmune conditions
solid organ transplants
stem cell/ bone marrow transplants

Targets: B cells, T cells, mediators (eg. cytokines)

Therapeutic agents for INDUCTION:
*high-potency, SHORT-course therapy provided ASAP to REDUCE existing damage & PREVENT worsening of autoimmune condition
- Lymphocyte-depleting agents -> cell lysis
eg. antithymocyte globulin & alemtuzumab
- Immune modulators -> prevent activation & proliferation of T cells (eg. basiliximab )

Therapeutic agents for MAINTENANCE:
- Calcineurin inhibitors (cyclosporin, tacrolimus)
- Antimetabolites (mycophenolate, azathioprine)
- Corticosteroids
- mTOR inhibitors (sirolimus, everolimus*)
- Biologics (adalimumab, belatacept)
*TDM recommended

Complications:
Immune related: infections (including opportunistic infections) [bacterial, viral, fungal, pneumocystis, parasites] // cancer (skin, lymphoproliferative disorders, donor-related/ recurrent)

Nonimmune related: Bone marrow suppression *Azathioprine, mycophenolate // hepatotoxicity *azathioprine, mycophenolate // Renal toxicity *cyclosporin, tacrolimus, WORSE when combined with mTOR inhibitors // HTN, HDL, Hyperglycemia *steroids, calcineurin inhibitors

Question 11

Approach to transplant therapy

Answer 11

1. Patient selection: match HLA & blood type as closely as possible
2. use INTENSIVE INDUCTION THERAPY - avoid inital rejection
   - 70% of patients given BIOLOGICS to delay use of calcineurin inhibitors
3. MULTIPLE MAINTENANCE agents -> target different mechanisms
   - common: calcineurin inhibitors + glucocorticoids + mycophenolate
   *increased nephrotoxicity: calcineurin inhibitor + mTOR
4. Reduce dosage/ withdraw drug if toxicity > benefit

Question 12

Complication of chronic corticosteroid therapy

Answer 12

HPA (Hypothalamus- Pituitary- Adrenal) Axis suppression

• Exogenous corticosteroids: DECREASED secretion of CRH (corticotropin releasing hormone) & ACTH (adrenocorticotropin hormone)

END RESULT: ADRENAL SUPPRESSION

“cut-off” (no clear cutoffs)
**Supraphysiologic doses of >5mg prednisone equivalent daily for >3 weeks
(also reported in pts on <5mg daily <4weeks of exposure, even following tapered withdrawal)

maintain degree of suspicion of adrenal insufficiency in ALL pts who are taking/ have taken corticosteroids