Anaphylaxis Urticaria Angioedema

Anaphylaxis Urticaria Angioedema
By:Niraj Patel, MD, MS
Section of Allergy and Immunology
Texas Children’s Hospital & Baylor College of Medicine

Objectives
* Know the clinical presentation, diagnosis and treatment of anaphylaxis.
* Understand the pathophysiology of urticaria and angioedema
* Outline an approach for evaluation and treatment of patients with urticaria and/or angioedema

What is anaphylaxis?
* Affects > 1 organ system: skin, respiratory, cardiovascular, GI symptoms
* 100,000 episodes per year in U.S.
* 1% fatality rate: shock, larnygeal edema
* IgE vs nonIgE mechanisms

Histamine
IgE-Mediated
IgE-receptor
* Protein digestion
* Antigen processing
* Some Ag enters blood

Mast cell
APC
B cell
T cell
Non-IgE Mediated
Pathophysiology: Immune Mechanisms
Causes of Anaphylaxis
* Foods – peanuts, egg, milk, shellfish, wheat, fish, soy
* Insect stings
* Drugs – PCN, NSAIDs
* Contrast media
* Opiods

Clinical Features and Diagnosis
* Skin: Erythema, pruritis, hives, angioedema
* Respiratory: laryngeal edema, wheezing, rhinitis, itching of palate, conjunctivitis
* Cardiovascular: LOC, fainting, palpitations, sense of impending doom
* GI: N/V/D, abdominal pain
* Diagnosis

Management of Systemic Reactions
Stabilize Epinephrine, IV, airway, O2 antihistamine, steroids
Observe 3 hours (mild reaction) 6 hours (severe reaction)
Prevent Epinephrine self administration Referral to an allergist

EpiPen
* EpiPen
o Injection carried with the patient at all times.
o Self-injection to lateral thigh.
o Use EpiPen, Jr. for children < 20kgs.
Urticaria
* Urticaria = Hives
* Common condition, 15-25% at some time in their lives
* Type I hypersensitivity reaction
* Causes: foods, drugs (no identifiable cause in 50%)
Urticaria vs. Angioedema
* Urticaria – superficial dermis
o Characterized by intense pruritis due to histamine effect
* Angioedema – deeper dermal and subcutaneous layers
o May be pruritic but often is a deeper and dull discomfort – burning quality

Chronic Urticaria/Angioedema (Mast cell driven)
Acute vs. Chronic Urticaria
* Acute Urticaria – lasts 6-8 weeks or less
o Viral syndromes (especially in young children)
o Insect bites or stings (fire ants, scabies)
o Food induced reactions (eat this - get that)
o Medication related (antibiotics, NSAIDs, narcotics, angioedema due to ACE inhibitors)
* Chronic Urticaria – lasting longer than 8 weeks
o Physical urticarias (dermographism, cholinergic, cold)
o Urticarial vasculitis
o Urticaria/angioedema associated with autoimmunity
o Autoimmune urticaria
o Idiopathic urticaria

Urticaria - Mechanisms
* Immunologic
* Non-Immunologic
Underlying Mechanisms of Urticaria
Physical Urticarias
Symptomatic Dermatographism
Cholinergic Urticaria
Cold-Induced Urticaria
Delayed Pressure Urticaria
Solar and Aquagenic Urticaria
Schnitzler’s Syndrome
Hypocomplementemic Urticarial Vasculitis Syndrome (HUVS)
Therapeutic Options
* Antihistamines for most with acute short-lasting urticaria
o Start with non-sedating, long-acting second generation H1 antagonists (Allegra, Zyrtec, Claritin) and supplement

with short-acting, sedating H1 antagonists prn.
* Combination therapy if H1 antagonists do not suffice (30% of cases)
* Steroids and other immunosuppressants reserved for severe urticaria associated with angioedema of oropharnyx or other

systemic signs, moderate to severe drug reactions, urticarial vasculitis, and refractory cases of CIU
H1 Antagonists
* Previously felt to be only histamine receptor blockers
* Recent research now reveals that most of the second generation antihistamines have some mild anti-inflammatory

properties
* Although less expensive, first generation antihistamines have potential for sedation and impaired performance

Why Add an H2 Antagonist?
Immunomodulation Cyclosporine / Tacrolismus
Cyclosporine
ANGIOEDEMA

* Inhibits C1r and C1s of the complement system
* Inhibits activated factor XIIa and kallikrein
* An inhibitor of factor XIa and plasmin
* Inhibits activation of C1
C1 Inhibitor Functions
Hereditary Angioedema
* Autosomal dominant with incomplete penetrance.
o Spontaneous mutations in 50%
o Diminished C4 between attacks
o Very low C4 during attacks
* HAE I
o Low levels of C1 esterase inhibitor
* HAE II
o Dysfunctional C1 INH
* HAE III (estrogen-dependent angioedema)
o Normal C1 INH amount and function
o Normal complement levels
Acquired Angioedema (AAE)
Drug Induced Angioedema
ACE Inhibitor Angioedema
Treatment of Hereditary Angioedema
* Patient education very important; test family
* No regular medication needed in many cases
* Prophylactic stanozolol or danozol
* Epsilon aminocaproic acid (EACA) an option
* Fresh frozen plasma before emergency surgery
* C1 inhibitor
* Symptomatic treatment during attacks
* Steroids and antihistamines are NOT effective!!!
Summary
* Through several mechanisms a variety of mediators may lead to urticaria or angioedema
* Clinically, a causative agent is much more often identified in acute than in chronic urticaria/angioedema
* A number of medications are available to control chronic urticaria while awaiting a spontaneous remission
* Patients with angioedema without urticaria should be tested for C1 inhibitor deficiency

Questions
Anaphylaxis Urticaria Angioedema

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Mechanism of Bone Metastases

Mechanism of Bone Metastases
by: Dr.Priya Gopalan

Outline
* Background
* Predictors of metastasis to bone
* Tumor cell homing to bone
* Tumor cell interaction with bone
* Therapeutic interventions

Bone Metastases
Types of bone metastases
Diagnosis
* Bone scan - best for osteoblastic lesions
* MRI
* CT scan with bone windows
* PET-CT
* Plain films
* Markers of bone turnover

Prognosis
Relative risk ratios during zoledronic acid therapy
(skeletal-related events)
NSCLC and solid tumors
High vs. low NTX levels
Reasons for preferential metastasis to bone
* Highly vascular organ (sluggish blood flow)
* Paget’s “seed-and-soil” hypothesis
o Bone marrow niche provides:
+ Chemotactic signal to home (e.g. SDF-1)
+ Adhesion receptors to extravasate
+ Growth factors to proliferate (e.g. TGF-b, IGF-1)
Predictors of metastasis to bone (Breast Cancer)
Tumor cell homing
* Organs that are primary sites of breast cancer metastasis produce high levels of SDF-1
* Blocking CXCR4 in vitro inhibited prostate cancer migration through bone marrow endothelial cells
* Blocking CXCR4 in vivo reduces bone metastases in breast and prostate cancers
* CXCR4/ SDF-1 axis also important in
o NSCLC:
o RCC:
* Integrins may also direct organ-specific mets
o When avb3 is overexpressed on breast cancer cells, bone metastases are enhanced
o CXCR4 binding to SDF-1 activates avb3 and mediates its binding to endothelial cells
o avb3 antagonist inhibits bone colonization by avb3-expressing tumor cells
o a2b1 on prostate cancer cells supports bone colonization
* Other chemokines produced by OBs
o Osteopontin
o Bone sialoprotein

Normal bone remodeling
Osteoprotegerin
Osteoblasts/osteoclasts interaction with tumor cells
Osteomimicry by tumor cells
Therapeutic targets
* Osteoblastic lesions
o Endothelin-1 (anti-receptor antibody)
* Osteolytic lesions
o Bisphosphonates
o RANKL (anti-RANKL antibody)
o PTHrP
o Osteoprotegerin (Fc-OPG)
* Endothelin A receptor inhibitor, Atrasentan
o M00-211 trial - Double-blinded, randomized, multi-institutional placebo-controlled Phase III trial with 809 patients with hormone-resistant metastatic prostate cancer

+ Endpoint - TTP
+ Results
# TTP HR 0.89 (CI 0.76,1.04, p=0.136)
# Median time to bone alk phos progression 505 vs 254 days (p<0.01)

Bisphosphonates
* Long-term treatment of osteolytic metastases
* Preferentially bind areas of high bone turnover
* Aminobisphosphonates
o e.g. zoledronate, aledronate, risedronate
o Block prenylation of osteoclast proteins (small GTP-binding proteins, e.g. ras and rho), leading to apoptosis
* Non-aminobisphosphonates
o e.g. clodronate, etidronate
o Inhibit ATP-dependent enzymes, leading to apoptosis
* Also may inhibit tumor adherence to bone, inhibit angiogenesis, reduce IL-6 production

Bisphosphonates-clodronate
* Clodronate approved in Europe but not US
* Double-blind, placebo-controlled, multicenter trial with 1,069 patients with operable breast cancer randomized to clodronate or placebo
o 1° endpoint - relapse in bone
o 2° endpoints - relapse in other sites, mortality, toxicity
o Significant reduction in bone metastases during medication period (HR 0.44, CI 0.22-0.86, p=0.016), but not in total follow-up period
o Reduced mortality (98 in clodronate arm, 129 in placebo arm, p=0.047)

Bisphosphonates-pamidronate
* 754 pts with metastatic breast cancer (with osteolytic bone metastases) randomized to pamidronate or placebo
o 1° objective - skeletal events per year and time to 1st skeletal-related event (SRE)
o Only 115 of 367 (31.3%) on pamindronate arm and 100 of 384 (26.0%) on placebo arm completed the study
o Pamidronate arm - 2.4 skeletal events/yr; placebo arm - 3.7 events/yr (p<0.001); also observed longer time to 1st SRE in pamidronate arm (12.7 vs 7 months, p<0.001)
o Limited by significant number of pts who did not complete study
Bisphosphonate - zoledronate

* 1803 premenopausal women with Stage I and II breast cancer randomized to tamoxifen/anastrozole ± zoledronic acid
* 1° endpoint DFS; 2° RFS, OS; explor: bone met-free survival
* DFS (HR 0.643 [CI 0.46-0.91], p=0.011)
* RFS (HR 0.653 [CI 0.46-0.92], p=0.014)
* No change in OS
* See effects outside bone

Bisphosphonates - zoledronate (prostate cancer)
* Zometa 039 trial: 643 men with hormone-refractory metastatic prostate cancer received zoledronate 4 mg, 8mg then 4mg, or placebo for 18 months
o Zometa decreased SREs and pain, but no difference in disease progression or performance status
* Trials with pamidronate and clodronate in metastatic prostate cancer showed no significant benefits
* Randomized, placebo-controlled Phase III trial, with 773 pts with lung, RCC, etc. metastatic to bone randomized to zoledronate vs placebo q3 months for 21 months
* 1° endpoint - % patients with ≥1 SRE
* Zolendronate delayed the onset and reduced risk of skeletal-related events compared to placebo in pts with bone metastases due to lung cancer or other solid tumors.
o Reduced time to 1st SRE with treatment (236 vx 155 days, p=0.009), decreased number of events/year (1.74 vs. 2.71, p=0.012), HR developing skeletal event reduced in zoledronate arm (HR 0.693, p=0.003)

Bisphosphonates
* Osteonecrosis of the jaw

Other therapies

Mechanism of Bone Metastases.ppt

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Cutaneous Toxicities of Cancer Therapy

Cutaneous Toxicities of Cancer Therapy
By:Dr.Saiama Waqar

Outline
* Alopecia
* Hyperpigmentation
* Hand-foot syndrome
* Radiation sensitivity and recall
* Hypersensitivity
* Nail dystrophies
* Extravasation injuries
* Skin toxicity from targeted therapies
* Conclusion

Alopecia
* Drugs that target rapidly dividing cells often affect the proliferating cells in the hair follicle
* Terminal hair follicles with rapid matrix formation more affected (scalp more than body hair, eyebrows, eyelashes)
o completely lost in a short time: transplant
o gradually lost over several weeks: cyclic chemotherapy
* Methotrexate: affects the follicle melanocytes, resulting in depigmented band of hair, “flag sign”
* Visible regrowth within 3-6 months
* Often regrows with a change in color or texture (switching from straight to curly), mechanism of change unclear
* Psychologically, one of the most stressful side effects

Grading of alopecia
Grade
Minimal loss, grade 1
< 25%; obvious to the patient but not necessarily to others

Moderate loss, grade 2
25 to 50 %; obvious thinning of scalp hair but not enough to lead to the use of a wig or alternate head covering

Severe loss, grade 3

> 50% of hair lost; generally indicates the need for a wig or alternate head covering in those for whom alopecia is a major concern

Chemotherapy drugs causing alopecia

* Often
o Bleomycin
o Etoposide
o Methotrexate
o Mitoxantrone
o Paclitaxel
* Common
o Cyclophosphamide
o Daunorubicin
o Doxorubicin
o Docetaxel
o Idarubicin
o Ifosphamide
o Paclitaxel
* Infrequent
o 5-FU
o Hydroxyurea
o Thiotepa
o Vinblastine
o Vincristine
o Vinorelbine
* Rare
o procarbazine

Prevention of alopecia
* scalp tourniquets:
o pneumatic device placed around the hairline during chemo infusion
o inflated to a pressure >SBP
o Several studies: effective for preventing hair loss
+ utilized different techniques, variation in chemotherapy regimens, tourniquet pressure, sample size, and criteria to assess alopecia (data difficult to interpret)
o Side effects: headache, varying degrees of nerve compression

Prevention of alopecia
* Hypothermia with scalp icing devices:
o Vasoconstriction of scalp blood vessels, less absorption of chemo as hair follicles less metabolically active at 24C
o ice turban, gel packs, cool caps, thermocirculator, room air conditioner
o 50-80% response, though variable chemotherapy regimens and definitions of alopecia, small sample size
* Not effective in liver disease
o Delayed drug metabolism, persistent levels beyond protective period
* Scalp metastases:
o mycosis fungoides, limited to scalp. CR after chemo without scalp cooling
o 61 pts with met breast cancer and liver dysfunction, 1 pt scalp met

Preventive devices
* 1990- FDA stopped sale of these devices citing absence of safety or efficacy data
* Cranial prostheses (wigs) and scarves use encouraged

Pharmacologic interventions for alopecia
* Topical minoxidil (shorten time to maximum regrowth, did not prevent alopecia)
* AS101(NSCLC pts: garlic-like halitosis and post-infusion fevers)
* Alpha tocopherol (cardioprotection for doxorubicin, noted less alopecia)
* Topical calcitriol (cell lines- protects cancer cells)
* IL-1(rats, cytarabine, cell cycle specific, protected)
* Inhibitors of p53 (mice deficient p53, no alopecia)

Hyperpigmentation
* usually resolves with drug discontinuation
o gingival margin pigmentation seen with cyclophosphamide is usually permanent
* Patterns of pigmentation:
o Diffuse
o Local at site of infusion
* Sites of pressure /trauma
o Hydrea and cisplatin
* Busulfan
o “busulfan tan” can mimic Addison's disease.
o Although busulfan can also cause adrenal insufficiency, the skin change is 2/2 toxic effect on melanocytes
o Distinguish busulfan toxicity from true Addison's disease by normal levels of MSH & ACTH
* Liposomal doxorubicin
o macular hyperpigmentation over the trunk and extremities, including the palms and soles
o not been described with unencapsulated doxorubicin

Drugs causing hyperpigmentation

HAND-FOOT SYNDROME
* also known as palmar–plantar erythrodysesthesia (PPE)
* originally described in patients receiving high-dose cytarabine
* skin lesions begin as erythema and edema of the palms or soles and is associated with sensitivity to touch or paresthesia
* can progress to desquamation of the affected areas and significant pain

Hand foot syndrome
Acral erythema from docetaxel

Pathogenesis
* Unclear: small capillaries in the palms and soles rupture with increased pressure from walking or use, creating an inflammatory reaction
* formulation of drugs and duration of exposure can impact the incidence
o liposome-encapsulated doxorubicin more than standard formulation
o 5-FU bolus lower than CIVI and capecitabine (converted into 5-FU in vivo)

Hand foot syndrome Grading
Grade
Signs and symptoms

1 Minimal skin changes or dermatitis (eg, erythema) without pain
2 Skin changes (eg, peeling, blisters, bleeding, edema) or pain, not interfering with function
3 Skin changes with pain, interfering with function

Treatment
* No proven preventive therapy
o Pyridoxine (vitamin B6) may help reduce the incidence and severity
o Celecoxib reported to reduce incidence
* Management largely symptomatic with reduction of drug doses where appropriate
* emollients and protective gloves can be helpful

Radiation sensitization and recall
* Some chemotherapeutic agents can sensitize the skin to radiation
* recall phenomenon in previously irradiated tissue (wks to yrs after RT)
o when chemotherapy is administered
* Exact mechanism not clearly understood,
o radiation effects on the microvasculature
o altered cutaneous immunologic responses
* maculopapular eruptions with erythema, vesicles, desquamation
o mild rash to severe skin necrosis

Radiation sensitization and recall
* No specific therapy recommended
o topical corticosteroids
o Ultraviolet radiation
* caution about sun exposure
o wear protective clothing
o sunscreen products
+ 5-FU increases photosensitivity to sunlight
+ MTX may reactivate a sunburnes of cancer therapy. Curr Opin Oncol. 2002 Mar;14(2):212-6

Hypersensitivity reactions
* Can occur either from drug itself or from solubility vehicle (eg. Cremophor for paclitaxel)
* Prevention: premedicate
o Steroids (dexamethasone), H1 blockers (benadryl), H2 blockers (pepcid)
* Management of hypersensitivity reactions:
o epinephrine, hydrocortisone, and histamine blockers, along with monitoring of BP

Drugs causing hypersensitivity
NAIL DYSTROPHY
* Color changes
o Mee’s lines - transverse white
o hyperpigmentation
* Beau’s lines - transverse grooves/lines
o related to the effect of chemotherapy causing decreased nail growth
* Paronychia -inflammation of the nail fold
o Seen with cetuximab

Beau’s lines
* Onycholysis (separation of the nail plate from the nail bed)
o can be painful
o anthracyclines, taxanes (especially weekly paclitaxel), and topical 5-fluorouracil
* frozen-glove study to prevent docetaxel-induced onycholysis & cutaneous toxicity
o 45 patients, frozen glove for 90 minutes on the right hand, using the left hand as control
o Frozen glove reduced the nail and skin toxicity

Grading of nail changes
Grade
Nail changes/toxicity

1 Discoloration, ridging (koilonychias), pitting
2 Partial or complete loss of nail(s), pain in nailbed(s)
3 Interfering with ADL
Nail changes with docetaxel

Drugs causing nail changes
* Pigmentary changes
o Bleomycin
o Busulfan
o Cisplatin
o Cyclophosphamide
o Docetaxel
o Doxorubicin
o Etoposide
o Fluorouracil
o Hydroxyurea
o Idarubicin
o Ifosfamide
o Melphalan
o Methotrexate
o Mitomycin
o Mitoxantrone

* Onycholysis
o Paclitaxel
o Docetaxel
o Gemcitabine
o Capecitabine
o Cyclophosphamide
o Doxorubicin
o Etoposide
o Fluorouracil
o Hydroxyruea
* Inflammatory changes
o Gefitinib
o Cetuximab
o Capecitabine
o Docetaxel
o Paclitaxel

Extravasation injury
* The accidental extravasation of intravenous drugs occurs in approximately 0.1% to 6% of patients receiving chemotherapy
* Depending on the agent and amount, the sequelae of extravasation can range from erythema and pain to necrosis and sloughing of the skin
* The most toxic drugs are the vesicants, such as the anthracyclines, vinca alkaloids, nitrogen mustards, as well as paclitaxel and cisplatin

Vesicants and irritants
Treatment of extravasation
* immediate discontinuation of the infusion
* cooling with ice packs
o warm soaks for vinca alkaloids
* for persistent/progressive local symptoms - surgical consult
* early local debridement of can reduce extent of later injury

Extravasation of vinblastine in a 57-year-old male receiving chemotherapy for bladder cancer

Antidotes for extravasation
o topical DMSO (dimethyl sulfoxide) to enhance absorption of the extravasated drug, routine use still controversial
o Thiosulfate -nitrogen mustard extravasation (injection of a 1/6 molar solution into the area of extravasation)
o Dexrazoxane - anthracycline extravasation
* Regardless of antidote, local therapy, and prompt surgical intervention is paramount

Skin Toxicity from targeted therapy
* Because the EGFR is also expressed by basal keratinocytes, sebocytes, the outer root sheath, and some endothelial cells, agents that inhibit EGFR are associated with dermatologic side effects
Erlotinib eruption on the arms

Cutaneous reactions associated with molecularly targeted agents
Monoclonal antibodies to EGFR
Infusion reactions; acneiform eruption; paronychial inflammation; photosensitivity
* Cetuximab, panitumumab

EGFR pathway inhibitors
Acneiform eruption; paronychial inflammation; photosensitivity
* Erlotinib
* Gefitinib
* Lapatinib

Multitargeted tyrosine kinase inhibitors
Skin exanthem; SJS; acute generalized exanthematous pustulosis; Sweets syndrome; hand-foot syndrome; photosensitivity; pigmentary changes, hair depigmentation; alopecia

* Imatinib
* Dasatinib
* Sorafenib
* Sunitinib

EGFR-inhibitor induced skin changes
* (a-c) stratum corneum thickness, (d) apoptosis (apoptotic cells by 10,000).
* On-therapy (gefitinib) biopsy specimen showing (e) keratin plugs and micro-organisms in dilated infundibula and (f) acute folliculitis.

Cetuximab skin toxicity
Moderate rosacea-like eruption from cetuximab
80 year old patient receiving cetuximab and radiation for nasopharyngeal cancer

Erlotinib rash treatment
Severity of Rash
Treatment Protocol
Mild
Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily.
Moderate
Topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required, until resolution of the rash by one severity grade. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water.
Severe
Stop erlotinib therapy for 1 week and restart at 100mg once-daily. Treatment of rash with topical clindamycin 2%, with hydrocortisone 1% in lotion base applied twice-daily AND oral minocycline 100mg twice-daily for a minimum of 4 weeks and continuing thereafter as required. Scalp lesions will be treated with a topical lotion clindamycin 2%, triamcinolone acetonide 0.1% in equal parts of propylene glycol and water until resolution.
Dose modification guidelines for cetuximab (Erbitux) based upon dermatologic toxicity

Cutaneous Toxicities of Cancer Therapy.ppt

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