4A. Arthritis and Gout Flashcards by J L

Arthritis
____ of a joint, usually accompanied by pain, swelling, and stiffness, and resulting from infection,
trauma, degenerative changes, metabolic disturbances, or other causes.

inflammation

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Rheumatoid Arthritis (RA)
(the most \_\_\_\_ \_\_\_\_, \_\_\_\_ arthritis)

common
autoimmune
inflammatory

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RHEUMATOID ARTHRITIS DEFINITION

Progressive, ____, inflammatory disorder
Predominantly affecting ____ membranes of diarthrodial joints; ____
____ manifestations occur in most
____ etiology
____ predisposed host

systemic
synovial
symmetric
extraarticular
unknown
genetically

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RHEUMATOID ARTHRITIS EPIDEMIOLOGY

About ____% of total adult population affected by RA
____ distribution
____ ethnic groups
Can occur at any ____
Peak incidence ages ____
Prevalence 2.5 x higher in ____
____ clusters
Triggers: ____, periodontal disease?, others

1
worldwide
all
age
30-50
women
familial
smoking

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Joint anatomy

This diagram can represent a knee or finger joint, it is meant to represent any joint

at end of bones you find ____ cartilage
lining the joint capsule, which provides structural integrity to the joint), is the ____
thin membrane that lines capsule and extends across the bone that is within this ____ space
provides ____ to the joint and lubricating fluid
inflammation from RA sets in the ____

articular
synovium
joint
lubrication
synovium

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Pathophysiology Cartoon

this is a knee joint:

bones
____ cartilage
joint capsule
synovium membrane lining the capsule
____ (specific to the knee)

In RA there is chronic inflammation developing in ____
-hypertrophy
-hyperplasia
As the disease becomes more chronic, the synovium becomes larger and can be seen and felt in examination (called ____ At this stage)

Synovium continues bringing in inflammatory cells to the joint and can ____ the bone around it causing damage. It is ____ at this point so the objective is to prevent the dx from getting to this stage.

articular
meniscus
synovium
pannus
erode
irreversible

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Pathophysiology, Slide 1
genetically \_\_\_\_ host
->
? exogenous factors,
? breach in tolerance
->
synovial membrane hyperplasia, \_\_\_\_ infiltration (lymphocytes, macrophages)
->
\_\_\_\_ inflammation

predisposed
cellular
chronic

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Pathophysiology Slide 2

chronic inflammation
->
____ production (TNF, IL1, IL6)
->
____ formation (synovial fibroblast hyperplasia)
->
structural damage of cartilage and ligaments; ____ of bone

cytokine
pannus
erosion

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RA affects ____ more often.

Ppl wake up feeling stiff for more than an hour (so more common in the ____)

In hands the ____ joints are most commonly affected (where the finger attaches to the hand).

Also the ____ joing in middle of the finger.

Other common joints: ____ (30% of pts), ____ spine (important for pts being anesthetized for surgery as they are at risk of spine damage due to inflammation). Rest of the joints are listed, RA doesn’t commonly affect ____.

hands and feet
mornings
MCP
PIP
TMJ
cervical
lower or middle back

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Rheumatoid Arthritis: Early Joint Involvement

____ region swelling in digit 2, 3 and 5. Sparing (sp?) at digit 4 Some ____ seem swollen.

Distal interphalangeal joints don’t have much swelling (doesn’t clarify which ones those are)

It will be roughly ____ in other hand

MCP
PIP
symmetrical

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RA: Late Disease

Late disease looks like this.

Prolonged inflammation around MCP joints causes ____ of the digits (fingers slide off and go in the ulnar wrist direction, known as ____)

Skin appears ____ and vessels are easily seen, which is common in RA

____ in PIP joints (doesn’t clarify what that means). Nodules of inflammation in subcutaneous tissue known as ____ usually on extensor surfaces of joints

Muscles appear less ____, wasting is common since fingers are no longer functional

subluxation
ulnar deviation

thin

nodules
rheumatoid nodules

developed

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Erosions

Pannus can eat away at ____ as seen in this ____ stage radiograph

Another example of the bone degradation. Top bone in image looks fine but bottom has a ____ taken out of it. Typical sign of erosion

bones
late

bite

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Extraarticular Manifestations of RA

Extraarticular manifestations:

skin ____
rheumatoid nodules
muscle wasting
____ eyes and mouth
scleritis (inflammation of part of the eye)
____(inflammation of lungs)
inflammations around heart
____ enlargement
splenomegaly
____ from chronic inflammation

thinning
dry
pleural effusions
lymph node
anemia

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Importance of Early Diagnosis

RA is ____, not benign
Structural damage occurs ____
Slower progression of disease is linked to ____ treatment
Advanced disease associated with increased morbidity and mortality
– Life expectancy shortened ____ years

progressive
early
earlier
10-15

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2002 ACR Treatment Algorithm for RA

this is an algorithm for treating RA -treat the disease ____

DMARD (diesase modifying anti-rheumatic drug): tx symptoms and slows down the ____
____ also used for tx disease
____ also used
Skips without reading anything else

early

progression
NSAIDs
corticosteroids

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Evolution of RA Treatment

Earl drugs include compounds with elemental ____ in them. Not used much anymore

Hydroxychloroquine (sp?) and corticosteroids initially synthesized around the 50s, sulfasalazine sp?), all still used
azathriapine is used not so much for RA but other conditions

D Penicilamin not used very frequently

____ is the standard of care for RA. Used aggressively in the 80s, only helped about ____% of pts

Biologic DMARDs (injectable and IV) target inflammatory cytokines and were developed in the 90s and 00s to supplement \_\_\_\_ DMARDs and MTX
More ppl go into remission now than in the past

gold
methotrexate
50
oral

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Non-steroidal Anti-inflammatory Drugs (NSAID’s)

PRO’s

____
analgesic
improve ____, Flexibility, ROM (range of motion)
improve quality of life

CON’s

no effect on disease ____
frequent ____ effects (liver, renal, gut, coagulation)

antiinflammatory
mobility
progression
side

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NSAIDs and Cyclo-oxygenase: Arachidonic Acid Metabolism

Mechanism of Action: Inhibit ____ which breaks down arachidonic acid to prostanoids and thromboxane

____ are the main cuprit in causing inflammation

cyclooxygenase

prostanoids

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Prostanoids as Mediators of Inflammation

• Inflammatory pain (____)
– ____
– ____ (2)

• Redness (____)
– ____
– ____ (2)

• Heat (____)
– Local ____,
central Fever
– ____ (1)

• Swelling (____)
– ____, edema and leucocyte filtration and chemotaxis
– ____ (3)

dolor
nociception
PGE2 and PGI2

rubor
vasodilation
PGE2 and PGI2

calor
vasodilation
PGE2

tumor
vasodilation
PGI2, PGE2, and PGD2

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NSAID MOA and Biological Effects

Antiinflammatory MOA:
1. Primary: inhibition of
biosynthesis of ____

Secondary (depends on NSAID):
- inhibition of ____
- down-regulation of IL-1
production
- decreased production of ____ and superoxide

Uses:

____
Anti-inflammatory
____
drug-specific indications

prostanoids
chemotaxis
free radicals
analgesic
antipyretic

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NSAID General Side Effects (i.e. What happens when you interfere with COX function?)

____: dyspepsia, stomach or duodenal ulceration; increased liver enzymes
____: fluid and salt retention, edema, hypertension, acute renal failure
blood: ____ bleeding time

Other: skin ____, heart failure, hyperkalemia, confusion, bronchospasm, rash

gastrointestinal
renal
increased
photosensitivity

Acetylsalicylic Acid: Aspirin

General:

____ NSAID
____ inhibits COX
____ bleeding time which requires 8-10 days for return to normal (lifetime of platelet)
Uses: pain relief; antipyretic; heart attack (MI) and stroke prevention; rheumatic fever …

Route: ____ (81 mg, 325 mg), ____ (per rectum)

Side Effects: similar to NSAID +
- Salicylism (overdose): ____, fever, vertigo, nausea, vomiting, and diarrhea; more severe intoxication can cause altered mental status, coma, noncardiac pulmonary edema, and death

Acid/Base Abnormalities (overdose): ____/metabolic acidosis (anion gap)

acetylated
irreversibly
increases
PO
PR
tinnitus
respiratory alkalosis

Non-Selective NSAIDs

Don’t memorize the table, just realize that there are different chemical classes of NSAIDs (6 different ones)

____
____
among others

salicylates

propionic acid

Non-Selective NSAIDs

Mechanism of action for all is the same but diff ppl react diff to each class, so if someone is on ibuprofen and it isn’t working, you might switch them over to ____

etodolac

COX-1 Vs COX-2 ``` COX-1: • ____ expressed in most cells • Modestly ____ during inflammation • Generates ____ for housekeeping functions • ____ tissue distribution ``` COX-2: • Constitutively expressed in ____ tissues (e.g. vasculature, kidney, brain) • Massively induced by ____ stimuli (cytokines, growth factors, tumor promoters) • Principle source of prostanoid formation in ____ and inflammation • ____ tissue distribution.

constitutively upregulated prostanoids broad some inflammatory cancer restricted

COX-2 Selective Inhibitors 1. Demonstrated ____ efficacy 2. Reduced risk of gastric and duodenal ulcers ____, but not of GI intolerance - Can be used with ____ such as warfarin or heparin 3. Side effects increased with exposure - ____ - Renal insufficiency - Myocardial infarction, cerebrovascular accidents Result: rofecoxib (Vioxx) and valdecoxib (Bextra) withdrawn ($$) ____ (Celebrex) only remaining COX2 selective drug 100, 200, 400 mg tabs given once or twice daily max = 400 mg/day

analgesic bleeding anticoagulants congestive heart failure celecoxib

COX-2 selectivity NSAIDS are not solely selective for COX1 or COX2, there is a ____ of selectivity as shown in the slide

range

* The risk of ____ or stroke can occur as early as the first weeks of using an NSAID. The risk may increase with ____ use of the NSAID. * The risk appears greater at ____ doses

heart attack longer higher

Naproxen Package Insert: GI Risks “Studies have shown that patients with a prior history of ____ disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than ____-fold risk for developing a GI bleed than patients with neither of these risk factors.... several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral ____, treatment with anticoagulants, ____ duration of NSAID therapy, smoking, ____, older age, and poor general health status.”

``` peptic ulcer 10 corticosteroids longer alcoholism ```

Conclusions - NSAIDs have well known side-effects that influence their use (e.g. never give to patients with moderate or severe ____ disease) - If one NSAID doesn’t work, try another one (individual variation in ____) - Giving 2 or more NSAIDs to one patient will not ____ efficacy but will ____ side effects (____ side effects). It’s best to use a different ____ of analgesic for further pain control (such as acetaminophen or a narcotic). - COX-2 inhibitors do not affect ____ and are easier on the stomach. It’s okay to use celecoxib with warfarin, but non- selective NSAIDs are contraindicated with ____. - Non-selective NSAIDs and aspirin ____ the bleeding time; these drugs should be held prior to ____. - Given at ____ doses and PRN for pain. Given at ____ doses and on a fixed schedule for anti-inflammatory effect. Worry about side effects with ____ term use and generally not with short term use. VERY DIFFERENT SIDE EFFECT PROFILES DEPENDING UPON ____ OF DRUG!

``` kidney efficacy improve worsen additive class platelets warfarin prolong surgeries lower higher long use ```

Corticosteroids Pros - ____ - immunosuppressive - used as a ____ to another therapy - ____ injections for joint flares Cons - unclear effect on disease progression (i.e. ____) - tapering difficult - significant ____

``` antiinflammatory bridge intraarticular erosions side effects ```

Corticosteroids 1. mimetics/derivatives of ____, a steroid hormone produced in the adrenal cortex 2. glucocorticoids: corticosteroids with effects on ____; anti-inflammatory properties mineralocorticoids: corticosteroids involved in ____ regulation 3. MOA: corticosteroids enter cells, bind to the steroid receptor and influence ____ of up to 20% of the cell’s genes 4. Effects: Potent ____ agents i. Decrease in ____ margination, migration, and accumulation at inflammatory sites ii. inhibition of neutrophil and macrophage ____, enzyme release, and pro-inflammatory cytokine production iii. indirect decrease in ____ and leukotriene production iv. decrease in ____ proliferation and interleukin-2 (IL-2) synthesis and secretion

``` cortisol metabolism salt transcription anti-inflammatory neutrophil phagocytosis prostaglandin T-cell ```

Intracellular mechanism of action of the glucocorticoid receptor. - When they are circulating they are bound to ____ - translocate to cell membrane and bind to glucocorticoid receptor, which can then disassociate after structural change from the hitchock (sp?) proteins and get into the nucleus to affect ____ and protein production. - steroids don’t work immediately since it takes a while to affect protein production (effects seen within ____ days)

corticosteroid binding globulin transcription 2-3

Effects of Glucocorticoids • Metabolic – ____ – Lipogenesis (insulin secretion) ``` • Catabolic – ____ catabolism (muscle) – Lipolysis (hormone sensitive lipase) – Bone – ____ – Wasting other tissues • lymphoid, connective tissue, skin ``` • Other – ____ / fluid homeostasis, blood pressure – Behavioral / mood effects

gluconeogenesis protein osteoporosis Na+

Effects of Glucocorticoids • Anti-inflammatory – Decrease in ____ – Inhibition of PLA2 – Decrease ____ • Immunosuppressive – ____ immunity – Reduced proliferation of ____, neutrophils and monocytes

cytokines mRNA COX cell mediated lymphocytes

Corticosteroid Side Effects and Administration Short- to Medium-term: increased appetite, bone demineralization, glucose intolerance/diabetes, nervousness, insomnia, psychosis, fluid retention (depends on mineralocorticoid activity of drug), delayed ____ healing, acne Medium- to Long-term: Short-term Side Effects + osteonecrosis (bone death), osteoporosis (severe bone demineralization), ____, hirsutism, muscle wasting, cataracts, glaucoma, depression, hyperpigmentation, fat redistribution (moon facies, buffalo hump), ____ insufficiency Administration: ____, IV, intra-articular (IA), IM, topical for RA: typically PO and IA Metabolism: generally ____

``` wounded infection secondary adrenal PO liver ```

Secondary Adrenal Insufficiency - cortisol is secreted in response to ____ (e.g. major surgery) - prolonged exogenous corticosteroid use leads to ____ ACTH levels and atrophy of cortisol-secreting cells in the adrenal gland. - Adrenal insufficiency: Inability of adrenal gland to synthesize sufficient ____ in response to stress - cortisol insufficiency can lead to: ____, shock, death, fever, nausea/vomiting, depressed mentation, fatigue, weakness, hypoglycemia - adrenal suppression seen after ____ 5mg daily for as few as 2 weeks -so, people on long-term steroids may need ____ steroids at the time of big stressors (e.g major surgery)

``` stress decreased cortisol hypotension prednisone more ```

Synthetic Compounds List of commercial ____ Point is to compare with ____ which is the endogenous steroid we make naturally Prednisone or Prednisolone is used to treat ____ and it is x____ stronger as an antiinflammatory than cortisol while it’s mineralcorticoid properties are about a ____ (less likely to cause fluid retention)

``` steroids hydrocortisone (cortisol) inflammation 4-5 1/3 ```

Disease Modifying Anti-Rheumatic Drugs (DMARDs) Non-corticosteroid containing medications that suppress the ____ and/or delay disease progression in RA. Goal: Get patients off of corticosteroid within ____ months and onto a ____.

immune ststem 6 DMARD

methotrexate (Rheumatrex, Trexall) – INDICATED FOR NEWLY ____ OR ESTABLISHED DISEASE – STANDARD OF CARE – 60-70% ____ Routes: ____: PO, SC (SC dosing gives levels ~30% > than equivalent PO dose) Cancer: ____, IM, intrathecal Dosage (Arthritis): 7.5-25 mg/week (2.5 mg tabs, 25 mg/mL solution) Metabolism/Elimination: eliminated via ____ mostly (decreased elimination when patient on NSAIDs can lead to increased methotrexate toxicity) MOA: At ____ doses (for arthritis treatment) the effect of methotrexate is thought to be the blockage of ____ biosynthesis at the step catalyzed by aminoimidazolecarboxamide (AICA) ribotide transformylase, indirectly resulting in elevated serum levels of ____, a T-lymphocyte toxin.

diagnosed improvement arthritis IV urine low purine adenosine

methotrexate (Rheumatrex, Trexall) MOA continued: At ____ doses (for cancer treatment) methotrexate irreversibly binds to dihydrofolate reductase inhibiting the formation of reduced folates, and thymidylate synthetase, resulting in inhibition of purine and thymidylic acid synthesis (inhibits ____). Actively proliferating tissues such as malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and cells of the urinary bladder are in general more sensitive to this effect of methotrexate. Response: observed in ____ weeks Adverse reactions: gastrointestinal, hematologic, pulmonary, hepatic, n/v, ____, malaise, ____ To minimize side effects: Give with ____ 1mg QD or leucovorin 5mg Q week. No ____ use (additive ____ toxicity). Monitor: ____, LFT’s, creatinine, albumin

``` high DNA synthesis and repair 4-6 stomatitis teratogenic folic acid alcohol liver CBC ```

Antimalarial: hydroxychloroquine (Plaquenil) - INDICATED FOR ____, MILD DISEASE - WAS FIRST DRUG OF CHOICE (US) IN THE PAST - ONSET ~ 3 MO IN 50% Route: ____ Dosage: 200 mg PO 1 or 2 times a day (max 6.5 mg/kg/day) Metabolism: Liver MOA: ____; likely multiple; inhibits ____ of neutrophils and chemotaxis of eosinophils; impairs complement-dependent antigen-antibody reactions, (reduced activation of Toll Like Receptors 7 and 9 in dendritic cells) Other: Benefit seen after 2-4 months Adverse effects: myopathy, headache, aplastic anemia, seizures, retinopathy, ototoxicity (also, ____ change) Monitor: Need dilated ____ eye exam every 12 months Other: firstline treatment for ____ (lupus)

``` early PO unknown locomotion mucosal pigmentation fundoscopic SLE ```

sulfasalazine (Azulfidine) – INDICATED FOR EARLY, MILD, SERONEGATIVE DISEASE – WAS FIRST DRUG OF CHOICE (EUROPE) IN THE PAST Route: ____ Dosage: 1-3 g/day; start at 500 mg/day Metabolism: colonic intestinal flora convert to ____ and 5-aminosalicylic acid (5-ASA); metabolites eliminated in urine MOA: 5-ASA inhibits ____ synthesis + ? Effect of sulfapyridine Other: Benefit seen after 1-2 months Adverse reactions: Common: ____, headache, rash Others: ____ syndrome, hepatitis, agranulocytosis, peripheral neuropathy, reversible decrease in sperm count Monitor: ____, kidney function, liver function

``` PO sulfapyridine prostaglandin nausea stevens-johnson CBC ```

Leflunomide (Arava) - “new” traditional DMARD - similar efficacy to methotrexate Route: ____ Dosage: 10-20mg PO every day Metabolism: ____; excreted in urine and feces; long half-life (about 2 weeks). The drug can be measured in the ____ for > 2 years after the last dose. Rapid detoxification requires administration of ____ (8g PO TID for eleven days). MOA: metabolite of leflunomide inhibits ____ which leads to inhibition of pyrimidine synthesis Adverse Reactions: ____, alopecia, diarrhea, nausea, weight loss, rash, hepatotoxicity, teratogenicity Monitor: ____, LFT’s, creatinine, albumin

``` PO hepatic metabolism serum cholestyramine dihydroorotate dehydrogenase myelosuppression CBC ```

azathioprine (Imuran, Azasan) - occasionally used for RA Route: PO, IV (PO for arthritis) Dosage: start at 50mg PO QD; Max: 3 mg/kg/day; increase by 25mg every 2 weeks to desired dose (typical dose 50-150 mg PO every day) Metabolism/Elimination: Hepatic metabolism; clearance of metabolites in urine MOA: active ____ leads to decreased synthesis of purine nucleotides (6-MP accumulates when patients given ____ - TOXICITY) Other: Response seen in 2-3 months Adverse Reactions: Common: ____, abdominal pain, rash, increased LFTs, myalgias, alopecia; Serious: ____, leukopenia, bone marrow suppression, hepatotoxicity, risk of neosplasm, hypersensitivity reaction, hepatic veno-occlusive disease Monitor: ____, LFTs

``` metabolite 6-mercaptopurine (6-MP) allopurinol diarrhea pancreatitis CBC ```

cyclosporine-A (Gengraf, Neoral, Sandimmune) - rarely used for RA Route: ____ (arthritis), IV, topical Dosage: 1-4 mg/kg/day; (typically 1-2 mg/kg/day) Metabolism: ____/feces MOA: Inhibits T-helper cell release of ____; bind to cyclophillin which blocks effects of ____ Adverse Reactions: ____, renal toxicity, infection, cancers, ____ hyperplasia, neurologic toxicity, hyperlipidemias, ____, numerous others Monitor: ____, kidney function; always looking for potential drug interactions which can potentiate renal damage

``` PO hepatic IL2 calcineruin hypertension gingival hyperglycemia blood pressure ```

Gold - rarely used for RA now 1. ____ gold (auranofin; Ridaura) Dosage: 3 mg PO 1-2 times a day; max of 9 mg/day. Benefit seen 4-6 months after starting therapy 2. ____ gold (aurothioglucose; Solganal) Dosage: 25-50 mg IM every 2-4 weeks. Benefit observed in 3-6 months MOA: unknown; may inhibit phagocytosis by ____ Adverse Reactions: ____, rash, pruritus, abdominal pain, ____, nausea, confusion, conjunctivitis, ____ (taste changes), elevated LFTs, proteinuria Serious: ____, ulcerative colitis, nephrotic syndrome, anemias, pulmonary fibrosis Monitor: ____ and urinalysis (to look for proteinuria)

``` oral injectable macrophages diarrhea stomatitis parageusia seizures CBC ```

penicillamine (Cuprimine, Depen) - rarely used for RA now Route: ____ Dosage: 250-1000 mg PO every day; take 0.5-1 hrs before meals Metabolism/Excretion: metabolized by ____, excreted in urine MOA: supresses ____ but not ____ activity; also chelates lead, copper, mercury Other: maximal response seen after 3-6 months of therapy Adverse reactions: ____, rash, n/v, nephropathy, taste changes, ____, hirsuitism, drug-induced lupus Rare: ____, pancreatitis, thrombocytopenia Monitor: ____ and urinalysis

``` PO liver T-cell B-cell pruritus stomatitis aplastic anemia CBC ```

cyclophosphamide (Cytoxan) - generally reserved for ____ extraarticular manifestations of RA - chemotherapeutic agent - more commonly used in Rheumatology for vasculitis or certain forms of kidney disease associated with Systemic Lupus Erythematosus Route: ____, IV Dosage: Oral: 50-100 mg/m2/day as continuous therapy; I.V.: Single doses: 500-1000 mg/m2 (30-50 mg/kg) per treatment course (1-5 days) which can be repeated at 4-week intervals Metabolism: Hepatic to ____ metabolites acrolein, 4-aldophosphamide, 4- hydroperoxycyclophosphamide, and nor-nitrogen mustard. Eliminated in urine. MOA: Cyclophosphamide is an ____ agent that prevents cell division by cross-linking ____ strands and decreasing DNA synthesis. Cyclophosphamide is a prodrug that must be metabolized to ____ metabolites in the liver.

``` PO active alkylating DNA active ```

cyclophosphamide (Cytoxan) Adverse Reactions: >10%: ____: Alopecia (40% to 60%); ____: Fertility: May cause sterility; ____: Nausea and vomiting, usually beginning 6-10 hours after administration; anorexia, diarrhea, mucositis, and stomatitis are also seen; ____: Severe, potentially fatal acute hemorrhagic cystitis (7% to 40%); ____: Thrombocytopenia and anemia are less common than leukopenia 1-10%: headache, flushing, rash <1%: multiple, including malignancy (e.g. ____ cancer), lung inflammation, heart dysfunction, liver toxicity Monitor: ____, kidney function, liver function

``` alopecia endocrine GI GU hematologic bladder CBC ```