IgE Mediated Anaphylaxis 

• Histamine - vasodilation (pruritis, swelling, hypotension, dairrhea), inc vascular permeability(utricaria, angioedema), bronchoconstriction (wheezing)
• Leukotrienes C4, D4 - bronchoconstriction and vasodilation
• Platelet activating factor (PAF) - bronchoconstriction and vasodilation
• C3, C5a - smooth muscle contraction (wheezing, cramping, uterine contractions), vasodilation

Pathology in Anaphylaxis 

• Laryngeal edema (in 2/3 of cases) - accumulation of non-inflam fluid in lamina propria of hypopharynx, epiglottis, larynx
• Pulmonary hyperinflation - found in 25-50% of fatal cases; inc bronchial mucosal secretions, bronchial submucosal edema and eosinophilic infiltration of bronchial walls
• Inc vascular permeability - urticaria and angioedema
• pulmonary edema nad intra-alveolar hemorrhage
• myocardial damage found in 80% of fatal anaphylaxis

Idiosyncrasy

• abnormal effect unrelated to intended pharmacologic action
• may be due to underlying abnormalities of metabolism, excretion, or bioavailability
• genetic susceptibility
• example: dapsone-induced hemolytic anemia w/ G6PD deficiency

Drug-Induced Hypersensitivity Syndrome

(DiSH)

• also termed DRESS (drug rash w/ eosinophilia and systemic Sx)
• severe hypersensitivity reaction, delayed onset; can persist for wks to mo after drug stopped
• Triad - rash, fever, organ involvement (+/- eosinophilia)
• liver, kidney, heart, lung involvement
• atypical lymphocytes (CD8) commonly present
• allopurinol (nephritis), anticonvulsants (hepatitis), abacavir (pneumonitis)

Genetic Factors of Drug Allergies

• allopurinol induced SJS/TEN - HLA-B*5801
• carbamazepine induced SJS/TEN - HLA-B*1502 (asians)
• Abacavir hypersensitivity - HLA-B*5701 (europeans) - 48% incidence in those positive compared to 0% in those neg

Pruritis

• an itch that rashes
• must have pruritis for it to be atopic dermatitis
• itching threshold is lowered
• allokinesis - ablity of surroudning skin to react to light stimuli with more itch
• excoriation - much more common than w/ urticarial - skin picking disorder
• triggers - irritants, aeroallergens, contact allergens, microbial, environmental

Topical Immunomodulators

• suppress T cell cytokine transcription
• Tacrolimus - binds cytoplasmic Fk506 binding protein, forms complex; inhibits calcineurin supresses dephosphorylation of major cytokine transcription factors
• Pimecrolimus - blocks synthesis, release of inflammatory cytokines

Systemic Immunomodulators

• mycophenolate mofetil - inhibits de novo purine biosyn; hence inh lymphocyte and cytokine produciton
• IFN-y - Th1 cytokine; suppresses IL-4 production in vitro
• IV Ig - reduced IL-4 production
• Zafirlucast, montelucast - leukotriene antagonist

Urticaria

• lesions which erupt in skin as a result of mast cell degranulation - red, raised, and pruritic
• type I hypersensitivity
• Histology - dilation of small venules, capillaries w/i superficial dermis
• also widened dermal papillae, flattening of rete pegs, and swollen collagen fibers
• causes - foods, drugs, venoms, arthropods, aeroallergens, infections
• causes - physical stimuli - pressure, heat/cold, cholinergic, vibration
• radiation contrast medium can cause direct mediate release without IgE interaction

Autoimmune Urticaria

• Urticarial vasculitis: lesions > 24 hours
• usually of lower limbs; "Palpable purpura"
• histology "Cell ghosts"
• 8-20% of patients possess anti-thyroid antibodies

Mastocytosis 

• hyperplasia of mast cells - gut, bone, skin
• Sx: pruritis, flushing, palpations, abdominal cramps, diarrhea, heartburn
• Childhood (favorable prognosis) - skin involvement typical; systemic involvement uncomon; half of isolated lesions resolve by adolescence
• Adults (variable prognosis) - systemic involvement more typical; skin involvement less common - leukemia, sarcoma

Angioedema

• similar processes as urticaria; similar etiologies and often part and parcel w/ utricaria 
• acquired form - ACE inhibitors - inc circulation of bradykinin by inh of bradykinase - resulting angioedema even yrs after treatment
• can be life threatening - laryngeal edema
• hereditary form - complement normal and complement abnormal (defect in C1 esterase inhibitor)

Allergic Rhinitis

• risk factors: family Hx, serum IgE >100IU/mL before 6yrs
• early phase reactions: congestion, rhinorrhea, sneeezing
• Late phase reactions: congestion and rhinorrhea
• types - seasonal and perennial
• physical signs: allergic shiners,s wollen, pale nasal turbinates and pharyngeal cobblestoning
• Pharm - antihistamines, nasal corticosteroids, decongestants, nasal antihistamines, intranasal anticholinergic, leukotriene antagonists

1st Generation Antihistamines

• bromopheniramine, chlorpheniramine, diphenhydramine
• short acting and lipophilic - cross BBB (sedation)
• sedation, drowsiness, cognitive/motor impairment
• poor selectivity - blocks adrenergic, 5-HT, D rec
• antichol effect - confusion, dry mouth, urine retention
• SNS effects - affects congitive function, potentiated by alcohol
• unfavorable risk/benefit ratio

2nd generation Antihistamines

• cetirizine, fexofenadine, loratadine
• long acting; greater selectivity - H1 rec
• little CNS penetration - large hydrophilic molc
• less sedation than 1st gen; as efficacious as 1st gen
• intranasal antihistamines are also effective but may cause drowsiness

Nasal Corticosteroids

• Beclomethasone, fluticasone, budesonide
• interfere w/ allergic inflam at several points
• block earlya nd late phase response
• exert effects by vasoconstriction, reduction of mucosal edema, inh of cytokine and mediator expression
• effects take longer - compliance issue

Decongestants

• pseudoephedrine, phenylephrine, oxymetazoline
• phenylephrine less effective - extensive 1st pass metabolism
• for short term therapy
• alpha adrenergic agonists -> vasoconstriction
• dec blood volume in sinus vessels which reduces blood uspply to mucosa; lowers mucosal edema and improves nasal patency
• systemic side effects: possible irritability, dizziness, headache, tremor, insomnia, tachycardia, and elevated blood pressure
• caution in pts w/ glaucoma, hyperthyroidism or CV
• topical use may lead to rhinitis medicamentosa

Nasal Antihistamines

• azelastine (small risk of sedation), olopatadine
• binds to nasal H1 rec locally; also good anticholinergic (drying, less rhinorrhea)

Intranasal Anticholinergic

• ipratropium bromide
• does not cross BBB (low solubility, not systemically distributed)
• only provides relief from excessive rhinorrhea (not itching or blockage)
• local side effects are dose related (nasal dryness, bloody discharge)

Leukotriene Antagonist

• montelukast (LTD-4 rec antagonist)
• similar benefit to loratadine; more effect possibly w/ co-existent mild asthma and/or nasal polyps
• mast cell stabilizer
• inhibits leukotriene mediated smooth muslce contraction, edema, capillary leak, mucous produciton, and chemoattractant mech
• LTD, LTC, LTE - found in mast cells, eosinophils, basophils
• cromolyn

Asthma Treatment

• Step 1 - mild intermittent: no daily medication
• Step 2 - mild persistent: low-dose inhaled corticosteroids (ICS)
• Step 3 - moderate persistent: low to medium dose ICS + long acting B2 agonist (LABA)
• Step 4 - severe persistant: high dose ICS + LABA + oral corticosteroids

Inhaled Corticosteroids (ICS)

• fluticasone, budesonide, mometasone, beclomethasone
• effective long term controller med for asthma
• reduces exacerbations and use of quick acting relief meds decreases
• lung function improves (increases FEV1)
• less mast cells, eosinophils, lymphocytes
• maintains epithelial integrity
• inhibits gene transcription of cytokines (IL-1, 2, 4, 5)
• inhibits arachidonic acid metabolism

X linked agammaglobulinemia

(Bruton's)

• lack of bruton's tyrosine kinase leads to B cell maturation defect
• very low B cell numbers and all Ab lvls low
• Sx - recurrent sinopulmonary infections, encapsulated organisms predominate, chronic GI virus shedding
• presents 6-9 mo after birth
• sparse lymphoid tissue - lack of tonsils
• CD19 < 2% total lymphocyte pool
• Tx - IV Ig (mainly IgG) - may still get sinus/otitis/GI trouble because cant replace secretory IgA

Common Variable Immune Deficiency

(CVID)

• B cells are mature but do NOT produce Ab
• Sx - recurrent sinopulm infections, encapsulation organisms, tonsils are present though
• onset later childhood or early adult
• higher incedence of autoimmune, lymphoid disease
• may have normal levels of IgA, IgM
• Tx - IV Ig and surveilence 

Severe Combined immune Deficiency 

(SCID)

• majority are X linked; early onset (begins at birth)
• poor development of T cells leads to arrest of immune system - poor Ab production/function
• unusual organisms causing infections; loss of tumor surveillance (CD8 T cells)
• poor prognosis (generally fatal)
• treatment - bone marrow transplant

DiGeorge's Syndrome

• 22q11 deletion leads to defective develop of 3rd and 4th brachial pouches
• thymic aplasia/hypoplasia, facial abnormalaties, tetralogy of fallot, hypocalcemia (parathyroid affected)
• dec T cells, poor T cell memory but normal Ab levels
• most serious issue at birth - cardiac defect
• Tx - bone marrow and thymic transplant

Chronic Granulomatous Disease

(CGD)

• X linked NADPH oxidase deficiency - usually converts O2 -> O2 -; deficiency - low H2O2
• infection w/ catalase positive organisms - staph, salmonella, pseudomonas
• granuloma formation occurs from accumulation of T cells due to lack of functional neutrophils
• hepatosplenomegaly, pneumonia, cellulitis, osteomyelitis
• NBT - yellow turns blue in company of normal neutrophils 

Complement Deficiency

• C2 deficiency - high assoc w/ autoimmune dz (SLE)
• C3 deficiency - common pyogenic infections, encapsulated organisms, inc glomerulonephritis
• C4 deficiency - C4a (SLE) and C4b(inc incidence of bactrial infections
• C5-9 deficiency - recurrent, disseminated neisseria infection

Melanin

• Eumelanin (darker) and pheomelanin (lighter)
• blocks/scatters UV radiation - converts radiant energy into heat
• quenches /traps free radicals
• rgulates VitD3 synthesis by keratinocytes

Sunburn

• acute cutaneous inflammatory reaction due to excessive UV irradiation
• DNA mutations -> keratinocyte apoptosis
• UVA - tanning, photoaging
• UVB - sunburn
• can lead to impetigo, skin cancer

Kaposi Sarcoma

• HIV-1/HHV-8 infection
• reduces number of langerhans cells in skin
• impairment of antigen presenting prevent sinduction of immune response to microbes and tumors

Ointment

• occlusive (improves absorption), greasy 
• can be medicated or unmedicated (used for effects of protectants/emollients)
• difficlt to spread, remove; non vanishing
• for smooth, non-hairy skin
• ideal fo dry, thick, hyperkeratoic lesions

Cream

• non-occlusive, non greasy
• for most skin types, including intertriginous areas, exudative inflammation
• useful in areas where skin touches skin (groin, etc)
• may sting (from preservaties)

Lotions and Gels

• Lotions - pourable liquid, for large hairy areas, less occlusive, less greasy, more viscous
• Gels - jelly like, least occlusive, greaseless, cooling effect, for acne, exudative inflammation, scalp, hairy areas

Topical Corticosteroid Potency

• Ultra-High - Clobetasol - for severe dermatoses over nonfacial, nonintertriginous areas (scalp, palms, soles, thick plaques on extensor surfaces) - for short term use
• Mid strength - Triamcinolone - for mild to moderate nonfacial/nonintertriginous ares - okay for flexural surfaces for limited periods
• Least potent - Hydrocortisone (OTC) - for large areas, thinner skin (face, eyelid, genital, intertriginous areas - for long term use

Topical Antibacterials

• Bacitracin - gram + bugs (staph, strep) - adv effect of allergic dermatitis
• Polymyxin-B - gram - bugs
• Neomycin - gram - bugs - can cause allergic dermatitis
• Triple antibiotic ointment (neosporin) contains all 3
• Mupirocin - reversibly binds to isoleucyl tRNA synthetase and inh protein synthesis - for gram + bugs including MRSA, staph, strep, impetigo and furuncles

Benzoyl peroxide

• MOA - antibacterial against P. acnes - comedolytic action (inc sloughing of epithelial cells
• adv effects - skin dryness, stinging, irritation, erythema, peeling, contact dermatitis, photosensitivity
• bleach hair and clothes

Oral Antibiotics for Acne

• tetracyclines - 6 month treatment 
• moa - antibacterial, anti-inflam
• adv effects - GI upset, photosensitivity, pseudotumor cerebri
• minocycline - vertigo, hyperpigmentation, drug induced lupus
• CI - pregnancy, children < 8 (risk of bone growth retardation and permanent teeth discoloration

Retinoids

• 1st generation - retinol, tretinoin and isotretinoin
• 2nd generation - acitretin and methoxsalen
• 3rd generation - adapalne, tazarotene, bexarotene
• uses - acne, psoriasis, T cell lymphoma, wrinkles, vitiligo
• MOA - bind, activate retinoic acid receptors (RARs) - redces P acnes colonization inderectly by reducing sebum production
• comedolytic - expulsion of open comedones and transform closed to open comedones
• also inc skin turnover for management of wrinkles
• adv effects - skin irritaiton (dryness, peeling, erythemia), pruritis, stinging, photosens -especially w/ first month of use

Isoretinoin

• vitamin A analog (13-cis retinoic acid)
• indicaiton - severe recalcitrant cystic/nodular acne
• moa - dec sebaceous gland size, sebum production
• teratogenic - catagory X - face, eyes,ears, skull, cNS, CV system, thymus abnormalities - us contraception even 1 month after
• adv effects - skin irritation, muscle/joint pain, hyperlipidemia (can cause pancreatitis), depression, psychosis, mood changes, hepatotoxicity, IBD, corneal opacities, 
• pseudotumor cerebri (esp when also taking tetracycline)

Terbinafine

• indication - onychomycosis - most potent antifungal against dermatophytes
• fungicidal - inh of squalene epoxidase interferes w/ ergosterol production that is needed to make cell wall
• adv effects - hepatotoxicity, taste disturbance
• inhibits CYP2D6 - inh metabolism of TCAs, SSRIs, MAO inhibitors

Itraconazole

• fungistatic (less effective than terbinafine)
• blocks formation of ergosterol (inh a CYP involved)
• adv effect - pruritis, rash, hepatotoxicity, dec testosterone
• Inh CYP3A4 - drug interactions statins, macrolides, quinidine, crabamzepine
• potentially cause V-tac, torsades de points - from inc lvls of quinidine, dofetilide, pimozide

Griseofulvin

• Indications - dermatophytes (epidermophyton)
• fungistatic - less effective than terbinafine or itraconazole
• disrupts mitotic spindle by interacting w/ polymerized microtubules
• adv effects - headache, photosensitivity, peripheral neuritis, leukopenia, hepatotixcity
• interferes w/ hepatic metabolism of porphyrins
• CI - acute intermittent porphyria, pregnancy

Topical Antifungals

• Imidazoles (ketoconazole)
• Oxaboroles (tavaborole) - fungicidal - enhanced nail penetration, effective for onychomycosis - inhibits tRNA synthetase (blocks protein syn)
• Allylamines, benzylamines - fungicidal - effective for dermatophytes
• Ciclopirox - fungistatic - loprox, penlac nail lacquer - effective for dermatophytes, candidia
• polyenes - fungistatic - nystatin - for candida

Imidazoles

• topical antifungal
• ketoconazole - topical shampoo for seborrheic dermatitis (board q)
• efinaconazole - enhanced penetration into nailbed for onychomycosis
• indications - candida, dematophytes
• MOA - fungistatic - hinder cell wall syn by blocking ergosterol synthesis

Localized Psoriasis Treatment

• topical corticosteroids
• Coal tar - antiproliferative, anti-inflam - may be combined w/ salicyclic acid (penetration) and UVB light phototherapy - messy, stains clothers - adv effects photosens, folliculitis, dermatitis
• VitD analogs - Calcipotriene/calcitriol - binds to lymphocytes and inh epidermal proliferation - adv effects skin irritaiton, erythemia
• Retinoids - tazarotene (also indicated for acne and rosacea) 

Cyclosporine

• systemic Tx for moderate to severe psoriasis
• inhibits calcineurin - supresses T cells by inh the first phase of T cell activation
• used primarily as an anti-rejection agent in solid organ transplant but is also indicated for psoriasis
• adv effects - nephrotoxicity, HTN, hyperkalemia, hyperuricemia, hyperglycemia, drug interactions
• toxicity limits long term use leading to potential relapse

Acitretin

• 2nd generation retinoid
• corrects abnormal cell differation of keratinocyte
• effective for pustular psoriasis
• adv effects - hypervitaminosis A (dry lips, mouth, nose, eyes, skin, hair loss), teratogen (avoid in pregnancy and w/ alcohol)
• it plus ethanol leads to formation of etretinate, a teratogenic metabolite w/ prolonged half life
• cannot donate blood for 3 yrs after Tx

Biologic Agents for Psoriasis

• T cell inhibition - alefacept
• TNF inhibition - etanercept (decoy rec), infliximab, adalimumab
• interleukin antagonist - ustekinumab (blocks IL-12, IL-23) and secukinumab (blcoks IL-17a)
• ADv effects - related to immunosuppresion - acue serious infections, precipitate latent TB, lymphoma, malignances

Imiquimob

• for actinic keratosis on face and scalp
• also for primary basal cell carcinoma, external genital warts, and common warts
• immune stimulant - stimulates local cytokine induction, resulting in antineoplastic action - release of TNFa, IL-1, IL-6, IL-8
• adv effects - local inflammatory reaciton, pruritis, erythema, erosions

Ingenol

• indicaiton - actinic keratosis
• dual MOA - disrupts cell membrane and mitochondria leading to cell necrosis; release of cytokines leading to cell death
• effectiveness similar to 5-FU but has an easier adm and shorter duration of action
• adv effects - erythema, flaking, scaling, crusting

Topical Calcineurin inhibitors

• tacrolimus - alt to topical steroids for moderate to severe atopic dermatitis
• pimecrolimus - alt to topical steroids for mild to moderate atopic dermatitis in nonimmunocompromised
• indicaiton - atopic dermatitis
• MOA - inh calcineurin which leads to: dec T cell activation leading to suppression of inflam response assoc w/ atopic dermatitis
• adv effects - well tolerated, minimal side effects
• Black box waring - rare cases of lymphoma and skin malignancy - not for children < 2 and reocmmended for short term use

Stasis Dermatitis

• cutaneous marker for udnerlying venous insufficiency 
• incompetence of valves leads to venous HTN which leads to capillary distention and dmgs permeable barrier -> microangiopathy + chronic inflammation (stasis dermatitis)
• cushion like pitting edema, erythema (may have brown hemosiderin pigment)
• typically bilateral and pruritis, NOT warm or tender
• lae stage - lipodermatosclerosis of the leg - looks like upside down wine bottle

Scabies

• sarcoptes scabiei - typically < 100 mites per affected
• crusted scabies may invovle thousand of mites
• Sx - intense pruritis accentuated at night - interdigital spaces, flexural wrists, ankles, feet, belt, penis,nipple
• Burrows - wavy threadlike, gray-white, 1-10mm in length
• erythematous papules w/ excoriations, vesicles, nodules, eczematous dermatitis
• Crusted Scabies - immunocomp hosts; highly contagious form of scabies
• dx - mineral oil prep micro - seek a burrow to scrape
• Tx - permethrin (applied at bedtime), ivermectin (for crusted scabies; CI in pregnancy)

Erthema Multiforme

• mucocutaneous manifestation of skin-directed immune reaciton during infection in predisposed person
• target lesions - multiple rings w/ dusky center best seen on palsm, soles (can have 3 zones)
• assoc w/ infections (HSV, mcoplasma), drugs (sulfa, Lactams, phenytoin), cancers, autoimmune disease
• Tx - treat undrlying cause, supportive; if severe prednisone

Seborrheic Keratosis

• most common cutaneous neoplasm - common in elderly whites
• location - trunk, extremities, head, neck (spares palms/soles)
• flat greasy pigmented squamous epithelial proliferaiton
• stuck on well circ, oval, brown-black greasy plaquepapule - if irritaed w/ crust and hyperkeratosis -> pink red and scaly
• pseudohorn cysts - keratin-filled cysts
• Leser-Trelat - sudden onset of multiple - indicates underlying internal malignancy
• Dermatosis papulosa nigra - multiple seborrheic keratoses, periorbital (face, neck, chest) - common in blacks and not assoc w/ internal malignancy

Psoriasis Vulgaris

• chronic relapsing papulosquamous dermatitis
• abnormal hyperproliferation of keratinocytes; assoc w/ HLA-Cw6
• extensor surfaces - elbows, knees, scalp, trunk, gluteal cleft
• well circ erythematous dry plaques w/ silvery scaling
• acanthosis - epidermal hyperplasia (spinosum)
• dec or absent stratum granulosum
• parakeratotic scaling (nuclei remain) and Auspitz sign (pinpoint bleeding spots from exposure of dermal papillae when scales are scraped off)
• neutrophilic microabscesses (Munro's)
• can be assoc w/ psoriatic arthritis or nail pitting
• Guttate (eruptive) variant in young pts asssoc w/ Group A B-strep infection pharyngitis
• Inverse variant - intertriginous, flexural areas; not as scaly
• Tendency to recur, persist; unpredictable course

Leukocytoclastic Vasculitis

(LCV)

• most common cutaneous vasculitits - symm, bilateral plaques, non blanchable, variable size
• etiology - drug induced, infectious, medications, immune mediated
• particularly in lower legs - palpable purpura (nonblanching), most cases are asymp w/o systemic sx
• pathologic features - perivascular neutrophilic infiltrate, karyorrhetic debris, vessel fibrinoid necrosis, extravasated RBCs
• prognosis - acute is self limited; chronic is from persistent underling etiology

Henoch-Schonlein Purpura

• usually preceded by URI
• Most common vasculitis in children: Males > Females
• localized to lower limbs, thighs, buttocks
• palpable purpura, abdominal pain, arthralgia, hematuria, intussesception
• renal deposition-proteinuria - monitor weekly
• Non-thrombo-cytopenic purpura - normal platelet count, PT and PTT
• same histo as LCV - perivascular neutrophlic infiltrate, karyorrhetic debris, vessel fibrinoid necrosis, extravasated RBCs
• Dx - IgA around vessel wall, glomeruli
• Tx - supportive; steroids used for renal dz or severe sx such as intussesception

Verrucous SCC

• 2-12% oral SCC; M>>F; age peak 5th decade
• variant htat is seen on oral, genital mucosa
• etiology - chronic irritation, inflam, impaired immune system
• oral - poor hygeine, ill fitting dentures, decaying teeth, tobacco
• genital - poor hygeine, phimosis
• clinical features - slow-growing, large, exophytic/endophytic papillomatous warty tumor

Eczema

• Spongiosis - epidermal accum of edematous fluid in intercellular space (btw keratinocytes; wet) - if severe can progress to vesicle/bulla formation
• epidermal hyperplasia, serum w/i hyperkeratosis, exocytosis infiltrate
• Acute phase - wet and crusting erythematous papules/vesicles (allergic contact dermatitis)
• Subacute - mixture-nummular dermatitis
• Chronic - scaly plaques (lichen simplex chronicus), related loosely to the chronologic evolution of the lesion

Nummular Dermatitis

• most common form of eczema that is biopsied
• location - extensor surfaces of extremities
• clinical features - intensely pruritis round to oval (coin shaped) scaly patches, plaques

Necrobiosis lipoidica diabeticorum

• well circumscribed, firm, depresed, waxy yellow-brown plaques +/- ulceration
• located on anterior shins
• 2/3 pts have DM
• control of DM does NOT affect course of disease

Cutaneous Manifestations of GI Dz

• sweet's syndrome - tender nodules, dermal edema and diffuse neutrophillic infiltrate of dermis w/o vascultitis - asoc w/ hematologic malignants and IBD
• Pyoderma gangrenosum - inflamm pustules that enlarge and become large painful ulcers w/ sharp marginated undermined violaceous border - assoc w/ IBD, leukema, myeloma, sLE, RA, HIV
• Dermatitis herpetiformis -pruritis papules on extensor surface (elbow), papillary dermal neutrophilic abscesses, deposits of IgA at tips of dermal papillae - villous atrophy of jejunum n inflam of small bowel (assoc w/ Celiac dz)

Cutaneous signs of renal disease

• Acquired perforating dermatosis - umbilicated keratotic dome shaped papules - very pruritis - altered components transepidermally elmiinated, assoc w/ renal failure
• Nephrogenic Systemic Fibrosis - pts w/ renal failure on dialysis - thickened sclerotic papules, plaques - dermal fibrosis, collagen deposition, septal fibrosis
• Calciphylaxis - fixed livedo reticularis becomes prupuric, bullous and eventually necrotic - calcificaiton of arterioles - sepsis common COD
• Leukocytocalstic vasculititis - palpable purpura - neutrophils w/i small blood vessels of dermis

Rubella Peds Dermatology

• blueberry muffin rash
• generalized maculopapular rash, enlarged occipitocervical nodes
• fetal complications in pregnancy
• Forchheimer's Sign - petichiae on soft palate
• Dx - acute and convalescent sera

Acrodrmatitis Enterohepatica

• triad - dermatitis, diarrhea and alopecia
• acral, periorofacial vesciobullous, pustular and eczematous eruption
• assoc w/ zinc deficiency
• possible nial dystrophy, glossitis, stomatitis, secondary bacterial infection

Pityriasis Rosea

• herald patch
• days later -> christmas tree distribution
• multiple plaques w/ collarette/cigarette scale
• oval lesions follows langer's lines
• adolescents and oung adults
• must rule out syphilis - check RPR
• self resolving in 6-8 wks

Lichen Planus

• mostly seen in adults
• 6 P's - pruritic, purple, polygonal, planar papules and plaques
• invovles wrists, legs, genitals, mucous membranes
• wickham striae - reticular white lines on mucous membranes (inside mouth)
• nail involvement - 10% - pterygium is most characteristic change
• sawtooth infiltrate of lymphocytes at dermal-epidermal junction
• assoc w/ Hepatitis C

Juvenile xanthogranuloma

• self limited disease of infants, children
• histiocytic cutaneous infiltrate
• solitary or multiple reddish-brown papules or nodules
• presents btw birth - 9 months
• ocular tumors are most frequent complication

Furuncles, carbuncles

• caused by S. aureus or MRSA
• inflamed, round, deep perifollicular abscess
• late stage - central suppuration (pus)
• carbuncle - multiple furuncles joined together
• location - any hair bearing areas
• treatment - warm compresses, oral antibiotics - tetracycline or sulfa for MRSA, incision and drainage if abscess is localized and fluctuant

Erysipelas

• group A B-hemolytic strep - children, adults
• Group B strep - newborns
• large tender, swollen, hot, erythematous plaque
• well demarcated, raised borders
• begins as small patch, spreads peripherally
• fever, chills, headache, leukocytosis
• distribution - most commonly face, legs
• Tx - oral PCN, cephalosporins, macrolides, cold compress

Erythrasma

• caused by corynebacterium minutissimum
• well-demarcated, dry, erythematous/tan patch
• woods lamp - coral fluorescence
• distribution - intertrignous areas
• Tx - oral erythromycin, clindamycin, miconazole

Green nail syndrome

• caused by pseudomonas aeruginosa
• onycholysis of distal part of nail w/ striking green discoloration below plate
• distribution any disrupted or traumatized nail
• Pseudomonas can also cause hot tub folliculitits - pruritic follicular papules, pustules occur few days after using hot tub - may have fever, headache, sore throat, malaise

Fungal Infections

Basal Cell Carcinoma (BCC)

• most common skin cancer; no known precursor lesion
• arise form nonkeratinizing keratinocytes that originate from the basal layer 
• UV radiation -> DNA dmg and PTCH mutation
• clinical - pink, pearly nodules, telangiectasias, rolled borders, central crusting, ulceration
• morpheaform - pitting (skin just indents)
• superifcial - scalling plaque; nodular - dome shaped bump
• infiltrating - red and ugly (mean); can be black necrosis
• pigmented - black dot; for all look for cover signs
• can be nevus sebaceous w/ BCC - light yellow color at birth on scalp w/ no hair and then raises at puberty
• histo - nests of basaloid cells in dermis; palisading nuclei; cystic (70%)

Squamous Cell Carcinoma (SCC)

• 2nd most common; sunlight, arsenic, immunosupr
• appears on face, lower lip, ears, hands
• prolonged UV exposure -> p53 mutations
• Bowen's Dz - slowly enlarging single red scaling plaque; only involves epidermis (SCC in situ)
• Cutaneous horn - extends far above thes kin surface
• Keratocanthoma - variant that grows rapidly (2-6 wks); dome shaped keratin filled nodule arising on sun exposed skin - may regress spont over mo
• histo - keratin pearls

Melanoma

• most common cancer in young adults btw 24-29
• 50% of melanoma occurs in pts under 50
• melanocyte origin - neuroectodrm
• assoc w/ sun - >5 sunburns inc risk by 80%
• driven by activating mutation in BRAF kinase (80%)
• risk of mets - depth; ABCDE's
• Lentigo maligna - melanoma in situ; slow; over 50yr
• superificial spreading - most common - classic ABCD
• Acral Lentiginous - palm/soles, nail beds, mucous - occurs in blacks/asians,, sunlight has NO role
• Nodular - rapidly growing; black blob look, E criteria, most common on backs of men and legs of women
• Histo - buckshot or pagetoid (large) cells
• prognosis - depth of invasion (breslow), ucleration, mitotic rate, # of lymph nodes (rather than size)
• Tx - excision, veurafenib (BRAF kinase inh)

Vemurafenib

• potent inh of mutated BRAF and has improved survival in V600E melanoma pts
• BRAF kinase is a protein kinase invovled in activaing the signaling pathway of melanocyte proliferation
• 50% of cases V600E mutation

Congenital Nevus

• large nevus (>20 cm) has 5-15% risk of becoming melanoma, often in 1st decade of life
• Ugly duckling sign - lesion stands out as different in size, color, pigment to rest of nevi; atypical/dysplastic nevi
• Dysplastic Nevi Syndrome - in familial setting lifetime risk is 100% by age 70; in acquired setting only 3-14%; prophylactic removal does NOT eliminate risk because it is a marker for risk not a precurser
• Halo nevi - melanocytic nevus surrounded by area of depigmentation; chldren/teenagers; may involve one or several moles and NO risk for malignancy

Toxic Epidermal Necrolysis

(TEN)

• >30% of body; SJS is < 10% and Erythema multiforme is even milder than SJS
• spearation of dermal-epidermal junction; full thckness necrosis - dusky red lesions -> gray hue
• initial sx - fever, stinging eyes, odynophagia precedes skin Sx by 1-3 days
• Skin Sx - first apear on trunk- erythematous, dusky red or prupuric macules (coalesce)
• Nikolsky + and Asboe-Hansen + (flaccid blisters; push down and blister spreads undr skin to other areas)
• erythema/erosion of buccal, ocular, genital mucosae (90%) - mucous membrane detachment
• fever, severe skin pain, anxiety, asthenia
• MOA - impaired capacity to detoxify reactive metabolites; activated CD8 T cells towars keratinocytes (fas w/ Fas L -> uncontrolled apoptosis)

Meningococcemia 

• n. meningitidis septicemia
• high assoc w/ DIC - petechiae correlates w/ degree of thrombocytopenia - indicator of potential for bleeding complications secondary to DIC
• Nonspecific to hemorhagic skin lesions - ocurs over several hours (rapid) - few macular, papular petechiae to extensive purpura, large necrotic patches - severe if DIC
• purpura fulminans - acute onset of cutaneous hemorrhage, necrosis due to vascular thormbosis and DIC 0 
• adenal hemorrhage - waterhouse-friderichsen syndrome

Nodular Fasciitis

• benign myofibroblastic proliferation
• rapidly growing solitary mass lesion (1-2wks); occurs often at site of previous trauma; half painful
• USP-6 gene mutation
• most common lesion misdiagnosed as sarcoma
• age - young adults; occurs mainly on upper extremitites and trunk

Fibromatosis

• benign myofibroblastic tissue prolif (desmoid tumor)
• abdominal/intra abd fibromatosis - more infiltrative and harde to get complete resection (poorly circ) - proliferating spindle cells in bundles - more agressive than superifical - high local recurrence and local infiltration of organs - APC mutation (inc B catenin) - F>>>M
• Extra-abd fibromatosis - benign, sperificial fibrous prol that is locally agressive - palmar is asoc w/ DM, epilepsy etc and slow growing nodule of hand that progresses to cord like band w/ contracture of 4th/5th digits

Fibrosarcoma

• malignant mesenchymal tumor
• Sx - solitary slow growing palpable mass, M>F
• solitary, lobulated, circ and encapsulated - may invade locally
• micro - spindle cells in storiform pattern (herring bone) w/ cytogenic atypia
• adult type - 30-55yrs - deep soft tissue of lower extremities; upper extremities, head and neck
• Infantile type - first 2 yrs, congenital; distal extremities; most have t(12;15) - ETV6-NTRK3
• IHC - vimentin + like most mesenchymal tumors
• half will recur; mets via bloodstream -> lung, bone

Benign Fibrous Histiocytoma

(dermatofibroma)

• Sx - solitary slow growing skin nodule
• age - 20-45yrs M=F
• most commonly occur on distal extremities
• small red-brown to blue nodule
• poorly circumscribed, non-encapsulated cellular proliferation of dermis - arranged in storiform pattern
• may contain foreign body (touton) giant cells; mitosis rare to absent
• IHC - CD10 and Factor XIII + (oppositve of DFSP)
• negative for CD34

Dermatofibrosarcoma protuberans (DFSP)

(intermediate)

• slow growing, non painful tumor; younger than dermatofibroma; M>F
• occurs on trunk, groin, proximal extremities (vs dermatofibroma)
• solitary mass of subcutin and skin; may ulcerate overlying skin w/ assoc hemorrhage, cystic change
• CD34+ and CD10 and Factor XIII neg
• fusion of COL1A1 and PDGF-B -> overexpression of PDGFβ and DFSP
• locally agressive and rarely metastasizes

Malignant Fibrous Histiocytoma

(MFH)

• undifferentiated high grade pleomorphic sarcoma
• painless, enlarging mass if on extremity
• retroperitoneal tumors - obstruction, anorexia
• fever, leukocytosis
• 50-70yrs; M>F
• occurs on lower extremitites (thigh), followed by upper and retroperitoneum
• high grade pleomorphic fibroblasts w/ non specific cytogenetic abnormalities
• Mets to Lung - usually w/i 12-24 mo of Dx

Rhabdomyosarcoma

• most common soft tissue sarcoma of children <15
• Embryonal rhabdo - botryoid, cambium layer; protrudes into mucous membranes
• Alveolar rhabdo - pattern resembles lung tissue; more common in extremities and has worse prognosis
• Males > Females
• micro - cross striations; atypia
• IHC - desmin and actin +
• alveolar has t(2,13) -> PAX3-FKHR gene (encodes Transcription factor)
• mets in 20% -> lung, bone, lymph nodes
• poor prognosis: alveolar> classic > botryoid embryonal

Limited Scleroderma

• limited to skin of fingers, face, benign clinical cours
• anti-centromere antibdoy
• CREST - Calcinosis, Raynaud phenomonon, esophageal dysmotility, sclerodactylyl, telangiectasia

Thanotophoric Dysplasia

• defect in FGFR3
• type 1 - curved femur (telephone receiver), flattened bones of spine (platyspondylyl), and shotened thoracic ribs
• Type 2 - cloverleaf skull (kleeblattschadel)

Osteogenesis imperfecta

• autosomal dominant - dec production of type I collagen: major component of osteoid; also skin, joints, and eyes
• defect in glycosylation of pro-a chain hydroxylysine residues (no procollagen)
• caused by variety of gene defects - 4 types - Type II is autosomal recessive and lethal in utero
• Sx - brittle bone dz, multiple fractures w/ minimal trauma, 
• blue sclera (translucency of CT over choroidal veins, hearing loss - 
• abnormal associles, 
• dental imperfections (lack of dentin),
•  severe skeletal deformity, limb shortening due to multiple fractures

HLA-B27

• histocompatibility antigens - proteins present on all nucleated cells
• codes for HLA MCH class I
• assoc w/ seronegative spondyloarthropathies - ankylosing spondylitis, psoriatic arthritis, reactive arthritis (Reiter), IBD

Synovial Fluid

• normal - clear color, good viscosity, 200 WBC/MM, <25% PMN
• non-inflam - osteoarthritis, trauma, SLE - clear to xanthochromic color, good viscosity, 200-2000 wBC/MM and <25% PMN
• Inflammatory - RA, crystal arthritis, spondyloarthritis, viral, sarcoid, sLE - xanthochromic to cloudly color, poor viscosity, 2k - 50k WBC/MM and >50% PMN
• Septic - bacterial, crystals - opaque color and poor viscosity, >50k WBC/MM and >75% PMN
• Hemorrhagic -trauma, fracture, tumor

Hyperuricemia

• underexcretion of uric acid (90%) - chronic renal disease and also obesity, idiopathic, thiazide diuretics, cyclosporine, tacrolimus, low does sallicylates, ethanol, levodopa
• Overproduction of uric acid (10%) - lesch nyhan syndrome (dec in HGPRT), PRPP excess, G6P deficiency

Acute Gout

• MSU crystal precipitation in and around joints - hyperuricemia is >6.8
• leads to inflammation - C3a and C5a activated by MSU crystal surfaces which lead to activation of neutrophils and macrophages (inflamasome) -> IL-1 release which acts on intravasc neutrhophils and vasc endothelium
• Sx - asymmetric joint distribution, swollen and red
• Podagra - painful MTP joint of big toe (90% of time)
• Dx - synovial fluid - MSU crystals w/ negative bifringence - yellow under parallel light, blue under perpendicular; negative culture w/ neutrophils

Chronic Gout

• persistent pain, but less intense; can mimic RA
• Tophus formation - aggregates of urate crysals surrounded by inflam - external ear, olecranon bursa, achilles tendon, etc
• Xray - bone erosions that are slightly removed from joint; atrophic and hypertrophic w/ overhanging edges
• joint space preserved until late in disease

Calcium Pyrophosphate Dehydrate Crystal Deposition Disease (CPPD)

• deposition of calcium pyrophosphate crystals in joint space
• chondrocalcinosis - calcium crystals in cartilage, synovial lining, ligaments, tendons, soft tissues
• Mostly occurs in knees - paina nd effusion of joint; acute inflammatory attacks; takes longer to reach peak intensity and lasts 3-120 days compared to gout
• lanthanic - asymptomatic cartilage deposition
• assoc w/ metabolic dz - hemochromatosis, hyperparathyroidism, hypothyroidism
• Dx - basophilic, rhomboid crystals - weakly birefringent (+) - crystals blue when parallel to light
• Xray - ligamental calcifications
• Tx - nsaids, aspiration and injection of corticosteroids

Paget's Disease

(osteitis deformans)

• localized disorder of bone remodeling - inc osteoclastic and osteoblastic activity
• possible paramyxovirus infection that might inc RANK activity
• 3 phases - replaces normal bone w/ reparative mosaic pattern of woven bone - osteolytic, mixed, osteoblastic phaes
• Sx - skull enlargment (inc hat size); can become scalloped like seashell, headache, hearing loss (auditory foramen narrowing), CN impairment, long bone chalk stick fractures
• high output cardiac failure - inc blood flow from AV shunts in new vasogenic bone
• inc risk of osteogenic sarcoma
• Labs - isolated inc ALP

Hematogenous Bone Infection

(osteomyelitis)

• most common in children (open growth plates) - often occurs in metaphysis of long bone
• bone is seeded through circulation form transient/persistent bacteremia - usually s aures
• bacterial seeding -> focal bone marrow cellulitis, which compromises blood flow (necrosis) from inflamation w/i confided space
• infection is forced through vascular channesl into cortex and spreads along periosteum
• Sequestrum - necrotic bone, reservoid for infection
• Involucrum - poorly constructed bone covering sequestrum

Giant Cell Tumor of Bone

• locally agressive benign tumor of osteoclast like multinucleated giant cells
• 20-40yrs; F>M
• usually occurs around knee; usually present w. pain
• location at long bone epiphysis
• behavior unpredictable and cannot based on histology
• Xray - soap bubble appearance

Osteochondroma

• most common benign tumor; males < 25yrs
• aberrant epiphyseal development due to dysplaced cartilage
• located at long bone metaphsyis (exophytic growth): knee>femur>humerus
• mature bone w/ cartilaginous cap covers end w/ bony continuity w/ underlying cortex - cap undergoes endochondral ossification
• Rarely transforms into chondrosarcoma

Osteoid Osteoma

• benign bone tumor < 2 cm in greatest dimension
• common in 10-20yr
• common in metaphysis of femur, tibia
• classic question - severe pain(nocturnal) relieved by NSAIDs/Aspirin (vs osteoblastoma)
• Xray - target lesion
• Treated by surgery but can recur

Osteoblastoma

• benign bone tumor common in 10-20yr olds
• more common in vertebrae
• dull, achy pain - NOT relieved by aspirin (vs osteoid osteoma) 
• treat by conservative surgery

Enchondroma

• majority are asymptomatic
• M=F; all ages
• Samll bones of hands > femur > humerus
• medullary locaiton
• therapy - curettage, bone graft

Osteosarcoma

• 2nd most common primar malignant bone tumor (after multiple myeloma)
• malignant cells making osteoid; occurs at metaphysis of long bones, arond knee
• Bimodal distribution - primary (10-20yr) and secondary (>65) from pagets disease
• Sx - pain, swelling of area, loss of motion, tender lump, malaise, fatigue
• Xray - codman triangle (elevation of periosteum) and sunburst pattern
• Tx - neoadjuvant; surgical en bloc resection w/ limb salvage

Ewing's Sarcoma

• peripheral neuroectodermal tumor (PNET)
• boys < 15 yrs old
• occurs in diaphysis of long bones, pelvis, scapula, ribs
• anaplastic small blue cell malignant tumor
• Xray- onion skin appearance
• Assoc w/ t(11;22)

Chondrosarcoma

• malignant cartilaginous tumor
• men 30-60yrs old
• occurs in diaphysis of pelvis, spin, scapula, humerus, tibia, femur
• may have developed from osteochondroma
• expansile glistening mass w/i medullary cavity
• Sx - back, thigh pain, sciatica, bladder Sx, unilateral edema

Fibrous Dysplasia

• benign tumor-like lesion of bone char by localized developmental arrest
• all components present but they do NOT differentiate into mature structures
• 3 clinical patterns - involve single bone (monostotic), involve multiple but not all bones (polystotic), polystotic disease assoc w/ cafe au lait spots and endocrine abnormalities such as precocious puberty
• Monostotic (70% cases) - usally asymptomtic and in early adolescence but can cause marked bone enlargement and distortion - ground glass on xray - stop growing at time of growth plate closure

Ankylosing Spondylitis

• chronic inflammatory disease of spine and sacroiliac joints - ankylosis (stiff spine from fusion) leads to bambo spine on xray
• Sx - back pain (before 40 and >3mo), sacroiliitis, limited lumbar motion and reduced chest expansion, uveitis, aortic regurgitaiton, other
• Dx - bilateral grade 2 to 4 sacroiliitis on xray or unilateral grade 3 to 4
• Tx - NSAIDs, disease modifying drugs, biologicals, physical therapy (improves back pain)

Reactive (Reiter's) Arthritis

• triad - conjunctivitis, urethritis, arthritis (seronegative asymm)
• cant see, cant pee, cant climb a tree
• preceding GI infection - shigella, salmonella, yersinia, campylobacter - infectious diarrhea
• Preceding Chlamydia infection - urethritis, cervicitis
• other assoc- inflam eye disease, balantis, oral ulcer, keratodermia, sacroilitis)

Psoriatic Arthritis

• asym , inflammatory arthirtis in DIP 
• Dactylititis - sausage fingers 
• Nail pitting or onycholysis
• seronegative (RF test neg)
• Xray - pencil in cup deformity at DIP
• patterns of arthritis - spondylitis, DIP arthritis, oligoarticular asym, polyarticular sym, arthirtis mutilans

Buchet's Syndrome

• recurrent oral ulcers w/ (2): recurrent genital ulcerations, eye lesions (uveitis), skin lesions (cutaneous vasculitits), positive pathergy test
• joint involvment in 50% of patients - arthralgia, migatory, monoarticular or oligoarticular non deforming arthritis

Osteoarthritis

• progessive loss of articular cartilage hallmark
• 2x risk in women and 2x risk in blacks
• soft tissue changes leads to chronic patchy synovitis and thickening of joint capsule which further restricts motion
• joint findings - subchondral cysts, sclerosis, osteophytes, nodes at DIP and PIP, Base of thumb (1st CMC) ulcerated cartilage and joint space narrowing
• pain occurs after activity, improves w/ rest
• AM stiffness < 30 mins (shorter than RA)
• crepitus - cracking, popping, gritting w/ motion
• synovial fluid is non-inflam - clear, yellow, 200-2kWBC; <25% PMNs
• Tx - exercise and weight loss first line

Fibromyalgia

• diffuse pain, aching, stiffness, fatigue 
• most common in females 20-50
• multiple tender pionts on physical; pain is all over for >3mo and assoc w/ poor sleep and fatigue
• allodynia - inc sensitizaiton to pain
• primarily a neural dz w/ central factors - polygenic, deficiency of noradrenergic-serotonin, excess substance P,
• lack of sleep amplifies pain
• use WPI/Widespread Pain Index
• Tx - exercise, antidepressants, gabapentin/pregabalin, tramadol, dopamine, betablockers

Celecoxib

• reversibly inhibits COX-2 only 
• inhibits inflammation and pain
• Clinical use- RA, osteoarthritis; patients w/ GI ulcers
• Spares COX 1 so maintains GI mucosa; also spares TXA2 production
• ADv effects - inc risk of thrombosis (inc TXA2)

Disease-Modifying Antirheumatic Drugs

(DMARDs)

• gold standard for Rheumatoid arthritis
• Methotrexate - adv effects of hepatitis, oral ulcers, cytopenia, teratogen (in males also)
• Hydroxychloroquine - antimalarial used for RA - interferes w/ Ag presentaiton, promotes lysosomal membrane stabilization and inh DNA metabolism - used in combo
• Sulfasalazine - sulfapyridine linked to 5-ASA absorbed in small intestines and cleaved by colonic bateria -> inh neurtophil func, reduces Ig lvls, interferes w/ T cells - Adv of GI iritation, hematologic, azoospermia
• Leflunomide - ihibits rate limiting enzyme in pyrimidine synthesis, prevents action of lymphocytes - monotherapy or in combo w/ MTX

Anti-TNF Agents

• Infliximab - antiTNFa Ab - induces complement response against cells that express TNFa - used in IBD, RA, ankylosing spondylitis, psoriasis
• Adalimumab, golimumab - IgG1 monoclonal Ab against TNFa - for pts not on MTX - use RA, psoriatic arthritis, ankylosing spondylitis
• Etanercept - decoy TNFa receptor - binds serum TNFa and TNFb
• Certolizumab pego - Fab against TNFa -couped to PEG
• Adverse effects - infection (resurgent TB), infusion reactions (infliximab), malignancies, DNA autoAb (SLE), CNS demyelination, CHF

Other Biologic DMARDs

(not anti-TNFa)

• Anakinra - IL-1 inhibitor - effectivein combo w/ MTX
• Abatacept - inhibits T cell activation - prevents co-stimulatory signal required for T cella ctivation
• Retuximab - anti-CD20 monoclonal Ab - CD20 found on B cells - used in NHL, RA - adv effects inc risk of PML
• Tocilizumab - IL-6 inh - adv reaction lipid derangements
• Tofacitinib - JAK inhibitor - for pts who intolerate MTX - adv effects - infection (TB or opportnistic)

Dermatomyositis

• similar to plymyositis (proximal muslce weakness)
• Malar rash, 
• gottron papules -scaly, erythematous papules on extensor surface of hand
• Heliotrope rash - erythematous rash of upper eyelid, often w/ edema
• Facial rash - includes nasolabial fold
• photosensitive rash - shawl sign
• biopsy -interface dermaittis by Immunofluorescence
• pathogenesis - hemoral mediated perimysial inflammation and atrophy involving CD4 T cells - myofiber necrosis, degeneration, regenration
• deposition of MAC complex on endothelial cells leading to capillary destruction and local ischemia
• Myxovirus-resistance protein A expressed on perifascicular fibers

Myositis (PM/DM)

• insidious onset of symmetric proximal muslce weakness - lower extremity before upper
• lungs most common extramuscler target organ - interstitial lung disease
• cardiac (arrythmias and effusions) and GI also involved
• Anti-synthetase syndorme (Anti-Jo-1) more common in PM than DM - raynauds phenomen and mechanics hand, arthirtis, interstitial lung dz in 50%
• Biopsy is gold standard for confirming; use EMG too
• myositis specifc Ab - anti Jo-1 (histidyl tRNA syn), anti Mi-2 (helicase), anti-SRP (severe disease)

Pathology of Scleroderma

• pathogenesis - Polarized TH2 response -> IL4, IL3, TGF-B (fbrosis) - leads to inappropriate fibroblast activation
• obliterative vasculopathy of arterioles; bland intimal proliferation - defective angiogenesis w/ VEGF overexpression, anti-endothelial Ab, inc ET-1 (vasoconstrictor, fibrogenic), dec NO and PGI2 (vasodilator)
• raynauds phenomenon - cold induced digital vasospasm - inc a2 rec sensitivity
• interstitial fibrosis of visceral organs - inc collagen deposition of reticular demris - puffy and taut skin w/ absence of wrinkles
• obliteration of hair follicles, sweat glands
• skin and soft tissue signs - edematous phase and fibrotic phase - tendon friciton rubs, calcinosis cutis, telangiectasias, digital piting infarcts, perioral skin tightening

Diffuse scleroderma

• widespread skin involvement, rapid progression
• Anti-Scl-70 antibody - distal and proximal skin change, torso - rapid progression 1-5 yrs
• early visceral involvement
• Pulmonary - most common COD - interstitial lung disease (NSI>>UIP) - 5x inc in lung Ca risk
• renal - scleroderma renal crisis - flash pulm edema, high freq RNA polymerase II Ab - abrumpt onset HTN
• CV - myocardial fibrosis, arrythmia, contraction band necrosis, pericardial effusion (poor prognosis), diastolic dysfunction>>> systolic dysfunction
• GI - esophageal hypomotility lower 2/3 (GERD, stricture), hypomotile small intestine, smooth muscle atrophy (circ > longitudinal)
• colon - wide mouth diverticulae
• musculoskelatal and neurologic

Anti-Th/To

• type of scleroderma
• limitied cutaneous disease, nucleolar Ab by ANA
• most predominant in caucasians, shorter duration of raynauds
• more frequent small bowel involvement
• both pulmonary fibrosis and PAH

Bisphosphonates

• alendronate, other -dronates
• pyrophosphate analog - binds to hydroxyapatitie in bone -> inhibits osteoclasts
• adv effects - GI distress, bone pain, atypical fractures, corrosive esophagitis, osteonecrosis of jaw (seen in high dose IV)
• reduces hip fracture in high risk pts (T < -2.5) but no effect among low risk pts
• two IV agents dec GERD risk?

Denosumab=Prolia

• RANKL inhibitor
• inhibits osteoclasts, suppresses bone turnover
• may inc very rare osteonecrosis of jaw
• can be used in Chronic Kidney Disease with a GFR <30 (unlike bisphosphonates)
• slight inc infection risk assoc

Most Sensitive SLE Criteria

• ANA (+) - other autoantibodies should also be present
• MCP/wrist tenderness, synovitis
• rashes - malar, others
• lymphopenia < 1,000, fever when viral infection excluded
• new photosensitivity rahses

SLE Flaire

• inc anti-dsDNA
• decreased C3/C4
• worsening proteinuria, creatinine
• new serositis
• new rashes, polyarthirtis

Cutaneous lupus

• NOT the same as SLE
• skin biopsy can NOT distinguish btw SLE and cutaneous lupus - dermal-epidermal junction immune complex deposition
• rashes, photosensitivity, oral ulcers
• positive labs for ANA, SS-A, SS-B

SLE Treatment

• Mild SLE: Cutaneous manifestations - sun avoidance, steroid creams, hydroxychloroquine
• Mild SLE: Joint swelling - NSAIDs, hydroxychloroquine, steroids, methotrexate
• Severe SLE: flare nephritis, CNS cerebritis, vasculitis - cyclophosphamide, steroids (IV high dose)
• Severe SLE: organ involvement - mycophenolate, azathiorine

Colchicine

• antimitotic - interferes w/ microtuble/spindle formaiton - inh leukocyte activation/migration
• dec crystal induced secretion of chemotactic factors and inh mast cell release of histamine
• about 2/3 of pts respond if given in first 24-48hrs
• lowest benefit to toxicity ratio
• Adv effects - GI irritaiton (nausea, vomiting, diarrhea in 50-80%), neutropenia, neuromyopathy (worse w/ statins
• caution w/ renal insufficiency
• drug interacitnos - pglycoprotein or CYP3A4 inh increase risk of adverse events

Xanthine Oxidase Inhibitors

• Allopurinol, febuxostat
• effective in both underexcreters and overproducers
• Allopurinal can cause sever rash (TEN), hepatitis, interstitial nephritis, eosinophila
• Allopurinol hypersensitivity syndrome - inc chance w/ renal insufficiency, HLA-B*5801 - seen mainly in asians
• Febuxostat can cause nausea, arthralgia and minor inc in ALT/AST - monitor LFTs periodically
• xanthine oxidase essential in metabolism of 6-MP andi ts prodrug azathioprine so do NOT give allopurinol w/ these drugs

Rheumatoid Nodules

• occur in 20-25%
• pressure areas - elbows, occiput, sacrum
• tenodns - fingers, achilles
• internal organs - lung, heart, eye, etc
• histology - central fibrinoid (non-caseating) necrosis
• palisade of radially arrange fibroblasts
• outer layer of granulation tissue w/ lymphocytes, plasma and giant cells

Giant Cell Arteritis 

(GCA)

• involves large and medium sized vessels preodminantly of the branches most commonly the external carotid artery
• clinical - plymyalgia rheumatic, headaches, fever, weight loss, visual sx
• average age 70 (unusual under 50)
• early recognition - elderly pt w/ new onset headaches, jaw claudication, cough, occipital
• temporal artery biopsy of symptomatic side - SKIP lesions, mononuc cell infiltrate w/ giant cells, internal elastic lamina damage
• complications - vision loss, cerebral vasc accident, aortic dissection (high mortality rate)
• Tx - begin prednisone as soon as suspected, even before biopsy is obtained

Polymyalgia Rheumatica

• related to Giant cell arteritis
• stiffness in the shoulder and pelvic girdle of pts >50
• morning stiffness can be severe
• minimal objective swelling
• elevated inflammation tests such as ESR
• marked improvement w/ low dose 

Takayasu's Arteritis

• inflammation of large and medium vessels; predominantly the aortic arch
• arm claudicaiton, heart failure, absent pulses, syncope, generally young women
• Dx - usually made by angiogram due to difficulty obtaining tissue form the aortic arch
• Tx - steroid and methotrexate

Kawasaki

(medium vessel vasculitis)

• 2nd most common vasculitis in children
• infants and children; high fever > 5 days
• 4/5criteria: cervical adenopathy, polymorphous exanthema, palmar erythema, bilateral conjunctiva injection, oral mucous membrane change-fissured lips, injected pharynx, strawberry tounge
• if less than 4/5 criteria but has coronary artery aneurysm then still kawasaki
• incomplete kawasaki - more likely in children over 5 - labs elevated ESR/CRP, elevated WBC, anemia, platelets >45k, pyuria, elevated AST and dec albumin
• Tx - IVIG and aspirin - combo way better than either alone (best prevention of coronary aneurysm)

Polyarteritis Nodosa

• necrotizing vasculitits of the medium sized arteries and minimal small vessel
• M>F; 
• renal and visceral arteries most common w/o pulmonary involvement
• no glomerulonephritis
• assoc w/ hepB
• Dx - biopsy or angiogram of abdominal artery
• mononuclear cells/PMNs infiltrate and fibrinoid necrosis - string and pearls
• ANCA negative
• Tx - steroids, cyclophosphamide

Granulomatosis w/ Polyangitis

(wegners or GPA)

• calssic AB mediated pathogenesis - generalized focal necrotizing vasculitis involving both arteries and veins
• Triad - upper respiratory tract necrotizing granulomas, lower respiratory tract granulomas, renal-focal necrotizing glomerulonephritis
• can get chronic sinusitis, saddle nose deformity
• ocular - proptosis, scleritits, uveitis, retinal and optic nerve vasculitits
• lower resp - cough, dyspnea, multiple nodules (+/- cavitation), diffuse alveolar infiltrate, hemoptysis w/ anemia
• Histo - usually biopsy best obtained from lung or sural nerve - giant cells, palisaded histiocytes around areas of necrosis
• Tx - steroids, cyclophosphamide, rituximab (CD20 Ab)

Microscopic Polyangiitis

• microscopic polyangiitis primarily renal disease but may have pulmonary hemorrhage from capillaritis
• no granulomas as in GPA
• C-ANCA positive
• both GPA and microscopic polyangitis are called pauci immune because there are few immune depositis seen on biopsy

Churgg-Strauss

• also called allergic granulomatosis w/ polyangiitis
• features similar to GPA except high assoc w/ pulmonary involvement
• more peripheral neuropathy and less renal involvement
• eosinophilic infiltrate on biopsy
• assoc w/ severe asthma
• peripheral eosinophilia and high IgE
• p-ANCA in 40% (remainder ANCA neg)
• Tx - steroids and cytoxan

Hypocomplementemic Urticarial Vasculitis

• type of Hypersensitivity small vessel vasculitits 
• urticarial lesions some which may not blanch
• hypocomplementemia
• usually cutaneous w/o other organs
• screen for other udnerlying connective tissue disease
• Tx - colchicine +/- steroids, antihistamines, H2 blockers