IgM > IgG / complement / ADCC / organ-specific (Goodpasture’s, pemphigus) / receptor-specific (Grave’s, Myasthenia gravis) / hemolytic anemia / Derm: pemphigus, bullous pemphigus, herpes gestationis, epidermolysis bullosa

Treatment: immunosuppression, plasmapheresis

Type III immune-complex (derm)

leukoclastic vasculitis (PAN) / fibrinoid necrosis / polyarthritis, skin, serum sickness, arthus reaction

Treatment: anti-inflammatory agents, immunosuppression

Type IV delayed-type hypersensitivity

Th-1 - contact dermatitis, Tb, sarcoidosis, Wegener’s, IBD

Treatment: corticosteroids, cytotoxic agents, antimicrobials

GVHD

Affects: skin, liver, GI tract, eye, kidney (reports)

Occurs following transplantation (e.g. BMT) / patients at high-risk for fungal infections for several weeks/months after engraftment (current debate over when and what to use for prophylaxis 1/07) / immunosuppressive agents used to prevent GVHD can look like EM [pic] [dermis]

Immunodeficiencies

Systemic Diseases Causing Defects of:

T-cells: HIV, sarcoidosis, steroids

B-cells: asplenia, SLE, CLL, steroids

Some genetic Immunodeficiencies may present in adulthood: CVID, CMC, more.

Defects of mainly T Cells

DiGeorge

no thymus (no T-cells), no parathyroids / failure of 3rd (upper parathyroids), 4th pharyngeal (lower parathyroids) pouches / presents with tetany owing to hypocalcemia

Chronic Mucocutaneous Candidiasis (CMC)

T-cells do not respond to Candida albicans

Defects of mainly B Cells

IgA deficiency

1 in 500 (most common immunodeficiency) / B-cells have it, but can’t secrete it / risk factor for celiac sprue

Presentation: recurrent sinusitis, GI infection (giardia), otitis media

Note: do NOT give IVIG due to presence of anti-IgA antibodies (44%)

Common variable immunodeficiency (CVID)

Most common primary immune deficiency requiring medical attention / 1 in 50,000

sporadic / 10% familial / 15-35 yrs

Mechanism: hypo-IgG from various defects (CD27+ memory B-cells cannot differentiate into plasma cells) / suspected genes involved (BAFF, APRIL, TACI, ICOS)

Presentation: pyogenic infections (e.g. respiratory), chronic diarrhea (e.g. giardia), and increased incidence of autoimmune diseases (sprue-like syndrome, gastric atrophy, bronchiectasis, pernicious anemia) / associated T-cell abnormalities (10%)

Diagnosis: can test for response to Ag (e.g. tetanus, pneumovax)

Related syndromes: hyper IgM type 3 (CD40), autoimmune lymphoproliferative disorder (ALPS), TNF-receptor associated periodic fever syndrome (TRAPS)

Treatment: IVIG q 2-3 wks / do NOT give live vaccines

Bruton’s X-linked agammaglobulinemia

XLR / no functional B-cells (cannot get EBV infection) / low Ig / recurrent bacterial infections beginning at age 6 months / low IG predisposes to chronic aseptic meningitis (with secondary dermatomyositis)

Duncan’s Syndrome (X-linked Lymphoproliferative Disease)

XLR / impaired response to EBV nuclear antigen (2/3 mortality ) / survivors develop hypogammaglobulinemia and/or B-cell lymphomas / decreased NK function and ADCC against EBV-infected cells

Defects of B and T Cells

Wiskott-Aldrich

XLR / mutation of WASP gene / B and T-cells regress / cannot mount IgM response to capsular polysaccharides

elevated IgA, normal IgE, low IgM / recurrent pyogenic infections, eczema, thrombocytopenia / increased incidence of lymphoreticular neoplasm

Ataxia-Telangiectasia

B and T-cell deficiency, with associated IgA deficiency / presents with ataxia, spider angiomas / recurrent infections / can get lymphomas / secondary diabetes mellitus?

Severe Combined Immunodeficiency Syndrome (SCIDS)

no functional B and T cells / defective IL-2 receptors, MHC II, or ADA (½ of autosomal

forms)

Adenosine deaminase deficiency (ADA)

excess ATP and dATP provides negative feedback on ribonucleotide reductase, prevents DNA synthesis, lowers lymphocyte count / can produce SCID

Defects of Phagocytes [NEJM]

Guideline: these are rare but important diseases, and can be diagnosed by examination of peripheral phagocytes and a few special stains / must catch these early and consider IFN-gamma, g-CSF, broad antibiotics

Cyclic Neutropenia

Autosomal dominant / ?mutation in neutrophil elastase (ELA2)

recurrent neutropenia ( < 200 cells/mL) lasts 3-6 days / cycle usually ~21 days, but in 30% of patients, ranges from 14-42 in 30%

During neutropenia: fever, apthous stomatitis, gingivitis, stomatitis, cellulitis, cervical LAD

Severe congenital neutropenia

Autosomal recessive in 90% (unknown mutation) / heterozygous in 10% /

Presents during first year of life / cellulitis, perirectal abscess, peritonitis, stomatitis, meningitis (Staph, Burkholderia) / increased risk for myelodysplasia, AML

Labs: < 500 neutrophils, but increased circulating monocytes, eosinophils

Treatments: nearly all improve with exogenous g-CSF

Schwachman-Diamond Syndrome

Autosomal recessive (rare) / Presents within first yr of life / average life expectancy 35 yrs

Exocrine pancreatic insufficiency, skeletal abnormalities, bone marrow dysfunction, recurrent infection / all have neutropenia (cyclic or intermittent), and 10-25% also have pancytopenia / increased risk of marrow aplasia, myelodysplasia, AML

Treatments: exogenous g-CSF (not considered a risk factor for malignant transformation)

CD18 (leukocyte adhesion deficiency type 1)

Autosomal recessive loss of B2 integrin adhesion molecules (from lack of CD18 or B-chain) / neutrophils cannot aggregate or bind endothelial cells / life expectancy is < 10 up to 40 yrs (depends on amount of CD18)

Delayed separation of umbilical cord, severe periodontitis (early tooth decay), recurrent infections of all mucosal surfaces, AND delayed wound healing (enlarging borders, dysplastic scars)

Leukocyte adhesion deficiency type 2

Growth retardation, dysmorphic features, neurological deficits / lack of sialyl-Lewis^x (ligand for selectins) / Treatment with oral fructose has proven helpful

Job’s syndrome

neutrophils fail to respond to chemotactic stimuli (C3a, 5a, LT-B4) / recurrent cold staph abscesses / dental problems / elevated IgE levels / ?Rac2 (predominant GTPase in neutrophils)

Defective INF-gamma/IL-12 Axis

Autosomal recessive and autosomal dominant forms / complete loss of ligand-binding chain causes disseminated NTM in infancy or fatal BCG vaccination / partial loss is less severe (NTM develops in early childhood) / defect of IFN-gamma receptor signaling chain resembles complete loss of ligand-binding chain / defect in IL-12 receptor (B1 chain) and IL-12 increases susceptibility to NTM and Salmonella infections

Treatment: all respond to exogenous INF-gamma except (complete loss of ligand and receptor signaling)

Chronic Granulomatous Disease

XLR (gp91^phox) make up 70% / presents within first 2 yrs / neutrophils lack hydrogen peroxide burst (myeloperoxidase system) /

Autosomal recessive (P47^phox) make up 30% / onset may be later

Organisms: S. aureus, Burkholderia cepacia, aspergillus, nocardia, serratia, proteus, E. coli

Obstructive granulomas of GI/GU tracts, pneumonia, skin infections, osteomyelitis, liver abscesses, draining adenopathy (at BCG injection site, but mycobacterial disease still rare)

Diagnosis: can be delayed by blunted fever, inflammatory symptoms / severe resistant facial acne and painful inflammation of nares, gingivitis, apthous ulcers, NOT periodontal disease

Nitroblue tetrazolium test or flow cytometry with dihydrorhodamine dye

Treatment: bactrim (one/day) may reduce serious infections from 1/yr to 1 every 4 yrs / IFN gamma reduces bacterial and fungal infections by 70% / stem-cell transplantation and gene therapy protocols under investigation

Myeloperoxidase deficiency

50% have complete loss / no chlorine formation in azurophilic (primary) granules / usually asymptomatic except in diabetics who have increased risk of disseminated candidiasis

Chediak-Higashi

Autosomal recessive mutation in LYST (microtubule and lysosomal defects)

Recurrent staph and strep, partial albinism, mental retardation, platelet dysfunction, severe periodontal disease, and in those patients surviving into 20s, striking peripheral nerve defects (nystagmus, neuropathy)

Labs: mild neutropenia and normal IG levels

Course: 85% have fatal infiltration of CD8+ and macrophages with eventual pancytopenia

Neutrophil-Specific Granule Deficiency

S. aureus, S. epidermidis, enteric bacteria (skin/lungs) / abnormal migration and atypical nuclear morphology / lack of primary granule defensins, lack of eosinophil-specific granules

Felty’s Syndrome (see rheumatology)

neutropenia, splenomegaly, from long standing RA

Complement deficiencies [labs]

most are recessive, all occur at similar rates (except C2 may be more common, 1% prevalence) / C3 (severe disease) / C5-8 à GC meningitis, arthritis

Biology of Complement [activation cascade]

Functions: lysis, opsonization, anaphylatoxins (degranulation), chemotaxis

Classical: Ag:Ab complex, C1, C4, C2

attachment, activation, amplification, attack

Alternative: microbe + P, D, B, C3b

Lectin (new): MBP opsonizes foreign carbohydrates

C3a, C5a also anaphylatoxins

C5a is also a chemotactic factor

Deficiency syndromes

Clq, C1r, C1s, C4, C2	SLE, some get infections
C3	Repeated infections, partial lipodystrophy, SLE / C3 or C4 nephritic factor stabilizes convertase of alternate or classical pathway
C5-C8	Neisseria infections, arthritis
D and properdin (XLR)	Recurrent meningococcal meningitis
C1 inhibitor (AD)	Hereditary angioedema / may occur in SLE, lymphoproliferative disorders, paraproteinemias
MBP (3^rd pathway)	Infections in SLE
DAF and CD59	Paroxysmal nocturnal hemoglobinuria
Factors H and I	Pyogenic infections, urticaria, glomerulonephritis, secondary C3 deficiency

Complement Studies

Normal C3 / Normal C4

Normal C3 / Decreased ↓C4

Alterations in vitro (improper specimen handling)

Coagulation-associated complement consumption

Inborn errors (other than C4 or C3)

Immune complex disease

Hypergammaglobulinemic states

Cryoglobulinemia

Hereditary angioedema

Inborn C4 deficiency

Decreased ↓C3 / Normal C4

Decreased ↓C3 / Decreased ↓C4

Acute glomerulonephritis

MPGN

Immune complex disease

Active SLE

Inborn C3 deficiency

Active SLE

Serum sickness

Chronic active hepatitis

Subacute bacterial endocarditis

Immune complex disease

C1 inhibitor (acquired or AD)

hereditary angioedema / may occur in SLE, lymphoproliferative disorders, paraproteinemias

recurrent GI attacks of colic are common / no pruritis or urticarial lesions

Allergy

Anaphylaxis

Most common à B-lactams / ⅓ of cases are idiopathic

5-60 minutes following exposure, but delayed reaction is possible

Angioedema with or without urticaria (not true anaphylaxis without life threatening hypotension or laryngeal edema)

Presentation: pruritis, flushing, urticaria, angioedema, diaphoresis, sneezing, rhinorrhea, congestion, hoarseness, stridor, laryngeal edema, dyspnea, tachypnea, wheezing, bronchorrhea, cyanosis, tachycardia, bradycardia, hypotension, cardiac arrest, arrhythmias, nausea, vomiting, diarrhea, abdominal cramping, dizziness, weakness, syncope, sense of impending doom, seizures

Treatment:

· Epinephrine, IM (anterolateral thigh is fastest absorbed)

· Recumbent position, elevate legs, oxygen

· Volume replacement, pressors as needed

· Benadryl 50 mg PO or IV every 4 hrs

Ddx: EM minor (urticarial or bullous lesions), SJS, TEN [these syndromes cause fever, headache, malaise, arthralgia, corneal ulcerations, arrhythmia, pericarditis, electrolyte abnormalities, seizures, coma, sepsis]

Dilantin hypersensitivity: very common, ranges from minor to life-threatening, mechanism unclear

Iodine allergy: not true allergic reaction; hyperosmolar dye causes degranulation of mast cells/basophils

Pretreatment protocol: 40 mg prednisone 24 hrs before then 12 hrs, etc… / H2 blockers (ranitidine), benadryl / avoid contrast dye with renal insufficiency and sickle cell disease / normal maximum dye load would be 2 CT scans within a 24 hour period (assuming normal renal function)

Drug Fever or Drug Rash

maculopapular rash, resolve after removal of agent

Timecourse: most occur several days after starting treatment, but can happen weeks after initiation of offending agent

Labs: elevated eosinophils, CRP, LFT’s (e.g. one study found increased LFT’s in 20% of cases of maculopapular rash)

Note: if you see it on the outside, the same thing can be happening on the inside (such as the liver, etc)

Serum Sickness

7-10 days after primary exposure, 2-4 days after secondary exposure

Findings: fever, polyarthralgia, urticaria, lymphadenopathy, glomerulonephritis

Treatment: removal of agent, antihistamines, NSAIDs

Atopy

asthma, eczema, and seasonal rhinitis and conjunctivitis

allergic rhinitis: varies with season, treated with antihistamines/topical nasal steroids, itchy

vasomotor rhinitis: perennial (no seasonal variation), not itchy

Food allergies

Most common à peanuts (soy beans, shellfish, eggs, milk, nuts) / incidence believe about 1 % / breastfeeding may reduce chance of developing in those predisposed / skin testing (radioallergosorbent tests or RAST ) not as good as a simple food diary / reactions usu. in GI and skin but can cause anaphylaxis/respiratory / best treatment is avoidance

Dust mite

common allergen / grow better in warm, humid environment (so humidifier actually makes worse) / can do skin testing for diagnosis of allergy

Insect allergies (e.g. hymenoptera)

range from local reactions to anaphylaxis / honeybee (Apis family) is not cross-reactive with Vespid family (e.g. wasps, hornets, yellow jackets) / venom immunotherapy is indicated with history and/or positive skin testing

Latex allergy

ranges from mild to anaphylaxis / can do scratch test

Rheumatology

Bone Malformations Bone Fractures Bone Cancer Osteomyelitis

Joint Rheumatoid arthritis, SLE , Scleroderma, Sjögren’s, MCTD, JRA, Sarcoidosis

Osteoarthritis (OA), gout, pseudogout

Infectious arthritis

Spondylarthropathies: AS, psoriatic, Reiter’s and Reactive, IBD

Fibromyalgia

Muscle Polymyositis/Dermatomyositis, PMR, RS3PE, eosinophilic fasciitis, eosinophilic myositis, other myopathy

Vascultides GCA, Takayasu’s, Kawasaki’s, PAN, Wegener’s, Churg-Strauss, Buerger’s

Ortho Low Back Pain, Knee Pain, carpal tunnel

[Rheum H&P] [HLA associations]

Rheum History and Physical Exam

History

General: CC/Chronology/demographics/functional impact/FH/ROS

Pain

Distal (RA), proximal (PMR, fibromyalgia)

Gentle activity often improves inflammatory but not pain of OA or fibromyalgia

Pain worse as day goes on (OA), wakens from sleep (severe OA, cancer)

Stiffness

Morning stiffness > 1 hr (RA, PMR)

gel phenomenon (worse on initiation/resumption of activity)

Swelling

Articular (arthritis), periarticular (tenosynovitis, ganglion cyst), entire limb (lymphedema), other (lipoma, tumor)

Dependent à worse as day goes on

Weakness

muscle vs. neurological

Constitutional

Fever, inflammation (weight loss) vs. chronic pain (weight gain)

Sleep

Fibromyalgia and inflammatory disease often poor sleepers (may also have sleep apnea, nocturia, narcolepsy)

Raynaud’s

Three Stages

Ischemic pallor - vasospasm (arteries/arterioles) [pic]

Cyanosis – dilation / deoxygenated blood pooling

Rubor – reactive hyperemia

Primary

Secondary

Collagen vascular disease (SLE, SSc, others)

Arterial occlusive disease

Pulmonary HTN

Neurologic disorders

Blood dyscrasias (e.g. Waldenstrom’s)

Trauma

Other: thoracic outlet syndrome (decreased blood flow, short rib)

Arthritis Ddx by category

Acute polyarthritis

Infectious: bacterial sepsis, Neisseria, HIV, other virus, Lyme, rheumatic fever

Non-infectious: sarcoid, many CTD’s, Spondylarthropathies, juvenile chronic arthritis, gout/CPPD, HSP, HOA, sickle cell, leukemia

Intermittent Arthritis

Mechanical: loose bodies, partial tears, ligament laxities

Crystals: gout, pseudogout, hydroxyapatite

Infectious: Lyme, whipple’s

Other: palindromic RA, episodic RA, intermittent hydrarthrosis, FMF, Sarcoid

Chronic Arthritis

RA, JRA, other CTD, crystals, spondylarthropathies, HOA, hypothyroid, metabolic/infiltrative bone/joint disease

Acute Monoarthritis

Note: these can present with only one joint first, of course

Trauma, sickle cell, osteonecrosis

Crystals, bacteria, spondylarthropathies, RA, palindromic RA, JRA

Chronic Monoarthritis

Non-inflammatory

OA, mechanical, osteonecrosis, neuropathic, reflex sympathetic dystrophy, adjacent bone lesion (tumor/infection)

Inflammatory

Tb, fungal, lyme, crystals, RA, JRA, spondylarthropathies, hemophilia, synovial neoplasm, pigmented villonodular synovitis

Low Back Pain

Etiologies:

Inflammatory: AS, Reiter’s, Psoriatic, enteropathic (reactive)

Infectious: infectious sacroiliitis, osteomyelitis

Musculoskeletal: vertebral compression, degenerative facet joint disease, herniated disc, muscular ligamentous injury

Neurologic

Psychogenic, worker’s comp

Visceral/vascular, referred pain

Primary or metastatic malignancy

Congenital

Conditions:

· musculoskeletal

o lumbar sprain or strain (70%): acute or chronic / young adults

o degenerative disk disease (10%)

o spinal stenosis (3%): pain often bilateral lower legs / usu. > 60 yrs / worse w/ extension, relieved by flexion, worse with walking (uphill)

o intervertebral (herniated disc) disease (4%): worse with sitting (lying may help)

o spondylosis: defect in pars interarticularis, either congenital or secondary to stress fracture

o spondylolisthesis: anterior displacement of upper vertebral body on the lower body (can mimic symptoms of spinal stenosis) / condition results from spondylosis or degenerative disk disease in elderly

o cauda equina syndrome: difficulty in micturation, loss of anal tone, saddle anesthesia, progressive motor weakness, sensory level

o facet joint syndrome: back pain referred to buttock, worse with extension, relieved by flexion / gradual, chronic / more in older patients / may have paravertebral muscle spasm at level

· inflammatory: onset < 40, morning stiffness, peripheral joints, iritis, rash, urethral discharge

· non-mechanical low back pain (1%)

· referred or visceral pain (2%)

Diagnosis: history and physical usually enough / don’t get XR unless suspecting tumor, infection because 60% of asymptomatic patients will have positive findings on XR (which will be useless information) / MRI reserved for severe cases and/or when considering surgery

o Straight-leg raising (not very sensitive or specific)

o Patrick maneuver distinguishes pain from sacral-iliac joint (patient externally rotates hip, flexes knee, crosses knee of other leg like a number four while examiner presses down on flexed knee and opposite pelvis)

Duration: acute: < 3 months / early: 3 to 6 months / intermediate: 6 to 24 months / late: > 2 yrs

Red flags: young or old presentation, previous CA, steroids, drugs, HIV, constant (non-mechanical), thoracic, wt loss, ESR > 25, vertebral collapse on XR

Treatment: most cases of acute low back pain resolve in 1-6 weeks w/ analgesics (NSAIDs, other), bed rest NOT recommended, physical therapy NOT necessary (3-5% remain disabled for > 3 months)

	Pain distribution	weakness	Reflex affected	Screening test
L3-4	anterolateral thigh, anteromedial calf to ankle	Quadriceps	knee	Squat and rise (L4)
L4-5	lateral thigh, anteromedial calf, medial dorsum of foot between 1^st and 2^nd toes	Dorsiflexion of foot	none	Heel walking (L5)
L5-S1	gluteal region, posterior thigh, posterolateral calf, lateral dorsum of sole and foot between 4^th and 5^th toes	Plantar flexion of foot	ankle	Walk on toes (S1)

Referred pain

facet joints, intervertebral discs

Lumbar à hip pain localizing to buttock, lateral thigh

Cervical à axilla, shoulder

hips à groin, anterior thigh

knee à

heart à shoulder, jaw, arm (pericarditis à trapezius ridge)

pancreas à back

liver à shoulder

renal (stones, etc) à flank/groin/testicle

uterine à lower back

PUD/spleen/pneumonia à right shoulder

throat à ear (via recurrent laryngeal nerve)

Joint Diseases [Synovial Fluid Table] [Polyarticular Ddx]

Inflammatory Joint Disease

Infectious arthritis

Crystal-induced: Gout, pseudogout, hydroxyapatite, calcium oxalate, LLM

Trauma: fracture, internal derangement, hemarthrosis

Osteoarthritis, RA and JRA

Spondylarthropathies: psoriatic arthritis, ankylosing spondylitis, Reiter’s, reactive arthritis

Ischemic (avascular) necrosis: Kasan’s, alcoholics, Gaucher’s

Foreign-body synovitis

Tumor: mets, osteoid osteoma, pigmented villonodular synovitis (benign, brown-yellow on MRI)

GI disease: intestinal bypass, Whipple’s, reactive arthritis (Shigella, Salmonella, Yersinia, Chlamydia, Campylobacter), IBD (Crohn’s and ulcerative colitis)

Viral infections: Parvovirus B19, rubella, HBV, HCV

Uncommon: mumps, coxsackie, echovirus, adenovirus, VZV, HSV, CMV

Other causes of arthropathy:

Relapsing polychondritis

Neuropathic joint disease

Hypertrophic osteoarthropathy and clubbing

Fibromyalgia

Psychogenic rheumatism

Reflex sympathetic dystrophy syndrome

Costochondritis or Tietze’s syndrome (with swelling)

Musculoskeletal disorders associated with hyperlipidemia

Arthropathy of acromegaly, hemochromatosis, hemophilia, hemoglobinopathies,

Polyarticular

Rheum: RA, OA, gout, CPPD, SLE, vasculitis, scleroderma, PM/DM,

Still’s, Behçet’s, relapsing polychondritis, sarcoidosis, palindromic rheumatism,

FMF, malignancy, hyperlipoproteinemia / seronegative: AS, psoriatic, IBD

Other: fibromyalgia, multiple bursitis/tendonitis, soft tissue abnormalities,

hypothyroidism, neuropathic pain, metabolic bone disease, depression, serum sickness

Infectious: lyme, endocarditis, viral (see above), gonococcal, Tb, other

Post-infectious or reactive: Reiter’s, rheumatic fever, enteric infection

HOA and clubbing

Primary HOA (pachydermoperiostosis)

AD / childhood / remits in 10-20 yrs

Secondary HOA

Causes: associated with intrathoracic malignancies, suppurative lung disease, congenital heart disease, and more / without clubbing (vascular grafting)

bronchogenic CA (usu. non-small cell) à RA-like picture (with effusions/arthralgia) can develop even before onset of clubbing

Mechanism: megakaryocyte shunting with R to L arteriolar trapping à release of PDGF à proliferation [doesn’t seem to explain the classic pattern of progressive development of clubbing from feet to hands seen with congenital heart disease]

Treatment: after lung tumor resection (or even just radiation of mets) or lung abscess drainage, symptoms and signs of arthropathy often subside rapidly; radiographic changes remit during weeks and months / NSAID’s, ASA, bisphosphonates, even trial of low-dose steroids may relieve bone pain in some pts

Diagnosis: clinical? / bone scan will show periosteal deposition [pic], plain films may reveal changes also

Periarticular disorders:

bursitis, rotator cuff tendonitis and impingement syndrome, calcific tendonitis, bicipital tendonitis and rupture, adhesive capsulitis, lateral epicondylitis (tennis elbow), medial epicondylitis

General Points about OA, RA, gout

· OA à affects many vertebrae, RA particularly C1/C2 (because there’s a bursa there)

· RA causes destruction and osteoporosis; gout causes destruction but not osteoporosis

Osteoarthritis (OA) most common joint disease

Causes: primary (80% of population > 70 yrs) or secondary 5% (previously damaged joints, weight-bearing joints, endocrinopathy, metabolic disease, neuropathy, avascular necrosis, Paget’s); 34% of patients presenting with acute knee pain

Clinical: age > 50 yrs, morning stiffness < 30 mins, crepitus, bony enlargement or tenderness; no inflammation (no heat), slow progression / normally pain worse with weigh-bearing, motion, but can progress to point where causes pain at rest, at night

ACR: osteophytes on XR + at least one of above signs is 90% sensitive, specific for OA

Findings:

Affected Joints: DIP > PIP > CMC, knee, hip, feet

Spared Joints: hands (except DIP/PIP/CMC), wrist, elbow, shoulder, spine

· Heberden’s nodes (DIP) and Bouchard’s (PIP) seen more in post-menopausal women with genetic predisposition [pic] / only wrist joint involved is 1^st CMC [pic]

· Knees: medial >> lateral involvement / may develop popliteal cysts

Radiographic (weight-bearing): osteophytes (77% sensitivity/83% specificity), subchondral sclerosis, subchondral cysts, joint space narrowing (erosions), malalignment, may see soft-tissue swelling

· Spondylosis is the formation of osteophytes in response to degenerative disc disease / thick and often project laterally (unlike in AS) / spinal stenosis can also occur from hypertrophy of posterior facet joints, spondylolisthesis, synovial cysts, Paget’s disease, epidural lipomatosis, and congenitally small spinal canal

· Schmorl’s nodes (invasion of disc into vertebral body) are common (often associated with Scheuermann’s disease, osteopenia and degenerative disc disease) / bony margin may be visible on roentgenogram

· Forestier’s disease (diffuse hyperostosis) can occur (usu. elderly) and may form “flowing ossification” (usu. on right side, thoracic vertebrae, but also can occur on ligamentous, tendinous attachments anywhere)

Labs: ESR < 40, RF < 1:40, non-inflammatory synovial fluid (< 2000/mm³)

Treatment: NSAIDs (some say glucosamine works in patients who cannot tolerate NSAIDs), when it’s bad enough, only treatment is joint replacement (knee/hip) (~95% 10 yr success rate) / chondroitin sulfate under investigation / multiple, short periods of rest throughout day better than one large period of rest / intraarticular steroids occasionally helpful (esp. in joint “lock up”)

Nodal OA DIP/PIP / runs in families

Rheumatoid Arthritis

females 4:1 / any age / mildly shortened life span

Findings: swollen, painful, warm joints (PIP, MCP, not DIP), ulnar deviation of MCP [pic], radial deviation of wrists, swan-neck fingers [pic], Boutonnière or button-hole deformities [pic][pic]

Joints: inflamed synovium (pannus) / penetrates to cause erosions, subchondral cysts / fibrin aggregates in joint space (rice bodies) / synovium eventually bridges and ossifies opposing surfaces

Skin: 25% have rheumatoid nodules (firm, oval, non-tender, fibrinoid necrosis, inflammation)

Vasculitis: rheumatoid vasculitis, ulcers, gangrene, splinter hemorrhages, raynaud’s

Neuro

· peripheral neuropathy (10%; ½ are slowly progressive, distal symmetrical sensory or sensory-motor polyneuropathy)

· mononeuritis multiplex

· entrapment neuropathy à carpal tunnel

Renal: early (drug-induced nephropathies), late (amyloid-like renal disease)

Lungs (almost always RF positive): [NEJM]

· pleuritis/pleurisy, effusion

· pulmonary nodules (CT will show them if CXR doesn’t)

· ILD

· alveolar hemorrhage

Heart: pericarditis > myocarditis, valves / conduction abnormalities

Eyes: (1^st dry eyes or keratoconjunctivitis sicca (Sjögren’s), 2^nd episcleritis – may be severe, perforate)

Heme: anemia of chronic disease

Diagnosis: r/o TB (also has RF)

Criteria: 4 of 7 required

morning stiffness > 1 hr

swelling of 3 or more joints

swelling of hand joints (PIP, MCP, wrist)

symmetrical swelling

rheumatoid nodules

positive RF

erosions of hand joints (X-ray)

Labs: 80% have RF (IgM to Fc of IgG), ANA / HLA DR4, HLA DR1 / anti-CCP (worse prognosis; ⅓ with negative RF will have positive anti-citric citrullinated peptide)

Radiography: early X-ray changes in feet (MTPs, very specific for RA), ulnar styloid changes (late becomes piano key sign), C1-2 subluxation (can be very serious and damage spinal cord, but if seen incidentally on lateral flexion c-spine at < 5 mm, can observe)

Course: usually insidious course

Treatment: aggressive therapy is the rule / immunosuppressive drugs from day one

· Steroids

· TNF-a inhibitors

· Others: Immuran

· Old school: gold, MTX, penicillamine

· New school (example of regimens): initial tapered high-dose prednisone + MTX and sulfasalazine or infliximab + MTX

Prognosis: more nodules, DR4, anti-CCP, more systemic Sx, are worse indicators

Palindromic RA

waxing and waning course / usually resolves within 24-48 hrs / joint involvement atypical compared to classic RA

Felty’s syndrome

neutropenia, splenomegaly, leg ulcers, polyarticular arthritis (RA~) or SLE

More: nodules (75%), weight loss (70%), Sjögren’s (55%), LAD (35%), leg ulcers (25%), pleuritis (20%), skin pigmentation (15%), neuropathy (15%), episcleritis (10%)

caused by autoantibodies and cytokine/T cell suppression of granulocytopoesis / more common in elderly patients with RA (especially if untreated) / may also have vasculitis etc.

Large Granular Lymphocytes (LGL)

Usually polyclonal, 20% have RA (the rest are considered neoplastic) / usually associated with Felty’s / course is variable

Juvenile Rheumatoid Arthritis (JRA) (Still’s disease)

children under 16

Presentation: fever, rash (transient, macular), hepatosplenomegaly, serositis

Findings: RF and nodules usually absent (only in older, more severe cases)

Complications: pericarditis, myocarditis, pulmonary fibrosis, glomerulonephritis, growth retardation, iridocyclitis (anterior uveitis – main systemic symptom in up to 25% of girls with mono/pauciarticular RA, insidious yet may lead to blindness), 40% incidence of myopia / 70% recover, 10% with severe deformities

Adult Onset Still’s Disease (AOSD)

Presents with fever, transient rash, joint inflammation / notable for persistent plaques and linear pigmentation

Labs: over 2/3 will have elevated AST/ALT (2-5x) and AST/GGT / (-) RF, ANA / often extremely elevated ferritin

Cogan’s syndrome

Still’s + hearing loss / Treatment: high-dose steroids and pulse Cytoxan

Infectious Arthritis

Infectious Monoarthritis

Neonates: group B strep, H. influenza

Children: S.aureus (45%), Strep A (25%), GNR (20%), Gonococcus (5%), Tb (1%)

Adults: Neisseria (50%), S. aureus (35%), Strep A (10%), GNR (5%), Tb (1%)

Other causes: Pseudomonas (IV drugs, wounds), Klebsiella/E. Coli (IV users, GU infections), lyme disease, Salmonella in sickle cell patients, syphilis (2^nd stage and Charcot’s joints) / HACEK organisms

Pathology: usually hematogenous spread / polymicrobial from surgical implantation or elderly with peripheral vascular disease / usually monostotic (except newborns and sickle cell pts)

Neonates: metaphyses, epiphyses

Children: usually metaphyseal only as growth plate prevents spread into joint

Adults: growth plate closed, vessels reunite, bacteria can go everywhere

Clinical symptoms:

early: fever, skin, arthralgias / knee is hot, tender (pain on active AND passive movement; joint movement that is NOT limited by passive motion suggests soft-tissue problem, e.g. bursitis))

Gonococcal: hand and feet lesions (erythematous, +/- pustular)

Non-gonococcal: another focus / debilitating illness / other? / pre-existing joint abnormality

Synovial fluid from joint aspiration or arthrocentesis of knee [video]

· WBC is a helpful value:

< 200 is normal ( < 25% WBC)

200-2000 is non-inflammatory ( < 25% WBC; PMNs)

2000-100,000 is inflammatory ( > 50% WBC)

> 80,000 is purulent/septic ( > 75% WBC)

Fungal: 10-40 WBC, 70% neutrophils Syphilis: 10-40 WBC in 2^nd

· glucose: 25% less than fasting blood glucose indicates infection

· culture and gram stain (60-80% sensitive)

· wet prep (not always used, many false negatives by non-expert labs)

· synovial biopsy (may be needed to diagnose Tb or hemochromatosis)

XR shows pale bone necrosis (sequestrum) / surrounding deposition of new bone (involucrum)

Treatment: empiric antibiotics / joint drainage

Tuberculous arthritis (see TB)

Usually knees / most common is chronic granulomatous monoarthritis / 1% of Tb / 10% of extrapulmonary Tb / onset is months/years / systemic symptoms only in ½ / Synovial fluid: 20 WBC 50% neutrophils, culture positive in 80%, gram stain positive in 1/3 / Pott’s (spine) / scrofula (TB of neck)

Poncet’s disease

reactive arthritis from Tb / bilateral, no organisms found in joints

Lyme arthritis (see Lyme Disease)

large joints, weeks to months duration, periods of remission, permanent deformities in 10%

Viral Arthritis (from systemic infection)

Parvovirus B19, rubella, HBV, HCV

Gout

usually not before 30 yrs / many are asymptomatic / asymptomatic intervals get shorter over time (severe cases can mimic RA)

Pathology: tophi may occur in joints, ligaments, tendons, soft tissue, earlobes, palms, soles, kidney (uric acid > 8 à causes gout, > 20 à causes renal damage (due to very rapid cell turnover)

· Hyperuricemia (10%) ( > 750 mg/dl)

?HGPRT deficiency

Increased turnover: myeloproliferative disorders, hemolytic anemias, lymphoproliferative malignancy, psoriasis, glycogen storage diseases

· Impaired renal excretion of uric acid (90%) ( < 700 mg/dl)

polygenic inheritance

hypovolemia (adrenal insufficiency, diabetes insipidus)

Toxins: heavy alcohol use / lead toxicity / ASA interferes with tubular secretion / organic acids compete for secretion (ketones, LA)

Other drugs: thiazide, radiocontrast agents, allopurinol/probenecid (if given during attack)

Presentation:

Some classify in stages:

I – asymptomatic hyperuricemia

II – acute gouty arthritis

more at night, last hours to weeks, 1^st attack usually only in one joint / Podagra (90%) – 1^st MTP (great toe)

III – intercritical gout

most patients have next attack within 1-2 years

IV – chronic tophaceous gout

erosion of underlying bone from chronic inflammation

Precipitation: dietary excess, alcohol, acute medical illness, surgical procedures, joint trauma

Renal complications: urate crystals in medullary interstitium (pyelonephritis, obstruction) / 20% of chronic gout die of renal failure (typical to have mild albuminuria, not glomerulonephritis)

Diagnosis: needle-shaped urate crystals in synovial fluid - yellow, parallel to polarizing light

Note: don’t rule out infection just because you see crystals as infection frequently coexists with hyperuricemia

Treatment:

Acute attack:

colchicine (0.6 mg bid or until diarrhea, unless renal impairment)

NSAIDs (indocin and tolectin thought to work best)

steroids (prednisone 40 mg qd x 2-3d with rapid taper)

Prevention: low purine diet / weight loss / avoid alcohol / colchicine (low dose daily)

Probenecid: frequent attacks / stones / tophi / do not use with renal insufficiency

Allopurinol: diminishes uric acid production (do not start during acute attack)

Pseudogout (CPPD) far less common than gout

elderly man/woman (over 85) / calcium pyrophosphate dihydrate in synovial membranes et al / usually asymptomatic rhomboid crystals / familial form chr 8q and chr 5p

Labs: mildly elevated ESR / chondrocalcinosis (+ / -) / CPPD crystals - coffin-shaped, weakly (+) positive birefringence (blue when parallel)

Presentation: warmth, erythema, tenderness, swelling, may have fever, leukocytosis / self-limited to several days / usually knee (50% of acute attacks) / pseudopodagra is almost impossible

Radiography: calcific deposits (chondrocalcinosis present in 26% of asymptomatic adults > 60 yrs) / hook-like osteophytes/subchondral cysts (similar to OA)

Associated metabolic conditions:

Hyperparathyroidism (primary or secondary)

Hemochromatosis (perform basic Fe studies), maybe Wilson’s, A1AT

Hypothyroidism

Gout

Hypomagnesemia (mild hypomagnesemia potentiates PTH action)

Hypophosphatemia

Amyloidosis

Neuropathic joints, aging, trauma/surgery

Note: urate gout and rheumatoid arthritis have a strong negative association (10x)

Work-up for newly diagnosed CPPD: Ca, Mg, PO4, Alk Phosphate, ferritin, Fe, TIBC, TSH (less Mg and PO4 in over 60 yrs?)

Treatment: symptomatic relief from NSAIDs (indomethacin), steroids (injection or PO), joint aspiration, joint immobilization, IV or PO colchicines (only if you can use high doses) /

correction of underlying metabolic problem does not always stop progression

Pseudogout (Type A) (25% of CPPD)

Almost never causes podagra / males / asymptomatic between attacks / usually have radiographic evidence (such as chondrocalcinosis seen in AP pelvis, PA wrists)

20% with hyperuricemia, 5% with urate gout

HC associated shows 2^nd/3^rd MCP enlargement and/or attacks of pseudogout

Pseudorheumatoid arthritis (Type B)

10% with low titre RF / joints inflamed “out of phase” (like gout, not like RA), osteophytes, CPPD, lack of typical erosion patterns on X-ray

can mimic sepsis in elderly patients (fever, WBCs, mental status, polyarthritis)

Hydroxyapatite (HA)

secondary to many systemic disease states (apparently, mostly with elevated Ca²⁺) / crystals so small, a special stain is required to detect / anti-inflammatory treatment may shorten duration of attacks, long-term changes cannot be undone?

Calcium oxalate (CaOx)

strong positive (+) birefringence

Primary: rare genetic disorder, death < 20 yrs

Secondary: renal failure or vitamin C abuse

Fibromyalgia

usu. middle-aged women / hypersensitivity to physical stimulation causing pain, fatigue, poor sleep(mechanism poorly understood)

Diagnosis: diagnosis by exclusion of other disorders and demonstrating ≥ 11 of 18 trigger points

Labs: no specific lab abnormalities

Treatment: no good treatment, but TCA’s might provide some relief

Relapsing polychondritis

Inflammation of cartilage (breakdown of chondroitin sulfate)

Findings: saddle-nose deformity, scleral thinning (scleromalacia), floppy ear, aneurysms, valvular insufficiency (AR, MR, TR), tracheal narrowing (steeple sign)

Liquid lipid microspherules?

Other Bone Disorders

Scoliosis

adolescent females > males / 20% with positive family history

slipped capital femoral epiphyses

20% with referred knee pain (can be misleading) / occurs in pubescent males, happens gradually, can be bilateral / Treatment: surgical with pinning

Villonodular synovitis (benign neoplasms)

aggregates of polyhedral cells, hemosiderin, foam cells, giant cells, zones of sclerosis

Treatment: surgery if possible, usually difficult to excise

pigmented villonodular synovitis (PVNS)

single or multiple, diffuse involvement, red-brown projections

giant cell tumor of tendon sheath (localized tenosynovitis)

small, discrete nodule

Bone Cancer

mets most common form: BLT2KP lung > breast (lytic) > prostate (blastic) > testes, kidney

primary malignant: OS, malignant fibrous histiocytoma, adamantinoma, chordoma

Osteochondroma

most common primary bone lesion / young males / sessile or stalked / cartilage cap / usually stops growing as bones mature

Chondroma

single or multiple (Olier’s Disease, Maffucci’s syndrome) / short bones of hands, feet / radiolucent [XR] / lobulated, hypercellular, disorganized / focal calcification w/in lesion / self-limited disease

Chondrosarcoma - good prognosis

proliferation of malignant cartilage / older males / axial skeleton / surgery only useful option

Osteoid osteoma

very common / young males / < 2 cm growth / appendicular skeleton / produces pain at night (relieved by aspirin) / radiolucent lesion surround by reactive bone formation / surgical removal / 25% relapse due to poor nidus locating by surgeon

Osteosarcoma (OS) - poor prognosis

pre-op and post-op chemotherapy / arm, leg bones / produces bone, cartilage, spindle cells usually have mets / cortical destruction w/ extension in soft tissues (Codman’s triangle)

Parosteal osteosarcoma (POS) - excellent prognosis

young, early middle age, women / long bones / radiolucent ‘string sign’ along cortex / spindle cells produce well-formed bone

Ewing’s sarcoma (variable prognosis)

small cell neoplasia / unknown histiogenesis / very young, males, lower extremities / XR: moth-eaten intramedullary pattern, ‘onion skin’ periosteal reactive bone / diaphysis to metaphysis / PAS+ cytoplasm / therapy evolving

Fibrous cortical defect

very common / young, males, long bones / XR: metaphysis, sub-cortical, soap bubbles, sclerosis at interface spindle cells, foamy macrophages, hemosiderin, chronic infiltrate / self-limiting at skeletal maturity

Fibrous dysplasia

very common / single, multiple / young, localization random / XR: radiopaque, ‘shepherd’s crook’ of proximal femur / spindle, cells, woven bone, lack of osteoblastic rimming, Chinese character appearance / no treatment unless symptomatic / excellent prognosis

Malignant fibrous histiocytoma (poor prognosis)

similar demographics to OS / XR: metaphysis, destructive, radiolucent / anaplastic spindle cells, storiform pattern / treatment same and prognosis slightly worse than OS

Giant cell tumor of bone

benign but aggressive local tumor / young, wide distribution / hemorrhage / surgery when possible / extended curettage (experimental) or resection / prosthesis / 98% monostotic / radiation contraindicated (secondary sarcomas)

Adamantinoma (good prognosis)

primary malignant bone tumor / young males, tibia/fibula / XR: may be multifocal (observe carefully) / epithelial or endothelial proliferation / complete surgical extirpation

Chordoma

malignant bone tumor arising from notochord / 40s to 60s / males / physaliferous cells in acid mucoid background / surgery and post-op radiation

survival: sacral 60% (fair) 5 yr, cervical (horrible) 50% 5 yr 0% 8 yr

Myositis ossificans

athletic adolescents, history of trauma (50%) / central fibroblast proliferation, intermediate zone of osteoid formation, peripheral shell of organized bone / Treatment: usually cured by excision

Connective Tissue Diseases

Rheumatoid arthritis (see bone)

Systemic Lupus Erythematosis (SLE)

1 in 300 black women / HLA-DR3 / HLA-DR2

Differential: psoriasis (i.e. avoid UV light therapy), lyme disease, drug reactions, tinea

Diagnosis: must meet 4 of 11 criteria (malar rash, discoid rash, photosensitivity, mucosal

ulcers, arthritis, serositis, renal, neurologic, hematologic, positive ANA, positive LE or anti-ds or anti-Sm)

Complications:

General: fatigue, weight loss, fever

Skin: malar rash (fixed erythema, flat or raised over malar area, tends to spare nasolabial folds), discoid rash (erythematous raised patches with adherent keratotic scaling and follicular plugging), photosensitivity, periungual telangiectasia, alopecia

Renal: many forms possible / note: 80-90% of SLE becomes dormant when ESRD occurs

· mesangial (earliest: may remit or transition to other forms)

· focal proliferative (50%)

· membranous (50%)

· diffuse proliferative (20%, worst)

Cardiovascular:

· endocarditis (Libman-Sacks/caused by APA syndrome)

· pericarditis

· hypercoagulability

· Raynaud’s (20-30%)

· purpuric lesions (see hematologic)

Hematologic:

· hypercoagulable state (in addition, there is arterial-specific hypercoagulability in SLE patients due to variant mannose-binding lectin genes)

· leukopenia (<4000/mm³), lymphopenia (<1500/mm³), thrombocytopenia (<100,000/mm³), hemolytic anemia

Pulmonary:

More common à pleuritis (LE cells are very specific, WBC’s with pushed aside nucleus, very characteristic appearance, but make sure pathologist looks for them), pleural effusion (mildly exudative, unilateral or bilateral)

Less common à ILD (including pneumonitis)

PE (from APA)

pulmonary HTN

diffuse alveolar hemorrhage (rare): 90% will have concurrent nephritis, abrupt onset, young women, association with pneumonia)

malignancy: ↑ risk of lung cancer > lymphoma

other: BOOP, shrinking-lung syndrome, lymphadenopathy, infections

GI: painless oral or vaginal ulcers, non-specific abdominal complaints / GI vasculitis (less common, serious)

Musculoskeletal: arthralgias (symmetric/peripheral, two or more joints, swelling, effusion,

tenderness but NOT erosive; only small percentage actually get joint deforming arthritis as in RA)

CNS: diffuse psychosis, depression or focal neurological deficits (including seizures) [Ddx] / 50% experience some degree of neuropsychiatric problems / may see cystoid bodies in fundus

Other: hepatosplenomegaly (functional hyposplenism), LAD

Labs:

decreased C3/C4 (can be marker of active disease, either can be depressed first depending on if classical or alternate pathway is activated, can also be decreased from poor synthesis such as in liver disease)

thrombocytopenia, anemia

schistocytes generally not seen without active vasculitis or major HTN

anticardiolipin Ab (30-50% have it, fewer actually have APA syndrome)

false positive VDRL

anti-nuclear antibodies (ANA) (labs)

98% sensitivity, often high titre (1:80 happens in many people is non-specific) / 10% of SLE in whites may be ANA only (no other positive Abs), this is rare in non-whites

Specific Patterns