406 (Continued) 1 Thiopurine methyl transferase \200\224deficiency of this enzyme can lead to bone marrow s uppression in the setting of azathioprine use. y g o o t a m u e h R Table 11.4 (Continued) l TNF Antagonists Adalimumab Etanercept Infliximab Golimumab Certolizumab Pegol IL-1 antagoni st Anakinra Janus kinase inhibitor Tofacitinib T-cell modulators: Abatacept B-cell depletion Rituximab IL-6 antagonist Tocilizumab Table 11.5 Forms of arthritis not associated with rheuma- toid factor (sero \200\223ve) Lyme disease, Beh et \200\231s, leukemia, pulmonary osteoarthropathy, endo- carditis, ac romegaly, Wilson \200\231s disease, familial Mediterranean fever, sar- coid, hemophilia, si ckle-cell, hemochromatosis, and infections, as from: Poststreptococcal Parvovirus B19 Vibri o parahaemolyticus Borrelia burgdorferi Chronic arthritis in children (i.e., before 16 yrs) takes several forms and is classified into juvenile idiopathic arthritis (JIA) subforms: \212 Hepatitis B Chl. pneumoniae Rubella Ureaplasma; HIV Clostridium difficile Systemic arthritis (or Still \200\231s disease) Oligoarthritis (1 \200\2234 joints affected in first 6 months) \212 \212 \212 \212 Polyarthritis (RhF \200\223ve, ANA +ve) Polyarthritis (RhF +ve) Psoriatic arthritis Enthes itis-related arthritis at ligament/tendon insertion into bone. \212 NB: JIA shares only some features with RA: JIA shares these in com- JIA and RA differ in these ways: mon with RA: Both display destruc- tive arthritis Autoimmune with autoantibodies Both have HLA associations Children with chronic arthritis need regular ophthalmic review to detect o ccult uveitis, as well as regular monitoring of growth and development. RA is more likely to run in families RA is more homogeneous than JIA RA has poorer outcomes than JIA 407 Osteoarthritis OA is the commonest joint condition. Women are prone to symptom- atic OA ( : 3:1). Mean age at onset : 50 yrs. OA is usually primary, but may be secondary to any joint disease/injury or some diseases (e.g., hemochromatosis). Signs and symptoms In si ngle joints, pain on movement, worse at end of day; background pain at rest; minimal stiffn ess; joint instability. In polyarticular OA with Heberden nodes ( \200\234nodal OA \200\235 ), the most commonly affected joints are DIP, thumb metacarpophalangeal joints, cervical an d lumbar spine, and knee. There may be joint tenderness, derangement bony swelling (e.g. , Heberden nodes; i.e. bony lumps at DIP joints), poor range of movement, and some (usually limited) synovitis. Imaging/tests Radiology: Loss of joint space, subchondral sclerosis an d cysts, osteophytes. CRP usually normal. Treatment Acetaminophen for pain. If ineffective, try NSAIDs. Reduce weight; use walking aids, supportive footwear; physical therapy. Do exe rcises (e.g., regular quadriceps exercises in knee OA) and keep active. Joint replacement f or end-stage OA. Fibromyalgia Fibromyalgia is a chronic, widespread pain disorder. Fibromyalgia is not due t o inflammation but to abnormal nerve conduction that causes pain. Tai Chi twice daily has b een shown to be beneficial in reducing pain. 2 Three medications have been FDA-approved for fibromyalgia: pregabalin, dulox- etine, and milnacipran. Narcotics are of no benefit in fi bromyalgia and can paradoxically increase pain. Crystal-induced arthritis Gout In the acute stage, there is severe pain, redness, and swell ing of the joint \200\224often the metatarsophalangeal joint of the big toe (podagra). Atta cks are due to the deposition of monosodium urate crystals in and around joints and may be precipitated by trauma, surgery, starvation, infection, or diuretics. With long-term hyperu ricemia, after repeated attacks, urate deposits (tophi) develop (e.g., finger pads, tendons , joints, pinna). \200\234Secondary \200\235 causes : Polycythemia, psoriasis, leukemia, c ytotoxics, renal impairment, long-term alcohol excess. Diagnosis depends on finding urate c rystals in tissues and synovial fluid (serum urate not always \206\221 ). Synovial \202 uid microscopy : Negatively birefringent crystals; neutrophils (+ingested crystals). X-rays may show only soft-tissue swelling in the early stages. Later, well-defined \200\234punch ed out \200\235 lesions are seen in juxta-articular bone. Sclerotic reaction develops later creating an \200\234overhanging edge \200\235 or \200\234rat-bite \200\235 erosion. Join t spaces are preserved until late. Prevalence: 0.5 \200\2231%. : 5:1. (See PLATE 16.) Treating acute gout Use an NSAID unless contraindicated (e.g., peptic ulcer, renal ins ufficiency). Steroids are effective (prednisone 30 \200\22340 mg PO with rapid taper over 6 \200\22310 d). Oral colchicine for acute gout flare treatment; use low-dose colchicine 1.2 mg followed by 0.6 mg in 1 h (1.8 mg total). Low-dose colchicine has both maximum plasma c oncentration and early gout flare efficacy comparable with that of high-dose colchicine, wi th a better safety profile. 3 408 2 Zhang F, et al. A randomized trial of tai chi for fibromyalgia. N Engl J Med . 2010;363:2 265 \200\22367. Preventing attacks The goal is to lower uric acid levels: Avoid prolonged fasts, alcohol ex cess, and high purine food. Lose weight. Allopurinol inhibits xanthine oxidase, metabolized by the kidney. Consider reducing serum urate with long-term allopurinol, but not until 3 w ks after an attack. Start with regular NSAID or colchicine cover (0.6 mg/d PO) as introduct ion of allopurinol may cause gout attack. Allopurinol dose: Start at low dose (100 mg/24 h PO), adjust monthly in light of serum urate levels to achieve <6 mg/dL or <5 mg/dL for toph aceous gout. Haste makes waste! Typically 300 \200\223400 mg/24 h for mild disease; up to 4 00 \200\223600/d for severe disease. SE : Rash, fever, WBC \206\223 . If simple treatment fails, refer to a rheumatologist. Febuxostat: 40 mg/d metabolized by the liver, PO administ ration. This is a therapeutic alternative when allopurinol is not tolerated (monitor for cy topenias and monitor liver function). Uricase : A recombinant mammalian uricase, reduces nu mber of tophi. Acute- ly lowers uric acid levels in patients refractory to conventional the rapy. Must check for G6PD deficiency. Dose : IV 8 mg/mL (2 mL) infuse over 2 h every 2 wks. SE : Gout flare, infusion reaction, antibody formation (anti-PEG anti- bodies). Uric acid increase after infusion may indicate antibody formation. Calcium pyrophosphate dihydrate ar thritis Risk factors : \212 y g o o t a m u e h R l Dehydration \212 Intercurrent illness Osteoarthritis \212 Hyper- parathyroidism Hemo- chromatosis \212 Myxedema \212 \212 \212 Acromegaly \212 PO 4 3 \200\223 \206\223 ; Mg 2+ \206\223 Acute CPPD monoarthritis (pseudogout): Similar to gout; affects different joints (mainly wr ist, knee, ankles). Chronic CPPD: Destructive changes like OA, but more severe; affects kne es (also wrists, shoulders, hips). Can pres- ent as polyarthritis (pseudorheumatoid). See F igure 11.2. Tests: Polarized light microscopy of joint fluid; crystals are weakly positivel y birefringent. Associated with soft-tissue calcium deposition on x-ray; e.g., triangular l igament in wrist or in knee cartilage (chondrocalcinosis). If ar- throcentesis is performed , it can be blood tinged. Treatment: NSAIDs help but are rarely sufficient and often contra indicated in the elderly; consider steroid joint injection for mono-arthritis, oral or pare nteral administration for >2 joints with taper over 1 \200\2232 wks. For chronic disease, c onsider colchi- cine 0.6 mg/d to prevent flares. See Table 11.6. 409 Table 11.6 Prescribing NSAIDs: Patient education Most patients prescribed NSAIDs do not need them all the time, but some patients obediently take them continuously, as prescribed, with potential serious side effects, such as GI ble eding. Explain to your patients that: \212 \212 On good days none may be needed . Drugs are for relief of symptoms: Abdominal pain may be a sign of impending problems: Stop the medi- cation and notify your physician. Ulcers may oc cur with no warning: ness at once . Don \200\231t supplement prescribed NSAIDs with ones bo ught over the counter (e.g., ibuprofen): Mixing NSAIDs can increase risks greatly. Smoking and alcohol increases NSAID risk. \212 Report black stool or light-headed- \212 \212 3 Terkeltaub RA. High versus low dosing of oral colchicine for early acute gout flare: Twen ty-four hour outcome of the first multicenter, randomized, double-blind, placebo-controlled , parallel-group, dose comparison study. A&R 2010;62:1060 \200\2231068. Figure 11.2 Autoimmune connective tissue diseases Included under this heading are SLE, diffuse/limited cutaneous systemic sclerosis, primary Sj gren \200\231s syndrome, idiopathic inflammator y myopathies, undifferentiated connective tissue disease, and relapsing polychondritis. The y overlap with each other, may affect many organ systems, and often respond to immunosuppre ssives. 410 Systemic lupus erythematosus SLE is a non-organ-specific autoimmune disease in which autoan tibodies are produced against a variety of autoantigens (e.g., ANA). Immunopathology result s in polyclonal B-cell secretion of pathogenic autoantibodies and sub- sequent formation of immune complexes that deposit in sites such as the kidneys. : 9:1. Prevalence 0. 2%. Common in: Pregnancy; African-Americans; Asians, and if HLA B8, DR2 or DR3 +ve. 10% of relatives of SLE patients are affected. It is a remitting and relapsing illness, with peak age at diagnosis being 30 \200\22340 yrs. Precipitants of lupus flares that should avoided include the sun, echinacea, alfalfa sprouts, melatonin, garlic, and granulocyte colony sti mulating factor . Clinical features: See Table 11.7. In addition: T \206\221 (77%), sple nomegaly, lymphadenopathy, alopecia (in 70%) recurrent abortion, retinal exudates, fibrosin g alveolitis, myalgia (50%), anorexia (40%), myositis, migraine (40%), ESR \206\221 (CRP o ften : Think of SLE whenever someone has a multisystem disorder and ESR \206\221 but CR P normal). Serologies >95% are ANA +ve. High titer of antibodies directed against double-st randed DNA is nearly exclusive to SLE. Its absence does not exclude it. 11% have false +ve syphilis serology from IgG anticardiolipin antibodies. Antibodies to Ro (SS-A), La (SS-B), and U1 ribonuclear protein help define over lap syndromes (e.g., with Sj gren \200\231s). Monitoring activity Important tests : (1) ESR, (2) complement C3 \206\223 , C4 \206\223 ; C3d \206\221 denotes degradation product s of C3, hence it moves in the opposite direction,(3) double-stranded (anti-DS) DNA antibod y titers, (4) urinalysis with spot protein/Cr ratio, and (5) CBC. Drug-induced lupus This c an be caused by isoniazid, hydralazine (in slow acetylators), procainamide, chlorpromazine, minocycline, TNF inhibitors. Lung and skin signs prevail over renal and CNS signs. It remi ts if the drug is stopped. Sulfonamides and birth control pills may exacerbate idiopathic S LE. Antiphospholipid syndrome SLE may occur with arterial or venous thrombosis, livedo rash , stroke, adrenal hemorrhage, migraine, miscarriages, myelitis, myocardial infarct, multi-i nfarct dementia, and cardiolipin antibodies. Presentation: Abdominal pain (55%), blood pres sure (BP) \206\223 (54%), fever (40%), nausea (31%), weakness (31%), altered mental status (19%). Venous thrombi occur more often if lupus anticoagulant is +ve; arterial thrombi occ ur if IgG or IgM antiphospholipid antibody or anti-b 2 glycoprotein 1 +ve. Treatment Refer to a rheumatologist. NSAIDs, sun-block creams. \212Hydroxychloroquine: Reduces flares by 5 0%, reduces end-organ damage, reduces progression to renal on CNS involvement, reduces lipi ds, reduces thrombotic risk, and improves survival 200 mg bid. SE : Irreversible retin- opa thy; annual ophthalmic referral is recommended. y g o o t a m u e h R l \212High-dose prednisone is kept for severe episodes of SLE ( 1 mg/kg/24 h PO with rapid tapering) 15 yrs after the diagnosis of lupus, 80% of permanent organ damage in SLE is secondary to prednisone. 4 Any dose of prednisone >6 mg increases later organ dam age by 50%. 5 The side effects of prednisone include but are not limited to muscle loss and weakness, cataracts, osteonecrosis, osteoporotic fracture, osteo- porosis, diabetes, dysli pidemia, weight gain, obesity, hypertension, and memory loss. For lupus flare, consider int ramuscular triamcinolone(100 mg IM)instead if initiating or increasing oral steroids; no mo re than quarterly. 6 for lupus nephritis; when used with hydroxychlo- Mycophenolate mofetil roquine improves three-fold the complete renal response. 7 Also found to be superior to az athioprine in maintaining a renal response and in preventing relapse. 8 \212 \212 \212 \212 411 \212Azathioprine 1 \200\2232.5 mg / kg/d PO can be a \200\234steroid-sparer \200\235 SE : Lymphoma. \212Belimumab for active musculoskeletal or cutaneous autoantibody-positive SLE . Inhibits B-lymphocyte stimulator. 10 mg/kg monthly IV. SE: Infusion reaction, nausea, dia rrhea. \212Cyclophosphamide: Monthly intravenous (IV) cyclophosphamide (750 mg/ m 2 body surface) for 6 months has been the standard induction regimen for lupus nephritis, followed by a ma intenance regimen of quarterly infu- sions for 2 yrs. 9 4 Gladman D, et al. Accrual of organ damage over time in patients with systemic lupus eryth ema- tosus. J Rheumatol . 2003;30: 1955 \200\2231959. 5 Thamer M, et al. Prednisone, lupus activity and permanent organ damage. J Rheumatol . 2009;36:560 \200\223564. 6 Danowski A, e t al. Flares in lupus: Outcome Assessment Trial (FLOAT), a comparison between oral methylpr ednisolone and intramuscular triamcinolone. J Rheumatol . 2006;33:57 \200\22360. 7 Ibid. 8 Dooley MA, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephri tis. N Engl J Med. 2011;17(365): 1886 \200\2231895. 9 Petri M., et al. High-dose cyclophosp hamide versus monthly intravenous cyclophosphamide for sys- temic lupus erythematosus: A pr ospective randomized trial. Arthritis Rheum . 2010;62(5):1487 \200\2231493. Table 11.7 Revised criteria for diagnosing SLE Malar rash (butterfly rash): Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds. Discoid rash: Erythematous raised patches with adherent keratotic scal- ing and follicular plugging atrophic scarring. Think of it as a three- stage rash affecting ears, cheeks, s calp, forehead, and chest: Erythema \206\222 pigmented hyperkeratotic edematous papules \206\222 atrophic depressed lesions. Photosensitivity on exposed skin representing unusual reaction to light. Oral ulcers: Oral or nasopharyngeal ulceration. Arthritis: Nonerosive arthritis involving \200\234 2 periphe ral joints, characterized by tenderness, swelling, or effusion. Joint involvement is seen i n 90% of patients. Deforming arthropathy may occur due to capsular laxity (Jaccoud arthropa thy). Aseptic bone necrosis also occurs. Serositis: (a) Pleuritis (pleuritic pain or rub; 80% of all patients have lung function abn ormalities; 40% have dyspnea), (b) pleural effusion, or (c) pericarditis (electrocardiogram [ECG], pericardial rub, or evidence of pericardial effusion). Renal disorders: (a) Persistent proteinuria >0.5 g/d (or >3+ on dipstick) or (b) cellular casts; may be red cell, granular, or mixed. CNS disorders: (a) Seizures, in the absence of causative drugs or known metabolic imbalance (e.g., uremia, ketoacidosis) or (b) psychosis in the absence of causative drugs/metabolic derangements, as above. Hematological disorders: (a) Hemolytic anemia with reticulocytosis or (b) leukopenia (i.e., WBC <4 \227 10 9 /L on 2 occasions), or (c) lymphopenia (i.e., <1.500 \227 10 9 /L on 2 occasions), or (d) thrombocytopenia (i.e., platelets <100 \227 10 9 /L in the absenc e of a drug effect). Immunological disorders: (a) Anti-DNA antibody to native DNA in abnormal titer, or (b) anti -Sm antibody to Sm nuclear antigen, or (c) antiphospholipid antibody +ve based on: (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) positive result for lupus anticoagulant using a standard method, or (3) false-positive serological test for syphilis, +ve for >6 months and confirmed by Trepon ema pallidum immobilization or fluorescent treponemal antibody absorption tests. 412 Antinuclear antibody: Positive in 95%. Diagnose SLE in the appropriate clinical setting if 4 out of the 11 criteria are present, serially or simultaneously. Renal transplantation may be needed; nephritis recurs in 50% on biopsy, but is a rare caus e of graft failure (graft survival is 87% at 1 yr and 60% at 5 yrs). Rituximab can be used for certain types of refractory severe SLE. Systemic sclerosis Scleroderma is a connective tissue disease that is characterized by functional and structural abnormalities that involv e changes in the skin, blood vessels, muscles, and internal organs. Scleroderma means hard skin. The disease can cause abnormal growth of connective tissue, the proteins that support the skin and organs. Symptoms of scleroderma include but are not limited to Raynaud phenom enon (constriction of blood vessels in the hands or feet with cold exposure or stress), eso phageal and GI dysmotility, sclerodactyly (thickening of the digital skin), telangiectasia, dyspnea, an d calcium deposits in connective tissues. There are several forms: Localized scleroderma (m orphea, linear morphea, linear scleroderma) mainly affecting the skin and subcutaneous tiss ues. Limited cutaneous systemic sclerosis has limited skin involvement typically of only th e fingers (sclerodactyly), less frequent fibrosis complications in other organs, but more s ignificant vascular disease overall. Associates pri- marily with anticentromere antibodies. Diffuse cutaneous systemic sclerosis: \200\234Diffuse \200\235 defines skin involvement; often associated with lung (anti-Topo I [scl-70] antibodies), cardiac, and renal changes. H igher risk for lung fibrosis and renal disease. Therapy : Calcium antagonists, ACE-inhibito rs and ARB for Raynaud \200\231s. Meticulous BP control (ACE-inhibitors) if a n y renal cri sis. Endothelin-1 receptor blockade (bosentan, ambrisentan, sildenafil, tadalafil) if pulmo nary hypertension. Undifferentiated connective tissue disease (UCTD) The existence of condi tions characterized by the presence of clinical and serological mani- festations suggestive of systemic autoimmune diseases but not fulfilling the classification criteria for defined connective tissue disease. Patients who do not meet criteria for lupus and have UCTD may b enefit from hydroxychloroquine. There is a 10% risk of progression of undiffer- entiated co nnective tissue disease to SLE over 10 yrs. 10 Researched showed that hydroxychloroquine (P laquenil) may prevent later lupus in patients who do not meet four SLE criteria. Sj gren \200\231s syndrome is a systemic disease in which the defining clinical features are dry m outh (xerostomia) and dry eyes (keratoconjunctivitis sicca) due to chronic lymphocytic infi ltration of salivary and lacrimal glands. Lymphocytic infiltrates replace functional epithe lium, leading to decreased exocrine secretions (exocrinopathy).It may occur either alone or associated with other autoimmune diseases, like RA or SLE. There can be an associ- ated po lyarthritis. Characteristic autoantibodies (anti-Ro/SS-A and anti-La/ SS-B) are produced. M ay affect the nervous system with peripheral neu- ropathy, a length-dependent or non-length dependent neuropathy. There is an associated increased risk for lymphoma. Relapsing polych ondritis attacks the pinna, nasal septum larynx (stridor). Association: Aortic valve dis ease; arthritis; vasculitis. Treatment: Steroids. y g o o t a m u e h R l 413 Polymyositis and dermatomyositis Both conditions cause symmetrical, proximal muscle weaknes s from muscle inflammation. Can be associated with malignancy (in 9 \200\22323%). Dysphagia , dysphonia, facial edema, or respiratory weakness may develop. Skin signs Macular rash (if over back and shoulder, the shawl sign is +ve). A lilac-purple (heliotrope rash) on cheeks , eyelids, and light-exposed areas in 25% nail-fold erythema (dilated capillary loops) a nd erythematous papules over extensor surfaces of phalanges ( Gottron papules; pathognomoni c if CK \206\221 + muscle weakness). Also mechanic \200\231s hands (rough, cracked skin on the lateral and palmar surfaces of the fingers and hands, with irregular \200\234dirty \200\235 lines, particularly in the antisynthetase syndrome [anti-Jo1]). Systemic signs Fev ers, Raynaud \200\231s; lung involvement (20%); polyarthritis/ arthralgia (40%); calcificat ions; retinitis (like cotton-wool patches); myocardial involvement (myocarditis, arrhythmia s); dysphagia; and gut dysmotility. 10 James JA, et al. Hydroxychloroquine sulfate treatment is associated with later onset of systemic lupus erythematosus. Lupus . 2007;16:401 \200\223409. Diagnosis Muscle enzymes (ALT, CK, and aldolase) \206\221 in plasma; electromyography (EMG ) shows fibrillation potentials; muscle biopsy. Autoantibody (ab) associations: Myositis-sp ecific: Anti-Mi-2, anti-Jo1 (look for lung fibrosis as well). Overlap syndromes: Scleroderm a with dermatomyositis (e.g., anti-PM-Scl +ve) or polymyositis/alveolitis (e.g., anti-Jo1 + ve). Differential diagnosis: Subacute weakness from inclusion-body myositis, muscular dystr ophies, SLE myositis, polymyalgia, systemic sclerosis, endocrine/metabolic myopathies, rhab domyolysis. Management Investigate extensively for malignancy; get expert help; rest and pr ednisone help (start with 1 mg/kg/24 h PO). Immunosuppressives (p. 406) and cytotoxics are also used early (e.g., azathioprine, methotrexate, cyclophosphamide, or cyclosporin). High- dose immune globulin has a role. Dapsone can help skin disease. A more aggressive form with prominent vasculitis occurs in children. Antisynthetase syndrome Up to 30% of patients wit h DM or PM have a group of clinical findings called \200\234the antisynthetase syndrome. \200\235 These findings include Raynaud \200\231s phenomenon, mechanic \200\231s hands, art hritis, and interstitial lung disease . These patients often have antisynthetase antibodies that are highly specific. Antisynthetase autoantibodies : Anti \200\223Jo-1, Anti \200\223 PL-7, Anti \200\223PL-12, Anti-EJ, Anti-OJ, Anti-KS, Anti-Zo, Anti-Ha. See Table 11.8. Incl usion body myositis ( IBM ) Affects men more than women. The mean age at onset of symptoms is 60 yrs. Patients with IBM present with the insidious onset of weakness. The average dur ation of symptoms before diagnosis is about 6 yrs. Proximal lower extremity weakness is usu ally the first sign, with subsequent involvement of upper extremity and distal muscle group s. Proximal muscle weakness is typically more pronounced. Weakness is accompanied by myalgi as in about 40% of cases. Muscle atrophy usually progresses in parallel with the duration a nd severity of weakness. Some patients, however, have profound atrophy of the upper arms or quadriceps. The muscles look \200\234scooped out. \200\235 Statin myopathy In addition to inducing a self-limited myopathy, statin use is associated with an immune-mediated necroti zing myopathy (IMNM), with autoantibodies that recognize 200-kd and 100-kd autoantigens. St atins upregulate the expression of HMG-COA reductase (HMGCR), the major target of autoantib odies in statin-associated IMNM. Regenerating mus- cle cells express high levels of HMGCR, which may sustain the immune response even after statins are discontinued. 414 Table 11.8 Plasma autoantibodies: Disease associations Antinuclear antibody (ANA) SLE RA JIA (p. 407) Chronic active hepatitis +ve in (%) Smooth muscle antibody (SMA) Chronic active hepatitis Primary biliary cirrhosis Idiopathic cirrhosis Viral infections +ve in (%) 95 32 76 75 40 \200\22390 30 \200\22370 25 \200\22330 80 Sj gren \200\231s 68 (Low titers) syndrome Systemic 64 \200\234Normal \200\235 controls 3 \200\22312 sclerosis \200\234Normal \200\235 controls 0 \200\2232 ( \206\221 with age: 20% at 70 yrs) (Continued) y g o o t a m u e h R Table 11.8 (Continued) l Gastric parietal cell antibody >90 Pernicious anemia Mitochondrial autoantibodies, AMA 60 \200\22394 Primary biliary cirrhosis (adults) Atrophic gastritis Females Males Autoimmune thyroid Chronic active hepatitis 60 Idiopathic cirrhosis 15 \200\22320 \200\234Normal \200\235 con trols 33 25 \200\22360 25 \200\22330 0.8 disease \200\234Normal \200\235 controls Myositis-associated autoantibodies: PM-Scl U1RNP Anti-SRP : Severe, acute, resistant necrotizing myopathy Anti \200\223Mi-2 DM with rash > muscle sym ptoms, treatment responsive Anti-HMGCR (anti-200/100) HMGCR Necrotizing myopathy related to statin use in majority; most patients are statin-exposed, but myopathy also reported in a minority of statin-naive patients Anti-MDA5 (anti \200\223CADM 140) CAM (cancer-associated myositis), DM with rapidly progressive lung disease. Antisynthetase antibodies Anti Jo-1, A nti PL-7, Anti PL-12, Anti EJ, Anti-OJ, Anti \200\223KS, Anti \200\223Zo, Anti-HA Thyroid 2 \200\22316 PM or DM/SSc overlap Microsomal (%) 70 \200\22391 Thyroglobulin (%) antibodies Hashimoto \200\231s thyroiditis Graves \200\231 disease Myxedema Thyrotoxicosis Juvenile 75 \200\22395 50 \200\22380 40 \200\22365 37 \200\22354 91 33 \200\22375 50 \200\22381 40 \200\22375 72 415 lymphocytic thyroiditis Pernicious anemia \200\234Normal \200\235 controls (50% in older women) Rheumatoid factor 55 10 \200\22313 6 \200\22310 +ve in (%) RA Sj gren \200\231s 70 \200\22380 80 Juvenile arthropathy Infective endocarditis 50 syndrome Felty \200\231s syndrome 100 Systemic SLE \200\234Normal \200\235 controls 40 5 \200\22310 30 sclerosis (Continued) Table 11.8 (Continued) ANCA-associated vasculitis: Two types: \212Classical antineutrophil cytoplasmic antibody ( c-ANCA): Target: Serine protease 3: +ve in granulomatosis with polyangiitis (p. 416) in >90 % of patients. \212Perinuclear antineutrophil cytoplasmic antibody (p-ANCA): Target: Myeloperoxidase; +ve in 80% pauci-immune crescentic glomerulone- phritis (p. 261) and systemic vasculitides (e.g., microscopic polyangiitis, a vasculitis of kidney lung, p-ANCA +ve in 75%). NB: Churg \200\223Strauss may be associated with p- and c-ANCA. Vasculitis and polyarteritis nodosa Vasculitis, defined as any inflammatory disorder of blo od vessels (typically noninfectious), can affect vessels of any organ. It may be occlusive (necro- tizing, as in SLE) or nonocclusive, as in Henoch \200\223Sch nlein purpura (p. 2 63). It can occur de novo , as in polyarteritis (see Table 11.9), Churg \200\223Strauss, Be h et \200\231s, giant cell arteritis (GCA), Takayasu \200\231s, and granulomatosis with polyangiitis (formerly known as Wegener \200\231s), be caused by drugs (cocaine) or infecti on (syphilis is an endarteritis obliterans), or be mediated by com- plement activation indu ced by immune complexes in autoimmunity (e.g., SLE, RA). Consider vasculitis as a diagnosis for any unidentified multisystem disorder . Organ involvement can be from acute vasculitis or end-organ dam- age resulting from recurrent vasculitis. Features seen in many vasculiti des \212General : Fever, malaise, weight \206\223 , arthralgia, myalgia, ESR \206\221 \212Skin : Purpura, ulcers, livedo reticularis, nail bed infarcts, digital gangrene \212Ey es : Episcleritis, ulceration, visual loss \212ENT : Epistaxis, nasal crusting, stridor, d eafness \212 : Hemoptysis, dyspnea \212 : Loss of pulses, heart failure, myocardial infar ction, angina GI \212 : Abdominal pain (any viscus may infarct), malabsorption because of Pulmonary Cardiac 416 chronic mesenteric ischemia Renal : Mononeuritis multiplex, sensorimotor neuropathy, hemipl e- Neurological gia, seizures, psychoses, confusion, cognition \206\223 , fluctuating mood , odd behavior \212 \212 : BP \206\221 hematuria, proteinuria, casts, acute/chronic renal failure Diagnosis is based on clinical findings, supported by histological and occasionally angiogr aphic findings. ANCA may be +ve (p. 416). Treatment Treat hypertension meticulously. Refer to experts. Use high- dose prednisone and cyclophosphamide if major organ involvement. Gran ulomatosis with polyangiitis (GPA) has a predisposition for certain organs. The classic org ans involved are the upper respiratory tract (sinuses, nose, ears, and trachea), lungs, and kidneys. May develop recurrent ear infections, hearing loss, nasal crusting, epistaxis, an d septal perforation. The bridge of the nose can collapse, resulting in a \200\234saddle \200\223nose deformity. \200\235 Inflammation can occur in different parts of the eye with episcleritis, scleri- tis, or uveitis, as well as inflammation behind the eye causing an or bital pseudotumor with proptosis. Infiltrates can be seen on chest x \200\223ray, and there can be bleeding in the lungs. Inflammation can happen in the kidney as well. Glomeruloneph ritis can lead to hematuria, proteinuria, and renal y g o o t a m u e h R Table 11.9 Polyarteritis nodosa (PAN) l PAN is a necrotizing vasculitis that causes aneurysms of medium-sized arteries. : 2:1. Sometimes PAN is associated with HBSAG. Signs and symptoms \212General features : Fev ers, abdominal pain, malaise, weight \206\223 , arthralgia \212Renal : 75% of cases. Main cause of death. Hypertension, hematuria, proteinuria, renal failure, intrarenal aneurysms, vasculitis \212Vascular : BP \206\221 ; claudication \212Cardiac : 80% of cases. Coronary arteritis and consequent infarction. \206\221 BP and heart failure. Pericarditis. In Kawasaki \200 \231s disease (childhood PAN variant), coronary aneurysms occur. \212Pulmonary : Pulmonary infiltrates and asthma occur in vasculitis (some say that lung i nvolvement is incompatible with PAN, calling it then Churg \200\224Strauss syndrome). CNS: 70% of cases. Mononeuritis multiplex, sensorimotor polyneu- ropathy, seizures, hemiplegia, psychoses GI: 70% of cases. Abdominal pain (any viscus may infarct), malabsorp- tion becaus e of chronic ischemia \212 \212 \212Skin : Urticaria, purpura, infarcts, livedo reticularis, nodules \212Blood : WBC \206\221 , eosinophilia (in 30%), anemia, ESR \206\221 , CRP \206\221 Diagnosis This is m ost often made from clinical features in combination with renal or mesenteric angiography. ANCA is classically negative. Treatment Treat hypertension aggressively. Refer to rheumatol ogy. Use high-dose prednisone, then cyclophosphamide. failure. Treatment for limited disease : Patients can be treated with trimethop- rim/sulfam ethoxazole, which may help to eradicate S. aureus colonization of the nasal cavity. Treatme nt for systemic ANCA-associated vasculitis: Remission induction with oral cyclophosphamide 2 mg/kg/d (adjust for the elderly and renal insufficiency) \227 6 months and prednisone 1 mg/kg/d \227 1 month fol- lowed by tapered dose. Initiate maintenance therapy with a stero id-sparing agent like MTX or azathioprine for 1 yr after the 6-month treatment course with cyclophosphamide. Beh et \200\231s diseas e involves small, medium, and large arteries a nd veins. HLA \200\223B51 is a risk factor. Uveitis, painful aphthous, scrotal or vaginal u lcers. Arthritis or arthralgias are common. Pustular skin lesions after trauma (pathergy). CNS involvement with headaches, aseptic meningitis, confusion, strokes, and personality cha nges. (See Plate 22.) 417 Polymyalgia rheumatica Polymyalgia rheumatica (PMR) is common in those >70 yrs who have sym metrical aching and morning stiffness in shoulders and proximal limb muscles for >1 month mild polyarthritis, tenosynovitis (e.g., carpal tunnel syndrome [p. 386]; occurs in 10%), depression, fatigue, fever, weight \206\223 , and anorexia. It may come on suddenly or ov er the course of weeks. It overlaps with GCA. : 2:1 Tests ESR usually >40 mm/h; CK usually ; alk phos \206\221 ; mild anemia Differential diagnosis Recent onset RA; hypo thyroid- ism, primary muscle disease, occult malignancy or infection, neck lesions, bilater al subacromial impingement lesions, spinal stenosis. Treatment Prednisone 15 \200\22320 mg/ 24 h PO; decrease dose slowly after symptoms have been controlled at least 1 month (in ligh t of symptoms and ESR). Most need steroids for \200\234 2 yrs. Preventing osteoporosis is essential (p. 305). Giant cell (temporal) arteritis GCA has PMR symptoms in up to 25% of people. Common in the elderly, it is rare under 55 yrs. Symptoms Headache, scalp and temporal artery tenderness ( e.g., on combing hair), jaw claudication, amaurosis fugax, or sudden blindness in one eye. Tests ESR \206\221 , CRP \206\221 , platelets \206\221 , alk phos \206\221 , anemia. If you suspect GCA, do an ESR, start prednisone 1 mg/kg/24 h PO immediately . Some advocate h igher doses IV (up to 1,000 mg) if visual symp- toms (ask an ophthalmologist). Osteoporosis prophylaxis is essential. Get temporal artery biopsy (several cm in length because skip le sions occur) in the next few days. NB : The immediate risk is blindness, but longer term, t he main cause of death and morbidity in GCA is steroid treatment! Reduce prednisone after 5 \200\2237 d in light of symptoms and ESR; increase dose if symp- toms recur. Typical cours e : 1 \200\2232 yrs, although it can reoccur. 418 This page intentionally left blank Oncology Daniel Laheru , M.D. y g o o c n l Contents Introduction 420 Looking after people with cancer 421 Epidemiology 422 Oncology and genetics 423 Screening: Colorectal and breast cancer 425 Scre ening: Lung, pancreatic, and prostate cancer 427 Oncological emergencies 429 Symptom contro l in severe cancer 431 Cancer therapy 433 Radiotherapy 435 O 2 1 Introduction Since Richard Nixon signed the National Cancer Act on December 23, 1971 to foc us and prioritize federal resources to advance cancer clinical and basic science research, there have been a number of notable achieve- ments in cancer treatment, particularly in sol id tumors such as germ cell tumors and hematologic malignancies including Hodgkin \200\231s lymphoma, acute lymphoblastic leukemia, acute myelogenous leukemia, and chronic myelog- en ous leukemia. The sequencing and analysis of the human genome in 2001, followed by the sequ encing of a number of cancers including colorectal cancer, breast cancer, brain tumors, pan creas and neuroendocrine cancers, and head and neck cancers provided researchers with the c ritical tools to begin to identify and differentiate cancer from normal tissue at the genet ic level. Although the implications of these landmark projects are still being realized, it is evident that the identification of critical genes and proteins involved in cell divisio n and growth and metastasis are just the beginning. The full compre- hension of how these g enes control nonlinear cellular signaling matrices has become the new discovery and treatme nt paradigm in oncology. The potential has raised expectations for unprecedented progress i n the near future. However, even as better treatments are being developed, the best treatme nt remains earlier diagnosis and improved screening methods for those at risk. This review will provide only a general overview of the epide- miology, genetics, screening, and treatm ent of some select cancers. 420 Looking after people with cancer y g o o c n O l Table 12.1 Looking after people with cancer No rules guarantee success, but there is no doubt that getting to know your patient, making an agreed management plan, and seeking out the right expert for each stage of treatment (w ith emphasis now in multi- discipline care) all need to be central activities in oncology. These issues focus around communication with patients and families but also with a team of disease-specific experts across disciplines including surgery, medical and radiation oncolo gy, pathology, radiology, interventional dis- ciplines, social work, nutrition, palliative care, and pain services. Psychological support Examples include: \212 Allowing the patient to express anger, fear \200\224or any negative feeling (anger can anes thetize pain). Counseling (e.g., with a breast cancer nurse for mastectomy preparation) Cog nitive and behavioral therapy reduces psychological morbidity associated with cancer treatm ents. Group therapy reduces pain, mood disturbance, and the frequency of maladaptive coping strategies. Meta-analyzes have suggested that psychological support can have some effect o n improving outcome measures such as survival. \212 \212 \212 \212 Advice on breaking bad news 1 Choose a quiet place where you will not be disturbed. 2 Find out what the patient already knows or surmises (often a great deal). 3 Find out how much the person wants to know. You can be surprisingly direct about this. \200\234Are you the sort of person who, if anything were amiss, would want to know all the details? \200\235 4 Give some warning (e.g., \200\234there is some bad news for us to address \200\235). 5 S hare information about diagnosis, treatments, and prognosis. Specifically list supporting p eople (e.g., nurses) and facilities (e.g., hos- pices). Try asking \200\234Is there anythi ng else you want me to explain? \200\235 Don \200\231t hesitate to go over the same ground repeatedly. Allow denial: Don \200\231t force the conversation. 6 Listen to any concerns raised; encourage the airing of feelings. 7 Summarize and make a p lan. Offer availability. 8 Follow through. The most important thing is to leave the patient with 421 the strong impression that you are with him or her. Don \200\231t imagine that a single blueprint will do for everyone. Be prepared to use what ever the patient gives you. This requires close observation of verbal and nonverbal cues. B ecause humans are very complex, we all frequently fail. Don \200\231t be put off: Keep tryi ng. Epidemiology The incidences of selected most-common cancers for men and women worldwide are identified in Table 12.2. These numbers do not include car- cinoma in situ of any site exc ept urinary bladder, nor do they include basal and squamous cell cancers of the skin. The i ncidence reflects an overall increase when compared to recent years. This is thought to be secondary to the continuing growth and aging of the worldwide population, as well as to ext ernal environmental factors such as smoking. The expected worldwide deaths are identified i n Table 12.3. Breast cancer remains the most common cause of cancer (23% of total cancer ca ses) and cancer death (14% of total cancer deaths) in women worldwide. In developing countr ies, breast cancer is now also the leading cause of cancer death, surpassing cervical cance r over the past decade. Lung cancer remains the most common cause of cancer (17% of total c ancer cases) and cancer death (23% of total cancer deaths worldwide) in men worldwide.