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Rheumatology Serologic Studies in Rheumatologic Disorders STUDY TABLE: Serologic Studies/Associations Test Comments ANA SLE, SSc, Sjogren syndrome, MCTD; titer does not correlate with disease activity Anti-Sm SLE; most specific for SLE but does not correlate with disease activity Anti-U1-RNP MCTD, SLE; high titer seen in MCTD (>1:10,000 but does not correlate with disease activity) Anticentromere pattern of ANA LcSSC and CREST syndrome; more likely to develop PH Anti-dsDNA antibody SLE; correlates with disease activiry especially kidney disease Anti-La/SSB antibody; anti-Ro/SSA Sjogren syndrome, SLE; RA, SSc, sicca symptoms, neonatal SLE antibody Anti-Scl-70 antibody DcSSc; more likely to develop pulmonary fibrosis Antihistone antibody Drug-induced lupus erythematosus; may be seen in primary SLE c-ANCA (anti-PR3 antibody) Granulomatosis with polyangiitis p-ANCA (anti-M PO anti body) Eosinophilic granulomatosis with polyangiitis and MPA Anti-Jo-1 antibody Polymyositis and antisynthetase syndrome Anti-CCP antibody RA; may be positive in RF-negative RA Rheumatoid factor RA, Sjogren syndrome; cryoglobulinemia; common in multiple other diseases (hepatitis C, endocarditis, SLE) sclerosis. DON'T BE TRICKED . An isolated positive ANA result associated with nonspecific symptoms and normal findings on clinical examination does not establish the diagnosis ofa connective tissue disease. . ANA subserology testing should not be routinely performed, even in the setting of a positive ANA result, without strong clinical suspicion ofan underlying connective tissue disease. Rheumatoid Arthritis Diagnosis RA is a symmetric inflammatory polyarthritis that primarily involves the small joints of the hands and feet. Characteristic findings include:

DON'T BE TRICKED . An isolated positive ANA result associated with nonspecific symptoms and normal findings on clinical examination does not establish the diagnosis ofa connective tissue disease. . ANA subserology testing should not be routinely performed, even in the setting of a positive ANA result, without strong clinical suspicion ofan underlying connective tissue disease. Rheumatoid Arthritis Diagnosis RA is a symmetric inflammatory polyarthritis that primarily involves the small joints of the hands and feet. Characteristic findings include: . morning stiffness lasting >1 hour . MCB PIP and MTP joints most common, but spares DIP joints o potential involvement of wrists, elbows, shoulders, knees, ankles, C-spine . synovitis characterized by soft-tissue swelling or effusion r subcutaneous nodules over bony prominences or extensor surfaces . symptoms present for >6 weeks Testing Laboratory findings include: o positive rheumatoid factor; sensitiv ity, 7 O' ; specifi city, B5'1, 1,, o positive anti-CCP antibody assay; sensitivity,TO'/"; speciflcity 95'1, 368

Rheumatology r elevated ESR or CRP level o normocytic anemia X-ray: Plain x ray of the hands and/or fbet is a standard imaging study for RA; radiographic changes include periarticular osteo- penia, marginal erosions, and joint space narrowing, although early radiographs may be normal. X rays are useful in classiflzing disease severity and pretreatment baseline. Ultrasonography is more sensitive than x ray for identification of synovitis and erosions. MRI is useful for detecting cervical spine subluxation or myelopathy. DON'T BE TRICKED o A negative rheumatoid factor does not exclude RA; anti-CCP antibody assay may be positive, or the patient may have seronegative RA. o A positive rheumatoid factor alone is not diagnostic of RA. . Fluctuations in rheumatoid factor do not mirror disease activity, and serial testing is not indicated. o Not all symmetric arthritis is RA. STUDY TABLE: Rheumatoid Arthritis Mimics lf you see arthritis and.. Diagnose this... Skin rash and leukopenia SLE Psoriasis or pitted nails Psoriatic arthritis Day care worker or contact with small children Parvovirus B19 infection (usually self-limited after 1-3 months) Raynaud phenomenon and sclerodactyly SSc Proximal muscle weakness Polymyositis or dermatomyositis Recent immunizations Post-rubel la immunization arthritis Tophi with small joint involvement of the hands and feet Chronic tophaceous gout DOil'T BE TRICKED o Viral infections can cause short-lived inflammatory arthritis involving small joints; symmetric joint inflammation present >6 weeks strongly suggests RA.

Proximal muscle weakness Polymyositis or dermatomyositis Recent immunizations Post-rubel la immunization arthritis Tophi with small joint involvement of the hands and feet Chronic tophaceous gout DOil'T BE TRICKED o Viral infections can cause short-lived inflammatory arthritis involving small joints; symmetric joint inflammation present >6 weeks strongly suggests RA. StU DY TA B LE s Extra-articular Manifestations of Rheumatoid Arthritis lf you see this in a patient with RA... Think this... Arm paresthesias and hyperreflexia C1-C2 subluxation (increased risk of cord compression with tracheal intubation) Coug h, fever, pulmonary infiltrates Bronchiolitis obliterans organizing pneumonia (BOOP) or methotrexate toxicity Foot drop or wrist drop Mononeuritis multiplex (vasculitis) Hoarseness Cricoarytenoid involvement Multiple basilar pulmonary nodules Caplan syndrome (pneumoconiosis related to occupational dust; characterized by rapid development of multiple basilar nodules and mild airflow obstruction) Dry eyes and/or mouth Sjogren syndrome Pleural effusion with low plasma glucose Rheumatoid pleuritis (<30 mg/dL) Pu lmona ry fibrosis Rheumatoid interstitial lung disease Skin ulcers, peripheral neuropathy Rheumatoid vasculitis Splenomegaly and granulocytopenia Felty syndrome Red, painful eye Scleritis, episcleritis, keratitis HF Rheumatoid disease or anti-TNF toxicity ASCVD Major cause of death in patients with RA Skin nodules Rheumatoid nodules typically in olecranon region 369

Rheumatology Other complications include increased risk of pulmonary infec tions and osteoporosis. DOil'T BE TRICKED . All patients with RA undergoing general anesthesia should have cervical spine x-rays to assess for atlantoaxial subluxation. Treatment "Treat to target," with the target being remission or low disease activity. . Select NSAIDs and low dose oral and intra-articular gluco- corticoids for quick symptomatic relief; these agents do not alter the course ofthe disease. Hand X-ray, Rheumatoid Arthritis: Carpal, metacarpal, and plp joints show o Methotrexate is the initial DMARD for most patients with periarticular o$eopenia, joint'space narrowing, and marginal erosions, all charac- RA and should be instituted immediately in patients with teristic of RA' erosive disease. It is continued indefinitely and can be used in combination with other nonbiologic and biologic DMARDS. o Monotherapy with hydroxychloroquine or sulfasalazine, or combination therapy with these agents, is for early, mild, and nonerosive disease, but they are more commonly used in combination with methotrexate (triple therapy). Biologic therapy: Indicated when disease control is not achieved with oral DMARDs. Initial therapy is a TNF inhibitor added to baseline methotrexate therapy. The TNF inhibitors include etanercept, infliximab, adalimumab, certolizumab, and golimumab. Tofacitinib is an example of one of several oral small molecule Janus kinase inhibitors with similar efficacy to that of the biologics. . Screen for and treat latent TB before starting biologic therapy. . Perform periodic TB screening during biologic therapy. Important adverse events of TNF inhibitor therapy include pancytopenia (and infections), positive ANA associated with lupus-like syndromes, HE and demyelinating disorders. Combination therapy with multiple biologic therapies is not recommended. Surgical intervention: Indications for surgical intervention include intractable pain, severe functional disability from joint destruction, or repair of ruptured tendons. Other treatment considerations: Smoking may impair the response to therapy and exacerbate rheumatoid lung disease. Manage secondary bone and CVD, and prevent infection:

Surgical intervention: Indications for surgical intervention include intractable pain, severe functional disability from joint destruction, or repair of ruptured tendons. Other treatment considerations: Smoking may impair the response to therapy and exacerbate rheumatoid lung disease. Manage secondary bone and CVD, and prevent infection: o DEXA scans to screen patients for osteoporosis o calcium/vitamin D supplementation for all patients . bisphosphonate therapy for osteoporosis o evaluation and treatment of standard cardiovascular risk factors . routine immunizations, including COVID-19 and annual influenza . pneumococcal vaccination . adjuvant physical and occupational therapy DOil'T BE TRICKED o Methotrexate is absolutely contraindicated in pregnancy and must be discontinued before conception. . Hydroxychloroquine and sulfasalazine can be used during pregnancy. 370

Rheumatology TEST YOURSELF A 46 year old man has a 3 month history of swelling of the PIP and MCP joints and 90 minutes t-rf morning stiffness. Rheumatoid factor is negative. ANSWER: For diagnosis, choose RA. For management, select anti CCP antibody assay. Sitigren Syndrome Diagnosis Sj6gren syndrome may occur as a primary disease process or may be associated with another autoimmune disease, most com monly RA and SLE. Sjdgren syndrome is characterized by: o kerutoconjunctivitis sic(r o xerostomia o salivary gland enlargement (occurs in nearly half of patients; most obviously in the parotid glands) Testing A cardinal feature is the presence olantibodies to Ro/SSA and La/SSB. A positive ANA, rheumatoid firctor, and hypergamma globulinemia are also frequently fbund. The presence of classic findings and anti Ro/SSA and anti I-a/SSB antibodies is suf'fi cient to diagnose Sjdgren syndrome; in unclear cases, a lip biopsy of minor salivary glands is the gold standard fbr diagnosis. Follow-up Patients with Sj6gren syndrome are at increased risk for non Hodgkin lymphoma compared with the general population, with large B cell and MALT lymphomas being the most common. Be alert to the development of neonatal heart block in newborns AeF of women with Sjogren syndrome because of the anti Ro/SSA and anti La/SSB antibodies. Treatment Parotid Gland Enlargement: Bilateral parotid gland enlargement in a patient Treatment is symptomatic. Select artificial tear replacement and with Sjogren syndrome artificial saliva and mouth lubricants. Systemic immunosuppressive therapy is indicated only in patients with severe systemic manifestations. Osteoarthritis OA is the most common form of arthritis. It affects all tissues of the joint and is characterized by cartilage and meniscal degeneration. Diagnosis OA most often affects the lower cervical and lumbar spine; hips; knees; and DIP, PIB and first carpometacarpal joints. 371

Rheumatology Characteristic flndings include: o joint pain that is exacerbated by activity and relieved with rest; morning stiffness lasting <30 minutes . reduced joint motion o crepitus o tenderness alongthejoint line o bony enlargement (including Heberden and Bouchard nodes) . involvement of the first carpometacarpal joint with squaring at the base of the thumb Two important variants are erosive OA of the hand and DISH. . Erosive inflammatory OA is characterized by pain and palpable swelling of the soft tissue in the PIP and DIP joints. This condition also may be associated with disease flares during which these joints become more swollen and painful. Compared with RA, erosive OA is common in the DIP joints; does not typically affect the wrists or elbows; and is not associated with rheumatoid factor, anti CCP antibodies, or an elevated ESR or CRP level. o DISH is an often asymptomatic form of OA that causes flowing ossification along the anterolateral aspect of the vertebral bodies, particularly the anterior longitudinal ligament, in >4 contiguous vertebrae. However, neither disk-space naffow- ing nor syndesmophytes are visible as they are in lumbar spondylosis or ankylosing spondylitis, respectively. Common complications attributable to DISH include dysphagia, unstable spinal fractures, spinal stenosis, and myelopathy. Secondary OA results from previous joint injury or metabolic diseases such as hemochromatosis. Consider metabolic causes when OA develops at an early age (<50 years) or in atypical joints (e.g., MCP, shoulder, or wrist joints). Testing In most cases, Iaboratory studies are not indicated. An x-ray is not helpful in the diagnosis of hand OA (clinical examination is more specific) but is the gold standard for hip and knee OA, showing joint space narrowing, subchondral sclerosis, and osteophytes. Synovial fluid is usually noninflammatory with a leukocyte count <2000/pL. Ultrasonography is useful in the diagnosis of a Baker cyst. DON'T BE TRTCKED . A ruptured Baker cyst (herniation of fluid-filled synovium of the posterior knee) or ruptured gastrocnemius muscle can mimic a DVT.

Testing In most cases, Iaboratory studies are not indicated. An x-ray is not helpful in the diagnosis of hand OA (clinical examination is more specific) but is the gold standard for hip and knee OA, showing joint space narrowing, subchondral sclerosis, and osteophytes. Synovial fluid is usually noninflammatory with a leukocyte count <2000/pL. Ultrasonography is useful in the diagnosis of a Baker cyst. DON'T BE TRTCKED . A ruptured Baker cyst (herniation of fluid-filled synovium of the posterior knee) or ruptured gastrocnemius muscle can mimic a DVT. Treatment lill.','.""1':?li',,lffil,lll]::i:ilil:iJffilTd the DrP joints and Nonpharmacologic treatment includes education on OA and joint protection; an exercise regimen, including quadriceps strengthening exercises for knee OA; weight loss; proper footwear; and assistive devices as appropriate. Pharmacologic treatment includes: o NSAIDs as initial therapy for hip and knee arthritis; consider topical NSAIDS before oral NSAIDs in knee and hand OA but not hip OA o duloxetine (has shown efficacy for pain from knee OA) : . tramadol; considered in limited circumstances if other treatments are contraindicated or ineffective \ o intra-articular glucocorticoids for acute exacerbations of knee OA . intra-articular hyaluronic acid injection for knee OA not responding to other treatments 372

Rheumatology Joint arthroplasty of the hip or knee is indicated for pain that does not respond to nonsurgical treatment, especiallywhen lifestyle or activities of daily living are affected. DON'T BE TRICKED . Patients with signs of inflammation should not undergo intra-articular glucocorticoid therapy until synovial fluid analysis excludes infection. o Do not select arthroscopic lavage, debridement, or closed lavage for knee OA. o Do not select oral supplements with glucosamine or chondroitin in patients with knee or hip OA. o Do not select oral NSAIDs for patients with CAD, HF, CKD, or ulcer disease. Hand X-lay, Osteoarthritis: Joint-space nanowing, sclerosis, and osteophyte formation are shown. Prom inent nvolvement of the Pl P a nd D I P joints ind icates 0A. i Knee X.ray. Osteoarthritis: Medial compart- ment joint-space narrowing and subchondral scle- rosis consistent with 0A are shown. Spondyloarthritis Key Considerations Spondyloarthritis comprises several systemic inflammatory joint disorders that share distinct clinical, radiographic, and genetic features. The spondyloarthritis disorders are: o psoriatic arthritis o reactive arthritis . ankylosing spondylitis o enteropathic arthritis Common characteristics include: : o inflammatory spine and sacroiliac disease i o asymmetric inflammation in <4 peripheral joints (bpically large joints) : o inflammation at the sites of ligament and tendon insertion (enthesitis) o the presence of HLA-B-27 373

Rheumatology o extra-articular conditions, such as aortitis, colitis, urethritis, uveitis, and psoriasis o absent rheumatoid factor and anti-CCP antibodies DON'T BETRICKED . HLA-B'27 testing may support, but cannot independently confirm or exclude, a diagnosis of ankylosing spondylitis or other forms of spondyloarthritis. Psoriatic Arthritis Characteristic findings are classic psoriasis and nail pitting in a patient with joint pain and stiffness. Skin involvement com- monly precedes joint inflammation, although 15o/o of patients first develop joint inflammation. Sausage-shaped fingers or toes (dactylitis), often involving the DIP joints, are seen in psoriatic arthritis and help distinguish psoriatic arthritis from RA. Testing: Explosive onset or severe flare-up of psoriatic arthritis should prompt testing for HIV infection. Treatment r Choose oral or topical NSAIDs or glucocorticoid injection for limited disease. . Select TNF inhibitor, methotrexate, or an interleukin-l7 inhibitor for more active disease. o Weight loss and smoking cessation may positively affect disease activity. o NSAIDs, antimalarial drugs, and withdrawal from oral glucocorticoids may exacerbate psoriasis. DO]I'T BE TRICKED . No relationship exists between the extent of skin and joint disease in patients with psoriatic arthritis. Dactylitb: Diffuse swelling of the left third and fourth toes and right fourth toe characteristic of dactylitis. Psorlasis: Tiny pits scattered over the nail plate resulting from psoriatic involvement of the nail matrix. Reactive Arthritis Reactive arthritis is an acute aseptic inflammatory arthritis that occurs 2 to 3 weeks after an infectious event originating in the GU or GI tract. Characteristic findings include o monoarthritis or acute asymmetric oligoarthritis (usually in weight-bearing joints) . dactylitis 374

I I I I I Rheumatology I L I . enthesopathy (especially ofthe Achilles tendon) i o sacroiliitis Patients may also have psoriasiform lesions on palms and soles (keratoderma blennorrhagicum) or glans penis (circinate : balanitis). L Testing/Treatment l i o Antibiotic treatment of reactive arthritis caused by enteric organisms is not usually warranted. i o Patients with severe infections or immunosuppression, or I those with Chlamgdia trachomatis infection, may benefit from antibacterial therapy. r In the absence of an ongoing infection, reactive arthritis : ! is usually self limited, and symptoms resolve within 6 months; select symptomatic treatment with NSAIDs : and glucocorticoid injections for these patients with mild : disease. : DON'T BE TRICKED ' The classic triad ofarthritis, conjunctivitis, and urethritis Keratoderma Blennorrhagicum: Keratoderma blennorrhagicum, a psoriasis, (or cervicitis) is found in only one third of patients with like lesion of the palms and s-oles, is associated with reactive arthritis. reactive arthritis. . Do not prescribe chronic antibiotic therapy for patients with reactive arthritis. TEST YOURSELF A 33-year old man has a 3 month history of left shoulder and right ankle pain and a left inflamed second toe. He had 4 days of bloody diarrhea 3 months ago. ANSWER: For diagnosis, choose reactive arthritis, consistent with a previous enteric infection. Ankylosing Spondylitis Ankylosing spondylitis primarily affects the spine and sacroiliac joints. It also may involve the shoulders and hips. The small peripheral joints are not affected. Ankylosing spondylitis occurs most often in patients <45 years and presents as chronic inflam- matory low back pain (more than t hour of morning stiffness). Characteristic symptoms are pain and stiffness that worsen at night and are relieved with physical activity or heat. Physical examination findings include: o decreased hyperextension, forward flexion, lateral flexion, and axial rotation . diminished chest expansion o enthesitis of the plantar fascia and Achilles tendon insertion

Ankylosing Spondylitis Ankylosing spondylitis primarily affects the spine and sacroiliac joints. It also may involve the shoulders and hips. The small peripheral joints are not affected. Ankylosing spondylitis occurs most often in patients <45 years and presents as chronic inflam- matory low back pain (more than t hour of morning stiffness). Characteristic symptoms are pain and stiffness that worsen at night and are relieved with physical activity or heat. Physical examination findings include: o decreased hyperextension, forward flexion, lateral flexion, and axial rotation . diminished chest expansion o enthesitis of the plantar fascia and Achilles tendon insertion Extra articular manifestations include acute anterior uveitis (most common), aortic valvular regurgitation, aortic aneurysm, cardiac conduction defects, apical pulmonary fibrosis and cavitation, and cauda equina syndrome. A patient with ankylosing spondylitis with increased pain and mobility of the neck following a minor accident may have a fracture and requires an urgent CT ofthe cervical spine. Laboratory testing: For patients with normal or nondiagnostic plain x rays of the spine and sacroiliac joints, a positive result on HIA-B'27 testing can be useful for deciding to pursue advanced imaging. 375

Rheumatology Imaging: X rays of the sacroiliac joints show sacroiliitis with erosions, pseudowidening of the joints, sclerosis. and ankylosis X rays ofthe spine show subchondral bony sclerosis, vertebral body squaring, and bony ankylosis ("bamboo spine"). When radiographic findings are equivocal or absent, MRI can detect the early changes of sacroiliitis. DON'T BE TRICKED . Ankylosing spondylitis occurs in both men and women. . HLA-B.27 is never diagnostic but can help determine risk for spondyloarthritis in uncertain situations. Treatment: Select exercise to preserve range of motion and strengthen the spine extensor muscles to prevent kyphosis. Drug therapy consists of o continuous NSAIDs (not aspirin) (disease modifying in ankylosing spondylitis) o glucocorticoid injections for recalcitrant enthesitis and per- sistent synovitis . TNF inhibitors if inadequate response of axial disease to X-rays, Ankylosing Spondylitis: Sclerosis and erosions of sacroiliac joints and NSAIDS bridging of the intervertebral disks by syndesmophytes are characteristic of anky- r sulfasalazine for peripheral joint disease losing spondylitis. DON'T BE TRICKED . Do not prescribe methotrexate, sulfasalazine, or hydroxychloroquine for patients with axial disease because they are ineffective. Select a TNF inhibitor. TESTYOURSELF A 40-year old man with ankylosing spondylitis has increasing neck pain alter a fall from the second rung of a ladder 5 days ago. ANSWER: For diagnosis, choose acute cervical fracture. For management, select neck immobilization and emergent CT. Enteropathic Anhritis Ankylosing spondyloarthritis. isolated sacroiliitis, and peripheral arthritis occur in patients with Crohn disease and ulcerative colitis. Treatment: For spondyloarthritis associated with bowel involvement, medications to address peripheral arthritis and bowel inflammation include sulfasalazine, azathioprine, methotrexate, and glucocorticoids. The TNF inhibitors are especially useful for bowel and joint symptoms, including spine disease. DON'T BE TRICKED . NSAIDS may result in worsening of associated IBD.

Treatment: For spondyloarthritis associated with bowel involvement, medications to address peripheral arthritis and bowel inflammation include sulfasalazine, azathioprine, methotrexate, and glucocorticoids. The TNF inhibitors are especially useful for bowel and joint symptoms, including spine disease. DON'T BE TRICKED . NSAIDS may result in worsening of associated IBD. Systemic Lupus Erythematosus Diagnosis Approximately 90'1, of adult patients with SLE are women. The most common presenting clinical features that differentiate patients with SLE from those with other mimicking conditions include malar rash, photosensitiviff, inflammatory arthritis, 376

L t t Rheumatology t weight loss, and fever along with laboratory features such as ANA positivity, low complement levels, and presence of t lupus specific antibodies. t L Ently Criterion t Antinuclear antibody at a titer >1:80 on Hep-2 cells or equivalent positive test result I L t lf absent, do not classi! as SLE t lf presenq apply additive criteria L I L t Additlve Crherla Do not count a criterion if there is a more likely explanation than SLE. Occurrence of a criterion on at least one occasion is L sufficient. SLE classification requires at least one clinical criterion and >1 0 points. Criteria need not occur simultaneously. I Within each domain, only the highest weighted criterion is counted toward the total score. I t I Clinical Domains and Critcria Welght lmmunologic Domainl and Crherla Weight ; Constitutional Antlphosphollpld antlbodicr t Fever (temperature >38.3 oC) 2 Anticardiolipin antibodies or Anti-pr-glycoprotein I antibodies or ; Lupus anticoagulant 2 Hematologic Complement proteln: Leukopenia (<4000/pL [4.0 x 1 O'lL]) 3 Low C3 or low C4 3 Thrombocytopenia (<1 00,000/pL [1 00 x 1 0'glL]) 4 Low C3 and low C4 4 Autoimmune hemolysis (with positive 4 direct antiglobulin test result)

Hematologic Complement proteln: Leukopenia (<4000/pL [4.0 x 1 O'lL]) 3 Low C3 or low C4 3 Thrombocytopenia (<1 00,000/pL [1 00 x 1 0'glL]) 4 Low C3 and low C4 4 Autoimmune hemolysis (with positive 4 direct antiglobulin test result) Neurcprychiatric SLE-spocifi c entibodies Delirium 2 Anti-dsDNA antibody or Psychosis (delusions and hallucinations in Anti-Smith antibody 6 absence of delirium) 3 Seizure (primary generalized or focal seizure) 5 Mucocutaneour (obcerved by cllnidan) Nonscarring alopecia 2 Oral ulcers 2 Subacute cutaneous or discoid lupus 4 Acute cutaneous lupus 6 Serosal Pleural or pericardial effusion 5 Acute pericarditis 6 Musculoskeletal Joint involvement (synovitis in >2 joints or tenderness of >2 joints with >30 minutes of morning stiffness) 6 Renal Proteinuria >0.5 gl24 h (or equivalent spot urine Protein-to-creatinine ratio) 4 Renal biopsy showing class ll or V lupus nephritis 8 Renal biopsy showing class lll or lV lupus nephritis 10 Classify as systemic lupus erythematosus with a score of 10 or more if entry criterion is fulfilled. Classifiotion Criteria for S[E: Hep-2 : human epithelial 2. 377

Rheumatology Additional SLE pearls: . Normocytic, normochromic anemia of inflammation is common; autoimmune hemolytic anemia occurs in approximately 10'7, of cases and correlates with SLE activity. o Joints are affected in 90% of patients with SLE; many patients have arthralgia, and a much smaller group exhibits arthritis. o Periarticular inflammation can result in reducible subluxation of the digits, swan neck deformities, and ulnar deviation (Jaccoud [nonerosive] arthropathy). . Pain or limitation of motion of the hips suggests osteonecrosis. o Active kidney disease should be suspected when there is active urine sediment or proteinuria >500 mgl24h. . Nephritis and a rising serum creatinine level are indications for urgent kidney biopsy. . SLE parenchymal lung involvement is rare, and lung infiltrates are more likely to be infectious. . Clinical manifestations of APLA/LAC include venous and arterial thrombosis, miscarriage, livedo reticularis, cytopenias, and cardiac valve thickening/vegetations. . Drug-induced lupus is most often caused by hydralazine, procainamide, isoniazid, minocycline, or TNF inhibitors; symptoms are usually limited to arthritis, fever, and serositis. DON'T BE TRICKED r Do not diagnose SLE in a patient with a positive ANA and facial rash that involves the nasolabial folds; consider rosacea instead. Testing The ANA assay is sensitive but not specific for diagnosing SLE. Assays for anti dsDNA and anti Sm antibodies are highly specific. Anti-dsDNA antibodies correlate with disease activity. Activation of the complement pathway, manifested by depressed serum C3 and C4 levels, often accompanies major flares of SLE. In drug-induced lupus, ANA assays are positive, but anti-dsDNA and anti-Sm antibody assays are negative. Antihistone antibody assay may be positive. DON'T BE TRICKED . An isolated low titer ANA by immunofluorescence assay (1:40-1:80) is not likely to indicate systemic lupus. . Myalgia, arthralgia, and fatigue are insufficient reasons by themselves to check an ANA panel. o Monitoring serial ANA titers is not warranted because these values do not reflect disease activity. Treatment Major therapeutic points:

DON'T BE TRICKED . An isolated low titer ANA by immunofluorescence assay (1:40-1:80) is not likely to indicate systemic lupus. . Myalgia, arthralgia, and fatigue are insufficient reasons by themselves to check an ANA panel. o Monitoring serial ANA titers is not warranted because these values do not reflect disease activity. Treatment Major therapeutic points: o Manage arthritis with NSAIDs and hydroxychloroquine. . Hydroxychloroquine should be continued indeflnitely in most patients to help prevent flares of SLE, even in patients with quiescent disease. o Manage photosensitive cutaneous lupus with protective clothing, sun block (UVA and UVB), topicat glucocorticoids, and hydroxychloroquine. o Manage life-threatening disease with high-dose glucocorticoids and (usually) cyclophosphamide or mycophenolate mofetil. . Reduce atherosclerosis risk factors in all patients. o Prescribe vitamin D and calcium supplements for all patients and bisphosphonates for those with osteoporosis and osteopenia. 374

Rheumatology DON'T BE TRICKED . Patients taking hydroxychloroquine require annual routine ophthalmologic examinations. . Medications that can be used in pregnant patients with SLE include hydroxychloroquine and prednisone. Matar Skin Rash: Bright red, sharply demarcated plaques in a butterfly pattern that spares the nasolabial folds and areas beneath the nose and lower lip are associ, ated with SLE. Systemic Sclerosis Diagnosis The presence of typical skin findings and one or more of the following features support a diagnosis: . Raynaud phenomenon (most common early manifestation) . digital pitting o interstitial lung disease . sclerodactyly (inability to tent the skin over the fingers) .PH . GERD and esophageal dysmotility . pseudo obstruction (small bowel) . malabsorption owing to small intestinal bacterial overgrowth . calcinosis (typically in the hands, forearms, elbows, gluteal region, and iliac crest) r inflammatory arthritis, particularly in the DIP joints and wrists (may develop acro osteolysis, or resorption of the terminal bony tuft of the fingers and toes) o kidney disease The primary cause of morbidity and mortality in patients with SSc is pulmonary disease. Scleroderma renal crisis is characterized by hypertension with microangiopathic hemolytic anemia, thrombocytopenia, and AKI with mild proteinuria and bland urine. It may be precipitated by use of glucocorticoids. Gastric antral vascular ectasia (GAVE, or "watermelon stomach") can result in recurrent bleeding and chronic anemia. SSc is classified according to the degree of skin involvement.

Scleroderma renal crisis is characterized by hypertension with microangiopathic hemolytic anemia, thrombocytopenia, and AKI with mild proteinuria and bland urine. It may be precipitated by use of glucocorticoids. Gastric antral vascular ectasia (GAVE, or "watermelon stomach") can result in recurrent bleeding and chronic anemia. SSc is classified according to the degree of skin involvement. STUDY TABIE: Differentiating Diffuse from Limited Cutaneous Systemic Sclerosis Findings Diffuse Cutaneous SSc Limited Cutaneous SSc Skin findings Skin thickening proximal to the elbows and knees, including Skin thickening distalto the elbows chest and abdomen; may affect the lateral face and knees; may affectthe lateral face j Antibodies ANA and anti-Scl-70 antibodies ANA and anticentromere antibodies Pulmonary disease lnterstitial lung disease more common PH more common Scleroderma renal crisis Present Absent CREST syndrome Usually absent May be present CREST = calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia 379

Rheumatology DOil'T BE TRICKED o Nailfold capillary destruction and dilated capillary loops distinguish early SSc with Raynaud phenomenon from primary Raynaud disease. Testing Pulmonary disease: All patients should undergo pulmonary function testing and high-resolution CT at the time of initial SSc diagnosis, and pulmonary function testing with Dt-co should be repeated every 6 to 12 months. Patients with SSc should undergo echocardiography annually, or more frequently, and for new or concerning symptoms suggestive of PAH. Right heart catheteri zation is required for definitive diagnosis. Small bowel bacterid overgrowth: Hydrogen breath test can diagnose small bowel bacterial overgrowth. Kidney disease: Up to 50% of patients have mild proteinuria, elevated plasma creatinine concentration, and/or hypertension, but most do not progress to AKI or CKD. Several diseases present with scleroderma-like features.

Testing Pulmonary disease: All patients should undergo pulmonary function testing and high-resolution CT at the time of initial SSc diagnosis, and pulmonary function testing with Dt-co should be repeated every 6 to 12 months. Patients with SSc should undergo echocardiography annually, or more frequently, and for new or concerning symptoms suggestive of PAH. Right heart catheteri zation is required for definitive diagnosis. Small bowel bacterid overgrowth: Hydrogen breath test can diagnose small bowel bacterial overgrowth. Kidney disease: Up to 50% of patients have mild proteinuria, elevated plasma creatinine concentration, and/or hypertension, but most do not progress to AKI or CKD. Several diseases present with scleroderma-like features. $YUDY T&&*"{r Scleroderma-like Conditions Condition Features Considerations Eosinophilic fasciitis Edema (orange peel induration) of proximal Skin biopsy shows lymphocytes, plasma cells, extremities; sparing of hands and face; and eosinophils peripheral eosinophilia Treat with glucocorticoids Nephrogenic system ic f brosis i Exposure to gadolinium in kidney disease; Changes in use and formulation of gadolinium brawny, wood-like induration of extremities, have reduced incidence, which is now rare sparing the digits Scleredema lndurated plaqueVpatches on back, Seen in long-standing diabetes shoulder girdle, and neck Scleromyxedema Waxy, yellow-red papules over thickened Associated with multiple myeloma orAL skin offace, uppertrunk, neck, and arms amyloidosis Chronic GVHD Lichen planus-like skin lesions or localized Occurs most commonly after HSCT or generalized skin thickening

$YUDY T&&*"{r Scleroderma-like Conditions Condition Features Considerations Eosinophilic fasciitis Edema (orange peel induration) of proximal Skin biopsy shows lymphocytes, plasma cells, extremities; sparing of hands and face; and eosinophils peripheral eosinophilia Treat with glucocorticoids Nephrogenic system ic f brosis i Exposure to gadolinium in kidney disease; Changes in use and formulation of gadolinium brawny, wood-like induration of extremities, have reduced incidence, which is now rare sparing the digits Scleredema lndurated plaqueVpatches on back, Seen in long-standing diabetes shoulder girdle, and neck Scleromyxedema Waxy, yellow-red papules over thickened Associated with multiple myeloma orAL skin offace, uppertrunk, neck, and arms amyloidosis Chronic GVHD Lichen planus-like skin lesions or localized Occurs most commonly after HSCT or generalized skin thickening Raynaud Phenomenon: Areas of vasospastic skin blanching seen in a patient *lercdactyly: Ihickening and induration of the skin over the finqers and wrists with Raynaud phenomenon. are characteristic of scleroderma. DO]{'T BE TRICKED . Skin thickening or tightening without Raynaud phenomenon is not SSc but another scleroderma-like condition. 380

Rheumatology Fibromyalgia Diagnosis Diagnostic clues include : o widespread pain . waking unrefreshed . cognitive symptoms o polysymptomatic distress across multiple systems Testing Avoid excessive testing. Initial laboratory studies may include a CBC, chemistry panel, TSH, and ESR or CRB which are normal. Treatment Nonpharmacologic therapy, such as assessment ofpsychosocial stressors, regular aerobic exercise, and CBT, should be initiated as first-line therapy in all patients. Pregabalin, duloxetine, and milnacipran are FDA approved for fibromyalgia. Each provides a modest benefit over placebo. DOil'T BE TRICKED r Do not obtain ANA, rheumatoid factor, or anti-CCP antibodies in the evaluation of fibromyalgia. o Do not diagnose flbromyalgia in the presence of red flags such as anemia, fever, synovitis, and weight loss. r Do not use opioids or NSAIDS in the treatment of flbromyalgia. Gout Diagnosis Gout progresses through three stages o acute intermittent gout . intercritical gout (the time between attacks of acute gout) o chronic recurrent and tophaceous gout (characterized by persistent synovitis and possible formation of tophi) Characteristic findings of acute intermittent gout include self-limited acute attacks of monoarticular arthritis (typically of the first MTP joint). Tophi are nodular deposits ofmonosodium urate that develop on extensor surfaces ofthe extremities, on finger pads, and along tendons. Hydrochlorothiazide is a common drug trigger of acute gout. Losartan, which has a modest uricosuric effect, is an effective antihypertensive in patients with gout. Transplantation-related gout is associated with the use ofcalcineurin antagonists (cyclo- sporine). Lead toxicity may present with gout, kidney disease, and abdominal pain. 382

L t t Rheumatology t t Testing I L Laboratory: I F . Monosodium urate crystals (needle-shaped, negatively I birefringent crystals) in the joint fluid and urate tophi are i diagnostic. Crystals within synovial fluid neutrophils define acute gout. o The synovial fluid leukocyte count ranges from 2000 to 100,000/pL. F o In all patients zuspected of having acute gout, synovial fluid Gram stain and cultures must be obtained to exclude infection. Imaging: X-rays of patients with chronic gout show bone erosions Monosodium Urate Crystals: Aspiration of a tophus showing monosodium urate with overhanging edges. Subcortical cysts and periarticular crystals (needle-shaped, negatively birefringent crystals) as viewed with polarized erosions may also be seen. m icroscopy. DON'T BE TRICKED o An elevated serum urate level alone is not diagnostic of gout. . A normal serum urate level at the time of an acute attack does not rule out gout. . Synovial fluid leukocyte counts greater than SO,OOO/pL should raise suspicion for a concurrent bacterial joint infection even when monosodium urate crystals have been identified. Treatment Acute Gout Flare . Use NSAIDs, colchicine, and glucocorticoids (in any form) as first-line therapies. o Select oral glucocorticoids when NSAIDs are unsafe (in older adult or postoperative patients, patients requiring anticoagu- lation, and those with CKD or PUD). r Prescribe intra articular glucocorticoids for a single joint if other interventions are ineffective or contraindicated. Urate-Lowering Therapy o Initiating urate lowering therapy is strongly recommended for any of the following: >1 subcutaneous tophi, evidence of radiographic damage, >2 gout flares annually. o Medications that raise serum urate levels, such as thiazide diuretics, should be discontinued if possible. Principles of treatment with a urate-lowering agent include:

Treatment Acute Gout Flare . Use NSAIDs, colchicine, and glucocorticoids (in any form) as first-line therapies. o Select oral glucocorticoids when NSAIDs are unsafe (in older adult or postoperative patients, patients requiring anticoagu- lation, and those with CKD or PUD). r Prescribe intra articular glucocorticoids for a single joint if other interventions are ineffective or contraindicated. Urate-Lowering Therapy o Initiating urate lowering therapy is strongly recommended for any of the following: >1 subcutaneous tophi, evidence of radiographic damage, >2 gout flares annually. o Medications that raise serum urate levels, such as thiazide diuretics, should be discontinued if possible. Principles of treatment with a urate-lowering agent include: r The American College of Rheumatolory and European League Against Rheumatism support a "treat-to-target" approach, reducing the serum urate level to less than 6.0 mg/dl. . Treat most patients with allopurinol. . Doses of allopurinol must be lowered for patients with kidney impairment. When starting allopurinol, also begin low dose colchicine (or an NSAID or prednisone) to prevent acute gout; colchicine (or NSAID) can be discontinued 3 to 6 months after the serum urate level stabilizes. . Allopurinol should be avoided in high-risk populations (Han Chinese, Taiwanese, Korean, Black patients) if positive for HLA-B-58:01. . Febuxostat is useful if patients cannot tolerate allopurinol and in patients with CKD. 383

I I \ I Rheumatology 'l Patients with kidney disease who are treated with allopurinol, I especially those taking hydrochlorothiazide, have an increased risk for a rare but potentially fatal hypersensitivity syndrome I characterized by severe dermatitis, fever, eosinophilia, hepatic I necrosis, and acute nephritis. 1 I I I : DOX'T BETRICKED t . Do not select NSAIDs for patients with gout who also have I l

Patients with kidney disease who are treated with allopurinol, I especially those taking hydrochlorothiazide, have an increased risk for a rare but potentially fatal hypersensitivity syndrome I characterized by severe dermatitis, fever, eosinophilia, hepatic I necrosis, and acute nephritis. 1 I I I : DOX'T BETRICKED t . Do not select NSAIDs for patients with gout who also have I l CKDoTPUD. . Urate-lowering therapy is of no benefit in the treatment i ofan acute gout attack. . Do not use allopurinol or febuxostat with azathioprine, Chronlc fophaceous Gout Swollen interphalangeal joints and multiple tophi because the combination can result in elevated characteristic of chronic tophaceous gout. azathioprine levels. . Do not use uricosuric therapy (e.g., probenecid) in patients with a low estimated GFR who are at risk for nephrolithiasis or CKD. o Do not prescribe colchicine for patients with kidney failure.

CKDoTPUD. . Urate-lowering therapy is of no benefit in the treatment i ofan acute gout attack. . Do not use allopurinol or febuxostat with azathioprine, Chronlc fophaceous Gout Swollen interphalangeal joints and multiple tophi because the combination can result in elevated characteristic of chronic tophaceous gout. azathioprine levels. . Do not use uricosuric therapy (e.g., probenecid) in patients with a low estimated GFR who are at risk for nephrolithiasis or CKD. o Do not prescribe colchicine for patients with kidney failure. TESTYOURSELF A 7S-year-old man has a 6-hour history of an acutely painful and swollen left first MTP joint. Two days ago, he had an MI. His serum creatinine level is 1.7 mg/dl. ANSWER: For diagnosis, select acute gout. For management, choose aspiration of the joint and treatment with an intra-articular glucocorticoid after infection is excluded. Calciu m Plrrophosphate Deposition Diagnosis The four clinical presentations ofCPPD are: o asymptomatic (chondrocalcinosis/cartilage calcification) . acute CPP crystal arthritis (pseudogout) o chronic CPP crystal inflammatory arthritis r OA with CPPD Characteristic findings in acute CPP crystal arthritis (pseudogout) are: o inflammation localized to one joint, affecting the knee, wrist, shoulde! or ankle . acute onset of several painful joints following trauma, severe illness, or surgery o rhomboid-shaped, positively birefringent synovial fluid crystals Characteristic findings in chronic CPP crystal arthropathy include: . two distinct patterns: chronic CPP crystal inflammatory arthritis and OA with CPPD o chronic CPP crystal inflammatory arthritis resembles RA o OA with CPPD exhibits OA findings in atypical locations including wrist, MCp, or shoulder joints 384

Rheumatology Characteristic findings in asymptomatic CppD are: o triangular fibrocartilage ol the wrist joint (space between the carpal bones and distal ulna) o menisci <,rf the knee joint (appearing as a line in the cartilage) . symphysis pubis CPPD may be associated with underlying metabolic disorders. Screen patients with CPPD who are <S0 years of age fbr: o hemochromatosis . hypomagnesemia . hyperparathyroidism X-ray of Knees, Chondrocalcinosis: Linear calcifications of the meniscus and ' hypothyrtlidism articular cartilage are characteristic of CPPD. DON'T BE TRICKED . The absence ofchondrocalcinosis on x ray does not rule out CPPD. Treatment For acute CPl'}D. local treatment is intra articular glucocorticoid injection; systemic treatr.nent includes NSAIDs, colchicine, and glucocorticoids (oral, intramuscular, or parenteral). For chronic inflammatory CPP, choose low dose colchicine, low dose NSAIDs, or low dose glucocorticoids. For OA with CPP, treatment is the same as for OA without CPPD. lnfectious Arthritis Diagnosis Infectious arthritis typically presents with pain, swelling, warmth, and erythema with lbver and constitutional symptoms. Previously damaged joints are at increased risk for invrilvement; new inflammation of a single joint in a paticltt with well controlled inflammatory arthritis is highly suggestive. Physical examination shows loss of'active and passive range of motion. Skir.r examination can reveal signs suggesting gonococcal infection (pustular skin lesions) or potential portals ofentry for pathogens (scratches, bites, or lbreign bodies). Common organisms causing infectious arthritis: . Gram positive organisms are the most common causes of infectious arthritis in aclults. Sfophglococcus oureus is the most common organism, regardless of age or underlying risk factors. . Gonococcal arthritis is the most common lorm of bacterial arthritis in young, sexually active persons. Disseminated gonococcal infection can produce two distinct syndromes: arthritis-dermatitis syndrome and purulent gonococcal arthritis.

. Gram positive organisms are the most common causes of infectious arthritis in aclults. Sfophglococcus oureus is the most common organism, regardless of age or underlying risk factors. . Gonococcal arthritis is the most common lorm of bacterial arthritis in young, sexually active persons. Disseminated gonococcal infection can produce two distinct syndromes: arthritis-dermatitis syndrome and purulent gonococcal arthritis. o Patients with the arthritis-dermatitis syndrome have cutaneous lesions that progress from papules or macules to pustules that are sterile on culture, tenosynovitis, and polyarthralgia. Fever and chills are comnlon. Obtain NAAT on santples from genital, rectal, and pharyngeal sites. . Patients with purulent gonococcal arthritis clo not have systernic f.eatures or dermatitis. Synovial fluid cultures for N. gonorrhoeae are positive in 507, ofintected patients. o Evaluate fbr deficiencies in terminal complement components for patients with recurrent episodes of disser.r.rinated gonococcal infection. 38s

Rheumatology Less common causes of infectious arthritis: o Gram-negative infections are more common in prosthetic joints; older, immunosuppressed, and postoperative patients; and in those with IV catheters. . Tuberculous arthritis is typically an indolent, monoarticular arthritis involving the hip or knee; it does not cause systemic features. Gram stain and culture of synovial fluid are positive in only 50'7,. Diagnosis is made by synovial biopsy' . Lyme arthritis is a late stage manifestation of Lyme disease most commonly affecting the knee. . Fungal arthritis typically manifests as subacute monoarthritis in patients with a systemic fungal infection' Always select arthrocentesis with Gram stain; polarized microscopy for crystals; cell count; and differential for an acutely swollen, painful joint (monoarthritis). DON'T BETRICKED . Infectious arthritis can develop in patients with gout or acute CPP crystal arthritis (pseudogout), and the presence of crystals in synovial fluid does not exclude a concomitant infection. . X rays are not helpful in the early diagnosis of acute native joint infection. Treatment Begin immediate empiric antibiotic therapy for suspected bacterial arthritis plus perform joint drainage. Drain reaccumu- lated purulent joint fluid. Manage infected prosthetic joints with surgery plus antibiotics, usually for 3 to 6 weeks.

DON'T BETRICKED . Infectious arthritis can develop in patients with gout or acute CPP crystal arthritis (pseudogout), and the presence of crystals in synovial fluid does not exclude a concomitant infection. . X rays are not helpful in the early diagnosis of acute native joint infection. Treatment Begin immediate empiric antibiotic therapy for suspected bacterial arthritis plus perform joint drainage. Drain reaccumu- lated purulent joint fluid. Manage infected prosthetic joints with surgery plus antibiotics, usually for 3 to 6 weeks. STUBY TABLE: lnfectious Ar.thritis Treatment Based on Suspected Pathogen Likely or ldentified Pathogen First-line Therapy SecondJineTherapy Comments Gram-positive cocci MRSA Vancomycin Clindamycin; Narrow treatment to MSSA daptomycin; linezolid coverage as appropriate based on sensitivity data MSSA Nafcillin; cefazolin Gram-negative bacilli Enteric gram-negative bacilli Third-generation cephalosporin Fluoroquinolones (e.g., ceftriaxone or cefotaxime) Pse u d o m o n as ae ru g i nosa Ceftazidime; cefepime; Carbapenems; piperacillin-tazobactam aztreonam; flu oroq u inolones

STUBY TABLE: lnfectious Ar.thritis Treatment Based on Suspected Pathogen Likely or ldentified Pathogen First-line Therapy SecondJineTherapy Comments Gram-positive cocci MRSA Vancomycin Clindamycin; Narrow treatment to MSSA daptomycin; linezolid coverage as appropriate based on sensitivity data MSSA Nafcillin; cefazolin Gram-negative bacilli Enteric gram-negative bacilli Third-generation cephalosporin Fluoroquinolones (e.g., ceftriaxone or cefotaxime) Pse u d o m o n as ae ru g i nosa Ceftazidime; cefepime; Carbapenems; piperacillin-tazobactam aztreonam; flu oroq u inolones Gram-negative cocci N. gonorrhoeae lV ceftriaxone for >7 days Fluoroq u inolones ln absence of specific culture (only if culture sensitivity data, "stepping Oral doxycycline, 100 mg orally sensitivities confirm down" to oral therapy is no twice daily for 7 days if susceptibility) longer recommended because Chlamydia infection not of increasing resistance of excluded N. gonorrhoeae to commonly used oral agents Suspected bacterial infection, no Gram stain Always initiate therapy with Vancomycin; vancomycin + Appropriate to start with broad coverage for MRSA; consider third-generation cephalosporin; antibiotic coverage; narrow patient risk factors and community or vancomycin + coverage if culture data patterns of infection; consider antipseudomonal antibiotic become available coverage for gram-negative organism if patient is immunocompromised and at risk for gonococcal infection (Continued on the next page)

Gram-negative cocci N. gonorrhoeae lV ceftriaxone for >7 days Fluoroq u inolones ln absence of specific culture (only if culture sensitivity data, "stepping Oral doxycycline, 100 mg orally sensitivities confirm down" to oral therapy is no twice daily for 7 days if susceptibility) longer recommended because Chlamydia infection not of increasing resistance of excluded N. gonorrhoeae to commonly used oral agents Suspected bacterial infection, no Gram stain Always initiate therapy with Vancomycin; vancomycin + Appropriate to start with broad coverage for MRSA; consider third-generation cephalosporin; antibiotic coverage; narrow patient risk factors and community or vancomycin + coverage if culture data patterns of infection; consider antipseudomonal antibiotic become available coverage for gram-negative organism if patient is immunocompromised and at risk for gonococcal infection (Continued on the next page) 386

Rheumatology STUDY TABLE: lnfectious Arthritis Treatment Based on Suspected Pathogen (Continued) Likely or ldentified Pathogen First-line Therapy Second-lineTherapy Comments Confirmed diagnosis Borrelia bu rgdorferi (lyme arthritis) Oral doxycycline, amoxicillin, or lf inadequate response, lV cefuroxime axetil x 28 days ceftriaxone x 2-4 weeks M yco b acte ri u m tu be rcu losi s 3- or 4-drug treatment (e.9., Duration may vary from isoniazid, pyrazinamide, 6 months or longer depending rifampin, ethambutol, on drug regimen (shorter streptomycin) treatment if rifampin is used) Fungal infections Amphotericin B, echinocandin, or Prolonged treatment courses of azoles (fluconazole, itraconazole, several months may be voriconazole, posaconazole) needed; maintenance therapy depending on suspected may be required in high-risk organism or culture data patients DON'T BE TRISKED r Suspect tubercular or fungal arthritis ifthe appropriate empiric antibacterial therapy is unsuccessful TESTYOURSELF A 28 year old woman has a 9-day history of arthritis, fever, and chills followed by pain and swelling of the second and third MCP joints. As swelling resolved, the right wrist became inflamed. As the wrist improved, the right knee became inflamed. She also has a s-mm vesicle surrounded by erythema on the forearm. ANSWER: For diagnosis, choose disseminated gonococcal infection. For management, select ceftriaxone for gonorrhea and doxy cycline for empiric treatment of chlamydia.

TESTYOURSELF A 28 year old woman has a 9-day history of arthritis, fever, and chills followed by pain and swelling of the second and third MCP joints. As swelling resolved, the right wrist became inflamed. As the wrist improved, the right knee became inflamed. She also has a s-mm vesicle surrounded by erythema on the forearm. ANSWER: For diagnosis, choose disseminated gonococcal infection. For management, select ceftriaxone for gonorrhea and doxy cycline for empiric treatment of chlamydia. I nflam matory Myopathies Diagnosis The major inflammatory myopathies are polymyositis, dermatomyositis, and inclusion body myositis. Certain medications (glucocorticoids, statins) or alcohol may also cause a toxic myopathy. The characteristic finding in polymyositis and dermatomyositis is the gradual onset of painless proximal muscle, pharyngeal, and respiratory muscle weakness. Photosensitivity rashes are commonly associated with dermatomyositis. The presence of Gottron papules (scaly, purplish papules and plaques over the metacarpal and interphalangeal joints) or a heliotrope rash (edematous lilac discoloration of periorbital tissue) is virtually diagnostic of dermatomyositis. An antisynthetase syndrome is characterized by interstitial lung disease, inflammatory polyarthritis, fever, Raynaud phenomenon, mechanic's hands (scaly, rough, dry cracked horizontal lines on the palmar and lateral aspects of the fingers), and increased risk of sudden death. It can be seen in patients with polymyositis or dermatomyositis but not with inclusion body myositis' Inclusion body myositis is characterized by the insidious onset of symptoms, which involve proximal and distal muscles, frequently with an asymmetric distribution. Quadriceps, wrist, and finger flexor muscle weakness is common' Testing Diagnostic tests for inflammatory myositis include measurement of serum CK and aldolase levels and EMG' Muscle biopsy is the definitive study. MRI may assess the degree of muscle inflammation and damage and may be helpful when other diagnostic studies are equivocal or to identify the most promising biopsy site' 387

Rheumatology Autoantibodies to aminoacyl-transfer (t)nNn synthetase enzymes (e.g., anti-Jo 1 antibodies) are associated with the antisyn- thetase syndrome. DON'T BE TRICKED . Serum AST and ALT levels may be elevated in myositis, mimicking liver disease. . Muscle pain in patients with an inflammatory myopathy is atypical and, if present, is generally mild. 3?UDY fABLE: Mimics of Polymyositis lf you see this... Diagnose this... Muscle {asciculations ALS Oculomotor weakness with ptosis MG Proximal muscle tenderness Polymyalgia rheumatica Muscle atrophy, hyporeflexia Peripheral neuropathy Goiter, delayed reflexes, weight gain Hypothyroidism Treatment with a statin Statin myopathy Symptoms of >2 connective tissue diseases associated with high titers of anti-RNP antibodies MCTD If myositis is unresponsive to treatment, consider a diagnosis of inclusion body myositis Malignancy and lnflammatory Myopathies The association betr,veen malignancy and inflammatory myositis is clear. Commonly associated cancers include ovarian, lung, pancreas, stomach, and colon cancers and lymphoma. Sex- and age-appropriate cancer screening should be performed at the time of diagnosis and at periodic intervals thereafter. Treatment High-dose oral glucocorticoid therapy is first line treatment for polymyositis and dermatomyositis. Adding methotrexate and/or azathioprine may be indicated if disease is refractory to high-dose glucocorticoid therapy or as glucocorticoid sparing agents. Inclusion body myositis usually does not respond to immunosuppression.

Treatment High-dose oral glucocorticoid therapy is first line treatment for polymyositis and dermatomyositis. Adding methotrexate and/or azathioprine may be indicated if disease is refractory to high-dose glucocorticoid therapy or as glucocorticoid sparing agents. Inclusion body myositis usually does not respond to immunosuppression. Baseline bone mineral density testing is indicated in patients who undergo long term high-dose glucocorticoid therapy. Begin prophylactic therapy for osteoporosis with calcium and vitamin D supplementation and bisphosphonates. DOil'T BE TRICKED . Suspect glucocorticoid-induced myopathy in patients with continued or new-onset worsening of proximal muscle weakness despite normalization of muscle enzyme levels. . Always check TSH levels when evaluating myopathy. Heliotrope Rash: The heliotrope rash of dermatomyositis is a distinctive purple or lilac, symmetrical erythema of the eyelids that may be accompanied by slight edema, generally focused around the orbits. 388

Rheumatology $T1"rPY YAEL€: Vasculitis Diagnosis (Continued) TyPe Presentation Testing Hypersensitivity vascu litis Palpable purpura (lower legs), cutaneous vesicles, Skin biopsy leu kocytoclastic vasculitis) ( pustules, maculopapular lesions, urticaria, recent viral infection, drug exposure, or diagnosis of malignancy Cryoglobulinemic vasculitis Skin lesions (red macules, palpable purpura, nodules, Serum cryoglobulins and HCV serologic or ulcers), GN, mononeuritis multiplex, and elevated studies serum aminotransferase levels Behqet syndrome Oral and genital ulcers; uveitis; pathergy; nonerosive, Clinical diagnosis asymmetric oligoarthritis; arterial and venous system inflammation (thrombosis and aneurysms) DOil'T BETRICKED . Aortic aneurysm and aortic dissection are potential complications of giant cell arteritis; aortic dissection may occur with orwithout preceding aneurysm formation. . Polyarteritis nodosa kidney disease does not involve the glomerulus (no urine erythrocytes, casts, or proteinuria). . Do not make a diagnosis of eosinophilic granulomatosis with polyangiitis in the absence of eosinophilia. Treatment STUDY TABLEs Treatment of Large-Vessel Vasculitis Disease Treatment Giant cell arteritis lnitial high-dose glucocorticoids plus tocilizumab; treat immediately to prevent blindness and obtain biopsy in <2 weeks Polymyalgia rheumatica Low-dose prednisone; relapse common and prolonged coursestypical(1-3 years) Takayasu arteritis Prednisone; steroid-sparing agents such as methotrexate or azathioprine STtl pY TA BLE : Treatment of Medium-Vessel Vasculitis Disease Treatment Polyarteritis nodosa Glucocorticoids and ryclophosphamide for severe organ-threatening disease; treat concomitant HBV infection

Treatment STUDY TABLEs Treatment of Large-Vessel Vasculitis Disease Treatment Giant cell arteritis lnitial high-dose glucocorticoids plus tocilizumab; treat immediately to prevent blindness and obtain biopsy in <2 weeks Polymyalgia rheumatica Low-dose prednisone; relapse common and prolonged coursestypical(1-3 years) Takayasu arteritis Prednisone; steroid-sparing agents such as methotrexate or azathioprine STtl pY TA BLE : Treatment of Medium-Vessel Vasculitis Disease Treatment Polyarteritis nodosa Glucocorticoids and ryclophosphamide for severe organ-threatening disease; treat concomitant HBV infection Primary angiitis of the CNS Prednisone and cyclophosphamide STUBY ?ABLt: Treatment of Small-Vessel Vasculitis Disease Treatment Granulomatosis with polyangiitis Prednisone and either rituximab (preferred) or cyclophosphamide Microscopic polyangiitis Prednisone and either rituximab (preferred) or cyclophosphamide Eosinophilic granulomatosis with Prednisone; cyclophosphamide or mepolizumab is added for severe multiorgan disease polyangiitis lgA vasculitis (Henoch-Schonlein Typically self-limited; glucocorticoids or cyclophosphamide for severe, persistent GN purpura) Hypersensitivity vascu litis lf drug associated, withdraw offending drug HCV-associated cryog lobulinemic Treat underlying HCV infection vasculitis lf organ dysfunction is severe, also treat with prednisone, ryclophosphamide, and plasmapheresis Behget syndrome Prednisone; steroid-sparing agents may be required for major disease mani{estations (uveitis, CNS, Gl, or large artery involvement); colchicine or apremilast for oral ulcers 390

Rheumatology TESTYOURSELF 472-year old woman has had a Ieft temporal headache for the past B days with blurred and double vision that lasted 15 minutes this morning. ANSWER: For diagnosis, choose giant cell arteritis. For management, select immediate prednisone plus tocilizumab and arrange for temporal artery biopsy within 2 weeks. 432-year old woman has a 6-month history of fever, myalgia, arthralgia, and weight loss. She is of Asian descent. Two days ago, she developed achy pain in her arms when working with her arms above her head. ANSWER: For diagnosis, choose Takayasu arteritis. NOTE: When ethnicity is identified in a board question, it is an essential key to the diagnosis. l! su. Adult-Onset Still Disease Palpable Purpun: The hallmark of leukorytocla$ic vasculitis is palpable purpura, consisting of bright red Diagnosis macules and papules and occasionally hemonhagic bullae confined to the lower leg and foot. The clinical features of AOSD include: o quotidian fever in which the temperature usually spikes once daily and then returns to subnormal o fatigue, malaise, arthralgia, and myalgia o proteinuria o serositis . evanescent pink rash o joint manifestations include a nonerosive inflammatory arthritis Testing Diagnosis is clinical, and other possible causes must be ruled out, including infection, malignancy, vasculitis, and drug reac- tion. Serum ferritin levels >2500 ng/ml are highly speciflc for this condition and reflect disease activity. Treatment Treatment is based on disease severity. NSAIDs are generally used as first-line agents in management of mild disease; gluco corticoids are useful in patients with more severe disease. Life threatening disease is treated with glucocorticoids and an interleukin 1 receptor antagonist, such as anakinra or canakinumab. 391