Section 12 Rheumatology

SECTION 12 Rheumatology

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CHAPTER 49

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Arthritis

992 Case: A 62-year-old man with subcutaneous nodules A 62-year-old man with a history of alcohol abuse and venous

insufficiency presents to the clinic for evaluation of a painful leftng the bases of the great toes, ankles, and knees. The episodes involve one resolve between attacks. He stopped drinking alcohol 4 years ago, and presentation when he was awoken from sleep with pain and swelling prescribed furosemide for lower extremity edema related to venous elbow. Medical history is notable for recurrent episodes of swelli and pain in various joints over a period of 15 years, mostly involving joint at any given time, usually last 7 to 10 days, and completely the episodes abated. He had done well until the night before of the left elbow. Approximately 1 month ago, the patient was stasis, but he takes no other medication. Temperature is 37.4°C. The left elbow is erythematous, warm, and

swollen (Figure 49-1A), and there is exquisite tenderness with passive subcutaneous nodules overlying the interphalangeal (IP) joints of both range of motion. There are multiple firm 1 to 2 cm nontender hands (Figure 49-1B).

FIGURE 49-1

What is the most likely cause of arthritis in this patient?

What is the difference between arthralgia and arthritis? What are the articular structures? What are the periarticular structures? What are the mimics of arthritis? How can physical examination help localize the source of pain to the joint (arthritis) rather than neighboring tissue (periarthritis)? What are the 2 general types of arthritis?

Arthralgia is the symptom of joint pain; arthritis is inflammation of any part of the joint. Arthralgia can be associated with arthritis and nonarthritic conditions. Articular structures include the synovium, synovial fluid, articular cartilage, intra-articular ligaments, joint capsule, and juxta-articular bone.1 Periarticular structures include supportive extra-articular ligaments, tendons, bursae, muscle, fascia, bones, nerves, and overlying skin.1 Conditions that can be confused for arthritis include bursitis, tendinitis, enthesitis, epicondylitis, ligament damage, cellulitis, deep vein thrombosis, polymyalgia rheumatica, myositis, and bone lesions (eg, metastasis). Articular involvement is more likely when there is pain and limited range of motion on both active and passive movement. Additional findings may include joint line tenderness on palpation, effusion, crepitation, instability, and locking. These additional findings may be absent in deep-seated joints. In contrast, nonarticular processes tend to be painful with active movement only; focal tenderness in regions adjacent to the joint may also be present.1 Arthritis can be noninflammatory or inflammatory.

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Williams & Wilkins; 2005.) It may seem contradictory to separate the term arthritis, which by definition implies the presence of inflammation, into inflammatory and noninflammatory categories. Although all forms of arthritis are associated with some degree of inflammation, the term “inflammatory arthritis” implies immune-mediated inflammation with special features that are discussed in more detail in this chapter.

What historical features are suggestive of inflammatory arthritis? What physical findings are suggestive of inflammatory arthritis? What is crepitus?

What is subluxation? What is synovitis? What is tenosynovitis? What is enthesitis?

What is dactylitis?

The presence of systemic symptoms (eg, fever, weight loss, night sweats), morning stiffness lasting >30 minutes, worsened symptoms with rest, and improved symptoms with activity are suggestive of an inflammatory condition.1

Inflammatory arthritis is suggested by the presence of the cardinal physical findings of inflammation, which are erythema (rubor), warmth (calor), pain (dolor), and swelling (tumor).1

Crepitus is a palpable, sometimes audible, crackling or vibratory sensation that occurs with motion of the joint. It can be associated with noninflammatory arthritis, particularly osteoarthritis (OA). The presence of crepitus, clicking, or snapping with joint movement commonly occurs as a result of ligamentous stretch in patients without arthritis.1 Subluxation refers to joint misalignment such that articular surfaces are not in contact. It can be associated with certain types of noninflammatory arthritis (eg, OA) and inflammatory arthritis (eg, rheumatoid arthritis [RA]). Synovitis is inflammation of the synovium. It is associated with inflammatory arthritis. Tenosynovitis is inflammation of a tendon and its sheath. It can be associated with certain types of inflammatory arthritis (eg, RA, disseminated gonorrhea). Enthesitis is inflammation of the site of attachment of tendons, ligaments, fascia, and joint capsule fibers to bone. It can be associated with certain types of inflammatory arthritis (eg, spondyloarthritis).2 Dactylitis is inflammation of an entire finger or toe (often called a “sausage” digit) resulting from the combination of synovitis, tenosynovitis, and enthesitis (Figure 49-2). It can be associated with certain types of inflammatory arthritis (eg, spondyloarthritis, gout, septic arthritis).2

FIGURE 49-2 Psoriatic arthritis involving the metacarpophalangeal and proximal interphalangeal joints of the index finger

What is spondyloarthritis?

What is migratory arthritis? What is symmetric arthritis? What general blood tests are helpful in the evaluation of inflammatory arthritis? What imaging studies can be helpful in the evaluation of

with associated flexor tenosynovitis and enthesitis. This combination of involvement gives rise to dactylitis (“sausage” digit). (From Koopman WJ, Moreland LW. Arthritis and Allied Conditions A Textbook of Rheumatology. 15th ed. Philadelphia, PA: Lippincott

Spondyloarthritis refers to a family of immune-mediated inflammatory diseases characterized by spondylitis (ie, inflammation of the axial skeleton including the vertebrae, entheseal attachments to the vertebral column, and axial synovial joints), along with inflammation of the peripheral joints. It is associated with extra-articular manifestations such as inflammation of the eye (eg, iris, conjuctiva), inflammatory bowel disease, and psoriasis. Migratory arthritis describes an arthritic process that begins in 1 or 2 joints, with subsequent improvement or resolution over a period of a few days, followed by involvement in a new joint. It can be associated with certain types of inflammatory arthritis (eg, acute rheumatic fever). Symmetric arthritis describes an arthritic process that affects pairs of joints on either side of the body. It can be associated with certain types of noninflammatory arthritis (eg, OA) and inflammatory arthritis (eg, RA). Inflammatory conditions can be suggested by peripheral leukocytosis and elevation of the acute phase reactants such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Other blood tests can be useful in the evaluation of specific causes of arthritis (eg, serum ferritin is markedly elevated in patients with adult-onset Still’s disease).1 Conventional radiography, ultrasonography, computed tomography, and magnetic resonance imaging can each be helpful in the evaluation of arthritis.

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arthritis?

What Arthrocentesis allows for the analysis of synovial fluid, which is essential in the evaluation of arthritis. procedure is most helpful in the evaluation of arthritis? What Common patterns of synovial fluid findings are provided in the table below.1,3,4 synovial fluid findings are suggestive of inflammatory arthritis? Normal Noninflammatory Inflammatory Septic Appearance Clear/straw Clear/amber Opaque Turbid WBCs/µL ≤200 ≤2000 >2000 >25,000 PMNs (%) <50% ≤75% >75% >90%

Total WBC count is the single most important synovial fluid test for identifying inflammatory arthritis. It is important to note that the numbers provided in the table represent a general rule of thumb, and there is considerable overlap, particularly between the inflammatory and septic categories (eg, it is not uncommon for septic arthritis to present with a synovial WBC count between 2000 and 25,000, particularly infections involving prosthetic joints). A diagnosis of septic arthritis cannot be made based on WBC count alone because nonseptic inflammatory arthritis is sometimes associated with a WBC count >25,000 (synovial fluid Gram stain and culture can be helpful in these situations).

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Noninflammatory Arthritis

What are the causes of noninflammatory arthritis?

A 64-year-old woman with obesity presents with chronic pain of the hips and knees when she shops and is found to have crepitus of both knees without overlying erythema or warmth. A 32-year-old woman presents with a painful and swollen ankle after stepping in a hole while exercising. A previously healthy 81-year-old woman presents with skin bruising and a swollen right knee without antecedent trauma and is found to have a positive mixing study (ie, there is no correction after mixing). Most commonly found in diabetic patients with peripheral neuropathy; the acute form of this joint condition can mimic cellulitis, septic arthritis, and deep vein thrombosis. This condition, which is commonly associated with glucocorticoid use, predominates in middle-aged and older patients, and may be identified on conventional radiography by the presence of the crescent sign, a line of subchondral lucency. A combination of arthritis and digital clubbing, usually in the setting of lung cancer. A 26-year-old woman with cystic fibrosis experiences episodes of acute polyarthritis that typically resolve within a few days, but does not have evidence of clubbing. Large doughy hands, protruding jaw (see Figure 41-4), and arthralgias. Skin hyperpigmentation and elevated serum ferritin.

Which joints are most commonly affected by osteoarthritis?

What clinical features are suggestive of traumatic

Osteoarthritis (ie, degenerative arthritis).

Trauma.

Hemarthrosis related to an acquired factor inhibitor.

Charcot joint.

Osteonecrosis (ie, avascular necrosis).

Hypertrophic osteoarthropathy.

Episodic arthritis of cystic fibrosis. Patients with cystic fibrosis can also develop hypertrophic osteoarthropathy.

Acromegaly.

Hemochromatosis.

OA is the most common cause of arthritis. The hallmark lesion in this condition is the loss of hyaline articular cartilage. Age and obesity are the most significant risk factors. The most commonly involved joints include those of the cervical and lumbosacral spine, hips, knees, hands, and feet. In the hands, the carpometacarpal joint at the base of the thumb, and the proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints are more likely to be involved. In the feet, the first metatarsophalangeal (MTP) joint is usually symptomatic. The elbow, wrist, metacarpophalangeal (MCP), and ankle joints are typically spared. Pain is often episodic at first, mirroring activity levels, but later becomes persistent.1 Traumatic arthritis is monoarticular in nature, usually associated with a history of antecedent trauma, and is often associated with additional pathology such as fractures or torn cartilage and ligaments.

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arthritis? What are the causes of hemarthrosis? What is the typical presentation of Charcot joint?

What is the most common and debilitating location of steroid- induced osteonecrosis? What are the 2 main forms of hypertrophic osteoarthropathy?

What extra-articular manifestations often accompany the episodic arthritis of cystic fibrosis? What are the clinical characteristics of the arthritis related to acromegaly? What are the clinical characteristics of the arthritis related to hemochromatosis?

Common causes of hemarthrosis include trauma and bleeding diatheses (eg, anticoagulation use, hemophilia, factor inhibitors); other causes include osteoarthritis, tumors (especially villonodular synovitis), and septic arthritis. Charcot joint most commonly affects the joints of the foot and ankle. There is an acute phase characterized by rapid-onset erythema, warmth, and swelling; pain is variable because of neuropathy. A chronic phase follows, in which the acute inflammation subsides but permanent deformities of the foot develop (eg, arch collapse, dislocations, subluxations).5 Hip involvement occurs most commonly in patients with steroid-induced osteonecrosis and is often bilateral. Typically, it is progressive and medical treatments are unsuccessful; resection of the femoral head and hip replacement may ultimately be necessary.6 The primary form of hypertrophic osteoarthropathy is hereditary and presents in childhood; the secondary (and more common) form occurs as a result of an underlying condition, most frequently intrathoracic malignancy. The associated arthritis usually involves the ankles, wrists, and knees. Digital clubbing is present in most patients.1 Fever and erythema nodosum are commonly associated with the episodic arthritis of cystic fibrosis. As the name implies, attacks occur intermittently. Cystic fibrosis patients who develop persistent arthritis and digital clubbing may have hypertrophic osteoarthropathy, which is more common than episodic arthritis in adults.7 Arthritis is a frequent manifestation of acromegaly and may be the first indication of the disease. The cervical and lumbar spines are the most common sites of involvement. The typical radiographic findings include widened joint spaces and severe osteophytosis.8 Arthritis is a frequent manifestation of hemochromatosis, affecting up to 40% of patients, and may be the first indication of the disease. The second and third MCP joints are often the first and most severely affected joints (an important clue to the diagnosis). The other joints of the hands and the larger joints (eg, hips, knees, shoulders, ankles) are less likely to be affected, and their involvement is usually less severe. Patients with hemochromatosis are also more likely to experience attacks of acute pseudogout.1

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Inflammatory Arthritis

What are the 3 subcategories of inflammatory arthritis based on the number of joints involved?

Inflammatory arthritis can occur in a monoarticular, oligoarticular, or polyarticular pattern.

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Monoarticular Inflammatory Arthritis How many joints are involved in monoarticular arthritis? Monoarticular arthritis involves 1 joint.

What are the causes of monoarticular inflammatory arthritis?

The diagnosis can be made using polarized light microscopy. A 24-year-old man with a history of intravenous drug use presents with a new heart murmur, Osler’s nodes, and an exquisitely painful, erythematous, warm, and swollen right knee. A 36-year-old woman living in Connecticut complains of recurrent episodes of right knee swelling and pain following a tick bite.

Crystal arthropathy. Acute septic arthritis.

Chronic infectious arthritis from Lyme disease.

What are the main types of crystals that Crystals that most commonly cause arthritis include monosodium urate (which causes gout) deposit within joints and cause and calcium pyrophosphate dihydrate (which causes calcium pyrophosphate dihydrate disease arthritis? [CPPD, or “pseudogout”]). Crystal arthropathy can be oligoarticular or polyarticular, particularly in older patients (especially women) and in those with longstanding disease.1,9 What is the appearance of monosodium Under polarized light, monosodium urate crystals are needle shaped with strongly negative urate (gout) crystals under polarized birefringence. light? What is the appearance of calcium Under polarized light, calcium pyrophosphate dihydrate crystals are rhomboid shaped with pyrophosphate dihydrate (pseudogout) weakly positive birefringence. crystals under polarized light? What are the most common organisms Staphylococcus aureus and Neisseria gonorrhoeae are the most common causes of acute infectious involved in acute infectious monoarticular arthritis in the industrialized world. Other organisms include Streptococcus monoarticular arthritis in adults? pneumoniae, β-hemolytic streptococci (particularly groups A and B), and gram-negative bacilli (eg, Haemophilus influenza). Septic arthritis related to Infective endocarditis often involves more than 1 joint at the time of presentation.1 What are the most common organisms Organisms involved in chronic infectious monoarticular arthritis in adults include Borrelia involved in chronic infectious burgdorferi (Lyme disease), Mycobacterium tuberculosis (tuberculosis), Nocardia species, Brucella monoarticular arthritis in adults? species, and fungi (eg, Candida species, Coccidioides immitis, Blastomyces dermatitidis, Sporothrix schenckii rypt coccus neoformans , ). 1 Monoarticular arthritis canCbeoan early manifestation of oligoarticular arthritis, particularly the peripheral spondyloarthritides (eg, psoriatic arthritis, reactive arthritis, enteropathic arthritis).

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Oligoarticular Inflammatory Arthritis How many joints are involved in oligoarticular arthritis? Oligoarticular arthritis involves 2 to 4 joints.

What are the causes of oligoarticular inflammatory arthritis?

Sexually transmitted. A 29-year-old man with erythema nodosum (see Figure 15-3), bloody diarrhea, and inflammatory arthritis of the right knee and left ankle. Corkscrew-shaped organisms (Figure 49-3).

A 38-year-old woman with erythema nodosum, bilateral ankle arthritis and periarthritis, and bilateral hilar lymphadenopathy (see Figure 21-4). More common in children than adults; this disease often presents with palpable purpura, Acute Kidney Injury, and oligoarticular arthritis. A 56-year-old man with chronic hepatitis C virus (HCV) infection develops palpable purpura and oligoarticular inflammatory arthritis. Fever, erythema nodosum, recurrent aphthous ulcers of the mouth and

Disseminated gonorrhea. Enteropathic arthritis.

Spirochetal arthritis (eg, Lyme disease, syphilis).

FIGURE 49-3 Electron micrograph demonstrating the “corkscrew” appearance of Borrelia burgdorferi. (From Johnson RC, Hyde FW, Rumpel CM. Taxonomy of the Lyme disease spirochetes. Yale J Biol Med. 1984;57:527-529, with permission.)

Löfgren’s syndrome (an acute form of sarcoidosis).

Henoch-Schönlein purpura (HSP, or immunoglobulin A vasculitis).

Cryoglobulinemia.

Behçet’s disease.

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genitalia, and oligoarticular inflammatory arthritis.

What are the clinical Disseminated gonorrhea is a common cause of inflammatory arthritis in young patients. It develops in the setting features of of bacteremia associated with acute infection or asymptomatic gonococcal colonization of the genitourinary tract or disseminated pharynx. Disseminated gonorrhea is characterized by a syndrome of fever, chills, pustular rash on the trunk and gonorrhea? extensor surfaces of the distal extremities, and nonpurulent migratory oligoarticular inflammatory arthritis associated with tenosynovitis. True septic gonococcal arthritis may follow this syndrome, typically presenting as purulent monoarticular inflammatory arthritis involving the hip, knee, ankle, or wrist. In either syndrome, it is difficult to identify gonococci from synovial fluid Gram stain and culture. Nucleic acid amplification assays are more sensitive. Testing other sites such as skin lesions and oropharyngeal and genitourinary mucosa should also be performed to increase yield.1 What are the The spondyloarthritides (also referred to as spondyloarthropathies) are a group of inflammatory disorders that spondyloarthritides? share certain clinical and genetic characteristics (eg, the presence of human leukocyte antigen [HLA]-B27). The main types include psoriatic arthritis, enteropathic arthritis, ankylosing spondylitis, and reactive arthritis. In addition to Musculoskeletal inflammatory conditions associated with the spondyloarthritides include spondylitis (particularly peripheral arthritis, sacroiliitis), enthesitis, and dactylitis.2 what musculoskeletal inflammatory conditions can be associated with the spondyloarthritides? What Nonmusculoskeletal inflammatory conditions associated with some of the spondyloarthritides include nonmusculoskeletal conjunctivitis, uveitis, pyoderma gangrenosum, erythema nodosum, aphthous stomatitis, urethritis, psoriasis, and inflammatory inflammation of bowel mucosa.1 conditions can be associated with the spondyloarthritides? Why should both Involvement of the hands and feet are common in psoriatic arthritis, marked by synovitis (including the DIP joints, the hands and feet which are spared by most other inflammatory arthritides), dactylitis (more common in feet than hands), shortening be carefully of digits as a result of osteolysis, and certain fingernail and toenail changes (eg, pitting, horizontal ridging, examined when onycholysis, yellow discoloration of the margins, dystrophic hyperkeratosis).1,2 psoriatic arthritis is suspected? What are the 2 main Enteropathic arthritis is subdivided based on the predominance of either axial or peripheral joint involvement. The subtypes of axial subtype precedes enteritis in onset, and its course is largely independent of the bowel disease. The peripheral enteropathic subtype may occur before, during, or after the enteritis, and its course usually parallels that of the bowel disease, arthritis? becoming active with flares and improving with treatment.10 What is the typical Ankylosing spondylitis is more common in men than women (around 2.5:1) and typically presents in late presentation of adolescence or early adulthood with dull low-back pain that improves with activity, worsens with rest, peaks ankylosing during the second half of the night, and is associated with significant morning stiffness (>30 minutes). Other spondylitis? associated symptoms may include enthesitis, osteitis, and peripheral inflammatory arthritis.1 Which joints are Reactive arthritis usually involves the joints of the lower extremities, including the knee, ankle, subtalar, MTP, and most commonly IP joints.1 involved in reactive arthritis? What are the Arthritis occurs in most patients with untreated disseminated Lyme disease. It typically begins as a migratory characteristics of inflammatory arthritis early in the course of infection, evolving to monoarticular or oligoarticular inflammatory arthritis related to arthritis primarily affecting the knees and other large joints later in the disease course. Without treatment, Lyme disease? symptoms typically wax and wane for months to years before eventually resolving. A small proportion of patients will develop joint erosions and damage. Polyarticular arthralgias without arthritis may also occur in patients with disseminated Lyme disease.11 What are the The arthritis of syphilis is usually oligoarticular, inflammatory, symmetric and nonmigratory in nature. It occurs characteristics of during secondary syphilis and is commonly associated with the typical nonpruritic papulosquamous rash of arthritis related to secondary syphilis, mucocutaneous lesions, and generalized lymphadenopathy. Tertiary syphilis can be associated syphilis acquired in with Charcot joint related to tabes dorsalis.1,12 adulthood? What is the Löfgren’s syndrome is an acute form of sarcoidosis characterized by the triad of arthritis (most often involving both prognosis of ankle joints), erythema nodosum, and bilateral hilar lymphadenopathy. It is more common in young white women Löfgren’s syndrome? of the Nordic countries and Spain; it is uncommon in blacks. Löfgren’s syndrome is self-limited in most cases and has an excellent prognosis with >90% of patients experiencing resolution within 2 years.1,13 What are the The arthritis of HSP usually presents as asymmetric oligoarticular inflammatory arthritis affecting the knees and characteristics of ankles. It occurs in more than one-half of adult patients with HSP, and incidence decreases with age.14 arthritis related to Henoch-Schönlein

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purpura in adults? What are the There are 2 distinct arthritic syndromes associated with chronic HCV infection: rheumatoid-like arthritis (two-characteristics of thirds of patients) and cryoglobulin-related arthritis (one-third of patients). Rheumatoid-like arthritis is arthritis related to characterized by a symmetric polyarticular inflammatory arthritis. Cryoglobulin-related arthritis usually occurs in HCV-associated older patients with long-standing HCV infection. It is an oligoarticular inflammatory arthritis of the medium and cryoglobulinemia? large joints that typically follows an intermittent and benign course.15 What are the Oligoarticular inflammatory arthritis is found in most patients with Behçet’s disease, including at the time of characteristics of diagnosis. It occurs most frequently in women, and the knees are the most common sites, followed by the ankles arthritis related to and wrists. It is generally nonerosive.16 Behçet’s disease? In addition to Arthralgias are more common in systemic vasculitis, but arthritis does occur, particularly with antineutrophil Henoch-Schönlein cytoplasmic antibody (ANCA)-associated small vessel systemic vasculitis (eg, granulomatosis with polyangiitis purpura, [GPA, or Wegener’s granulomatosis]) and polyarteritis nodosa. The typical presentation is migratory oligoarticular cryoglobulinemia, inflammatory arthritis of the large joints, but polyarticular inflammatory arthritis also occurs.17 and Behçet’s disease, what other systemic vasculitides are associated with art Oligoarticular arthritis can be an early manifestation of polyarticular hritis? arthritis.

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Polyarticular Inflammatory Arthritis How many joints are involved in polyarticular arthritis? Polyarticular arthritis involves >4 joints.

What are the causes of polyarticular inflammatory arthritis?

Symmetric polyarticular inflammatory arthritis more common in women and associated with anti– cyclic citrullinated peptide antibodies and joint erosions on radiography. This etiology is associated with positive antinuclear and double-stranded deoxyribonucleic acid (dsDNA) antibody titers. A 32-year-old woman develops symmetric polyarticular inflammatory arthritis of the hands and knees several weeks after one of her children was diagnosed with “slapped- cheek syndrome.” Proximal muscle weakness and elevated serum creatine kinase with or without skin manifestations. Associated with markedly elevated serum ferritin. A disease of developing countries caused by group A streptococcal infections of the upper respiratory tract, associated with migratory inflammatory arthritis. A 25-year-old man with a history of lung transplantation for cystic fibrosis complicated by acute rejection is treated with horse antithymocyte globulin and a week later develops polyarticular inflammatory arthritis. A granulomatous disease that most commonly affects the lung but can be associated with extrapulmonary manifestations, including polyarticular inflammatory arthritis.

Which joints are most

Rheumatoid arthritis.

Systemic lupus erythematosus (SLE).

Parvovirus B19.

Dermatomyositis (DM) or polymyositis (PM).

Adult-onset Still’s disease. Acute rheumatic fever.

Serum sickness.

Sarcoidosis.

RA is a chronic systemic inflammatory condition characterized by symmetric destructive polyarticular

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rheumatoid arthritis? common in women (2 to 3:1). It affects up to 1% of adults worldwide, with some populations at higher risk (eg, Native American Yakima, Pima, and Chippewa tribes). The pathogenesis is not known. The wrist, MCP, PIP, and MTP joints are the most commonly involved in RA. Chronic joint destruction leads to several classic physical findings of the hands, including ulnar deviation and subluxation of the MCP joints, hyperextension of the PIP joint with flexion of the DIP joint (swan-neck deformity), and flexion of the PIP joint with hyperextension of the DIP joint (Boutonnière deformity) (Figure 49-4).1

FIGURE 49-4 Rheumatoid arthritis. A, Ulnar deviation at the metacarpophalangeal joints. B, Swan-neck

What are the characteristics of the arthritis associated with systemic lupus erythematosus? Which viruses are associated with polyarticular inflammatory arthritis? What is the antisynthetase syndrome?

Which joints are most commonly involved in adult-onset Still’s disease?

How common is polyarticular inflammatory arthritis in patients with acute rheumatic fever?

What are the other clinical manifestations of serum sickness?

Which joints are most commonly involved in the chronic arthritis of sarcoidosis?

deformity. C, Boutonnière deformity. (From Hunder GG. Atlas of Rheumatology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:11.)

Arthritis is a common manifestation of SLE, affecting most patients. It is typically a nonerosive polyarticular inflammatory arthritis that most commonly affects the MCP, PIP, and knee joints.18

Viruses most commonly associated with polyarticular inflammatory arthritis include human immunodeficiency virus (HIV), parvovirus B19, hepatitis B virus, HCV, rubella, and several vector-borne viruses such as chikungunya and dengue fever.19 The antisynthetase syndrome occurs in some patients with DM or PM and significantly increases the likelihood of arthritis. It is associated with a constellation of clinical manifestations, including fever, interstitial lung disease, inflammatory myopathy, polyarticular inflammatory arthritis, Raynaud’s phenomenon, and mechanic’s hands (see Figure 47-4). Affected patients have serum autoantibodies to aminoacyl-tRNA synthetase enzymes, the most recognized of which is the anti-histidyl-tRNA synthetase (anti-Jo-1) antibody.20 Adult-onset Still’s disease is a systemic inflammatory condition that is characterized by the triad of fever, arthralgias or arthritis, and salmon-colored evanescent skin rash. The arthritis most often affects the knees, wrists, ankles, and elbows. The DIP joints are also frequently involved (which are spared by most other inflammatory arthritides except for psoriatic arthritis).21 Arthritis occurs in most patients with acute rheumatic fever. It is classically asymmetric, migratory, and inflammatory and affects the large joints most frequently (eg, knees, ankles, hips, elbows). It is highly responsive to salicylates and other nonsteroidal anti-inflammatory drugs (NSAIDs). Polyarticular arthralgias without arthritis also occur in patients with acute rheumatic fever. Note, because of the migratory nature of acute rheumatic fever, at any given time <4 joints may be involved, which would present as oligoarticular arthritis or monoarticular arthritis.1 Serum sickness is a flu-like illness that occurs as a result of tissue deposition of immune complexes, which form in response to the presence of foreign protein or serum (eg, horse antithymocyte globulin). It typically develops 1 to 2 weeks after exposure. In addition to polyarticular inflammatory arthritis, serum sickness presents with fever, cutaneous manifestations (eg, urticaria), and lymphadenopathy. Withdrawal of the offending agent usually results in resolution; however, severe cases may benefit from systemic glucocorticoids.1 Arthritis related to sarcoidosis most commonly occurs acutely in the setting of Löfgren’s syndrome. However, chronic arthritis related to systemic sarcoidosis does occur in a small proportion of cases, usually involving the knees, ankles, wrists, hands, and feet.22

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1005 Case Summary A 62-year-old man with a history of alcohol abuse and recurrent

episodes of monoarticular arthritis presents with acute monoarticular diuretic medication, and is found to have nontender subcutaneous inflammatory arthritis of the left elbow after recently starting a nodules overlying the IP joints of the hands.

What is the most likely cause of arthritis in this patient? Gout.

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Bonus Questions

What is gout? Gout is the manifestation of intra-articular deposition of urate crystals related to hyperuricemia. Under normal temperature and pH, the limit of urate solubility is around 6.8 mg/dL. Less than one-half of all patients with hyperuricemia experience gout. 9 What is the nature of The subcutaneous nodules in this case (see Figure 49-1B) are tophi, which are deposits of urate crystals in the joints and soft tissues. the subcutaneous nodules in this case? significance of tophi? between attacks. Tophi are typically painless but may become acutely inflamed. Patients with tophaceous gout have erosive and destructive arthritis.9ms What is the Tophi are a manifestation of longstanding and poorly controlled gout. Patients with tophaceous gout can experience polyarticular attacks and sympto What other arthritic OA is associated with osteophytes around the DIP joints (ie, Heberden’s nodes) and the PIP joints (ie, Bouchard’s nodes); RA is associated with subcutaneous conditions are nodules that appear in areas subject to repeated trauma such as the forearm, sacral prominences, and the Achilles tendon. 1 associated with subcutaneous nodules? What was the most Triggers for acute flares of gout include alcohol use, hospitalization, surgery, and diuretic use. In this case, it is likely that alcohol served as the trigger for past likely trigger for the flares, whereas the diuretic medication that was recently started triggered the current flare. 9 episode of acute gout in this case? Is gout more common Gout affects middle-aged men more frequently than women (3 to 4:1), related in part to the uricosuric effects of estrogen. The incidence of gout in women rises in men or women? after menopause. 9 Should serum uricase? At the time of an acute attack of gout, serum uric acid levels may not be elevated. If the underlying diagnosis of gouttis proven, then serum uric acid levels How is the diagnosis Gout can be definitively diagnosed with arthrocentesis and evaluation of synovial fluid. The presence of needle-shaped crystals with strongly negative acid levels be should be evaluated between attacks with a goal of maintaining it within the normal range, often through a combina ion of lifestyle modification and measured in this c pharmacologic agents. 9 of gout definitively birefringence under polarized light is pathognomonic. Synovial WBC count >2000 cells/µL with a predominance of PMNs would also be expected. made? Should arthrocentesis Arthrocentesis should be performed to prove the diagnosis and to rule out other crystal arthritides (eg, calcium pyrophosphate dihydrate) and septic arthritis be performed in this (patients with joint damage from a history of aseptic inflammatory arthritis are predisposed to developing septic arthritis). case? term pharmacologice colchicine are contraindicatedtor poorly tolerated. Monoarticular attacks can be managed with intra-articular glucocorticoids. Therapy with an interleukin-1d What is the short- First-line pharmacologic agen s used to control acute gout flairs include NSAIDs and colchicine. Systemic glucocorticoids can also be used when NSAIDs an gout? management of acut receptor antagonist (eg, anakinra) can be used in some circumstances (eg, recalcitrant disease). 9 What is the long-term The prevention of recurrent attacks of gout by maintaining serum uric ac d levels <6 mg/dL is the cornerstone of the long-term management of gout. Lifesty management of gout? modification, including reduction in alcohol consumption, is paramount.iPharmacologic urate-lowering therapy (eg, xanthine oxidase inhibitors, uricosuricleic agents, uricase agents) to prevent acute attacks and the development of tophi should be considered based on the frequency of attacks and other patient-specif factors (eg, patient preference). 9

1007 Key Points

Arthritis describes inflammation involving any structure within a Articular structures include the synovium, synovial fluid, articular joint. cartilage, intra-articular ligaments, joint capsule, and juxta- articular bone.

Mimics of arthritis include bursitis, tendinitis, enthesitis, polymyalgia rheumatica, myositis, and periarticular bone lesions.h palpation. epicondylitis, ligament damage, cellulitis, deep vein thrombosis, An articular process is suggested by the presence of pain with bot active and passive range of motion and joint line tenderness on Arthritis can be noninflammatory or inflammatory. The cardinal signs of inflammation include erythema, warmth, pain, and swelling. Other inflammatory musculoskeletal conditions such as

tenosynovitis, enthesitis, and dactylitis can occur with certain Synovial fluid WBC count is the single most important laboratory >2000 cells/µL is consistent with inflammatory arthritis).nclude types of inflammatory arthritis. test in the evaluation of inflammatory arthritis (WBC count The most common causes of noninflammatory arthritis i osteoarthritis and trauma. Inflammatory arthritis can occur in a monoarticular (1 joint),

oligoarticular (2-4 joints), or polyarticular (>4 joints) pattern.umber peripheral spondyloarthritis, polyarticular gout). Inflammatory arthritides can generally be classified by the n of joints involved, but exceptions occur (eg, monoarticular

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References 1. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012.

1. MeaseiPJ. Distinguishing inflammatory from noninflammatory arthritis, enthesitis, and dactyl tis in psoriatic arthritis: a report from the GRAPPA 2010 annual meeting. J Rheumatol. 2012;39(2):415-417. McGillicuddy DC, Shah KH, Friedberg RP, Nathanson LA, Edlow JA. How sensitiv

2. the synovial fluid white.blood cell count in diagnosing septic arthritis? Am J Emerge is Med. 2007;25(7):749-752

3. Shmerling RH, Delbanco TL, Tosteson AN, Trentham DE. Synovial fluid tests. What should be ordered? JAMA. 1990;264(8):1009-1014.

4. Gouveri E, PapanaslN. Charcot osteoarthropathy in diabetes: a.brief review with an 6. Mankin HJ. Nontraumatic necrosis of bone (osteonecrosis). N Engl J Med. emphasis on clinica practice. World J Diabetes. 2011;2(5):59-65 1992;326(22):1473-1479.

5. Dixey J, Redington AN, Butler RC, et al. The arthropathy of cystic fibrosis. Ann Rheum Dis. 1988;47(3):218-223.

6. Killinger Z, Kuzma M, Sterancakova L, Payer J. Osteoarticular changes in acromegaly. Int J Endocrinol. 2012;2012:839282.

7. Neogi T. Clinical practice. Gout. N Engl J Med. 2011;364(5):443-452.

8. Peluso R, Di Minno MN, Iervolino S, et al. Enteropathic spondyloarthritis: from diagnosis to treatment. Clin Dev Immunol. 2013;2013:631408.

9. Puius YA, Kalish RA. Lyme arthritis: pathogenesis, clinical presentation, and management. Infect Dis Clin North Am. 2008;22(2):289-300, vi-vii. . Reginato AJ, Schumacher HR, Jimenez S, Maurer K. Synovitis in secondary syphilis.

12Clinical, light, and electron microscopic studies. Arthritis Rheum. 1979;22(2):170-176. 13. Mañá J, Gómez-Vaquero C, Montero A, et al. Lofgren’s syndrome revisited: a study of 186 patients. Am J Med. 1999;107(3):240-245. . Pillebout E, Thervet E, Hill G, Alberti C, Vanhille P, Nochy D. Henoch-Schonlein

14Purpura in adults: outcome and prognostic factors. J Am Soc Nephrol. 2002;13(5):1271- 1278.

1. KemmertNM, Sherman KE. Hepatitis C-related arthropathy: diagnostic and treatment considera ions. J Musculoskelet Med. 2010;27(9):351-354.
2. Kim HA,:Choi KW, Song YW. Arthropathy in Behcet’s disease. Scand J Rheumatol. 1997;26(2) 125-129.

3. Agard C, Mouthon L, Mahr A, Guillevin L. Microscopic polyangiitis and polyarteritis nodosa: how and when do they start? Arthritis Rheum. 2003;49(5):709-715.

4. Grossman JM. Lupus arthritis. Best Pract Res Clin Rheumatol. 2009;23(4):495-506.

5. Calabrese LH, Naides SJ. Viral arthritis. Infect Dis Clin North Am. 2005;19(4):963-980, x.

6. Katzap E, Barilla-LaBarca ML, Marder G. Antisynthetase syndrome. Curr Rheumatol Rep. 2011;13(3):175-181.

7. Gopalarathinam R, Orlowsky E, Kesavalu R, Yelaminchili S. Adult onset Still’s atol. disease: a review on diagnostic workup and treatment options. Case Rep Rheum 2016;2016:6502373.

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1. Sweiss NJ, Patterson K, Sawaqed R, et al. Rheumatologic manifestations of sarcoidosis. Semin Respir Crit Care Med. 2010;31(4):463-473.

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CHAPTER 50

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Systemic Vasculitis

1012 Case: A 67-year-old man with hemoptysis deA previously healthy 67-year-old man presents to the emergency intermittent fever. He has been seen in the clinic several times over the nasal and sinus symptoms have not responded to antibiotics. He has partment after coughing up blood. He describes progressive shortness of breath over the past few weeks with dry cough and past few months for persistent nasal congestion and sinusitis. The experienced weight loss of 12 pounds over this time. On the morning of presentation, the cough became productive of bloody sputum. The

patient estimates that he has produced 2 tablespoons of blood over the past 6 hours. Temperature is 37.5°C; heart rate, 103 beats per minute; blood

pressure, 110/30 mm Hg; and respiratory rate, 28 breaths per minute. midportion of the nasal bridge. There are multiple red-purple papules Breathing appears labored. There is marked depression of the ranging from 5 mm to 2 cm in diameter with some areas of confluence over the shins and ankles. There is diffuse expiratory wheezing.

thSerum creatinine is 1.9 mg/dL. Evaluation of urine sediment reveals tomography (CT) imaging of the chest is shown in Figure 50-1. e presence of dysmorphic red blood cells and red blood cell casts. Serum antibodies to PR3 (c-ANCA) are present. Computed

FIGURE 50-1 (From Elicker BM, Webb WR. Fundamentals of High-Resolution Lung CT: Common Findings, Common Patterns, Common Diseases, and Differential Diagnosis. Philadelphia, PA: Wolters Kluwer Health; 2013.)

What is the most likely diagnosis in this patient?

What is vasculitis?

What is the difference between vasculitis and vasculopathy? What are the clinical manifestations of vasculitis? What is systemic vasculitis?

Vasculitis describes a heterogeneous group of diseases that share the defining feature of blood vessel wall inflammation. The inflammatory process can involve blood vessels of virtually any type, size, and location in the body and can lead to partial or complete luminal compromise, with ensuing ischemia of the related tissues. Vasculitis can be a primary disorder or occur secondary to an underlying systemic disease.1 Vasculitis is a specific term that is defined by blood vessel wall inflammation. Vasculopathy is a broader term that includes conditions such as atherosclerosis and Buerger’s disease (ie, thromboangiitis obliterans), where there is no histologic evidence of vessel wall inflammation. The manifestations of vasculitis are protean owing to variability in the size and location of blood vessel involvement; it may be confined to a single organ (eg, skin), or it may affect a range of organ systems (eg, pulmonary-renal syndrome). Vasculitis should be considered when multiple systems are involved or characteristic physical findings are present. distinguished by the presence of unique clinicopathologic features (eg, giant cell arteritis [GCA], polyarteritislly Systemic vasculitis refers to a group of named primary vasculitides that are immune mediated and individua

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nodosa [PAN], microscopic polyangiitis [MPA]). What is limited Limited systemic vasculitis refers to systemic vasculitis involving only 1 organ system, (eg, upper respiratory tract– systemic vasculitis? limited granulomatosis with polyangiitis [GPA, or Wegener’s granulomatosis]).1 What is vasculitis Vasculitis associated with systemic disease describes the occurrence of vasculitis in the setting of an underlying associated with systemic disease known to cause vasculitis (eg, rheumatoid vasculitis).1 systemic disease? What is vasculitis Vasculitis associated with probable etiology describes the occurrence of systemic vasculitis in the setting of a known associated with and likely provoking factor (eg, malignancy-associated vasculitis).1 probable etiology? What is single- Single-organ vasculitis refers to vasculitis involving a single organ without any features suggestive of systemic organ vasculitis? vasculitis; it is distinct from limited systemic vasculitis. Distribution within the involved organ may be unifocal or multifocal (diffuse). Some patients initially diagnosed with single-organ vasculitis may go on to develop features of systemic vasculitis and should be reclassified accordingly (eg, cutaneous small vessel vasculitis [CSVV] over time may meet the diagnostic criteria of PAN).1 What are the single- Examples of single-organ vasculitis include CSVV, primary angiitis of the central nervous system, and isolated organ vasculitides? aortitis (eg, related to thoracic radiation treatment). Importantly, these organs may be involved in systemic vasculitis. What is LCV is a histologic term that describes neutrophilic infiltration within the walls of small-sized blood vessels. This leukocytoclastic term is often used synonymously with CSVV.2 vasculitis (LCV)? What are the Physical findings of vasculitis are variable, depending on the type of vasculitis and extent of organ involvement. physical findings of Particular findings can indicate involvement of certain types of blood vessels and, in some cases, specific vasculitis? vasculitides. What are the Systemic vasculitis can be suggested by peripheral leukocytosis and elevation of acute phase reactants such as laboratory features erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Other laboratory studies can be useful in the of systemic evaluation of specific causes of systemic vasculitis (eg, serum antineutrophil cytoplasmic antibodies [ANCA]). vasculitis? What conditions Other systemic conditions with protean manifestations can be confused for systemic vasculitis, including infection can mimic the (eg, bacterial endocarditis), malignancy (eg, lymphoma), drug toxicity (eg, amphetamines), connective tissue disease presentation of (eg, systemic lupus erythematosus), sarcoidosis, thrombotic microangiopathy (eg, thrombotic thrombocytopenic systemic vasculitis? purpura), and atheroembolic disease.3 What are the 3 Systemic vasculitis can involve the large vessels, medium vessels, or small vessels. categories of systemic vasculitis based on the size of involved blood vessels?

Which vessels are Large-sized vessels include the aorta and its branches and the analogous veins; medium-sized vessels are distal to included within the large-sized vessels and include the main visceral arteries (eg, renal, hepatic, coronary, and mesenteric arteries) and large-, medium-, their initial branches and the analogous veins; small-sized vessels are distal to medium-sized vessels, are and small-sized microscopic in size, and refer to arterioles, capillaries, and venules.1 cat Individual vasculitides are capable of affecting blood vessels of more than 1 egories? size (eg, large and medium vessels or medium and small vessels). However, most conditions predominantly affect vessels of 1 particular size, and that principle will be used in this chapter.

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Large Vessel Systemic Vasculitis

What physical findings are associated with large vessel vasculitis?

Physical findings of large vessel vasculitis may include asymmetric pulses, discrepancies in blood pressure between extremities, bruits, and thrills. In addition, specific findings can be associated with certain vasculitides (eg, tender and thickened superficial temporal artery in GCA). In some cases, large vessel vasculitis occurs in association with medium vessel vasculitis, which may lead to other findings.

What are the causes of large vessel systemic vasculitis?

A 67-year-old man Giant cell arteritis (ie, temporal arteritis). complains of prandial headache and jaw pain and is found to have a palpable and tender subcutaneous cord-like mass in the lateral forehead (Figure 50-2).

FIGURE 50-2 Temporal artery inflammation in a patient with giant cell arteritis. The temporal artery may be

This entity can present in nonsmoking younger patients (<50 years of age) with pulseless extremities and discrepant blood pressure measurements between extremities.

What other rheumatologic disease often coexists with giant cell arteritis?

What populations are at highest risk of Takayasu arteritis?

What are the secondary causes of large vessel vasculitis? What is Cogan’s syndrome?

tender, red, enlarged, tortuous, or nodular, and can have Decreased pulsation. (controversies, and practical tips. Postgrad Med J. 2013;89(1051):284-292, Copyright © 2013, British Medical Journal.) , From Mackie SL, Pease CT. Diagnosis and management of giant cell arteritis and polymyalgia rheumatic: challenges

Takayasu arteritis.

GCA is a disease found almost exclusively in patients above 50 years of age, with a predilection for women. Patients develop inflammation of the extracranial branches of the aorta, typically sparing the intracranial vessels. Diagnosis is confirmed with biopsy of the temporal artery. GCA is associated with polymyalgia rheumatica (PMR), which is characterized by pain and stiffness of the muscles of the neck, shoulders, hips, and thighs. PMR most often occurs in isolation but develops in close to one-half of patients with GCA. Of those who present with isolated PMR, around 15% will ultimately develop GCA.3,4 Individuals at highest risk for developing Takayasu arteritis include adolescent girls and women in their second and third decades of life from Japan, Southeast Asia, India, and Mexico. Involvement of the large elastic arteries can lead to dilatation, aneurysm formation, and thrombosis. Renal artery involvement can result in severe hypertension. Cardiac involvement occurs in some patients and can lead to manifestations such as aortic regurgitation and dilated cardiomyopathy. Carotid artery involvement can result in cerebral ischemia (eg, stroke).4 Secondary causes of large vessel vasculitis include aortitis associated with probable etiology, such as infection-associated vasculitis (eg, syphilis, tuberculosis, Salmonella species), and aortitis associated with systemic disease (eg, ankylosing spondylitis).3 Cogan’s syndrome is a chronic inflammatory condition that typically affects young white patients, characterized by interstitial keratitis, vestibulo-auditory symptoms, and, in some cases, vasculitis. Although the vasculitis can affect vessels of any size, there is a predilection for the aorta.3,5

1015

Medium Vessel Systemic Vasculitis

What physical findings are associated with medium vessel vasculitis?

Physical findings of medium vessel vasculitis are related to nerve involvement (eg, mononeuritis multiplex, polyneuropathy, radiculopathy, plexopathy); vascular changes (eg, diminished peripheral pulses); and cardiac involvement (eg, pericardial friction rub). In some cases, medium vessel vasculitis occurs in association with large vessel or small vessel vasculitis, which may lead to other findings.

What are the causes of medium vessel systemic vasculitis?

A 49-year-old man with chronic hepatitis B infection presents with recurrent fever, weight loss, testicular pain, hypertension, livedo reticularis, and a foot drop. This entity usually occurs in children and presents with a constellation of findings such as fever, conjunctival injection, oral mucosal findings (eg, erythema and cracking of the lips, “strawberry” tongue), cervical lymphadenopathy, peripheral extremity changes (eg, swelling of the hands or feet), and skin rash.

What are the arteriographic findings of polyarteritis nodosa?

Polyarteritis nodosa.

Kawasaki disease.3

PAN affects medium and small vessels, most frequently the renal and visceral arteries. The presence of microaneurysms (1-5 mm in diameter) is a hallmark of PAN but is not universal (Figure 50-3). Other findings include stenotic segments and obliteration of vessels. These changes mainly occur in the mesenteric, renal, and hepatic arteries.3,6

FIGURE 50-3 Right renal angiogram demonstrating multiple

What is the treatment for Kawasaki disease?

What are the secondary causes of medium vessel vasculitis?

renal arterial microaneurysms (arrowheads) in a patient with polyarteritis nodosa. (From Brant WE, Helms CA. Fundamentals of Diagnostic Radiology, 4th ed. Philadelphia, PA: Wolters Kluwer Health; 2012.)

Kawasaki disease typically occurs in children. It is generally self-limited but can be associated with long-term complications (eg, coronary artery aneurysms) and has an overall mortality rate of up to 3%. Early treatment with the combination of intravenous immunoglobulin (IVIG) and aspirin improves outcomes.3,7 Secondary causes of medium vessel vasculitis include vasculitis associated with systemic disease (eg, rheumatoid vasculitis) and vasculitis associated with probable etiology (eg, hepatitis B–associated PAN).

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1017

Small Vessel Systemic Vasculitis

What physical findings are associated with small vessel vasculitis?

What is the typical distribution of palpable purpura? What are the cutaneous manifestations of small vessel vasculitis? What are the 2 subcategories of small vessel systemic vasculitis based on serological testing?

What does ANCA refer to? In ANCA-positive patients, which 2 patterns may be seen on immunofluorescence microscopy?

Physical findings of small vessel vasculitis are usually related to cutaneous involvement (eg, palpable purpura), pulmonary involvement (eg, wheezing), and ocular involvement (eg, conjunctivitis). In addition, specific findings can be associated with certain vasculitides (eg, saddle nose deformity in GPA). In some cases, small vessel vasculitis occurs in association with medium vessel vasculitis, which may lead to other findings.3 Palpable purpura usually occurs in dependent areas of the body (eg, lower extremities).3

While palpable purpura is the most common cutaneous finding of small vessel vasculitis, other potential manifestations include papules, petechiae, vesicles, ulcers, and subcutaneous nodules.3 Small vessel systemic vasculitis can be ANCA-associated or non–ANCA-associated.

Antineutrophilic cytoplasmic antibodies are a group of autoantibodies directed against proteins found in the cytoplasm of neutrophils, including proteinase 3 (PR3) and myeloperoxidase (MPO). Under immunofluorescence microscopy, the presence of antibodies to PR3 results in a cytoplasmic pattern (c-ANCA), whereas antibodies to MPO are associated with a perinuclear pattern (p-ANCA). Enzyme-linked immunosorbent assays (ELISA) can specifically detect the presence of PR3 and MPO antibodies in the serum of affected patients.2

1018

ANCA-Associated Small Vessel Systemic Vasculitis

What are the causes of ANCA-associated small vessel systemic vasculitis?

A 63-year-old man presents with hemoptysis, hematuria, and Acute Kidney Injury and is found to have positive c-ANCA titers. This condition, most commonly associated with p-ANCA, is distinguished from the other causes of ANCA-associated small vessel vasculitis by the absence of granulomatous inflammation. A 43-year-old woman with a recent diagnosis of asthma presents with palpable purpura and a wrist drop.

What systems are most commonly involved in granulomatosis with polyangiitis?

Granulomatosis with polyangiitis.

Microscopic polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA, or Churg-Strauss syndrome).

Upper airway involvement (eg, sinus disease) occurs in virtually all cases of GPA (around 95%) (Figure 50-4). Lower airway (eg, pulmonary capillaritis), renal (eg, glomerulonephritis), cutaneous (eg, palpable purpura), musculoskeletal (eg, arthralgias or arthritis), and eye involvement (eg, episcleritis) are also common. Nervous system involvement (eg, mononeuritis multiplex) and cardiac involvement (eg, pericarditis) occur less frequently. Notably, GPA commonly presents with limited disease (eg, sinus disease only).3

FIGURE 50-4 Saddle nose deformity in a patient with granulomatosis with polyangiitis (Wegener’s

What systems are most commonly involved in microscopic polyangiitis?

Why is a complete blood count (with differential) helpful in the workup of eosinophilic granulomatosis with polyangiitis?

granulomatosis). (From Rubin R, Strayer DS. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2008.)

MPA affects small and medium vessels. Renal involvement is by far the most common manifestation of MPA (>80%), ranging from asymptomatic proteinuria to rapidly progressive glomerulonephritis. Like GPA, other systems can be involved, including the nervous, cutaneous, Gastrointestinal, and pulmonary systems.8 Peripheral eosinophilia (typically >1500 cells/µL or >10%) often occurs in patients with active EGPA and can be supportive of the diagnosis. The presence and degree of peripheral eosinophilia correlates with disease activity; in patients with known EGPA, relapses can be predicted by the occurrence of or rise in peripheral eosinophilia. Patients with asthma who do not have EGPA can develop peripheral

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eosinophilia, but it is typically mild (<10%).9 What are the secondary causes of Secondary causes of ANCA-associated small vessel vasculitis include vasculitis associated with ANCA-associated small vessel probable etiology, such as drug-associated p-ANCA vasculitis (eg, hydralazine, propylthiouracil) and vasculitis? levamisole-associated p-ANCA vasculitis (this entity should be considered in cocaine users who present with necrosis of the ears and nose). Some small vessel vasculitides associated with systemic disease can present with positive ANCA in a minority of cases (eg, rheumatoid vasculitis).3 ANCA-associated small vessel systemic vasculitides can occur in the absence of ANCA positivity and should remain on the differential diagnosis of any small vessel systemic vasculitis until a clear diagnosis has been made.

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Non–ANCA-Associated Small Vessel Systemic Vasculitis

What are the causes of non–ANCA-associated small vessel systemic vasculitis?

Abdominal pain, palpable purpura, Acute Kidney Injury, and arthritis in a patient with a normal platelet count. A 54-year-old man with chronic hepatitis C virus (HCV) infection presents with palpable purpura and glomerulonephritis. “Silk road disease.” A 26-year-old man presents with hemoptysis, hematuria, and Acute Kidney Injury, and immunofluorescence microscopy of renal tissue shows linear deposition of immunoglobulins along the glomerular basement membrane. Itchy and tender urticarial lesions that remain fixed for more than 24 hours.

What is the hallmark immunofluorescence finding from a skin biopsy in patients with Henoch- Schönlein purpura? What are the laboratory features of cryoglobulinemic vasculitis?

What are the most common clinical manifestations of Behçet’s disease?

How common is pulmonary involvement in patients with anti–glomerular basement membrane disease?

What is the role of serum complement levels in the

Henoch-Schönlein purpura (HSP, or immunoglobulin A vasculitis).

Cryoglobulinemia.

Behçet’s disease. Anti–glomerular basement membrane (anti-GBM) disease.

Urticarial vasculitis (UV).

HSP is more common in children, but does occur in adults. Palpable purpura is present in most patients, and is typically distributed over the buttocks and lower extremities. Other clinical manifestations include arthralgias or arthritis, abdominal pain, and glomerulonephritis. Immunofluorescence demonstrating IgA deposits within the walls of cutaneous blood vessels is pathognomonic of HSP.3 Cryoglobulins refer to monoclonal or polyclonal immunoglobulins that precipitate on exposure to cold (ie, cryoprecipitates). Clinical manifestations include systemic vasculitis, arthritis, peripheral neuropathy, and glomerulonephritis. Hypocomplementemia is present in most patients with cryoglobulinemic vasculitis (around 90%); C4 is often more profoundly affected than C3. Rheumatoid factor is often positive, and circulating cryoprecipitates can be detected. Anemia and elevated ESR are also common. All patients with cryoglobulinemia should be tested for HCV.3 Recurrent painful oral ulcers are often the earliest manifestation of Behçet’s disease (ultimately occuring in up to 90% of patients). Genital ulcers also affect most patients and are more specific than oral ulcers. Ocular disease involving the retina and uvea occurs commonly and can lead to blindness. Cutaneous manifestations are also common and include papulopustular rash, acne-like lesions, and erythema nodosum (especially in women). Neurologic, cardiovascular, pulmonary, Gastrointestinal, and articular manifestations occur less commonly. Pulmonary artery aneurysm is one of the most dreaded complications of Behçet’s disease (occurring in approximatley 1% of cases) and carries a high mortality rate.10 In approximately one-half of patients with anti-GBM disease, pulmonary hemorrhage occurs along with glomerulonephritis (ie, Goodpasture’s syndrome). In rare cases, there is pulmonary hemorrhage in the absence of glomerulonephritis. Goodpasture’s syndrome has a predilection for 2 populations in particular: young men in the third decade of life and women in the seventh and eighth decades of life. Clinical manifestations tend to be more dramatic in the younger population (eg, fever, hemoptysis [particularly among smokers], dyspnea, hematuria). Prognosis is more favorable in patients with pulmonary hemorrhage when compared with.older patients who tend to present with renal manifestations only, particularly when there is oliguria 3,11 UV is ultimately diagnosed in around 10% of patients who present with chronic or recurrent urticarial lesions. An underlying systemic disease is present in the majority of cases. Serum complement levels have

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urticarial vasculitis?

What are the secondary causes of non–ANCA-associated small vessel vasculitis?

with idiopathic UV and portend a more benign course; low complement levels often indicate a potentially serious underlying condition such as SLE, hypocomplementemic urticarial vasculitis syndrome (HUVS), or Sjögren’s syndrome. 12 Secondary causes of non-ANCA-associated small vessel vasculitis include vasculitis associated with systemic disease and vasculitis associated with probable etiology. Vasculitis associated with systemic disease includes lupus vasculitis, rheumatoid vasculitis, sarcoid vasculitis, relapsing polychondritis vasculitis, and Sjögren’s vasculitis. Vasculitis associated with probable etiology includes drug-associated vasculitis, infection-associated vasculitis (eg, subacute bacterial endocarditis, HCV, Epstein-Barr virus, human immunodeficiency virus, histoplasmosis), malignancy-associated vasculitis (eg, lymphoma), and serum sickness–associated vasculitis.1

1022 Case Summary subacute sinusitis, nasal congestion, dyspnea, and weighttloss presents A previously healthy 67-year-old man with a recent his ory of with acute-onset hemoptysis and is found to have a saddle nose

deformity, palpable purpura, and abnormal findings on chest imaging. What is the most likely diagnosis in this patient? Granulomatosis with polyangiitis.

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Bonus Questions

What general features in this The combination of multisystem involvement, including the upper.and lower airways, skin, and kidneys, and the presence of constitutional features such systemic vasculitis? case are suggestive of as fever and weight loss raises the possibility of systemic vasculitis Which clinical features in Upper airway involvement is present in virtually all patients with GPA, including sinusitis, purulent or bloody nasal discharge, and nasal septal

this case are consistent with perforation with associated saddle nose deformity (collapse of the nasal bridge, see Figure 50-4). In addition, active GPA is associated with c-ANCA in the diagnosis of most patients (approximately 90%). 3 granulomatosis with polyangiitis? What findings are present on CT imagingiof the chesttinfthis case (see Figure 50-1) demonstrates cavitary lesions. These lesions can be found in up to one-half of patients with What is the typical age of ith GPA can occur at any age, but the peak age of onset is between 65 and 75 years.14 case? imaging of the chest in this pulmonary nvolvemen o GPA. Pulmonary nodules, particularly subpleural in location, are even more common. 13 onset of granulomatosis w polyangiitis? What are the 3 distinctivef The 3 distinctive histopathologic features of GPA are (1) vasculitis of small vessels or small and medium vessels, (2) granulomatous inflammation, and (3) granulomatosis with histopathologic features o tissue necrosis. 13 polyangiitis? active granulomatosis with phase dependsion severity and extent oftdisease (limitedior generalized). Induction regimens for severe disease usually consist of glucocorticoids intherth What is the treatment for Active GPA is treated with immunosuppressive medicat ons, with an induction phase followed by maintenance therapy. The choice of agents for ei polyangiitis? combination w th either cyclophosphamide or rituximab. Methotrexate or azathioprine is usually used for maintenance. Limited GPA can be treated wi prednisone, methotrexate, or even trime hoprim-sulfamethoxazole. 13 What is the prognosis of Without treatment, generalized GPA is invariably fatal within months of diagnosis. In the era of immunosuppressive therapy, 5-year survival is granulomatosis with approximately 75%. Relapse occurs in around one-half of cases. 3,13 polyangiitis?

1024 Key Points

Vasculitis describes a heterogeneous group of diseases that share Vasculitisican involve blood vessels of virtually anyltype, size, and the defining feature of blood vessel wall inflammation. location in the body and can lead to partial or comp ete luminal comprom se, with ensuing ischemia of the related tissues. Systemic vasculitis refers to a group of named primary vasculitides that are immune mediated and individually

distinguished by the presence of unique clinicopathologic features. may be confined to a single organ or affect a range of organ Systemic vasculitis should be considered when particular physical Systemic vasculitis can involve the large vessels, medium vessels, medium, or large vessels, but are capablefof affecting vessels of The primary large vessel systemic vasculitides are giant cell The clinical manifestations of systemic vasculitis are protean; it systems. findings are present or multiple systems are involved. or small vessels. Individual vasculitides predominantly af ect either small, more than 1 size. arteritis and Takayasu arteritis. The primary medium vessel systemic vasculitides are polyarteritis Small vessel systemic vasculitis can be ANCA-associated or non– The primary ANCA-associated small vessel systemic vasculitides granulomatosis), microscopic polyangiitis, and eosinophilic). vasculitides include Henoch-Schönlein purpura, cryoglobulinemia, nodosa and Kawasaki disease. ANCA-associated. include granulomatosis with polyangiitis (Wegener’s granulomatosis with polyangiitis (Churg-Strauss syndrome The primary non–ANCA-associated small vessel systemic Behçet’s disease, anti-glomerular basement membrane disease, and urticarial vasculitis.

Systemic vasculitis can be associated with a variety of secondary conditions (eg, systemic disease, infection, drugs).

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4. Migliori G, Battisti E, Pari M, Vitelli N, Cingolani C. A shifty diagnosis: Cogan’sl. syndrome. A case report and review of the literature. Acta Otorhinolaryngol Ita 2009;29(2):108-113.

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8. Vaglio A, BuziofC, Zwerina J. Eosinophilic granulomatosis with polyangiitis (Churg-10. Zeidan MJ, Saadoun D, Garrido M, Klatzmann D, Six A, Cacoub P. Behcet’s disease Strauss): state o the art. Allergy. 2013;68(3):261-273. physiopathology: a contemporary review. Auto Immun Highlights. 2016;7(1):4.

9. Troxell ML,JHoughton DC. Atypical anti-glomerular basement membrane disease. Clin Kidney . 2016;9(2):211-221.

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14disease): an updated review of ocular disease manifestations. Intractable Rare Dis Res. 2016;5(2):61-69.

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