Harrisons Principles of Internal Medicine Self-Assessment and Board Review 18th Ed.

SECTION IX. Rheumatology and Immunology


DIRECTIONS: Choose the one best response to each question.

IX-1. All of the following are key features of the innate immune system EXCEPT:

A.  Exclusively a feature of vertebrate animals.

B.  Important cells include macrophages and natural killer lymphocytes.

C.  Nonrecognition of benign foreign molecules or microbes.

D.  Recognition by germ line–encoded host molecules.

E.  Recognition of key microbe virulence factors but not recognition of self molecules.

IX-2. A 29-year-old male with episodic abdominal pain and stress-induced edema of the lips, the tongue, and occasionally the larynx is likely to have low functional or absolute levels of which of the following proteins?

A.  C1 esterase inhibitor

B.  C5A (complement cascade)

C.  Cyclooxygenase

D.  IgE

E.  T-cell receptor, α chain

IX-3. Which of the following statements best describes the function of proteins encoded by the human major histo-compatibility complex (MHC) I and II genes?

A.  Activation of the complement system

B.  Binding to cell surface receptors on granulocytes and macrophages to initiate phagocytosis

C.  Nonspecific binding of antigen for presentation to T cells

D.  Specific antigen binding in response to B-cell activation to promote neutralization and precipitation

IX-4. A 37-year-old man has recently been diagnosed with systemic hypertension. He is prescribed lisinopril as initial monotherapy. He takes this medication as prescribed for 3 days and on the third day notes that his right hand is swollen, mildly itchy, and tingling. Later that evening his lips become swollen and he has difficulty breathing. Which of the following statements accurately describes this condition?

A.  His symptoms are due to direct activation of mast cells by lisinopril.

B.  His symptoms are due to impaired bradykinin degradation by lisinopril.

C.  His symptoms are unlikely to recur if he is switched to enalapril.

D.  Peripheral blood analysis will show deficiency of C1 inhibitor.

E.  Plasma IgE levels are likely to be elevated.

IX-5. A 35-year-old female comes to the local health clinic for recurrent urticarial lesions that occasionally leave a residual discoloration for the last 6 months. She also has had arthralgias. The sedimentation rate now is 85 mm/h. The procedure most likely to yield the correct diagnosis in this case would be:

A.  A battery of wheal-and-flare allergy skin tests

B.  Measurement of total serum IgE concentration

C.  Measurement of C1 esterase inhibitor activity

D.  Skin biopsy

E.  Patch testing

IX-6. A 28-year-old woman seeks evaluation from her primary care doctor for recurrent episodes of hives and states that she is “allergic to cold weather.” She reports that for more than 10 years she has developed areas of hives when exposed to cold temperatures, usually on her arms and legs. She has not sought evaluation previously and states that over the past several years the occurrence of the hives has become more frequent. Other than cold exposure, she can identify no other triggers for the development of hives. She has no history of asthma or atopy. She denies food intolerance. Her only medication is oral contraceptive pills, which she has taken for 5 years. She lives in a single-family home that was built 2 years ago. On examination, she develops a linear wheal after being stroked along her forearm with a tongue depressor. Upon placing her hand in cold water, her hand becomes red and swollen. In addition, there are several areas with a wheal and flare reaction on the arm above the area of cold exposure. What is the next step in the management of this patient?

A.  Assess for the presence of antithyroglobulin and anti-microsomal antibodies.

B.  Check C1 inhibitor levels.

C.  Discontinue the oral contraceptive pills.

D.  Treat with cetirizine, 10 mg daily.

E.  Treat with cyproheptadine, 8 mg daily.

IX-7. A 23-year-old woman seeks evaluation for seasonal rhinitis. She reports that she develops symptoms yearly in the spring and fall. During this time, she develops rhinitis with postnasal drip and cough that disrupts her sleep. In addition, she will also have itchy and watery eyes. When the symptoms occur, she takes nonprescription loratadine, 10 mg daily, with significant improvement in her symptoms. What is the most likely allergen(s) that is/are causing this patient’s symptoms?

A.  Grass

B.  Ragweed

C.  Trees

D.  A and B

E.  B and C

F.  All of the above

IX-8. Which of the following autoantibodies is most likely to be present in a patient with systemic lupus erythematosus?

A.  Anti-dsDNA

B.  Anti-RNP

C.  Anti-Ro

D.  Antiphospholipid

E.  Antiribosomal P

IX-9. A 23-year-old woman is evaluated by her primary care physician because she is concerned that she may have systemic lupus erythematosus after hearing a public health announcement on the radio. She has no significant past medical history, and her only medication is occasional ibuprofen. She is not sexually active and works in a grocery store. She reports that she has had intermittent oral ulcers and right knee pain. Physical examination shows no evidence of alopecia, skin rash, or joint swelling/inflammation. Her blood work shows that she has a positive antinuclear antibody (ANA) at a titer of 1:40, but no other abnormalities. Which of the following statements is true?

A.  Four diagnostic criteria are required to be diagnosed with systemic lupus erythematosus; this patient has three.

B.  Four diagnostic criteria are required to be diagnosed with systemic lupus erythematosus; this patient has two.

C.  If a urinalysis shows proteinuria, she will meet the criteria for systemic lupus erythematosus.

D.  She meets the criteria for systemic lupus erythematosus because she has three criteria for the disease.

E.  The demonstration of a positive ANA alone is adequate to diagnose systemic lupus erythematosus.

IX-10. A 32-year-old woman with a long-standing diagnosis of systemic lupus erythematosus is evaluated by her rheumatologist as routine follow-up. A new cardiac murmur is heard and an echocardiogram is ordered. She is feeling well, and has no fevers, weight loss, or preexisting cardiac disease. A vegetation on the mitral valve is demonstrated. Which of the following statements is true?

A.  Blood cultures are unlikely to be positive.

B.  Glucocorticoid therapy has been proven to lead to improvement in this condition.

C.  Pericarditis is frequently present concomitantly.

D.  The lesion has a low risk of embolization.

E.  The patient has been surreptitiously using injection drugs.

IX-11. A 24-year-old woman is newly diagnosed with systemic lupus erythematosus. Which of the following organ system complications is she most likely to have over the course of her lifetime?

A.  Cardiopulmonary

B.  Cutaneous

C.  Hematologic

D.  Musculoskeletal

E.  Renal

IX-12. A 27-year-old female with systemic lupus erythematosus (SLE) is in remission; current treatment consists of azathioprine 75 mg/d and prednisone 5 mg/d. Last year she had a life-threatening exacerbation of her disease. She now strongly desires to become pregnant. Which of the following is the least appropriate action to take?

A.  Advise her that the risk of spontaneous abortion is high.

B.  Warn her that exacerbations can occur in the first trimester and in the postpartum period.

C.  Tell her it is unlikely that a newborn will have lupus.

D.  Advise her that fetal loss rates are higher if anticardiolipin antibodies are detected in her serum.

E.  Stop the prednisone just before she attempts to become pregnant.

IX-13. A 45-year-old African-American woman with systemic lupus erythematosus (SLE) presents to the emergency department with complaints of headache and fatigue. Her prior manifestations of SLE have been arthralgias, hemolytic anemia, malar rash, and mouth ulcers, and she is known to have high titers of antibodies to double-stranded DNA. She currently is taking prednisone, 5 mg daily, and hydroxychloroquine, 200 mg daily. On presentation, she is found to have a blood pressure of 190/110 mmHg with a heart rate of 98 beats/min. A urinalysis shows 25 red blood cells (RBCs) per high-power field with 2+ proteinuria. No RBC casts are identified. Her blood urea nitrogen is 88 mg/dL, and creatinine is 2.6 mg/dL (baseline 0.8 mg/dL). She has not previously had renal disease related to SLE and is not taking nonsteroidal anti-inflammatory drugs. She denies any recent illness, decreased oral intake, or diarrhea. What is the most appropriate next step in the management of this patient?

A.  Initiate cyclophosphamide, 500 mg/m2 body surface area IV, and plan to repeat monthly for 3–6 months.

B.  Initiate hemodialysis.

C.  Initiate high-dose steroid therapy (IV methylprednisolone, 1000 mg daily for 3 doses, followed by oral prednisone, 1 mg/kg daily) and mycophenolate mofetil, 2 g daily.

D.  Initiate plasmapheresis.

E.  Withhold all therapy until renal biopsy is performed.

IX-14. A 25-year-old African-American woman was has been followed in SLE clinic since her diagnosis 6 months ago. At that time she had evidence of mild joint disease, photosensitivity, malar rash, positive ANA, and anti-dsDNA. Her renal function and urinalysis were normal. She has been maintained on acetaminophen and hydroxychloroquine. She comes to the emergency department after a recent outing to the beach with friends. Over the past 2 days she’s noticed a marked increase in her fatigue and morning stiffness. She also has red-tinged urine. Physical examination is notable for a skin rash in sun-exposed areas, and diffuse wrist, knee, and ankle synovial thickening. Her platelet count has fallen from normal values to 45,000 and she has new leukopenia. In addition, her serum creatinine is 2.5 and there are RBC casts on urine analysis. An emergent renal biopsy is consistent with active diffuse lupus nephritis. After receiving methylprednisolone 1 g IV for 3 days, all of the following are appropriate treatment regimens EXCEPT:

A.  Prednisone 60 mg/d

B.  Prednisone 60 mg/d plus azathioprine

C.  Prednisone 60 mg/d plus cyclophosphamide

D.  Prednisone 60 mg/d plus mycophenolate mofetil

E.  Rituximab

IX-15. A 27-year-old woman is admitted to the intensive care unit after delivery of a full-term infant 3 days prior. The patient was found to have right hemiparesis and a blue left hand. Physical examination is also notable for livedo reticularis. Her laboratories were notable for a white blood cell count of 10.2/μL, hematocrit 35%, and platelet count of 13,000/μL. Her BUN is 36 mg/dL and her creatinine is 2.3 mg/dL. Although this pregnancy was uneventful, the three prior pregnancies resulted in early losses. A peripheral smear shows no evidence of schistocytes. Which of the following laboratory studies will best confirm the underlying etiology of her presentation?

A.  Anticardiolipin antibody panel

B.  Antinuclear antibody

C.  Doppler examination of her left arm arterial tree

D.  Echocardiography

E.  MRI of her brain

IX-16. A 28-year-old woman comes to the emergency department complaining of 1 day of worsening right leg pain and swelling. She drove in a car for 8 hours returning from a hiking trip 2 days ago then noticed some pain in the leg. At first she thought it was due to exertion but it has worsened over the day. Her only past medical history is related to difficulty getting pregnant with 2 prior spontaneous abortions. Her physical examination is notable for normal vital signs and heart and lung examination. Her right leg is swollen from the mid-thigh down and is tender. Doppler studies demonstrate a large deep venous thrombosis in the femoral and ileac veins extending into the pelvis. Laboratory studies on admission prior to therapy show normal electrolytes, normal white blood cell (WBC) and platelet counts, normal prothrombin time, and an activated partial thromboplastin time 3× normal. Her pregnancy test is negative. Low-molecular-weight heparin therapy is initiated in the emergency department. Subsequent therapy should include:

A.  Rituximab 375 mg/m2 per week for 4 weeks

B.  Warfarin with INR goal of 2.0–3.0 for 3 months

C.  Warfarin with INR goal of 2.0–3.0 for 12 months

D.  Warfarin with INR goal of 2.5–3.5 for life

E.  Warfarin with an INR goal of 2.5–3.5 for 12 months followed by daily aspirin for life

IX-17. Which of the following is the most frequent site of joint involvement in established rheumatoid arthritis (RA)?

A.  Distal interphalangeal joint

B.  Hip

C.  Knee

D.  Spine

E.  Wrist

IX-18. In patients with established rheumatoid arthritis, all of the following pulmonary radiographic findings may be explained by their rheumatologic condition EXCEPT:

A.  Bilateral interstitial infiltrates

B.  Bronchiectasis

C.  Lobar infiltrate

D.  Solitary pulmonary nodule

E.  Unilateral pleural effusion

IX-19. Which of the following is the earliest plain radiographic finding of rheumatoid arthritis?

A.  Juxtaarticular osteopenia

B.  No abnormality

C.  Soft-tissue swelling

D.  Subchondral erosions

E.  Symmetric joint space loss

IX-20. Which of the following statements regarding rheumatoid arthritis is true?

A.  Africans and African Americans most commonly have the class II major histocompatibility complex allele HLA-DR4.

B.  Females are affected three times more often than are males, and this difference is maintained throughout life.

C.  The earliest lesion in rheumatoid arthritis is an increase in the number of synovial lining cells with microvascular injury.

D.  There is an association with the class II major histocompatibility complex allele HLA-B27.

E.  Titers of rheumatoid factor are not predictive of the severity of rheumatoid arthritis or its extraarticular manifestations.

IX-21. A 46-year-old woman presents to your clinic with multiple complaints. She describes fatigue and general malaise over 2–3 months. Her appetite has decreased. She thinks she has unintentionally lost approximately 5.5 kg. Lately, she notes pain and stiffness in her fingers on both hands that is worse in the morning and with repetitive movement. She has a grandmother and a sister who have rheumatoid arthritis, and she is very concerned that she now has it as well. Which of her complaints represents the most common manifestation of established rheumatoid arthritis?

A.  Fatigue and anorexia for more than 2 months with concomitant joint pain

B.  Morning joint stiffness lasting for more than 1 hour

C.  Pain in symmetric joints that is worsened with movement

D.  Positive family history with two relatives with RA

E.  Weight loss of more than 4.5 kg during period of active disease

IX-22. All of the following are characteristic extraarticular manifestations of rheumatoid arthritis EXCEPT:

A.  Anemia

B.  Cutaneous vasculitis

C.  Pericarditis

D.  Secondary Sjögren’s syndrome

E.  Thrombocytopenia

IX-23. All of the following agents have been shown to have disease-modifying antirheumatic drug (DMARD) efficacy in patients with rheumatoid arthritis EXCEPT:

A.  Infliximab

B.  Leflunomide

C.  Methotrexate

D.  Naproxen

E.  Rituximab

IX-24. Which of the following is the most common clinical presentation of acute rheumatic fever (ARF)?

A.  Carditis

B.  Chorea

C.  Erythema marginatum

D.  Polyarthritis

E.  Subcutaneous nodules

IX-25. A 19-year-old recent immigrant from Ethiopia comes to your clinic to establish primary care. She currently feels well. Her past medical history is notable for a recent admission to the hospital for new-onset atrial fibrillation. As a child in Ethiopia, she developed an illness that caused uncontrolled flailing of her limbs and tongue lasting approximately 1 month. She also has had three episodes of migratory large-joint arthritis during her adolescence that resolved with pills that she received from the pharmacy. She is currently taking metoprolol and warfarin and has no known drug allergies. Physical examination reveals an irregularly irregular heart beat with normal blood pressure. Her point of maximal impulse (PMI) is most prominent at the midclavicular line and is normal in size. An early diastolic rumble and a 3/6 holosystolic murmur are heard at the apex. A soft early diastolic murmur is also heard at the left third intercostal space. You refer her to a cardiologist for evaluation of valve replacement and echocardiography. What other intervention might you consider at this time?

A.  Glucocorticoids

B.  Daily aspirin

C.  Daily doxycycline

D.  Monthly penicillin G injections

E.  Penicillin G injections as needed for all sore throats

IX-26. A patient with a diagnosis of scleroderma who has diffuse cutaneous involvement presents with malignant hypertension, oliguria, edema, hemolytic anemia, and renal failure. You make a diagnosis of scleroderma renal crisis (SRC). What is the recommended treatment?

A.  Captopril

B.  Carvedilol

C.  Clonidine

D.  Diltiazem

E.  Nitroprusside

IX-27. A 57-year-old woman with depression and chronic migraine headaches reports several years of dry mouth and dry eyes. Her primary complaint is that she can no longer eat her favorite crackers, though she does report photosensitivity and eye burning on further questioning. She has no other associated symptoms. Examination shows dry, erythematous, sticky oral mucosa. All of the following tests are likely to be positive in this patient EXCEPT:

A.  La/SS-B antibody

B.  Ro/SS-A antibody

C.  Schirmer’s I test

D.  Scl-70 antibody

E.  Sialometry

IX-28. Which of the following is the most common extra-glandular manifestation of primary Sjögren’s syndrome?

A.  Arthralgias/arthritis

B.  Lymphoma

C.  Peripheral neuropathy

D.  Raynaud’s phenomenon

E.  Vasculitis

IX-29. A 44-year-old woman presents for evaluation of dry eyes and mouth. She first noticed these symptoms more than 5 years ago and the symptoms have worsened over time. She describes her eyes as gritty feeling, as if there were sand in her eyes. Sometimes her eyes burn, and she states that it is difficult to be outside in bright sunlight. In addition, her mouth is quite dry. In her job, she is frequently asked to give business presentations and finds it increasingly difficult to complete a 30- to 60-minute presentation. She has water with her at all times. Although she reports good dental hygiene without any recent changes, her dentist has had to place fillings twice in the past 3 years for dental caries. Her only other past medical history is treated tuberculosis that she contracted while in the Peace Corps in Southeast Asia when in her 20s. She takes no medication regularly and does not smoke. Ocular examination reveals punctuate corneal ulcerations on Rose Bengal stain, and the Schirmer’s test shows greater than 5 mm of wetness after 5 minutes. Her oral mucosa is dry with thick mucous secretions, and the parotid glands are enlarged bilaterally. Laboratory examination reveals positive antibodies to Ro and La (SS-A and SS-B). In addition, her chemistries reveal a sodium of 142 meq/L, potassium 2.6 meq/L, chloride 115 meq/L, and bicarbonate of 15 meq/L. What is the most likely cause of the hypokalemia and acidemia in this patient?

A.  Diarrhea

B.  Distal (type I) renal tubular acidosis

C.  Hypoaldosteronism

D.  Purging with underlying anorexia nervosa

E.  Renal compensation for chronic respiratory alkalosis

IX-30. A patient with primary Sjögren’s syndrome that was diagnosed 6 years ago and treated with tear replacement for symptomatic relief notes continued parotid swelling for the last 3 months. She has also noted enlarging posterior cervical lymph nodes. Evaluation shows leukopenia and low C4 complement levels. What is the most likely diagnosis?

A.  Amyloidosis

B.  Chronic pancreatitis

C.  HIV infection

D.  Lymphoma

E.  Secondary Sjögren’s syndrome

IX-31. The histocompatibility antigen HLA-B27 is present in what percentage of patients with ankylosing spondylitis?

A.  10%

B.  30%

C.  50%

D.  90%

E.  100%

IX-32. Which of the following is the most common extra-articular manifestation of ankylosing spondylitis?

A.  Anterior uveitis

B.  Aortic insufficiency

C.  Inflammatory bowel disease

D.  Pulmonary fibrosis

E.  Third-degree heart block

IX-33. A 25-year-old man sees his primary care physician for evaluation of low back pain. The pain is severe, is worse in the morning, and is relieved with exercise and is worse with rest; in particular, nighttime sleeping is difficult. He does feel quite stiff in the morning for at least 30 minutes. An MRI of his lower back is obtained and shows active inflammation in the sacroiliac joint. On further questioning, he reports a history of unilateral eye redness treated with corticosteroids about 2 years ago. A test for HLA-B27 is positive. Which of the following is first-line therapy for his condition?

A.  Infliximab

B.  Naproxen

C.  Prednisone

D.  Rituximab

E.  Tramadol

IX-34. A 27-year-old man is seen at his primary care physician’s office for evaluation of painful arthritis involving the right knee that is associated with finger welling diffusely. He is otherwise healthy, but does recall a severe bout of diarrheal illness about 3–4 weeks prior that spontaneously resolved. He takes no medications and reports rare marijuana use. On review of systems, he reports painful urination. Examination shows inflammatory arthritis of the right knee, dactylitis, and normal genitourinary examination. He is diagnosed with reactive arthritis. Which of the following is the most likely etiologic agent of his diarrhea?

A.  Campylobacter jejuni

B.  Clostridium difficile

C.  Escherichia coli

D.  Helicobacter pylori

E.  Shigella flexneri

IX-35. A 28-year-old woman undergoes evaluation for weight loss and bloody diarrhea that is ultimately diagnosed as Crohn’s disease. She has been diagnosed with dactylitis and bilateral sacroiliitis within the past 6 months. She is scheduled to begin treatment with infliximab in 2 weeks for her Crohn’s disease. Which of the following statements is true regarding the effect of infliximab on her arthritis?

A.  Although infliximab is likely to improve her arthritic symptoms, NSAIDs should be tried first.

B.  Although infliximab is very effective therapy for Crohn’s disease, it will have no effect on her arthritis.

C.  Her arthritis is unrelated to Crohn’s disease, and because of this she should undergo a thorough evaluation for infectious causes before undergoing immunosuppressive therapy.

D.  Infliximab is very effective therapy for this type of arthritis.

E.  None of the above.

IX-36. Which of the following statements regarding the arthritis of Whipple’s disease is true?

A.  Arthritis is a rare finding in Whipple’s disease.

B.  Joint manifestations are usually concurrent with gastrointestinal symptoms and malabsorption.

C.  Radiography frequently shows joint erosions.

D.  Synovial fluid examination is unlikely to show polymorphonuclear cells.

E.  None of the above.

IX-37. A 35-year-old man has severe ankylosing spondylitis that is unresponsive to NSAID therapy. Therapy with infliximab has been recommended and he is wondering about potential side effects. All of the following are common potential side effects from this medication EXCEPT:

A.  Demyelinating disorders

B.  Disseminated tuberculosis

C.  Exacerbation of congestive heart failure

D.  Hypersensitivity pneumonitis

E.  Pancytopenia

IX-38. Which of the following definitions best fits the term enthesitis?

A.  Alteration of joint alignment so that articulating surfaces incompletely approximate each other

B.  Inflammation at the site of tendinous or ligamentous insertion into bone

C.  Inflammation of the periarticular membrane lining the joint capsule

D.  Inflammation of a saclike cavity near a joint that decreases friction

E.  A palpable vibratory or crackling sensation elicited with joint motion

IX-39. A 35-year-old female presents to her primary care doctor complaining of diffuse body and joint pain. When asked to describe which of her joints are most affected, she answers, “All of them.” There is no associated stiffness, redness, or swelling of the joints. No Raynaud’s phenomenon has been appreciated. Occasionally she notes numbness in the fingers and toes. The patient complains of chronic pain and poor sleep quality that she feels is due to her pain. She previously was seen in the clinic for chronic headaches that were felt to be tension related. She has tried taking over-the-counter ibuprofen twice daily without relief of pain. She has no other medical problems. On physical examination, the patient appears comfortable. Her joints exhibit full range of motion without evidence of inflammatory arthritis. She does have pain with palpation at bilateral suboccipital muscle insertions, at C5, at the lateral epicondyle, in the upper outer quadrant of the buttock, at the medial fat pad of the knee proximal to the joint line, and unilaterally on the second right rib. The erythrocyte sedimentation rate is 12 seconds. Antinuclear antibodies are positive at a titer of 1:40 in a speckled pattern. The patient is HLA-B27 positive. Rheumatoid factor is negative. Radiograms of the cervical spine, hips, and elbows are normal. What is the most likely diagnosis?

A.  Ankylosing spondylitis

B.  Disseminated gonococcal infection

C.  Fibromyalgia

D.  Rheumatoid arthritis

E.  Systemic lupus erythematosus

IX-40. A 42-year-old male presents with complaints of a rash and joint pain. He first noticed the rash 6 months ago. It is primarily on the hands (Figure IX-40), the extensor surfaces of the elbows, and the knees, low back, and scalp. Although he complains of the appearance of these lesions, they do not itch or hurt. He has not been previously evaluated for them and has recently noticed changes in the nail beds. For the last 2 weeks, the patient has had increasingly severe pain in the distal joints of the hands and feet. His hands are so painful that he is having trouble writing and holding utensils. He denies fevers, weight loss, fatigue, cough, shortness of breath, or changes in bowel or bladder habits. Which of the following is the most likely diagnosis?


FIGURE IX-40 (See color atlas)

A.  Arthritis associated with inflammatory bowel disease

B.  Gout

C.  Osteoarthritis

D.  Psoriatic arthritis

E.  Rheumatoid arthritis

IX-41. All of the following vasculitic syndromes are thought to be due to immune complex deposition EXCEPT:

A.  Cryoglobulinemic vasculitis

B.  Henoch-Schönlein purpura

C.  Polyarteritis nodosa associated with hepatitis B

D.  Serum sickness

E.  Granulomatosis with polyangiitis (Wegener’s)

IX-42. A 53-year-old man presents with a vasculitis syndrome. His cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCA) is positive. Which of the following syndromes is he most likely to have?

A.  Churg-Strauss syndrome

B.  Henoch-Schönlein purpura

C.  Microscopic polyangiitis

D.  Ulcerative colitis

E.  Granulomatosis with polyangiitis (Wegener’s)

IX-43. A 40-year-old male presents to the emergency department with 2 days of low-volume hemoptysis. He reports that he has been coughing up 2–5 tablespoons of blood each day. He reports mild chest pain, low-grade fevers, and weight loss. In addition, he has had about 1 year of severe upper respiratory symptoms including frequent epistaxis and purulent discharge treated with several courses of antibiotics. Aside from mild hyperlipidemia, he is otherwise healthy. His only medications are daily aspirin and lovastatin. On physical examination he has normal vital signs, and the upper airway is notable for saddle nose deformity and clear lungs. A CT of the chest shows multiple cavitating nodules, and urinalysis shows red blood cells. Which of the following tests offers the highest diagnostic yield to make the appropriate diagnosis?

A.  Deep skin biopsy

B.  Percutaneous kidney biopsy

C.  Pulmonary angiogram

D.  Surgical lung biopsy

E.  Upper airway biopsy

IX-44. An 84-year-old woman sees her primary care physician for evaluation of severe headaches. She noted these several weeks ago and they have been getting worse. Although she has not had any visual aura, she is concerned that she has been intermittently losing vision in her left eye for the last few days. She denies new weakness or numbness, but she does report jaw pain with eating. Her past medical history includes coronary artery disease requiring a bypass grafting 10 years prior, diabetes mellitus, hyperlipidemia, and mild depression. Full review of symptoms is notable for night sweats and mild low back pain that is particularly prominent in the morning. Which of the following is the next most appropriate step?

A.  Aspirin 975 mg po daily

B.  Measurement of erythrocyte sedimentation rate

C.  Prednisone 60 mg daily

D.  Referral for temporal artery biopsy

E.  Referral for ultrasound of temporal artery

IX-45. A 54-year-old man is evaluated for cutaneous vasculitis and peripheral nephropathy. Because of concomitant renal dysfunction he undergoes kidney biopsy that shows glomerulonephritis. Cryoglobulins are demonstrated in the peripheral blood. Which of the following laboratory studies should be sent to determine the etiology?

A.  Hepatitis B surface antigen

B.  Cytoplasmic ANCA

C.  Hepatitis C polymerase chain reaction (PCR)

D.  HIV antibody

E.  Rheumatoid factor

IX-46. A 54-year-old man is admitted for persistent lower abdominal and groin pain that began 7 months previously. Two months before his present admission, he required exploratory laparoscopy for acute abdominal pain and presumed cholecystitis. This revealed necrotic omental tissue and pericholecystitis necessitating omentectomy and cholecystectomy. However, the pain continued unchanged. He currently describes it as periumbilical and radiating into his groin and legs. It becomes worse with eating. The patient has also had episodic severe testicular pain, bowel urgency, nausea, vomiting, and diuresis. He has lost approximately 22.7 kg over the preceding 6 months. His past medical history is significant for hypertension that has recently become difficult to control.

Medications on admission include aspirin, hydrochlorothiazide, hydromorphone, lansoprazole, metoprolol, and quinapril. On physical examination, the patient appears comfortable. His blood pressure is 170/100 mmHg, his heart rate is 88 beats/min, and he is afebrile. He has normal first and second heart sounds without murmurs, and an S4 is present. There are no carotid, renal, abdominal, or femoral bruits.

His lungs are clear to auscultation. Bowel sounds are normal. Abdominal palpation demonstrates minimal diffuse tenderness without rebound or guarding. No masses are present, and the stool is negative for occult blood. During the examination, the patient develops Raynaud’s phenomenon in his right hand that persists for several minutes. His neurologic examination is intact. Admission laboratory studies reveal an erythrocyte sedimentation rate of 72 mm/h, a BUN of 17 mg/dL, and a creatinine of 0.8 mg/dL. The patient has no proteinuria or hematuria. Tests for antinuclear antibodies, anti–double-stranded-DNA antibodies, and antineutrophil cytoplasmic antibodies are negative. Liver function tests are abnormal with an AST of 89 IU/L and an ALT of 112 IU/L. Hepatitis B surface antigen and e antigen are positive. Mesenteric angiography demonstrates small, beaded aneurysms of the superior and inferior mesenteric veins. What is the most likely diagnosis?

A.  Hepatocellular carcinoma

B.  Ischemic colitis

C.  Microscopic polyangiitis

D.  Mixed cryoglobulinemia

E.  Polyarteritis nodosa

IX-47. An 18-year-old man is admitted to the hospital with acute onset of crushing substernal chest pain that began abruptly 30 minutes ago. He reports the pain radiating to his neck and right arm. He has otherwise been in good health. He currently plays trumpet in his high school marching band but does not participate regularly in aerobic activities. On physical examination, he is diaphoretic and tachypneic. His blood pressure is 100/48 mmHg and heart rate is 110 beats/min. His cardiovascular examination shows a regular rhythm but is tachycardic. A II/VI holosystolic murmur is heard best at the apex and radiates to the axilla. His lungs have bilateral rales at the bases. The electrocardiogram demonstrates 4 mm of ST elevation in the anterior leads. On further questioning regarding his past medical history, he recalls having been told that he was hospitalized for some problem with his heart when he was 2 years old. His mother, who accompanies him, reports that he received aspirin and γ-globulin as treatment. Since that time, he has required intermittent follow-up with echocardiography. What is the most likely cause of this patient’s acute coronary syndrome?

A.  Dissection of the aortic root and left coronary ostia

B.  Presence of a myocardial bridge overlying the left anterior descending artery

C.  Stenosis of a coronary artery aneurysm

D.  Vasospasm following cocaine ingestion

E.  Vasculitis involving the left anterior descending artery

IX-48. Which of the following is required for the diagnosis of Behçet’s disease?

A.  Large-vessel vasculitis

B.  Pathergy test

C.  Recurrent oral ulceration

D.  Recurrent genital ulceration

E.  Uveitis

IX-49. A 25-year-old female presents with a complaint of painful mouth ulcerations. She describes these lesions as shallow ulcers that last for 1–2 weeks. The ulcers have been appearing for the last 6 months. For the last 2 days, the patient has had a painful red eye. She has had no genital ulcerations, arthritis, skin rashes, or photosensitivity. On physical examination, the patient appears well developed and in no distress. She has a temperature of 37.6°C (99.7°F), heart rate of 86 beats/min, blood pressure of 126/72 mmHg, and respiratory rate of 16 breaths/min. Examination of the oral mucosa reveals two shallow ulcers with a yellow base on the buccal mucosa. The ophthalmologic examination is consistent with anterior uveitis. The cardiopulmonary examination is normal. She has no arthritis, but medially on the right thigh there is a palpable cord in the saphenous vein. Laboratory studies reveal an erythrocyte sedimentation rate of 68 seconds. White blood cell count is 10,230/μL with a differential of 68% polymorphonuclear cells, 28% lymphocytes, and 4% monocytes. The antinuclear antibody and anti-dsDNA antibody are negative. C3 is 89 mg/dL, and C4 is 24 mg/dL. What is the most likely diagnosis?

A.  Behçet’s syndrome

B.  Cicatricial pemphigoid

C.  Discoid lupus erythematosus

D.  Sjögren’s syndrome

E.  Systemic lupus erythematosus

IX-50. What is the best initial treatment for the patient in question IX-49?

A.  Colchicine

B.  Intralesional interferon α

C.  Systemic glucocorticoids and azathioprine

D.  Thalidomide

E.  Topical glucocorticoids including ophthalmic prednisolone

IX-51. Relapsing polychondritis may be a primary disease or may be associated with other rheumatologic diseases. All of the following conditions are associated with relapsing polychondritis EXCEPT:

A.  Myelodysplastic syndrome

B.  Primary biliary cirrhosis

C.  Scleroderma

D.  Spondyloarthritides

E.  Systemic lupus erythematosus

IX-52. A 47-year-old man is evaluated for 1 year of recurrent episodes of bilateral ear swelling. The ear is painful during these events, and the right ear has become floppy. He is otherwise healthy and reports no illicit habits. He works in an office and his only sport is tennis. On examination, the left ear has a beefy red color, and the pinna is tender and swollen; the earlobe appears minimally swollen but is neither red nor tender. Which of the following is the most likely explanation for this finding?

A.  Behçet’s syndrome

B.  Cogan’s syndrome

C.  Hemoglobinopathy

D.  Recurrent trauma

E.  Relapsing polychondritis

IX-53. A 25-year-old African-American woman is evaluated for bilateral hilar lymphadenopathy found on a routine chest radiograph performed before a laparoscopic cholecystectomy. She undergoes mediastinoscopy, and multiple noncaseating granulomas are identified in her lymph nodes. All of the following may explain this finding EXCEPT:

A.  Alveolar proteinosis

B.  Atypical mycobacteria

C.  Beryllium exposure

D.  Histoplasmosis

E.  Malignancy

F.  Sarcoidosis

IX-54. A 34-year-old woman has a history of cutaneous sarcoidosis that has been managed with hydroxychloroquine for the last 5 years. After an episode of right flank pain and hematuria, she is diagnosed with renal calculus. Which of the following statements regarding her renal calculus is true?

A.  Exogenous vitamin D and sunlight exposure in patients with sarcoidosis may exacerbate hypercalcemia and associated renal calculus.

B.  Hypercalcemia is rare in sarcoidosis and is unlikely to contribute to the patient’s calculus.

C.  Hypercalcemia in sarcoidosis occurs through increased production of 25-dihydroxyvitamin D by the skin.

D.  If she is to begin therapy with oral calcium to treat the renal stone, a 24-hour urine phosphate should be obtained before and after initiation of therapy.

E.  None of the above.

IX-55. All of the following agents have been shown to improve symptoms or function in patients with sarcoidosis EXCEPT:

A.  Etanercept

B.  Hydroxychloroquine

C.  Infliximab

D.  Methotrexate

E.  Prednisone

IX-56. All of the following statements regarding the clinical manifestations of sarcoidosis are true EXCEPT:

A.  Cardiac involvement occurs in 25% of patients.

B.  Eye involvement is typically anterior uveitis.

C.  Liver involvement is typically manifest by elevation of alkaline phosphatase.

D.  Lung involvement occurs in over 90% of cases.

E.  Skin involvement occurs in approximately one-third of patients.

IX-57. You are seeing a 56-year-old woman for complaints of joint pain and stiffness. All of the following signs or symptoms would be indicative of inflammatory causes of arthritis EXCEPT:

A.  Elevations in erythrocyte sedimentation rate

B.  Fatigue, fever, or weight loss

C.  Persistence for longer than 6 weeks

D.  Presence of soft-tissue swelling around affected joints

E.  Prolonged morning stiffness

IX-58. A 22-year-old man is seen for a shoulder injury that occurred while pitching in a baseball game. He describes feeling a snap then acute pain in the shoulder of his left arm while throwing the ball. Which of the following findings would be most concerning for a tear of one of the rotator cuff muscles?

A.  Inability to hold the arm at 90° following passive abduction

B.  Inability to actively raise the arm more than 90° with forward flexion

C.  Pain with palpation over the bicipital groove while rotating the arm internally and externally

D.  Pain with palpation while applying pressure anteriorly along the joint and rotating the arm internally and externally

E.  Pain with passive abduction of the arm

IX-59. A 62-year-old white male presents with a chief complaint of right knee pain and swelling. Past medical history is significant for obesity with a body mass index (BMI) of 34 kg/m2, diet-controlled Type 2 diabetes mellitus, and hypertension. His medications include hydro-chlorothiazide and acetaminophen as needed for pain. Physical examination is remarkable for a moderately sized effusion of the right knee, with range of motion limited to 90° of flexion and 160° of extension. There is minimal warmth and no redness. He has crepitus with range of motion. With weight bearing, he has outward bowing of the legs bilaterally. A radiogram of the right knee shows osteophytes and joint space narrowing. Which of the following is the most likely finding on joint fluid examination?

A.  A Gram stain showing gram-positive cocci in clusters

B.  A white blood cell count of 1110/μL

C.  A white blood cell count of 22,000/μL

D.  Positively birefringent crystals on polarizing light microscopy

E.  Negatively birefringent crystals on polarizing light microscopy

IX-60. A 62-year-old woman presents complaining of hand pain bilaterally that has been gradually progressive over the past year. She has previously worked as a seamstress in a factory making gloves for more than 35 years. You suspect osteoarthritis. All of the following factors on history or physical examination are characteristic of this diagnosis EXCEPT:

A.  Evidence of bilateral swelling and warmth affecting the wrists only

B.  Joint space narrowing and osteophytes at the proximal and distal interphalangeal joints on x-ray

C.  Pain that becomes worse when preparing meals

D.  Presence of Heberden’s nodes

E.  Stiffness that is worse after brief periods of rest with occasional locking of the more affecting joints

IX-61. A 73-year-old woman with a medical history of obesity and diabetes mellitus presents to your clinic complaining of right knee pain that has been progressive and is worse with walking or standing. She has taken over-the-counter nonsteroidal anti-inflammatory drugs without relief. She wants to know what is wrong with her knee and what may have caused it. X-rays are performed and reveal cartilage loss and osteophyte formation. Which of the following represents the most potent risk factor for the development of osteoarthritis?

A.  Age

B.  Gender

C.  Genetic susceptibility

D.  Obesity

E.  Previous joint injury

IX-62. A 53-year-old man presents to your clinic complaining of bilateral knee pain. He states that the pain worsens with walking and is not present at rest. He has been experiencing knee pain intermittently for many months and has had no relief from over-the-counter analgesics. He has a history of hypertension and obesity. When he was in high school and college, he played football and basketball. Which of the following represents the best initial treatment strategy for this patient?

A.  Avoidance of walking for several weeks

B.  Light daily walking exercises

C.  Low-dose, long-acting narcotics

D.  Oral steroid pulse

E.  Weight loss

IX-63. A 74-year-old man is seen by his primary care provider 6 weeks following an acute gout attack. He has a prior history of gout presenting similarly on two prior occasions within the past 6 months. His past medical history is significant for congestive heart failure, hypercholesterolemia, and stage III chronic kidney disease. He is taking pravastatin, aspirin, furosemide, metolazone, lisinopril, and metoprolol XL. His glomerular filtration rate is 38 mL/min, creatinine is 2.2 mg/dL, and uric acid level is 9.3 mg/dL. He is wondering if there is any therapy that might lessen his likelihood of repeated gout attacks. Which of the following medication regimens is most appropriate for the treatment of this patient?

A.  Allopurinol 800 mg daily

B.  Colchicine 0.6 mg bid

C.  Febuxostat 40 mg daily

D.  Indomethacin 25 mg twice daily

E.  Probenecid 250 mg twice daily

IX-64. A 64-year-old man with congestive heart failure presents to the emergency department complaining of acute onset of severe pain in his right foot. The pain began during the night and awoke him from a deep sleep. He reports the pain to be so severe that he could not wear a shoe or sock to the hospital. His current medications are furosemide 40 mg twice daily, carvedilol 6.25 mg twice daily, candesartan 8 mg once daily, and aspirin 325 mg once daily. On examination, he is febrile to 38.5°C (101.3°F). The first toe of the right foot is erythematous and exquisitely tender to touch. There is significant swelling and effusion of the first metatarsophalangeal joint on the right foot. No other joints are affected. Which of the following findings would be expected on arthrocentesis?

A.  Glucose level of less than 25 mg/dL

B.  Positive Gram stain

C.  Presence of strongly negatively birefringent needle-shaped crystals under polarized light microscopy

D.  Presence of weakly positively birefringent rhomboidal crystals under polarized light microscopy

E.  White blood cell (WBC) count greater than 100,000/μL

IX-65. A 24-year-old woman is admitted to the hospital with symptoms of fever and a swollen, painful right knee. About 3 weeks prior to the current syndrome, the patient had systemic symptoms including fevers, chills, and migratory joint pains affecting the hands, wrists, knees, hips, and ankles. At that time, she noticed a few small papules on her upper chest and hands. These have subsequently resolved. She has no significant past medical history. She currently works as a landscape designer and does not recall any recent tick or insect bites. Her only medication is an oral contraceptive. She is unmarried and has multiple sexual partners. On physical examination, the patient has a temperature of 38.4°C (101.2°F), heart rate of 124 beats/min, respiratory rate of 24 breaths/min, and blood pressure of 102/68 mmHg. Her right knee demonstrates redness, warmth, swelling, and pain with movement. An arthrocentesis demonstrates a white blood cell count of 66,000/μL (90% neutrophils). No crystals or organisms are seen. Which of the following would be most likely to yield the correct diagnosis?

A.  Bacterial cultures of the cervix

B.  Bacterial cultures of the synovial fluid

C.  Blood cultures

D.  IgG directed against Borrelia burgdorferi

E.  Rheumatoid factor

IX-66. A 66-year-old woman with a history of rheumatoid arthritis and frequent attacks of pseudogout in her left knee presents with night sweats and a 2-day history of left knee pain. Her medications include methotrexate 15 mg weekly, folate 1 mg daily, prednisone 5 mg daily, and ibuprofen 800 mg three times daily as needed for pain. On physical examination, her temperature is 38.6°C (101.5°F), heart rate is 110 beats/min, blood pressure is 104/78 mmHg, and oxygen saturation is 97% on room air. Her left knee is swollen, red, painful, and warm. With 5° of flexion or extension, she develops extreme pain. She has evidence of chronic joint deformity in her hands, knees, and spine. Peripheral white blood cell (WBC) count is 16,700 cells/μL with 95% neutrophils. A diagnostic tap of her left knee reveals 168,300 WBCs per μL and 99% neutrophils, and diffuse needle-shaped birefringent crystals are present. Gram stain shows rare gram-positive cocci in clusters. Management includes all of the following EXCEPT:

A.  Blood cultures

B.  Glucocorticoids

C.  Needle aspiration of joint fluid

D.  Orthopedic surgery consult

E.  Vancomycin

IX-67. A 42-year-old woman is seen in her primary care doctor’s office complaining of diffuse pains and fatigue. She has a difficult time localizing the pain to any particular joint or location, but reports that it affects her upper and lower extremities, neck, and hips. It is described as achy and 10 out of 10 in intensity. She feels that her joints are stiff but does not notice that it is worse in the morning. The pain has been present for the past 6 months and is increasing in intensity. She has tried both over-the-counter ibuprofen and acetaminophen without significant relief. The patient feels as if the pain is interfering with her ability to get restful sleep and is making it difficult for her to concentrate. She has missed multiple days of work as a waitress and fears that she will lose her job. There is a medical history of depression and obesity. The patient currently is taking venlafaxine sustained release 150 mg daily. She has a family history of rheumatoid arthritis in her mother. She smokes 1 pack of cigarettes daily. On physical examination vital signs are normal. Body mass index is 36 kg/m2. Joint examination demonstrates no erythema, swelling, or effusions. There is diffuse pain with palpation at the insertion points of the suboccipital muscles, at the midpoint of the upper border of the trapezius muscle, along the second costochondral junction, at the lateral epicondyles, and along the medial fat pad of the knees. All of the following statements regarding the cause of this patient’s diffuse pain syndrome are true EXCEPT:

A.  Cognitive dysfunction, sleep disturbance, anxiety, and depression are common comorbid neuropsycho-logical conditions.

B.  Pain in this syndrome is associated with increased evoked pain sensitivity.

C.  Pain in this syndrome is often localized to specific joints.

D.  This syndrome is present in 2–5% of the general population, but increases in prevalence to 20% or more of patients with degenerative or inflammatory rheumatic disorders.

E.  Women are nine times more likely than men to be affected by this syndrome.

IX-68. A 36-year-old woman presents to your office with diffuse pain throughout her body associated with fatigue, insomnia, and difficulty concentrating. She finds the pain difficult to localize, but reports that it is 7–8 out of 10 in intensity and is not relieved by nonsteroidal anti-inflammatory medications. She has a long-standing history of generalized anxiety disorder and is treated with sertraline 100 mg daily as well as clonazepam 1 mg twice daily. On examination, she has pain with palpation at several musculoskeletal sites. Her laboratory examination demonstrates a normal complete blood count, basic metabolic panel, erythrocyte sedimentation rate, and rheumatoid factor. You diagnose her with fibromyalgia. All of the following therapies are recommended as part of the treatment plan for fibromyalgia EXCEPT:

A.  An exercise program that includes strength training, aerobic exercise, and yoga

B.  Cognitive-behavioral therapy for insomnia

C.  Milnacipran

D.  Oxycodone

E.  Pregabalin

IX-69. A 53-year-old woman presents to your clinic complaining of fatigue and generalized pain that have worsened over 2 years. She also describes irritability and poor sleep, and is concerned that she is depressed. She reveals that she was recently separated from her husband and has been stressed at work. Which of the following elements in her history and physical examination would meet American College of Rheumatology criteria for diagnosis of fibromyalgia?

A.  Diffuse chronic pain and abnormal sleep

B.  Diffuse pain without other etiology and evidence of major depression

C.  Major depression, life stressor, chronic pain, and female gender

D.  Major depression and pain on palpation at 6 of 18 tender point sites

E.  Widespread chronic pain and pain on palpation at 11 of 18 tender point sites

IX-70. A 42-year-old man is found to have the following finding on a physical examination (Figure IX-70). All of the following conditions are associated with this finding EXCEPT:


FIGURE IX-70 (Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, Copyright 1991, 1995. Used by permission of the American College of Rheumatology.)

A.  Chronic obstructive pulmonary disease

B.  Cyanotic congenital heart disease

C.  Cystic fibrosis

D.  Hepatocellular carcinoma

E.  Hyperthyroidism

IX-71. A 64-year-old woman sees her primary care physician complaining of hip pain for about 1 week. She localizes the pain to the lateral aspect of her right hip and describes it as sharp. It is worse with movement, and she finds it difficult to lie on her right side. The pain began soon after the patient planted her garden. She has a medical history of obesity, osteoarthritis of the knees, and hypertension. Her medications include losartan 50 mg daily and hydrochlorothiazide 25 mg daily. For the pain, she has taken ibuprofen 600 mg as needed with mild to moderate relief of pain. On physical examination, the patient is not febrile and her vital signs are unremarkable. On examination of the hip, pain is elicited with external rotation and resisted abduction of the hip. Direct palpation over the lateral aspect of the upper portion of the femur near the hip joint reproduces the pain. What is the most likely diagnosis in this patient?

A.  Avascular necrosis of the hip

B.  Iliotibial band syndrome

C.  Meralgia paresthetica

D.  Septic arthritis

E.  Trochanteric bursitis

IX-72. A 32-year-old woman is seen in the clinic with a complaint of left knee pain. She enjoys running long distances and is currently training for a marathon. She is running on average 30–40 miles weekly. She currently is experiencing an aching pain on the lateral aspect of her left knee. There is a burning sensation that also continues up the lateral aspect of her thigh. She denies any injury to her knee, and she has not felt that it was hot or swollen. She is otherwise healthy and takes no medications other than herbal supplements. Physical examination of the knee reveals point tenderness over the lateral femoral condyle that is worse with flexing the knee. The patient is asked to lie on her right side with her right knee and hip flexed at 90°. Her left leg is extended at the hip and slowly lowered into adduction behind the bottom leg, reproducing the patient’s left knee pain. All of the following treatments can be recommended for this patient EXCEPT:

A.  Assessment of the patient’s running shoes to ensure a proper fit

B.  Glucocorticoid injection so as not to interfere with the patient’s continued preparation for the upcoming marathon

C.  Ibuprofen 600–800 mg every 6 hours as needed for pain

D.  Referral for physical therapy

E.  Referral for surgical release if conservative therapy fails

IX-73. A 58-year-old female presents complaining of right shoulder pain. She does not recall any prior injury but notes that the shoulder has been getting progressively stiffer over the last several months. She previously had several episodes of bursitis of the right shoulder that were treated successfully with NSAIDs and steroid injections. The patient’s past medical history is also significant for diabetes mellitus, for which she takes metformin and glyburide. On physical examination, the right shoulder is not warm or red but is tender to touch. Passive and active range of motion is limited in flexion, extension, and abduction. A right shoulder radiogram shows osteopenia without evidence of joint erosion or osteophytes. What is the most likely diagnosis?

A.  Adhesive capsulitis

B.  Avascular necrosis

C.  Bicipital tendinitis

D.  Osteoarthritis

E.  Rotator cuff tear

IX-74. A 32-year-old woman presents to the clinic with right thumb and wrist pain that has worsened over several weeks. She has pain when she pinches her thumb against her other fingers. Her only other history is that she is a new mother with an 8-week-old infant at home. On physical examination she has mild swelling and tenderness over the radial styloid process, and pain is elicited when she places her thumb in her palm and grasps it with her fingers. A Phalen maneuver is negative. Which condition is most likely?

A.  Carpal tunnel syndrome

B.  De Quervain’s tenosynovitis

C.  Gouty arthritis of the first metacarpophalangeal joint

D.  Palmar fasciitis

E.  Rheumatoid arthritis