IX-1. The answer is A. (Chap. 314) The innate immune system is phylogenetically the oldest form of immunologic defense system, inherited from invertebrates. This defense system uses germ line–encoded proteins to recognize pathogen-associated molecular patterns. Cells of the innate immune system include macrophages, dendritic cells, and natural killer lymphocytes. The critical components of the innate immune system include recognition by germ line–encoded host molecules, recognition of key microbe virulence factors but not recognition of self molecules, and nonrecognition of benign foreign molecules or microbes. Adaptive immunity is found only in vertebrate animals and is based on the generation of antigen receptors on T and B lymphocytes by gene rearrangements, such that individual T or B cells express unique antigen receptors on their surface capable of recognizing diverse environmental antigens.
IX-2. The answer is A. (Chap. 314) Complement activity, which results from the sequential interaction of a large number of plasma and cell membrane proteins, plays an important role in the inflammatory response. The classic pathway of complement activation is initiated by an antibody–antigen interaction. The first complement component (C1, a complex composed of three proteins) binds to immune complexes with activation mediated by C1q. Active C1 then initiates the cleavage and concomitant activation of components C4 and C2. The activated C1 is destroyed by a plasma protease inhibitor termed C1 esterase inhibitor. This molecule also regulates clotting factor XI and kallikrein. Patients with a deficiency of C1 esterase inhibitor may develop angioedema, sometimes leading to death by asphyxia. Attacks may be precipitated by stress or trauma. In addition to low antigenic or functional levels of C1 esterase inhibitor, patients with this autosomal-dominant condition may have normal levels of C1 and C3 but low levels of C4 and C2. Danazol therapy produces a striking increase in the level of this important inhibitor and alleviates the symptoms in many patients. An acquired form of angioedema caused by a deficiency of C1 esterase inhibitor has been described in patients with autoimmune or malignant disease.
IX-3. The answer is C. (Chap. 315) The human major histocompatibility complex genes are located on a 4-megabase region on chromosome 6. The major function of the MHC complex genes is to produce proteins that are important in developing immunologic specificity through their role in binding antigen for presentation to T cells. This process is nonspecific, and the ability of an HLA molecule to bind to a particular protein depends on the molecular fit between the amino acid sequence of a particular protein and the corresponding domain on the MHC molecule. Once a peptide has bound, the MHC-peptide complex binds to the T-cell receptor, after which the T cell must determine if an immune response should be generated. If an antigen is similar to an endogenous protein, the potential antigen will be recognized as a self-peptide and tolerance to the antigen will be continued. The MHC I and II complexes have been implicated in the development of many autoimmune diseases, which occur when T cells fail to recognize a peptide as a self-peptide and an immune response is allowed to develop. MHC I and II genes also play a major role in tissue compatibility for transplantation and are important in generating immune-mediated rejection. The other answers listed refer to functions of immunoglobulins. The variable region of the immunoglobulin is a B cell–specific response to an antigen to promote neutralization of the antigen through agglutination and precipitation. The constant region of the immunoglobulin is able to nonspecifically activate the immune system through complement activation and promotion of phagocytosis by neutrophils and macrophages.
IX-4. The answer is B. (Chap. 317) The patient has classic symptoms of angioedema with rapid onset of facial swelling often involving the lips, frequently with preceding limb symptoms. Angioedema and urticaria are grouped by the underlying etiology. In this case, ACE inhibitor use is associated with increased levels of bradykinin that in a predisposed individual can result in angioedema. Hereditary angioedema is associated with chronically depressed levels of C1 inhibitor that is involved in the degradation of bradykinin. IgE-mediated angioedema occurs due to specific antigen sensitivity. Complement-mediated disease may be due to vasculitis, serum sickness, or reactions to blood products. Non-immunologic causes of angioedema include direct mast cell–releasing agents such as opiates and agents that alter arachidonic acid metabolism, most commonly NSAIDs. IgE levels are not elevated in bradykinin-mediated angioedema. Because of the potentially life-threatening nature of the disease, rechallenge with a second ACE inhibitor is not recommended.
IX-5. The answer is D. (Chap. 317) Urticaria and angioedema are common disorders, affecting approximately 20% of the population. In acute urticarial angioedema, attacks of swelling are of less than 6 weeks’ duration; chronic urticarial angioedema is by definition more long standing. Urticaria usually is pruritic and affects the trunk and proximal extremities. Angioedema is generally less pruritic and affects the hands, feet, genitalia, and face. This female has chronic urticaria, which probably is due to a cutaneous necrotizing vasculitis. The clues to the diagnosis are the arthralgias, the presence of residual skin discoloration, and the elevated sedimentation rate, which would be uncharacteristic of other urticarial diseases. The diagnosis can be confirmed by skin biopsy. Chronic urticaria rarely has an allergic cause; hence, allergy skin tests and measurement of total IgE levels are not helpful. Measurement of C1 esterase inhibitor activity is useful in diagnosing hereditary angioedema, a disease that is not associated with urticaria. Patch tests are used to diagnose contact dermatitis.
IX-6. The answer is D. (Chap. 317) This patient presents with symptoms of cold urticaria, an IgE-dependent urticarial reaction to cold exposure. After exposure to cold, urticarial lesions appear in exposed areas and usually last for less than 2 hours. Histologic examination of the urticarial lesion would demonstrate mast cell degranulation with edema of the dermis and subcutaneous tissues. In experimental exposure to a cold challenge such as an ice water bath, elevated levels of histamine in venous blood may be demonstrated if assessed in the extremity exposed to a cold environment, whereas the histamine levels would be normal in a nonexposed extremity. The appearance of a linear wheal after a firm stroke is indicative of dermatographism. This condition can be seen in 1–4% of the population and is often found in individuals with cold urticaria. In general, cold urticaria is a localized process without adverse consequences. However, vascular collapse may occur if an individual is submerged in cold water. Many individuals request treatment because they are embarrassed by their condition or are symptomatic from the recurrent urticaria and pruritus. Treatment with H1 histamine receptor blockers is usually adequate for symptom control. Cyproheptadine or hydroxyzine can be added to therapy if H1 antihistamines are inadequate. In this patient, there is a clear precipitant for developing urticaria—cold exposure. Thus, no other evaluation is necessary. In the evaluation and management of chronic urticaria, the identification and elimination of precipitating factors is important. Possible etiologic factors include foods, pollens, molds, and medications. In this case the urticaria predates the use of oral contraceptive medications; thus, stopping oral contraceptives is unlikely to be helpful. Assessment of antithyroglobulin and antimicrosomal antibodies can be helpful in individuals with chronic urticaria in whom a cause is not otherwise identified. Deficiency of C1 or the presence of a C1 inhibitor presents as recurrent angioedema rather than urticaria.
IX-7. The answer is E. (Chap. 317) Allergic rhinitis is a common problem in the United States and North America. It is estimated that about 1 in 5 individuals experiences allergic rhinitis. The incidence is greatest in childhood and adolescence, and the symptoms tend to regress with aging. Complete remissions, however, are uncommon. Many individuals experience seasonal symptoms only. These symptoms are due to pollen production by weeds, grasses, and trees that are dependent on wind currents, rather than insects, for cross-pollination. The timing of the pollination events predicts the seasonal severity of symptoms and varies little from year to year within a particular locale. Based on this pattern, one is able to predict which allergens are most likely responsible for a patient’s symptoms. In the temperate regions of North America, trees pollinate in the spring, and ragweed pollinates in the fall. Grasses are responsible for seasonal allergic symptoms in the summer months. Mold allergens can have a variable pattern of symptoms, depending on climatic conditions that allow them to sporulate. Perennial rhinitis does not have a seasonal pattern and is more continually present. Allergens that cause perennial rhinitis include animal dander, dust, and cockroach-derived proteins.
IX-8. The answer is A. (Chap. 319) Antinuclear antibodies are nearly ubiquitous in patients with systemic lupus erythematosus, with demonstration in 90% of affected patients. There are many other antibodies that can be demonstrated. The next most common antibodies are anti-dsDNA and anti-histone. Anti-dsDNA is very specific to SLE and may correlate with disease activity, nephritis, and vasculitis. Antihistone is more frequent in drug-induced SLE. Antiphospholipid antibodies can be demonstrated in about half of affected patients, while the remainder is present in less than half of SLE cases.
IX-9. The answer is B. (Chap. 319) There are well-published, strict diagnostic criteria for systemic lupus erythematosus. They include four or more of the following criteria from Table IX-9.
TABLE IX-9 Diagnostic Criteria for Systemic Lupus Erythematosus
The patient described does not meet the arthritis criteria; thus her only criteria are oral ulcers and weakly positive ANA.
IX-10. The answer is A. (Chap. 319) The patient has Libman-Sacks endocarditis associated with her SLE. This results in fibrinous endocarditis and can lead to valvular insufficiencies, most often mitral or aortic, or embolism. It is not generally found with concomitant pericarditis, though this is another common cardiac manifestation of systemic lupus erythematosus. Although glucocorticoids and anti-inflammatory therapies have no proven benefit in this condition, they are often used in conjunction with supportive care. Because Libman-Sacks endocarditis is a culture-negative endocarditis and is not thought to be due to microbial infection, blood cultures will not be positive.
IX-11. The answer is D. (Chap. 319) Systemic lupus erythematosus is a multisystem disease with diverse organ involvement and multiple different manifestations within an organ system. The system most commonly involved is the musculoskeletal system, with 95% of patients having involvement, usually as arthralgias or myalgias. Arthritis is also common and is one of the diagnostic criteria for SLE. Cutaneous and hematologic disease occurs in approximately 80–85% of patients. Neurologic and cardiopulmonary diseases affect approximately 60% of patients, while renal and gastrointestinal diseases occur in less than 50% of cases.
IX-12. The answer is E. (Chap. 319) Although most clinicians believe that females with SLE should not become pregnant if they have active disease or advanced renal or cardiac disease, the presence of SLE itself is not an absolute contraindication to pregnancy. The outcome of pregnancy is best for females who are in remission at the time of conception. Even in females with quiescent disease, exacerbations may occur (usually in the first trimester and the immediate postpartum period), and 25–40% of these pregnancies end in spontaneous abortion. Fetal loss rates are higher in patients with lupus anticoagulant or anticardiolipin antibodies. Flare-ups should be anticipated and vigorously treated with steroids. Steroids given throughout pregnancy usually have no adverse effects on the child. In this case, the fact that the female had a life-threatening bout of disease a year ago would argue against stopping her drugs at this time. Neonatal lupus, which is manifested by thrombocytopenia, rash, and heart block, is rare but can occur when mothers have anti-Ro antibodies.
IX-13. The answer is C. (Chap. 319) This patient is presenting with acute lupus nephritis with evidence of hematuria, proteinuria, and an acute rise in creatinine. Together with infection, nephritis is the most common cause of mortality in the first decade after diagnosis of SLE and warrants prompt immunosuppressive therapy. It is important to assess for other potentially reversible causes of acute renal insufficiency, but this patient is not otherwise acutely ill and is taking no medications that would cause renal failure. The urinalysis shows evidence of active nephritis with hematuria and proteinuria. Even in the absence of RBC casts, therapy should not be withheld to await biopsy results in someone with a known diagnosis of SLE with consistent clinical presentation and urinary findings. This patient also has other risk factors known to predict the development of lupus nephritis, including high titers of anti-dsDNA and African-American race. The mainstay of treatment for any life-threatening or organ-threatening manifestation of SLE is high-dose systemic glucocorticoids. Addition of cytotoxic or other immunosuppressive agents (cyclophosphamide, azathioprine, mycophenolate mofetil) is recommended to treat serious complications of SLE, but their effects are delayed for 3–6 weeks after initiation of therapy, whereas the effects of glucocorticoids begin within 24 hours. Thus, these agents alone should not be used to treat acute, serious manifestations of SLE. The choice of cytotoxic agent is at the discretion of the treating physician. Cyclophosphamide in combination with steroid therapy has been demonstrated to prevent the development of end-stage renal disease better than steroids alone. Likewise, mycophenolate also prevents the development of end-stage renal disease in combination with glucocorticoids, and some studies suggest that African Americans have a greater response to mycophenolate than to cyclophosphamide. Plasmapheresis is not indicated in the treatment of lupus nephritis but is useful in cases of severe hemolytic anemia or thrombotic thrombocytopenic purpura associated with SLE. This patient has no acute indication for hemodialysis and, with treatment, may recover renal function.
IX-14. The answer is E. (Chap. 319) This patient clearly has a flare of her SLE induced by ultraviolet sunlight, a common inciting factor for lupus flares. It is thought that the UV sunlight induces skin apoptosis that initiates the SLE flare. Furthermore, this patient has severe acute lupus nephritis. Aggressive therapy with high-dose methylprednisolone is life saving and gives the best chance of renal recovery. Therapy for severe lupus derives from studies of lupus nephritis. These have shown that after a “pulse” of high-dose intravenous methylprednisolone, subsequent therapy with prednisone improves renal recovery. Studies of cytotoxic agents in lupus nephritis have been conducted in combination with corticosteroid treatment. These studies have shown that cyclophosphamide, mycophenolate mofetil, and azathioprine have efficiency for induction of improvement in severely ill patients. It appears that African Americans are more likely to respond to mycophenolate. Good improvement of lupus nephritis occurs in 80% of patients receiving cyclophosphamide or mycophenolate at 1–2 years; however, many patients have flares and are more likely to progress to end-stage renal disease. The utility of biologics, including rituximab, in SLE is under vigorous investigation. Some have advocated their use in patients with refractory disease based on open-label studies. Based on this patient’s first episode of lupus nephritis, there would not be an indication for rituximab at this point.
IX-15. The answer is A. (Chap. 320) The patient has multiple clinical manifestations of arterial thrombosis in her hand and brain. Combined with the likely history of placental insufficiency in the three prior pregnancies, the possibility of antiphospholipid antibody syndrome is likely. In addition, she has evidence of acute kidney injury, suggesting multisystem disease. Thrombocytopenia may be due to hemolytic anemia, but the absence of schistocytes makes it less likely that she has thrombotic thrombocytopenic purpura. Although MRI of her brain and extremity duplex may confirm the presence of thrombosis, these will not diagnose antiphospholipid antibody syndrome. An anticardiolipin antibody screening panel will look for evidence of antibodies directed against cardiolipin and β2 glycoprotein I. Additional testing for lupus anticoagulant determined by clotting assays such as the Russell viper venom time, false-positive RPR, and the aPTT may also be useful. Antinuclear antibody is likely to be positive given the common overlap with systemic lupus erythematosus, but is nonspecific.
IX-16. The answer is D. (Chap. 320) This patient has a typical presentation of antiphospholipid syndrome (APS) with a deep venous thrombosis (DVT), history of spontaneous abortion, and isolated elevated aPTT due to a lupus anticoagulant. Additional clinical features of APS involving the arterial or venous circulation include livedo reticularis (24%), pulmonary embolism (14%), stroke (20%), transient ischemic attack (TIA) (10%), myocardial infarction (10%), migraine (20%), preeclampsia (10%), thrombocytopenia (30%), and autoimmune hemolytic anemia (10%). Laboratory criteria include demonstration of lupus anticoagulant (elevated aPTT that does not correct on mixing) in conjunction with the presence of anticardiolipin and/or anti–β2 glycoprotein I on two occasions 3 months apart. After diagnosis of a thrombotic event due to APS, patients should receive warfarin for life with a goal INR of 2.5–3.5 alone or in combination with daily aspirin. During pregnancy patients should receive heparin plus aspirin. Patients who develop recurrent thrombosis while on effective anticoagulation may benefit from a 5-day infusion of intravenous gamma globulin or 4 weeks of rituximab therapy. The optimal therapy for patients with APS without a thrombotic event is not known; however, daily aspirin (80 mg) protects patients with SLE and antiphospholipid antibodies from thrombotic events. Warfarin for 3 months with an INR goal of 2.0–3.0 is recommended therapy for DVT with a known reversible precipitating event. Warfarin for 6–12 months with an INR goal of 2.0–3.0 is recommended therapy for first-episode idiopathic DVT.
IX-17. The answer is E. (Chap. 321) Once the disease process of rheumatoid arthritis is established, the most common joints of involvement are the wrists, metacarpophalangeal joints, and proximal interphalangeal joints. Distal interphalangeal joint involvement is rarely due to rheumatoid arthritis and more often due to coexisting osteoarthritis.
IX-18. The answer is C. (Chap. 321) There is potential involvement of multiple organ systems in RA. The most common pulmonary complication is pleural effusion that is typically exudative and presents with chest pain and dyspnea. RA is associated with a form of diffuse interstitial lung disease that may present with dyspnea and bilateral interstitial infiltrates that may be extensive enough to develop into a honeycomb pattern. Pulmonary nodules associated with RA may be solitary or multiple. They often occur in conjunction with cutaneous nodules. Bronchiectasis and respiratory bronchiolitis may also be due to RA. Many of these manifestations respond to immunosuppressive therapy. Lobar infiltrate has not been described due to RA and is more commonly due to an acute infectious etiology, often as a complication of RA immunosuppressive therapy.
IX-19. The answer is A. (Chap. 321) Joint imaging is a critical tool for both the diagnosis and monitoring of disease status in RA. Plain radiographs, because of their ready availability and ease of film comparison, are most commonly ordered. The earliest clinical sign of RA is juxtaarticular osteopenia, though this may be difficult to appreciate on newer, digitized films. Other findings include soft-tissue swelling, symmetric joint space loss, and subchondral erosions most frequently in the wrists, metacarpophalangeal, and proximal interphalangeal joints, and the metatarsophalangeal joint.
IX-20. The answer is C. (Chap. 321) The prevalence of RA is 0.8%, and females are three times more likely to be affected than males. However, as the population ages, the prevalence increases and the sex difference diminishes. RA is found throughout the world and affects people of all races. Age of onset is most commonly 35–50 years. Family studies show a clear genetic predisposition. First-degree relatives have approximately four times the expected rate of RA. Other risk factors for RA include the class II major histocompatibility antigen HLA-DR4. Approximately 70% of patients with RA have HLA-DR4. However, this association is not true in Africans or African Americans, among whom 75% do not show this allele. The role of this allele in the pathogenesis of RA remains unknown because the cause of RA is unknown. The earliest lesion in RA is microvascular injury with an increase in the number of synovial lining cells. Increased numbers of mononuclear cells are seen in the synovial lining, and this is thought to be under the control of CD4+ T lymphocytes. As the inflammation continues, the articular matrix is degraded by collagenases and cathepsins produced by the inflammatory cells. Other cytokines produced by the inflammatory cells include IL-1 and TNF-α. Over time, bone and cartilage are destroyed, leading to the end-stage clinical manifestations. Rheumatoid factor (RF) is an IgM molecule directed against the Fc portion of IgG and is found in two-thirds of patients with RA. However, this molecule is found in approximately 5% of healthy persons and more than 10% of persons older than age 60. It is not known to have a role in the pathogenesis of the disease, but titers of RF are shown to be predictive of the severity of clinical manifestations or the presence of extraarticular manifestations.
IX-21. The answer is C. (Chap. 321) Rheumatoid arthritis is chronic, symmetric, inflammatory polyarthritis. In two-thirds of patients, an initial clinical presentation of fatigue, anorexia, and weakness precedes joint complaints. In established RA (i.e., in patients known to be diagnosed with this disorder), the most common manifestation is pain in affected joints that is worsened by movement. Morning stiffness of an hour or more is very common in these patients as well, but it is worth noting that this clinical finding does not allow differentiation between inflammatory and noninflammatory arthritides. Arthritic pain comes from the joint capsule itself, which is innervated and very sensitive to distention. Ten percent of patients with RA will have a first-degree relative with the disease. Weight loss is a nonspecific symptom and is not definitively associated with active disease.
IX-22. The answer is E. (Chap. 321) Anemia is common in RA and parallels the degree of inflammation as measured by C-reactive protein or ESR. Felty’s syndrome, typically occurring in late-stage, poorly controlled disease, is characterized by the triad of neutropenia, splenomegaly, and rheumatoid nodules. Rheumatoid vasculitis is not common and typically occurs in long-standing disease. It is associated with hypocomplementemia. The cutaneous signs are typical of vasculitic lesions with palpable purpura, digital infarcts, livedo reticularis, and ulcers. Clinical manifestations of pericarditis occur in 10% of patients, with echocardiographic or autopsy findings in about half of those cases. Secondary Sjögren’s syndrome manifest as keratoconjunctivitis sicca or xerostomia occurs in approximately 10% of patients with RA. RA also appears to increase the risk of developing B-cell lymphoma by two to four times in the general population. The risk of lymphoma appears to correlate with high levels of disease activity or the presence of Felty’s syndrome. Platelet counts in RA are typically elevated in association with the acute phase response of inflammation. Immune thrombocytopenia is rare.
IX-23. The answer is D. (Chap. 321) The therapy of RA has changed dramatically in the past two decades with the development of drugs that modify the disease course of RA. Methotrexate is the DMARD of first choice for treatment of early RA. Other conventional DMARDs include hydroxychloroquine, sulfasalazine, and leflunomide. Leflunomide, an inhibitor of pyrimidine synthesis, is efficacious as a single agent or in combination with methotrexate. Hydroxychloroquine and sulfasalazine are typically reserved for mild disease. The biologic DMARDs have dramatically improved the treatment of RA in the past decade. There are currently five anti-TNF agents, including infliximab, approved for use in patients with RA. Rituximab, an anti-CD20 antibody, is approved for refractory RA in combination with methotrexate. It is more efficacious in seropositive than seronegative patients. Other biologics approved for use in RA include anakinra (IL-1 receptor antagonist), abatacept (CD28/CD80/86 antagonist), and tocilizumab (IL-6 antagonist). Nonsteroidal anti-inflammatory drugs, including Naprosyn (naproxen), were formally utilized as core RA therapy; however, they are now utilized as adjunctive treatment for symptom management.
IX-24. The answer is D. (Chap. 322) Acute rheumatic fever (ARF) is almost universally due to group A streptococcal disease at the present time, though virtually all streptococcal disease may be capable of precipitating rheumatic fever. Although skin infections may be associated with rheumatic fever, far and away the most common presentation is with preceding pharyngitis. There is a latent period of approximately 3 weeks from an episode of sore throat to presentation of ARF. The most common manifestations are fever and polyarthritis, with polyarthritis being present in 60–75% of cases. Carditis may also be present, though somewhat less frequently in 50–60% of cases. Chorea and indolent carditis may have a subacute presentation. Chorea is present in 2–30% of affected individuals, while erythema marginatum and subcutaneous nodules are rare. Sixty percent of patients with ARF progress to rheumatic heart disease, with the endocardium, pericardium, and myocardium all potentially involved. All patients with ARF should receive antibiotics sufficient to treat the precipitating group A streptococcal infection.
IX-25. The answer is D. (Chap. 322) This patient has a history very suggestive of recurrent bouts of ARF with evidence of mitral regurgitation, mitral stenosis, and aortic regurgitation on physical examination. This and the presence of atrial fibrillation imply severe rheumatic heart disease. Risk factors for this condition include poverty and crowded living conditions. As a result, ARF is considerably more common in the developing world. Daily aspirin is the treatment of choice for the migratory large-joint arthritis and fever that are common manifestations of ARF. Practitioners sometimes use steroids during acute bouts of carditis to quell inflammation, though this remains a controversial practice and has no role between flares of ARF. Secondary prophylaxis with either daily oral penicillin or, preferably, monthly IM injections is considered the best method to prevent further episodes of ARF, and therefore prevent further valvular damage. Primary prophylaxis with penicillin on an as-needed basis is equally effective for preventing further bouts of carditis. However, most episodes of sore throat are too minor for patients to present to a physician. Therefore, secondary prophylaxis is considered preferable in patients who already have severe valvular disease. Doxycycline is not a first-line agent for group A Streptococcus, the pathogen that incites ARF.
IX-26. The answer is A. (Chap. 323) The prognosis for patients with scleroderma renal disease is poor. In SRC patients prompt treatment with an ACE inhibitor may reverse acute renal failure. In recent studies the initiation of ACE inhibitor therapy resulted in 61% of patients having some degree of renal recovery and not needing chronic dialysis support. The survival rate is estimated to be 80–85% at 8 years. Among patients who needed dialysis, when treated with ACE inhibitors, over 50% were able to discontinue dialysis after 3–18 months. Therefore, ACE inhibitors should be used even if the patient requires dialysis support.
IX-27. The answer is D. (Chap. 324) The patient presented with classic symptoms for Sjögren’s syndrome including dry mouth and eyes. This condition may be primary, as in this case, or secondary in association with another connective tissue disease such as scleroderma or rheumatoid arthritis. Many autoantibodies may be demonstrated in the serum of patients with Sjögren’s including antibodies to Ro/SS-A or La/SS-b. Sialometry will demonstrate decreased production of saliva, and MRI or MR sialography of the major salivary glands is used also. Ocular involvement with decreased tear production is demonstrated by the Schirmer’s I test. Scl-70 antibody is associated with scleroderma and should not be positive in primary Sjögren’s syndrome.
IX-28. The answer is A. (Chap. 324) Although Sjögren’s syndrome most commonly affects the eyes and mouth, there are a number of common extraglandular sites of involvement. The most common is arthritis or arthralgias that complicated up to 60% of cases. Raynaud’s phenomenon is the second most common extraglandular site. Lung involvement and vasculitis are found in less than 20% of patients. Lymphoma, though a concerning and highly morbid complication, is relatively rare, affecting only 6% of patients with Sjögren’s syndrome.
IX-29. The answer is B. (Chap. 324) The patient in this vignette is presenting with severely dry eyes and mouth in the presence of autoantibodies to Ro and La (SS-A and SS-B, extractable nuclear and cytoplasmic antigens) consistent with the diagnosis of Sjögren’s syndrome. This autoimmune disorder is associated with the lymphocytic infiltration of exocrine glands that results in decreased tear and saliva production as the most prominent symptoms. Sjögren’s syndrome affects women nine times more frequently than men and usually presents in middle age. Other autoimmune diseases often have associated xerostomia and dry eyes (secondary Sjögren’s syndrome). High titers of antibodies to Ro and La are associated with longer disease duration, salivary gland enlargement, and the development of extraglandular involvement, especially cutaneous vasculitis and demyelinating syndromes. One-third of patients with Sjögren’s syndrome have extraglandular involvement of the disease, most commonly in the lungs and kidneys. In this patient with acidemia and hypokalemia, the possibility of renal disease due to Sjögren’s syndrome should be considered. Interstitial nephritis is a common manifestation of Sjögren’s syndrome in the kidneys. Distal (type I) renal tubular acidosis is also frequent, occurring in 25% of individuals with Sjögren’s syndrome. Diagnosis could be confirmed by obtaining urine electrolytes to demonstrate a positive urine anion gap. Renal biopsy is not necessary. Treatment does not require immunosuppression as the acidemia can be treated with bicarbonate replacement. Diarrhea could cause similar electrolyte abnormalities with a non–anion gap acidosis, but the patient would be symptomatic. Furthermore, gastrointestinal symptoms do not commonly occur in Sjögren’s syndrome. Hypoaldosteronism is associated with a type IV renal tubular acidosis that results in hyperkalemia and a non–anion gap acidosis. Renal compensation for respiratory alkalosis should not result in hypokalemia. Purging in anorexia nervosa could result in hypokalemia and increased risk of dental caries, but it would be associated with metabolic alkalosis rather than acidosis.
IX-30. The answer is D. (Chap. 324) Lymphoma is well known to develop specifically in the late stage of Sjögren’s syndrome. Common manifestations of this malignant condition include persistent parotid gland enlargement, purpura, leukopenia, cryoglobulinemia, and low C4 complement levels. Most of the lymphomas are extranodal, marginal zone B cell, and low grade. Low-grade lymphomas may be detected incidentally during a labial biopsy. Mortality is higher in patients with concurrent B symptoms (fevers, night sweats, and weight loss), a lymph node mass greater than 7 cm, and a high or intermediate histologic grade.
IX-31. The answer is D. (Chap. 325) Ankylosing spondylitis is closely correlated with the presence of the histocompatibility antigen HLA-B27. In North American whites, the prevalence of B27 is 7%, but in patients with ankylosing spondylitis it is 90%. Not all persons with B27 develop ankylosing spondylitis; the disease is only present in 1–6% of B27-positive individuals.
IX-32. The answer is A. (Chap. 325) Although the most serious spine complication of ankylosing spondylitis is fracture, there are a number of important extraarticular manifestations. Anterior uveitis is the most common, occurring in 40% of patients with ankylosing spondylitis. Inflammatory bowel disease has been reported to be frequently present. Less common complications include aortic insufficiency, third-degree heart block, pulmonary nodules and upper lobe fibrosis, cardiac dysfunction, retroperitoneal fibrosis, prostatitis, and amyloidosis.
IX-33. The answer is B. (Chap. 325) Nonsteroidal anti-inflammatory drugs are the first line of pharmacologic therapy for ankylosing spondylitis, of which this patient has a classic presentation. These agents have been shown to reduce pain and tenderness and increase mobility. There is even some evidence that they slow disease progression. Given their proven efficacy, tolerability, and safety, they remain first-line therapy. Anti–TNF-α agents have been reported to have dramatic effects in ankylosing spondylitis, with infliximab, etanercept, adalimumab, and golimumab having published reports of success. Because of their potential side effects, including serious infections, hypersensitivity reactions, and others, these agents should be reserved for patients who fail therapy with NSAIDs.
IX-34. The answer is E. (Chap. 325) Reactive arthritis refers to an acute, nonpurulent arthritis that occurs after an infection elsewhere in the body. Often presenting with lower joint inflammatory arthritis occurring 1–4 weeks after a diarrheal episode, reactive arthritis may also include uveitis or conjunctivitis, dactylitis, urogenital lesions, and characteristic mucocutaneous lesions such as keratoderma blennorrhagica. The most common organism associated with reactive arthritis is Shigella species, although Yersinia, Chlamydia, and, to a much lesser extent, Salmonella and Campylobacter have been described.
IX-35. The answer is D. (Chap. 325) The patient has a spondyloarthritic syndrome with enthesitis and sacroiliitis associated with inflammatory bowel disease. This is a common association called enteropathic arthritis. Generally, enteropathic arthritis responds well to suppression of gastrointestinal disease using anti–TNF-α agents such as infliximab. Other treatments for inflammatory bowel disease are also effective in the resolution of arthritis, such as glucocorticoids and sulfasalazine. NSAIDs may be helpful, but there is significant concern for the precipitation of flares of inflammatory bowel disease and precipitation of ulcers.
IX-36. The answer is E. (Chap. 325) Whipple’s disease is a rare chronic bacterial infection of the gastrointestinal tract most commonly affecting middle-aged men. Arthritis is a common early manifestation of the disease, with arthritis predating gastrointestinal symptoms by 5 years or more. Large and small joints may be affected and sacroiliitis is common. Arthritis is often migratory and lasts several days with spontaneous recovery. Synovial fluid is generally inflammatory. Radiographs rarely show joint erosions, though sacroiliitis may be demonstrated. Diagnosis is often made by PCR amplification of genetic material from Tropheryma whippelii in biopsied material, most commonly the gut.
IX-37. The answer is D. (Chap. 325) Although anti–TNF-α drugs such as infliximab are potent and relatively safe, several types of side effects are not rare. These include serious infections such as disseminated tuberculosis, fungal (histoplasmosis, aspergillus, pneumocystis) and bacterial (legionella, pneumococcus) infections, hematologic disorders such as pancytopenia, demyelinating disorders, systemic lupus erythematosus-related autoantibodies, and potential risk of lymphoma. Additionally, clinical features such as exacerbation of congestive heart failure, hypersensitivity infusion or injection site reactions, and severe liver disease have been described. There are some isolated reports of hypersensitivity pneumonitis, but these are confounded by coadministration of known pulmonary toxic agents.
IX-38. The answer is B. (Chap. 325) Enthesopathy or enthesitis is the term used to describe inflammation at the site of tendinous or ligamentous insertion into bone. This type of inflammation is seen most frequently in patients with seronegative spondyloarthropathies and various infections, especially viral infections. The other definitions apply to other terms used in the orthopedic and rheumatic examination. Subluxation is the alteration of joint alignment so that articulating surfaces incompletely approximate each other. Synovitis refers to the inflammation of the periarticular membrane lining the joint capsule. Inflammation of a saclike cavity near a joint that decreases friction is the definition of bursitis. Finally, crepitus is a palpable vibratory or crackling sensation elicited with joint motion.
IX-39. The answer is C. (Chap. 325) This patient complains of symptoms consistent with a diagnosis of fibromyalgia. Patients with fibromyalgia frequently complain of diffuse body pain, stiffness, paresthesias, disturbed sleep, easy fatigability, and headache. The prevalence of fibromyalgia is approximately 3.4% of females and 0.5% of males. This disorder is thought to represent a disturbance of pain perception. Disturbed sleep with a loss of stage 4 sleep has been implicated as a factor in the pathogenesis of the disease. Serotonin levels in the cerebrospinal fluid have also commonly been seen and may play a role in the pathogenesis. A diagnosis of fibromyalgia is based on the American College of Rheumatology criteria, which combine symptoms and physical examination. The patient must exhibit diffuse pain in all areas of the body with tenderness to palpation at 11 of 18 designated tender point sites. These sites include the occiput, trapezius, cervical spine, lateral epicondyles, supraspinatus muscle, second rib, gluteus, greater trochanter, and knee. Digital palpation should be performed with a moderate degree of pressure. Examination of the joints shows no evidence of inflammatory arthropathy. There are no laboratory tests that are specific for the diagnosis. Positive antinuclear antibodies may be seen, but at the same frequency as in the normal population. HLA-B27 is found in 7% of the white population, but only 1–6% of people with HLA-B27 will develop ankylosing spondylitis. Radiograms are normal in these patients.
IX-40. The answer is D. (Chap. 325) This patient shows the typical features of psoriatic arthritis. Five to ten percent of patients with psoriasis will develop an arthritis associated with the rash. In 60–70% of cases, the rash precedes the diagnosis. However, another 15–20% of patients will have joint complaints as the presenting symptom of their psoriasis. The disease typically begins in the fourth or fifth decade of life. Psoriatic arthritis has varied joint presentations with five commonly described patterns of joint involvement: (1) arthritis of the distal interphalangeal (DIP) joints, (2) asymmetric oligoarthritis, (3) symmetric polyarthritis similar to RA, (4) axial involvement, and (5) arthritis mutilans with the typical “pencil in cup” deformity seen on hand radiography. Erosive joint disease ultimately develops in almost all these patients, and most of them become disabled. Nail changes are prominent in 90% of patients with psoriatic arthritis. Changes that are frequently seen include pitting, horizontal ridging, onycholysis, yellowish discoloration of the nail margins, and dystrophic hyperkeratosis. The diagnosis of psoriatic arthritis is primarily clinical. Thus, in patients with joint symptoms that precede the onset of rash, the diagnosis is frequently missed until dermatologic or nail changes develop. A family history of psoriasis is important to ascertain in any patient with an undiagnosed inflammatory polyarthropathy. The differential diagnosis of DIP arthritis is short; only osteoarthritis and gout are commonly seen in these joints. Radiography may show typical changes, particularly in patients with arthritis mutilans. Treatment is directed at both the rash and the joint disease simultaneously. Anti–TNF-α therapy has recently been shown to be helpful for both the dermatologic and joint manifestations of disease. Other treatments include methotrexate, sulfasalazine, cyclosporine, retinoic acid derivatives, and psoralen plus ultraviolet light.
IX-41. The answer is E. (Chap. 326) Although the molecular pathology of most vasculitic syndromes is poorly understood, the deposition of immune complexes is commonly thought to play an important role in vasculitis associated with Henoch-Schönlein purpura, cryoglobulinemic vasculitis associated with hepatitis C, serum sickness and cutaneous vasculitic syndromes, and polyarteritis nodosa–like vasculitis associated with hepatitis B. Granulomatosis with polyangiitis (Wegener’s), Churg-Strauss, and microscopic polyangiitis are thought to be due to production of antineutrophilic antibodies. Pathogenic T lymphocyte responses are also implicated in giant cell arteritis, Takayasu’s arteritis, granulomatosis with polyangiitis (Wegener’s), and Churg-Strauss syndrome.
IX-42. The answer is E. (Chap. 326) ANCAs are antibodies directed at proteins in the cytoplasmic granules of neutrophils and monocytes. cANCA, or cytoplasmic ANCA, is directed against proteinase-3, a proteinase present in neutrophil azurophilic granules. More than 90% of patients with granulomatosis with polyangiitis (Wegener’s) will be cANCA positive. Perinuclear ANCA or pANCA refers to a more localized perinuclear staining pattern and antibodies are most commonly directed against myeloperoxidase, though other antigens have been described. pANCA has been reported in variable percentages in microscopic polyangiitis, Churg-Strauss syndrome, and granulomatosis with polyangiitis (Wegener’s) and its variants. Additionally, pANCA staining that is not due to antimyeloperoxidase antibodies has been described in a number of other conditions including rheumatic and nonrheumatic autoimmune disease and inflammatory bowel disease.
IX-43. The answer is D. (Chap. 326) The patient presents with classic symptoms for granulomatosis with polyangiitis (Wegener’s), also known as granulomatosis with polyangiitis. The average age of diagnosis is 40 years and there is a male predominance. Upper respiratory symptoms often predate lung or renal findings and may even present with septal perforation. The diagnosis is made by demonstration of necrotizing granulomatous vasculitis on biopsy. Pulmonary tissue offers the highest yield. Biopsy of the upper airway usually shows the granulomatous inflammation but infrequently shows vasculitis. Renal biopsy may show the presence of pauci-immune glomerulonephritis.
IX-44. The answer is C. (Chap. 326) The patient has a classic presentation for giant cell arteritis with associated polymyalgia rheumatica including headache, jaw claudication, and visual disturbances. Her age makes this diagnosis highly likely as well. The diagnosis is confirmed by temporal artery biopsy; however, in the presence of visual symptoms, initiation of therapy should not be delayed pending a biopsy, as the biopsy may be positive even after approximately 14 days of glucocorticoid therapy. Delay in therapy risks irreversible visual loss. Additionally, a dramatic response to therapy may lend further support to the diagnosis. The primary therapy is prednisone at 40–60 mg daily for 1 month with gradual tapering. Although erythrocyte sedimentation rate is nearly universally elevated, it is not specific for the diagnosis. Temporal artery ultrasound may be suggestive but is not diagnostic.
IX-45. The answer is C. (Chap. 326) The most common manifestations of cryoglobulinemic vasculitis are cutaneous vasculitis, arthritis, peripheral neuropathy, and glomerulonephritis. The demonstration of circulating cryoprecipitates is a critical component of the diagnosis, and often rheumatoid factor can be found as well. Because hepatitis C infection is present in the vast majority of patients with cryoglobulinemic vasculitis, infection should be sought in all patients with this clinical syndrome.
IX-46. The answer is E. (Chap. 326) This patient has polyarteritis nodosa associated with hepatitis B infection. Polyarteritis nodosa (PAN) is a small- and medium-vessel vasculitis that classically involves the muscular mesenteric and renal arteries. Pulmonary arteries are spared. Classic PAN is a rare disease, but its exact prevalence is unknown because reported cases frequently also include other vasculitides such as microscopic polyangiitis. Prior to the Chapel Hill Consensus Conference of 1992, microscopic polyangiitis and PAN were considered as the same disease, but it has been recognized that these are two separate diseases with different serologic markers and vascular predilection. Clinical manifestations of PAN are commonly vague, and often patients have been ill for several months prior to diagnosis. Symptoms include fatigue, weight loss, abdominal pain, headache, and hypertension. The pathologic lesion of PAN is necrotizing inflammation of the small- and medium-sized muscular arteries, and diagnosis relies on demonstration of this lesion on biopsy. However, in the absence of easily obtainable tissue, the presence of multiple aneurysmal dilatations on mesenteric angiogram is highly suggestive of PAN in the appropriate clinical setting. There are no serologic tests that are diagnostic of PAN. It is rare to have positive antibodies to pANCA or cANCA in PAN. Interestingly, 30% of cases of PAN are associated with active hepatitis B infection, as in this patient, and it is thought that circulating immune complexes may play a role in the pathogenesis of this disease. Unlike PAN, microscopic polyangiitis (MPA) involves venules and capillaries in addition to small arteries. The histopathologic lesion of MPA is a necrotizing vasculitis that is pauci immune with minimal deposition of immune complexes. Typical presenting features are rapidly progressive glomerulonephritis and pulmonary hemorrhage, which are distinctly uncommon features of PAN. Antimyeloperoxidase antibodies (pANCA) are frequently present. Mixed cryoglobulinemia is a small-vessel vasculitis most often associated with hepatitis C infection. Skin involvement with leukocytoclastic vasculitis and palpable purpura are the most common presenting features. Proliferative glomerulonephritis is present in 20–60% of individuals and is the most common cause of morbidity. Ischemic colitis typically presents with abdominal pain out of proportion to the examination as in this case, but the mesenteric angiogram would show atherosclerotic narrowing rather than aneurysmal dilatation. Hepatocellular carcinoma is not associated with vasculitis and typically presents with vague abdominal pain and obstructive jaundice.
IX-47. The answer is C. (Chap. 326; JW Newberger et al: Circulation 110:2747, 2004.) The most likely cause of the acute coronary syndrome in this patient is thrombosis of a coronary artery aneurysm in an individual with a past history of Kawasaki disease. Kawasaki disease is an acute multisystem disease that primarily presents in children less than 5 years of age. The clinical manifestations in childhood are nonsuppurative cervical lymphadenitis; desquamation of the fingertips; and erythema of the oral cavity, lips, and palms. Approximately 25% of cases are associated with coronary artery aneurysms that occur late in illness in the convalescent stage. Early treatment (within 7–10 days of onset) with IV immunoglobulin and high-dose aspirin decreases the risk of developing coronary aneurysms to about 5%. Even if coronary artery aneurysms develop, most regress over the course of the first year if the size is smaller than 6 mm. Aneurysms larger than 8 mm, however, are unlikely to regress. Complications of persistent coronary artery aneurysms include rupture, thrombosis and recanalization, and stenosis at the outflow area. Dissection of the aortic root and coronary ostia is a common cause of death in Marfan’s syndrome and can also be seen with aortitis due to Takayasu’s arteritis. In this patient, there is no history of hypertension, limb ischemia, or systemic symptoms that would suggest an active vasculitis. In addition, there are no other ischemic symptoms that would be expected in Takayasu’s arteritis. Myocardial bridging overlying a coronary artery is seen frequently at autopsy but is an unusual cause of ischemia. The possibility of cocaine use as a cause of myocardial ischemia in a young individual must be considered, but given the clinical history it is a less likely cause of ischemia in this case.
IX-48. The answer is C. (Chap. 327) Recurrent oral ulceration is required for the diagnosis of Behçet’s disease. The ulcers may be single or multiple, are shallowly based with a yellow necrotic base, and are painful. They are generally small, less than 10 mm in diameter. The diagnosis of Behçet’s also requires two of the following: recurrent genital ulceration, eye lesions, skin lesions, and pathergy test. Nonspecific skin inflammatory reactivity to any scratches or intradermal saline injection (pathergy test) is common and specific.
IX-49 and IX-50. The answers are A and C, respectively. (Chap. 327) Behçet’s syndrome is a multisystem disorder of uncertain cause that is marked by oral and genital ulcerations and ocular involvement. This disorder affects males and females equally and is more common in persons of Mediterranean, Middle Eastern, and Far Eastern descent. Approximately 50% of these persons have circulating autoantibodies to human oral mucosa. The clinical features are quite varied. The presence of recurrent aphthous ulcerations is essential for the diagnosis. Most of these patients have primarily oral ulcerations, although genital ulcerations are more specific for the diagnosis. The ulcers are generally painful, can be shallow or deep, and last for 1–2 weeks. Other skin involvement may occur, including folliculitis, erythema nodosum, and vasculitis. Eye involvement is the most dreaded complication because it may progress rapidly to blindness. It often presents as panuveitis, iritis, retinal vessel occlusion, or optic neuritis. This patient also presents with superficial venous thrombosis. Superficial and deep venous thromboses are present in one-fourth of these patients. Neurologic involvement occurs in up to 10%. Laboratory findings are nonspecific with elevations in the erythrocyte sedimentation rate and the white blood cell count. Treatment varies with the extent of the disease. Patients with mucous membrane involvement alone may respond to topical steroids. In more serious or refractory cases, thalidomide is effective. Other options for mucocutaneous disease include colchicines and intralesional interferon α. Ophthalmologic or neurologic involvement requires systemic glucocorticoids and azathioprine or cyclosporine. Life span is usually normal unless neurologic disease is present. Ophthalmic disease frequently progresses to blindness.
IX-51. The answer is C. (Chap. 328) Relapsing polychondritis is a disease of unknown cause characterized by inflammation of the cartilage predominantly in the ears, nose, and laryngotracheobronchial tree. Although it may be a primary disorder, relapsing polychondritis is often associated with a number of other conditions including systemic vasculitis, systemic lupus erythematosus, Sjögren’s syndrome, spondyloarthritides, Behçet’s disease, inflammatory bowel disease, primary biliary cirrhosis, and myelodysplastic syndrome. It is not associated with scleroderma, which causes distinct skin changes that are typically not inflammatory and are not associated with cartilaginous inflammatory disease.
IX-52. The answer is E. (Chap. 328) Relapsing polychondritis most often presents with recurrent painful swelling of the ear. Although other cartilaginous sites may be involved such as the nose and the tracheobronchial tree, these are less frequent. Episodes of ear involvement may result in floppy ears. Typically the pinna is affected while the earlobe is spared, as there is no cartilage in the lobe. Cogan’s syndrome is a rare vasculitic syndrome involving hearing loss, but cartilage inflammation is not a feature. Recurrent trauma or irritation is a consideration but the history is not suggestive, and would be less likely to be bilateral and accompanied by inflammatory findings and a relatively spared ear lobe.
IX-53. The answer is A. (Chap. 329) The finding of noncaseating granulomas is highly suggestive of sarcoidosis, but not confirmatory. To make a specific diagnosis, two or more organs must be affected; however, a suggestive radiograph and positive biopsy are often adequate. Prior to a definitive diagnosis, however, other conditions that may cause noncaseating granulomas should be ruled out. These include beryllium exposure, often in workers in the nuclear industry; atypical mycobacterial infection; and fungal infection such as histoplasmosis. Many malignancies, including testes, and a number of lymphomas may have granulomas, particularly in reactive areas near tumor deposits. Adequate tissue sampling must be ensured to rule out malignancy. Pulmonary alveolar proteinosis is a disease characterized by PAS-positive protein deposits in the alveolar spaces. It is not typically associated with acute or chronic inflammation in the absence of secondary infection.
IX-54. The answer is A. (Chap. 329) Hypercalcemia and/or hypercalciuria occurs in approximately 10% of patients with sarcoidosis and is thought to be due to increased production of 1, 25-dihydroxyvitamin D by the granuloma itself, with resultant increased gut calcium absorption. Sun and exogenous vitamin D can exacerbate the problem. Because of this, renal calculi are relatively common. If a patient with sarcoidosis is to begin therapy with calcium supplementation, 24-hour urine for calcium excretion should be performed before and after initiation of therapy. Often small doses of glucocorticoids are adequate to control this problem.
IX-55. The answer is A. (Chap. 329) The treatment of sarcoidosis depends on whether it is in the acute or chronic form. In many cases, acute disease without abnormalities of neurologic, cardiac, ocular, or metabolic systems may not require therapy. The mainstay of systemic therapy remains to be glucocorticoids. In the chronic form, treatment is dependent on the response to corticosteroids and the tolerability of tapering to low doses (<10 mg/d). Hydroxychloroquine has been shown to be effective in skin disease due to sarcoidosis. Methotrexate works in approximately two-thirds of patients, regardless of disease manifestations. Azathioprine is another cytotoxic agent that is often used in chronic disease, although the evidence in support of this therapy is mostly retrospective. Prospective studies of etanercept and infliximab in patients have shown that etanercept has a limited role as a steroid-sparing agent. In contrast, infliximab, when added to a regimen including prednisone and a cytotoxic agent, improved lung function. The difference in responses to these anti-TNF agents may have to do with the difference in mechanism (receptor antagonism vs. antibody).
IX-56. The answer is A. (Chap. 329) Sarcoidosis is often discovered on routine chest radiograph by the presence of bilateral hilar adenopathy, often in asymptomatic patients. The Scadding method of scoring the standard chest radiograph is still utilized despite CT being more sensitive. Stage 1 is hilar adenopathy (+/− right paratracheal adenopathy) alone; stage 2 is adenopathy plus parenchymal infiltrates; stage 3 is parenchymal infiltrates alone; and stage 4 is fibrosis. When parenchymal disease is present, the upper lobes often predominate in contrast to most other lung disorders. Skin involvement includes erythema nodosum, maculopapular lesions, hyper- and hypopigmentation, keloid formation, subcutaneous nodules, and lupus pernio. Erythema nodosum is usually seen in the acute form of sarcoidosis and often portends a positive prognosis. Liver involvement is difficult to assess. Granulomas may be seen in over 50% of liver biopsies in patients with sarcoidosis, but approximately 20% have evidence by laboratory studies. The typical pattern is an elevation of alkaline phosphatase typical of all forms of granulomatous hepatitis. There may be some accompanying elevation of transaminases. Eye disease is most commonly anterior uveitis, although posterior (retinal and pars planitis) involvement may occur. There is a marked racial difference in eye involvement due to sarcoidosis. In Japan, over 70% of patients have eye disease, whereas in the United States the prevalence is about 30% (with it being more common in African Americans than white Americans). Cardiac involvement varies dramatically by race. In the United States and Europe, less than 5% of patients develop cardiac disease, whereas in Japan the prevalence is over 25%. There is no difference between whites and African Americans. Cardiac manifestations are conduction and systolic dysfunction due to granulomatous inflammation and infiltration.
IX-57. The answer is C. (Chap. 331) Inflammatory arthritis can have a variety of causes, either acute or chronic, and affect single or multiple joints. Acute causes of inflammatory arthritis most commonly include infectious etiologies (Neisseria gonorrhoeae, septic arthritis, Lyme disease) and crystal-induced arthropathies (gout, pseudogout). Chronic inflammatory arthritis is more likely to be related to autoimmune diseases such as rheumatoid arthritis, reactive arthritis, or psoriatic arthritis. A frequent feature of inflammatory arthritis is the presence of morning stiffness. The stiffness of inflammatory arthritis is more severe after a prolonged rest period, which is why it is characteristically worse in the morning. The stiffness can persist as long as an hour or more, is quite severe, and improves with movement. In contrast, noninflammatory arthritis such as osteoarthritis is more typically associated with stiffness that occurs after a brief rest, lasts less than 60 minutes, and worsens with increased activity. Individuals with inflammatory arthritis also frequently have associated systemic symptoms such as fatigue, fever, rash, or weight loss. On physical examination, one should observe the affected joints for signs of inflammation including redness, swelling, warmth, and pain with movement. Nonspecific laboratory evidence of inflammation is often present, including elevation of erythrocyte sedimentation rate, C-reactive protein, and platelet count, anemia of chronic disease or hypoalbuminemia.
IX-58. The answer is A. (Chap. 331) Rotator cuff tendinitis or tear is a common cause of shoulder pain. The rotator cuff is formed by the tendons of four muscles that attach to the humerus. These muscles are responsible for stabilizing the humerus within the glenohumeral joint and are important in lifting and rotating the arm, especially in abduction. The muscles that comprise the rotator cuff are the supraspinatus, infraspinatus, teres minor, and subscapularis muscles. In young individuals, it is uncommon to have a complete tear of the rotator cuff unless there is trauma. In most cases, rotator cuff tendinitis is the more common cause of pain due to rotator cuff injuries. Rotator cuff tendinitis is demonstrated by pain with active, but not passive, abduction of the arm. Other symptoms of rotator cuff tendinitis include pain over the lateral deltoid muscle, night pain, and the impingement sign. The impingement sign is positive if pain is elicited with forward flexion of the arm at less than 180°. However, individuals who engage in activities that cause repetitive stress to the rotator cuff can develop tears in the tendons that would require surgery. Examples of such activities include baseball, rowing, and tennis. To evaluate for a tear of the rotator cuff, the arm is passively abducted and the individual is asked to maintain the arm in abduction. The test is positive if the individual is not able to maintain the arm at 90° of abduction. Pain with palpation over the bicipital groove is a sign of bicipital tendinitis. Pain with palpation anteriorly when the arm is rotated internally and externally is a sign of problems within the glenohumeral joint.
IX-59. The answer is B. (Chap. 331) This patient has degenerative arthritis. His obesity predisposes him to degenerative joint disease that will be worse in the large weight-bearing joints. The physical examination findings of decreased range of motion, crepitus, and varus deformity that is exacerbated on weight bearing are consistent with this diagnosis. The radiogram of the knee demonstrates narrowing of the joint space with osteophyte formation. Occasional effusions may be seen, especially after overuse injuries. The joint fluid analysis in patients with degenerative disease reveals a clear, viscous fluid with a white blood cell count less than 2000/μL. Positively birefringent crystals on polarizing light microscopy will be seen in pseudogout that most commonly affects the knee, whereas negatively birefringent crystals are characteristic of gout. Joint fluid in these inflammatory conditions would generally have a white blood cell count of less than 50,000/μL and is yellow and turbid in character. Septic arthritis presents with fevers and a very warm and tender joint. The joint fluid can have the appearance of frank pus and is opaque. The white blood cell count is usually higher than 50,000/μL and can have a positive Gram stain for organisms.
IX-60. The answer is A. (Chap. 332) Osteoarthritis (OA) is one of the most common causes of disability among older adults and is more common among women than men. OA characteristically affects some joints but spares others. The joints in the hands most commonly affected by OA are the distal and proximal interphalangeal joints and the base of the thumb. It is uncommon for OA to affect the wrist. In addition, OA also is more common in the hips, knees, and cervical and lumbosacral spine. The pain that occurs in OA occurs during or just after joint use, gradually resolving with rest. Thus, the pain of OA in the hands would be expected to be worse while preparing meals (option C) or sewing. The stiffness of OA is not prominent in the mornings as is common in inflammatory arthritis. Rather, stiffness in OA is most marked following brief periods of rest. It can also be associated with the gel phenomenon in which a joint can lock following brief rest periods. On physical examination of the hands of an individual with OA, one may note the presence of bony swellings of the distal and proximal interphalangeal joints. These are known as Heberden’s and Bouchard’s nodes, respectively. No blood tests are routinely required for the evaluation of OA when the history and physical examination are consistent with the diagnosis. If radiographs are performed, one would expect joint space narrowing due to loss of cartilage. In addition, osteophytes and bony enlargement can be seen. Findings of joint swelling, warmth, and erythema are more common in inflammatory causes of arthritis, and furthermore, it would be unlikely for OA to affect only the wrists.
IX-61. The answer is A. (Chap. 332) Osteoarthritis (OA) represents joint failure in which pathologic changes have occurred in all structures of the affected joint. The central pathology in OA is articular cartilage loss. The components leading to the development of OA can be separated into those that contribute to joint loading and those that increase joint vulnerability. The most potent risk factor for OA is aging, which affects joint vulnerability. Radiographic evidence of OA is rare in individuals younger than 40; however, more than 50% of individuals older than 70 will have changes of OA. A young joint has in place protective mechanisms that allow it to tolerate excessive loading without lasting damage. Specifically, the cartilage of younger joints is more responsive to dynamic loading, whereas older cartilage fails to respond, leading to breakdown of the cartilage matrix. Women are more susceptible to OA than men, especially after the sixth decade, but the relationship is not as strong as with aging and OA. Joint injury is a strong predictor of the future development of osteoarthritis. Obesity is a well-recognized risk factor in hip and knee arthritis likely due to increased loading forces. Obesity appears to play a role in OA of the hand as well, suggesting that obesity has both a mechanical and metabolic mechanism of action. The genetics of OA are not well understood. Inherited polymorphisms appear to play a role in hand and hip OA but not as much in other joints.
IX-62. The answer is E. (Chap. 332) This patient presents with symptoms suggestive of OA. OA is primarily a disease that is mechanically driven, and nonpharmacologic therapy should be a first-line treatment for disease that is mild or intermittent. Avoiding activities that cause pain and overload the joint, strengthening and conditioning the adjacent muscle groups, and supporting or unloading the joint with a brace or crutch are all examples of fundamental treatments aimed at reversing the pathophysiology of OA. In this patient, weight loss should be the primary goal of therapy. Each pound of weight increases loading across a weight-bearing joint three- to six-fold. This patient would benefit from a daily minimal-weight-bearing exercise regimen combined with nutritional goals aimed at slow, consistent weight loss. Avoidance of walking is impractical; a cane or supportive device to lessen the joint load can be offered. Steroids and narcotics are not indicated in this case.
IX-63. The answer is C. (Chap. 333) This individual has had three recent acute gout attacks and has risk factors for recurrence including chronic kidney disease and the need for diuretic therapy. In this setting, he demonstrates elevation of his uric acid levels. When considering initiation of hypouricemic therapy, one should consider the number of attacks, the serum uric acid levels outside of an acute attack, and the patient’s willingness to commit to lifelong therapy. In addition, individuals with uric acid stones or tophaceous gout should also receive hypouricemic therapy. Current agents that are commonly used to treat hyper-uricemia include uricosuric agents and xanthine oxidase inhibitors. Probenecid is the most commonly used uricosuric agent. It is started at a dose of 250 mg twice daily, but can be titrated as high as 3 g daily. However, it is generally not effective when the serum creatinine is greater than 2.0 mg/dL. Benzbromarone is a uricosuric agent that is more effective in individuals with renal failure, but it is not available in the United States. The medication most commonly prescribed in individuals with recurrent gout is allopurinol. This xanthine oxidase inhibitor lowers serum uric acid levels in overproducers, but has multiple associated toxicities including toxic epidermal necrolysis, bone marrow suppression, and renal failure. The initial starting dose is typically 300 mg daily and can be increased to as high as 800 mg daily. However, caution must be taken in individuals with renal failure. Febuxostat is a newer chemically unrelated xanthine oxidase inhibitor. It has been demonstrated to lower uric acid levels as effectively as allopurinol. The initial dose of febuxostat is 40–80 mg daily, and dose adjustment is not required in mild to moderate renal failure. Colchicine is a microtubule stabilizer that decreases inflammation in acute gout attacks. It does not affect levels of uric acid. However, it is commonly used as adjunctive therapy in individuals to prevent gout flares that occur as uric acid levels decline. Indomethacin is a nonsteroidal anti-inflammatory agent that is commonly used in acute gout flares. It does not have a role in the treatment of hyperuricemia or outside of the acute gout attack. Caution should be taken in using nonsteroidal anti-inflammatory drugs in individuals with renal insufficiency.
IX-64. The answer is C. (Chap. 333) Acute gouty arthritis is frequently seen in individuals on diuretic therapy. Diuretics result in hyperuricemia through enhanced urate reabsorption in the proximal tubule of the kidney in the setting of volume depletion. Hyperuricemia remains asymptomatic in many individuals but may manifest as acute gout. Acute gout is an intensely inflammatory arthritis that frequently begins at night. While any joint may be affected, the initial presentation of gout is often in the great toe at the metatarsophalangeal joint. There is associated joint swelling, effusion, erythema, and exquisite tenderness. A typical patient will complain that the pain is so great that he or she is unable to wear socks or allow sheets or blankets to cover the toes. Arthrocentesis will reveal an inflammatory cloudy-appearing fluid. The diagnosis of gout is confirmed by the demonstration of monosodium urate crystals seen both extracellularly and intracellularly within neutrophils. Monosodium urate crystals appear strongly negatively birefringent under polarized light microscopy and have a typical needle- and rod-shaped appearance. The WBC count is usually below 50,000/μL with values above 100,000/μL being more likely to be associated with a septic arthritis. Likewise, very low glucose levels and a positive Gram stain are not manifestations of acute gout but are common in septic arthritis. Calcium pyrophosphate dihydrate crystals appear as weakly positively birefringent rhomboidal crystals and are seen in pseudogout.
IX-65. The answer is A. (Chap. 334) This patient presents with a history consistent with a true septic arthritis due to gonococcal infection. Although gonococcal infection has generally declined in incidence in the past several decades, Neisseria gonorrhoeae is responsible for about 70% of acute infectious arthritis in individuals younger than 40 years. Women are two to three times more likely to develop disseminated gonococcal infection than men, likely related to the fact that asymptomatic cervical infection is more common in women. Women appear to be at greatest risk for disseminated gonococcal infection during menses or pregnancy. Disseminated gonococcal infection presents with fevers, chills, migratory arthritis and tenosynovitis, and a papular rash on the trunk and the extensor surfaces of the distal extremities. The rash can progress to hemorrhagic pustules. The joint symptoms and rash are thought to represent immune-complex deposition. In disseminated gonococcal infection, the synovial fluid from inflamed joints usually contains only 10,000–20,000 leukocytes/μL. In this setting, synovial cultures are negative and blood cultures are positive less than 45% of the time.
In this patient, there is evidence of a true septic arthritis with involvement of a single joint and a high leukocyte count (>50,000/μL). Septic arthritis due to N. gonorrhoeae is less common than disseminated gonococcal infection but always follows this syndrome. In the clinical scenario presented, the symptoms of fevers, chills, migratory arthralgias, and rash occurred 3 weeks prior to presentation with monoarticular septic arthritis. Blood cultures are almost always negative, and synovial fluid cultures are positive less than 40% of the time. The diagnostic procedure of choice is a culture of a potentially infected mucosal site, including the cervix, urethra, or pharynx.
Individuals with Lyme disease who are untreated frequently develop joint symptoms. Most commonly, this presents as waxing and waning episodes of mono- or oligoarthritis. Ten percent of individuals can develop an inflammatory erosive arthritis that leads to destructive disease of the joint if untreated. This patient’s symptoms are not consistent with Lyme arthritis and testing for Borrelia burgdorferi is not indicated. Likewise, this patient presents with findings of monoarticular arthritis, which is not consistent with rheumatoid arthritis, and a rheumatoid factor is not indicated.
IX-66. The answer is B. (Chap. 334) Although the crystals suggest that the patient may have active pseudogout, the more important acute medical problem is septic arthritis. This is highly probable based on the joint leukocyte count above 100,000/μL, high percentage of PMNs, and positive Gram stain. Crystal-induced, rheumatoid, and other noninfectious causes of arthritis typically have WBC counts in the 30,000–50,000/μL range. WBC counts in indolent infections such as fungal or mycobacterial arthritis are commonly in the 10,000–30,000/μL range. The bacteria of septic arthritis usually enter the joint via hematogenous spread through synovial capillaries. Patients with rheumatoid arthritis are at high risk of a septic arthritis due to Staphylococcus aureus because of chronic inflammation and glucocorticoid therapy. The concurrent presence of pseudo-gout does not preclude the diagnosis of septic arthritis. In adults, the most common bacterial pathogens are Neisseria gonorrhoeae and S. aureus. Antibiotics, prompt surgical evaluation for drainage, and blood cultures to rule out bacteremia are all indicated. Prompt local and systemic treatment of infection can prevent the destruction of cartilage, joint instability, or deformity. Direct instillation of antibiotics into the joint fluid is not necessary. If the smear shows no organisms, a third-generation cephalosporin is reasonable empirical therapy. In the presence of gram-positive cocci in clusters, antistaphylococcal therapy should be instituted based on the community prevalence of methicillin resistance or recent hospitalization (which would favor empirical vancomycin). Typically, acute flairs of pseudogout can be addressed with glucocorticoids. However, this could portend a higher risk in the context of infection. Nonsteroidal anti-inflammatory agents might be a possibility depending on the patient’s renal function and gastrointestinal history.
IX-67. The answer is C. (Chap. 335) This patient presents with a characteristic history for fibromyalgia, a diffuse pain syndrome associated with increased sensitivity to evoked pain. The underlying pathophysiology of pain in fibromyalgia is felt to be related to altered pain processing in the central nervous system. Epidemiologically, women are affected nine times more frequently than men. The worldwide prevalence of fibromyalgia is 2–3%, but in primary care practices it is as high as 5–10%. The disorder is even more common in patients with degenerative or inflammatory rheumatic disorders, with a prevalence of 20% or higher. The most common presenting complaint is diffuse pain that is difficult to localize. Pain is both above and below the waist and affects the extremities as well as the axial skeleton. However, it does not localize to a specific joint. The pain is noted to be severe in intensity, difficult to ignore, and interferes with daily functioning. While this patient demonstrates pain at several tender points, the American College of Rheumatology no longer includes tender point assessment in the diagnostic criteria for fibromyalgia. Rather, the new criteria focus on clinical symptoms of widespread pain and neuropsychological symptoms that have been present for at least 3 months. Some of the neuropsychological conditions that are frequently observed in fibromyalgia include sleep disturbance, impaired cognitive functioning, fatigue, stiffness, anxiety, and depression. The lifetime prevalence of mood disorders in patients with fibromyalgia is 80%. Sleep disturbances can include difficulty falling asleep, difficulty staying asleep, and nonrestorative sleep, among others.
IX-68. The answer is D. (Chap. 335) Fibromyalgia is a common disorder affecting 2–5% of the population. It presents as a diffuse pain syndrome with associated neuropsycho-logical symptoms including depression, anxiety, fatigue, cognitive dysfunction, and disturbed sleep. Treatment for fibromyalgia should include a combination of non-pharmacologic and pharmacologic approaches. Patient education regarding the disease is important to provide a framework for understanding symptoms. The focus of treatment should not be on eliminating pain, but rather improving function and quality of life. Physical conditioning is an important part of improving function and should include a multifaceted exercise program with aerobic exercise, strength training, and exercises that incorporate relaxation techniques such as yoga or Tai Chi. Cognitive behavioral therapy can be useful in improving sleep disturbance and also in decreasing illness behaviors.
Pharmacologic therapy in fibromyalgia is targeted at the afferent and efferent pain pathways. The two most common categories of medications for fibromyalgia are antidepressants and anticonvulsants. Amitriptyline, duloxetine, and milnacipran have all been used with some efficacy in fibromyalgia. Duloxetine and milnacipran have been approved by the U.S. Food and Drug Administration for the treatment of fibromyalgia. The anticonvulsants that are predominantly used in fibromyalgia are those that are ligands of the α-2-δ subunit of voltage-gated calcium channels. These include gabapentin and pregabalin, which are also FDA approved for treatment of fibromyalgia.
Anti-inflammatory medications and glucocorticoids are not effective in fibromyalgia. However, if there is a comorbid triggering condition such as rheumatoid arthritis, appropriate therapy directed at the underlying disorder is critical to controlling symptoms of fibromyalgia as well. Opioid analgesics such as oxycodone should be avoided. They have no efficacy in treating fibromyalgia and may induce hyperalgesia that can worsen both pain and function.
IX-69. The answer is A. (Chap. 335) Fibromyalgia is characterized by chronic widespread musculoskeletal pain, stiffness, paresthesia, disturbed sleep, and easy fatigability. It occurs in a 9:1 female-to-male ratio. It is not confined to any particular region, ethnicity, or climate. While the pathogenesis is not clear, there are associations with disturbed sleep and abnormal pain perception. Fibromyalgia is diagnosed by the presence of widespread pain, a history of widespread musculoskeletal pain that has been present for more than 3 months, and the presence of neuropsychological dysfunction (fatigue, waking unrefreshed, or cognitive symptoms). In the prior diagnostic criteria, it was required to demonstrate pain on palpation at 11 of 18 tender point sites. However, this was abandoned in the updated criteria because it was felt that strict application of a threshold of pain could lead to under-diagnosis of the disorder. Besides pain on palpation, the neurologic and musculoskeletal examinations are normal in patients with fibromyalgia. Psychiatric illnesses, particularly depression and anxiety disorders, are common comorbidities in these patients but do not help satisfy any diagnostic criteria.
IX-70. The answer is A. (Chap. 336) The finding shown in Figure IX-70 is characteristic of clubbing. Clubbing occurs in the distal portions of the digits and is characterized by widening of the fingertips, convexity of the nail contour, and loss of the normal 15° angle between the proximal nail and cuticle. Clinically, it sometimes can be difficult to ascertain whether clubbing is present. One approach to the diagnosis of clubbing is to measure the diameter of the finger at the base of the nail and at the tip of the finger in all 10 fingers. For each finger, a ratio between the base of the nail and the tip of the finger is determined. If the sum of all 10 fingers is greater than 1, then clubbing is felt to be present. A simpler approach is to have an individual place the dorsal surfaces of the distal fourth digits from each hand together. In a normal individual, there should be a diamond shaped space between the digits. When an individual has clubbing, this space is obliterated.
Clubbing most commonly occurs in advanced lung disease, especially bronchiectasis, cystic fibrosis, and interstitial lung diseases like sarcoidosis or idiopathic pulmonary fibrosis. Clubbing was originally described in individuals with empyema and can occur in chronic lung infections, including lung abscess, tuberculosis, or fungal infections. Pulmonary vascular lesions and lung cancer also are associated with clubbing. However, chronic obstructive pulmonary disease does not cause clubbing.
The causes of clubbing are not limited, however, to the pulmonary system alone. Clubbing can be a benign familial condition and is also associated with a variety of other disorders. This includes cyanotic congenital heart disease, subacute bacterial endocarditis, Crohn’s disease, ulcerative colitis, celiac disease, and cancer of the esophagus, liver, small bowel, and large bowel. In untreated hyperthyroidism clubbing can occur in association with periostitis in a condition called thyroid acropachy. While these numerous clinical associations have been described for many centuries, the cause of clubbing remains unknown.
IX-71. The answer is E. (Chap. 337) Trochanteric bursitis is a common cause of hip pain and results from inflammation within the bursa that surrounds the insertion of the gluteus medius onto the greater trochanter of the femur. Bursae lie throughout the body with the purpose of facilitating movement of tendons and muscles over bony prominences. Bursitis has many causes including overuse, trauma, systemic disease, or infection. Trochanteric bursitis typically presents with acute or subacute hip pain with a varying quality. The pain localizes to the lateral aspect of the hip and upper thigh. Direct palpation over the posterior aspect of the greater trochanter reproduces the pain, and often sleeping on the affected side is painful. Pain is also elicited with external rotation and resisted abduction of the hip. Treatment of trochanteric bursitis includes the use of nonsteroidal anti-inflammatory medications and avoidance of overuse. If the pain persists, steroid injection into the affected bursa may be beneficial.
Other causes of hip pain include osteoarthritis, avascular necrosis, meralgia paresthetica, septic arthritis, occult hip fracture, and referred pain from lumbar spine disease. In patients with true disorders of the hip joint such as osteoarthritis, avascular necrosis, and occult hip fracture, the pain is most commonly localized to the groin area. Meralgia paresthetica (lateral femoral nerve entrapment syndrome) causes a neuropathic pain in the upper outer thigh with symptoms ranging from tingling sensations to a burning pain. When degenerative spinal disease is the cause of referred hip pain, there is typically back pain as well. In addition, palpation over the lateral joint would not reproduce the pain. Iliotibial band syndrome causes lateral knee pain but not hip pain.
IX-72. The answer is B. (Chap. 337) The iliotibial band is comprised of thick connective tissue that runs along the outer thigh from the ilium to the fibula. When this band becomes tightened or inflamed, pain most commonly occurs where the band passes over the lateral femoral condyle of the knee, leading to a burning or aching pain in this area that can radiate toward the outer thigh. This overuse injury is most often seen in runners and can be caused by improperly fitted shoes, running on uneven surfaces, and excessive running. It is also more common in individuals with a varus alignment of the knee (bowlegged). Treatment of iliotibial band syndrome includes rest, NSAIDs, physical therapy, and addressing risk factors such as poorly fitted shoes or running on uneven surfaces. Glucocorticoid injection at the lateral femoral condyle may alleviate pain, but running must strictly be avoided for 2 weeks following injection. In refractory cases, surgical release of the iliotibial band may be beneficial.
IX-73. The answer is A. (Chap. 337) Adhesive capsulitis is characterized by pain and restricted motion of the shoulder. Usually this occurs in the absence of intrinsic shoulder disease, including osteoarthritis and avascular necrosis. It is, however, more common in patients who have had bursitis or tendinitis previously, as well as patients with other systemic illnesses, such as chronic pulmonary disease, ischemic heart disease, and diabetes mellitus. The etiology is not clear, but adhesive capsulitis appears to develop in the setting of prolonged immobility. Reflex sympathetic dystrophy may also occur in the setting of adhesive capsulitis. Clinically, this disorder is more commonly seen in females over age 50. Pain and stiffness develop over the course of months to years. On physical examination, the affected joint is tender to palpation, with a restricted range of motion. The gold standard for diagnosis is arthrography with limitation of the amount of injectable contrast to less than 15 mL. In most patients, adhesive capsulitis will regress spontaneously within 1–3 years. NSAIDs, glucocorticoid injections, physical therapy, and early mobilization of the arm are useful therapies.
IX-74. The answer is B. (Chap. 331) Inflammation of the abductor pollicis longus and the extensor pollicis brevis at the radial styloid process tendon sheath is known as De Quervain’s tenosynovitis. Repetitive twisting of the wrist can lead to this condition. Pain occurs when grasping with the thumb and can extend radially along the wrist to the radial styloid process. Mothers often develop this tenosynovitis by holding their babies with the thumb outstretched. The Finkelstein sign is positive in De Quervain’s tenosynovitis. It is positive if the patient develops pain by placing the thumb in the palm, closing the fingers around the thumb and deviating the wrist in the ulnar direction. Management of De Quervain’s tenosynovitis includes nonsteroidal anti-inflammatory drugs and splinting. Glucocorticoid injections can be effective. A Phalen maneuver is used to diagnose carpal tunnel syndrome and does not elicit pain. The wrists are flexed for 60 seconds to compress the median nerve to elicit numbness, burning, or tingling. Gouty arthritis will present as an acutely inflamed joint with crystal-laden fluid. Rheumatoid arthritis is a systemic illness with characteristic joint synovitis and radiographic features.