Rheumatology Summer Board Review Session 2 Mashkur Husain

1. Rheumatology Summer Board Review Session 2 Mashkur Husain

2. Question 10 • A 49-year-old man is evaluated for a 10-year history of gout. He is currently asymptomatic but is interested in reducing the frequency of attacks. Previous attacks were rare, but for the past 3 years he has had four to five attacks per year. His father has a history of chronic tophaceous gout. The patient's only medication is ibuprofen as needed for gout attacks. • On physical examination, temperature is 37.0 °C (98.6 °F), blood pressure is 118/80 mm Hg, pulse rate is 72/min, and respiration rate is 13/min. BMI is 29. The general physical examination is normal. There is no evidence of tophi, and the joint examination is unremarkable. • Laboratory studies, including complete blood count, serum chemistries, and liver chemistry tests, are normal; erythrocyte sedimentation rate is 16 mm/h, and serum uric acid level is 9.2 mg/dL (0.54 mmol/L). • Radiographs of the hands and feet are normal.

3. Answer Choice Which of the following is the most appropriate initial treatment? A allopurinol B Colchicine C Colchicine and allopurinol D Febuxostat

4. Answer Choice Which of the following is the most appropriate initial treatment? A allopurinol B Colchicine C Colchicine and allopurinol D Febuxostat

5. Explanation • This patient has frequent, symptomatic gout attacks and requires initial treatment with colchicine concurrent with urate-lowering therapy such as allopurinol. Gout manifests as acute, intermittent attacks of severe pain, redness, and swelling of a joint accompanied by intracellular urate crystals seen on polarized light microscopy of the synovial fluid. NSAIDs, corticosteroids, and colchicine are appropriate management strategies for acute gout attacks; choice of treatment is based on relative efficacy and, most importantly, the side-effect profiles of the agents and the risk of toxicity in the individual patient. • Gout is associated with hyperuricemia, and patients with recurrent episodes (≥2 attacks in 1 year) require urate-lowering therapy to prevent both future attacks and occult urate deposition. However, the addition of urate-lowering therapy transiently increases the risk for acute gout attacks for at least 3 to 6 months; accordingly, prophylaxis with an anti-inflammatory agent such as colchicine, at least during that period, is indicated concurrent with urate-lowering therapy. • Along with this treatment regimen, management of risk factors can help to lower serum urate concentrations, including reducing purine and fructose and increasing dairy intake, within the limits of individual tolerance; weight loss; and reducing alcohol consumption. Medications that raise serum uric acid levels, including thiazide diuretics and low-dose salicylates, should be discontinued if alternative therapy is appropriate.

6. Explanation • Use of either allopurinol or febuxostat would be appropriate but only in the setting of concurrent prophylaxis. Both febuxostat and allopurinol should be dosed to achieve a serum urate level ≤6.0 mg/dL (0.35 mmol/L), rather than at a fixed dose. The relative effectiveness of these two agents is not well established; febuxostat is more potent on a per-mole basis but is also more expensive than allopurinol. • Treatment with colchicine alone might lower the risk of gout attacks in this patient but would not address the underlying problem of urate deposition, which would likely worsen progressively over time. Key Point • Colchicine or other anti-inflammatory therapy is indicated concurrent with initiation of urate-lowering agents in patients with frequently recurring gout attacks.

7. Gout Diagnosis Gout is caused by the inflammatory reaction to monosodium urate crystal deposition in synovial tissue, bursae, and tendon sheaths. Gout is often precipitated by use of diuretics. Gout progresses through three stages: • asymptomatic hyperuricemia, which may last several decades • acute intermittent gout • chronic tophaceous gout, which usually develops only after years of acute intermittent episodes • Monosodium urate crystals (needle-shaped, negatively birefringent crystals) in the joint fluid and uric acid tophi are diagnostic. Other characteristic findings of acute intermittent gout include monoarticular arthritis (typically of the first MTP or tarsal joints), self-limited acute attacks, and hyperuricemia. If disease presents classically at the first MTP joint (podagra), synovial fluid analysis is not required to make the diagnosis.

8. Gout • With time, attacks of gout may become more frequent and involve more joints. Patients may progress to have a chronic, smoldering arthritis. Tophi are yellowish nodular deposits of monosodium urate, sometimes with surrounding erythema, that develop on extensor surfaces of the extremities, on finger pads, and along tendons. Transplantation-associated gout is associated with the use of calcineurin antagonists (cyclosporine). • X-rays show bone erosions with overhanging edges. The synovial fluid leukocyte count ranges from 2000 to 75,000/microliter. Monosodium urate crystals may be visible on joint aspiration when an acute flare is not occurring. Don't Be Tricked • An elevated uric acid level alone is not diagnostic of gout. • A normal uric acid level at the time of an acute attack does not rule out gout. • Leukocyte counts higher than 50,000/microliter should raise suspicion for a concurrent bacterial joint infection, even when monosodium urate crystals have been identified.

9. Therapy • Dietary purine restriction, weight loss, and discontinuation of alcohol may help to decrease uric acid levels in patients with mild hyperuricemia and symptomatic gout. Medications that raise serum uric acid levels, such as thiazide diuretics and low-dose salicylates, should be discontinued. • For an acute gouty flare, NSAIDs are first-line therapy. Use oral corticosteroids when NSAIDs are unsafe (in older adult or postoperative patients, patients requiring anticoagulation, and those with chronic kidney disease or peptic ulcer disease). Prescribe intra-articular corticosteroids for a single joint if other interventions are ineffective or contraindicated. • Patients with 2 or more attacks each year or with the presence of tophi or kidney stones require allopurinol to achieve a serum uric acid level <6 mg/dL. More than 50% of patients require allopurinol, >300 mg/d, to reach this target serum uric acid level. Doses must be adjusted (lowered) for patients with kidney impairment. When starting allopurinol, also begin low-dose colchicine to prevent acute gout; colchicine can be discontinued when the uric acid level stabilizes. Febuxostat is useful if patients cannot tolerate allopurinol and in patients with chronic kidney disease.

10. Patients with kidney disease, especially those concomitantly taking hydrochlorothiazide, who are treated with allopurinol have an increased risk for a rare but potentially fatal hypersensitivity syndrome characterized by severe dermatitis, fever, eosinophilia, hepatic necrosis, and acute nephritis. Don't Be Tricked • Do not select NSAIDs for patients with gout who also have chronic kidney disease or peptic ulcer disease. • Do not use allopurinol and azathioprine together, because azathioprine is metabolized through xanthine oxidase, which is inhibited by allopurinol. • Do not begin allopurinol during an acute attack of gout; wait 1 or 2 weeks. • Do not use uricosuric therapy (e.g., probenecid) in patients with a low estimated GFR who are at risk for nephrolithiasis or chronic kidney disease. • Do not prescribe colchicine for patients with kidney failure.

11. Swollen interphalangeal joints and multiple tophi characteristic of chronic tophaceous gout.

12. Question 11 • A 74-year-old woman is evaluated for a 2-year history of progressive pain of the fingers and knees, along with morning stiffness lasting 20 minutes. She has no other pertinent personal or family medical history. Her only medication is acetaminophen as needed for pain. • On physical examination, temperature is 37.0 °C (98.6 °F), blood pressure is 118/70 mm Hg, pulse rate is 66/min, and respiration rate is 12/min. BMI is 19. Musculoskeletal examination reveals tenderness, erythema, some soft-tissue swelling, and bony hypertrophy of the second and third metacarpophalangeal joints bilaterally. Bony hypertrophy and fluctuance of the knees is noted bilaterally. • Laboratory studies, including erythrocyte sedimentation rate and serum ferritin, iron, and total iron-binding capacity levels, are normal; transferrin saturation is not elevated. Rheumatoid factor and anti–cyclic citrullinated peptide antibodies are negative. • Radiographs of the hands reveal joint-space narrowing, particularly of the second and third metacarpophalangeal joints; osteophytes, subchondral sclerosis, and linear calcification of the cartilage are noted. The triangular fibrocartilage of the wrists also demonstrates calcification. Radiographs of the knees show diffuse joint-space narrowing with osteophytes and cartilaginous calcification. There are no marginal erosions or periarticular osteopenia.

13. Answer Choice Which of the following is the most likely diagnosis? A Calcium pyrophosphate arthropathy B Hemochromatosis C Osteoarthritis D pseudogout E Rheumatoid arthritis

14. Answer Choice Which of the following is the most likely diagnosis? A Calcium pyrophosphate arthropathy B Hemochromatosis C Osteoarthritis D pseudogout E Rheumatoid arthritis

15. Explanation • This patient has chronic calcium pyrophosphate (CPP) arthropathy. CPP arthropathy is a clinical diagnosis made by observing typical osteoarthritis features, along with chondrocalcinosis, in locations atypical for osteoarthritis such as the metacarpophalangeal joints. A chronic inflammatory condition may result, leading to progressive joint destruction. This patient has a polyarthritis with radiologic findings that resemble osteoarthritis (subchondral sclerosis and osteophytes); however, involvement includes the second and third metacarpophalangeal joints, which are not typically involved in osteoarthritis. There also is evidence of calcium deposition in the cartilage of the affected joints and in the wrists. This constellation of findings is pathognomonic for chronic CPP arthropathy. • Hemochromatosis may overlap with CPP arthropathy and can cause osteoarthritis-like arthritis in atypical joints. However, this patient has no evidence of iron overload (normal serum ferritin, iron, total iron-binding capacity, and transferrin saturation) that is characteristic of hemochromatosis. • Although the patient has radiographic findings consistent with osteoarthritis, the involvement of metacarpophalangeal joints and the presence of chondrocalcinosis are not typical for the disorder.

16. Explanation • Pseudogout is an acute inflammatory arthritis caused by CPP crystals in the joint. Although this patient has CPP deposition, there is no evidence of a current or prior acute inflammatory arthritis. This patient's 2-year history of joint pain is not consistent with acute pseudogout. • This patient's findings, including involvement of only the second and third metacarpophalangeal joints; limited morning stiffness and soft-tissue swelling; negative rheumatoid factor and anti–cyclic citrullinated peptide antibody results; and no marginal erosions or periarticular osteopenia, do not support a diagnosis of rheumatoid arthritis. Key Point • Calcium pyrophosphate arthropathy is characterized by osteoarthritis-like arthritis in atypical joints such as the metacarpophalangeal joints along with the presence of chondrocalcinosis.

17. Calcium Pyrophosphate Deposition Disease Diagnosis • CPDD is caused by crystallization of calcium pyrophosphate dihydrate (CPPD) crystals in articular tissues. CPDD has varied presentations with symptoms that may suggest other diagnoses. Characteristic findings in acute pseudogout syndrome include: • inflammation localized to one joint, affecting the knee, wrist, shoulder, or ankle • acute onset of several painful joints following trauma or surgery Characteristic findings in chronic pseudogout syndrome include: • asymmetric involvement of the shoulders, wrists, MCP joints, or knees • swelling and deformity of joints and morning stiffness

18. Characteristic findings in asymptomatic chondrocalcinosis include calcification of the: • triangular fibrocartilage of the wrist joint (space between the carpal bones and distal ulna) • menisci of the knee joint (appearing as a line in the cartilage) • symphysis pubis CPDD may be associated with underlying metabolic disorders. Screen patients with CPDD who are <50 years of age for: • hemochromatosis • hyperparathyroidism • hypothyroidism • gout

19. The definitive diagnosis of CPDD requires both the presence of positively birefringent, rhomboid-shaped crystals and typical cartilage or joint capsule calcification on x-ray. Don't Be Tricked • The absence of chondrocalcinosis on x-ray does not rule out CPDD. Therapy • NSAIDs are appropriate as initial therapy for most patients. Prescribe colchicine for patients with any variant of CPPD deposition disease that does not respond to NSAIDs. Intra-articular corticosteroids are indicated for acute pain after infection is ruled out. This is always the correct treatment for a patient with a noninfectious inflammatory monoarticular arthritis who cannot take NSAIDs because of an elevated serum creatinine level.

20. Linear calcifications of the meniscus and articular cartilage are characteristic of CPDD.

21. Diagnosis • Hypertrophic osteoarthropathy causes a proliferation of skin and osseous tissue at the distal parts of the extremities. Characteristic findings are digital clubbing, painful periostosis of long bones, synovial effusions, and new periosteal bone formation. Pain is generally alleviated by elevating the affected limbs. Associated disorders include lung cancer, chronic pulmonary infections, and right-to-left cardiac shunts. Test Yourself • A 64-year-old man has a 1-month history of bilateral ankle pain. Elevating his feet alleviates the discomfort. On physical examination, his lower legs are warm. Pitting edema begins 6 cm above the malleoli; this area is very tender to palpation. An x-ray shows new periosteal bone formation of the tibia above the ankle joints. • ANSWER: The probable diagnosis is hypertrophic osteoarthropathy. Order a chest x-ray to determine the cause.

22. Hypertrophic osteoarthropathy in this patient is characterized by clubbing of the toes (particularly the great toes), ankle effusions, and lower extremity edema.

23. Question 12 A 22-year-old woman seeks preconception counseling and treatment of recently diagnosed systemic lupus erythematosus. She reports fatigue and hand pain accompanied by morning stiffness lasting 15 minutes. On physical examination, vital signs are normal. Malar erythema is noted. There is tenderness of the proximal interphalangeal joints bilaterally; no other synovitis is present. Recent ophthalmologic examination findings, including visual fields, are normal. Laboratory studies: Leukocyte count 3300/µL (3.3 × 109/L), with an absolute lymphocyte count of 1200/µL (1.2 × 109/L) C3 Normal C4 Decreased Serum creatinine Normal Antinuclear antibodies Titer of 1:160 (homogeneous pattern) Anti–double-stranded DNA antibodies Positive IgG-specific anticardiolipin antibodies Positive Urinalysis Normal

24. Answer Choice Which of the following is the most appropriate treatment? A Azathioprine B Hydroxychloroquine C Mycophenolate mofetil D Prednisone E No treatment at this time

25. Answer Choice Which of the following is the most appropriate treatment? A Azathioprine B Hydroxychloroquine C Mycophenolate mofetil D Prednisone E No treatment at this time

26. Explanation Treatment with hydroxychloroquine is indicated for this patient with systemic lupus erythematosus (SLE). Although hydroxychloroquine has been used anecdotally for many years in patients with SLE, numerous recent studies document significant benefits of this agent. High levels of evidence show that hydroxychloroquine prevents lupus flares and increases survival in patients with SLE; there also is moderate evidence suggesting protection against irreversible organ damage, thrombosis, and bone mass loss. Hydroxychloroquine should be continued indefinitely to prevent disease reactivation, even if the disease has been quiescent for many years. This patient has mild SLE without evidence of significant internal organ involvement; she is also trying to conceive, which further impacts choice of medication. Although hydroxychloroquine is a pregnancy category C medication, expert consensus states that this agent is relatively safe in pregnancy, and studies support a reduction in flares without harm to the fetus. Given the demonstrated benefits of hydroxychloroquine in patients with SLE, which are suggested to be time-dependent, it is appropriate to treat this patient at this time, unless the patient refuses or has a contraindication to therapy. Pregnancy outcomes in patients with SLE are better in the absence of active disease, and patients should be counseled to wait to try to conceive until they have had quiescent disease for a minimum of 6 months.

27. Explanation Azathioprine and mycophenolate mofetil have a steroid-sparing effect and have been shown to improve outcomes in patients with severe SLE, particularly those with kidney involvement. Azathioprine, but not mycophenolate mofetil, is generally considered the most acceptable of these agents for use during pregnancy, despite its pregnancy category D rating. This patient does not have severe disease and is not currently taking corticosteroids; therefore, treatment with these medications is not indicated. This patient is stable with minimal disease activity, both clinically and serologically; therefore, there is no indication for treatment with prednisone unless her symptoms worsen. Prednisone, when necessary, is considered relatively safe for use in pregnancy; about two thirds of the active drug is metabolized by placental enzymes to an inactive form, limiting the amount of fetal exposure. Key Point Although hydroxychloroquine is a pregnancy category C medication, this agent is relatively safe in pregnancy and can reduce lupus flares without harm to the fetus.

28. Systemic Lupus Erythematosus Diagnosis SLE is a chronic multisystem autoimmune disease with immune complex deposition of unknown cause. Diagnosis is established based on characteristic clinical features and laboratory studies. Diagnose SLE when any four of the following are present: positive ANA malar (“butterfly”) rash that spares the nasolabial folds and areas beneath the nose and lower lip discoid rash characterized by erythematous, raised patches with keratotic scaling and follicular plugging photosensitivity

29. Systemic Lupus Erythematosus oral ulcers arthritis (oligoarticular or polyarticular, or asymmetric or symmetric); joint pain is frequently the presenting symptom serositis (pleural, pericardial, abdominal) kidney disorder (new-onset hypertension, proteinuria with or without hematuria) neurologic disorder (peripheral neuropathy, mononeuritis multiplex, cranial neuritis, transverse myelitis, aseptic meningitis, stroke, encephalitis, psychosis, seizures) hematologic disorder (autoimmune hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia) immunologic disorder (antiphospholipid antibody syndrome [venous and arterial thrombosis, recurrent fetal loss])

30. Don't Be Tricked • Do not diagnose SLE in a patient with a positive ANA and facial rash that involves the nasolabial folds; consider rosacea instead. • The ANA assay is sensitive but not specific for diagnosing SLE. Assays for anti-dsDNA and anti-Sm antibodies are highly specific. Anti-dsDNA antibodies correlate with disease activity. • Activation of the complement pathway, manifested by depressed serum C3 and C4 levels, often accompanies major flares of SLE. Additional manifestations: • livedo reticularis (anticardiolipin antibodies and thrombophilia) • nonbacterial endocarditis • increased risk of cardiovascular disease, including stroke • neonatal heart block (high-titer anti-Ro/SSA antibodies) • Drug-induced lupus is most often caused by hydralazine, procainamide, isoniazid, minocycline, or TNF-α inhibitors. Symptoms are usually limited to fever, serositis, and arthritis. ANA assays are positive, but anti-dsDNA and anti-Sm antibody assays are negative. Antihistone antibody assay may be positive.

31. Don't Be Tricked • Monitoring ANA titers is not warranted because these values do not reflect disease activity. Therapy • Cardiovascular disease is the major cause of death in patients with SLE; reduce atherosclerosis risk factors in all patients. Prescribe vitamin D and calcium supplements for all patients and bisphosphonates for those with osteoporosis and osteopenia. Manage arthritis with NSAIDs and hydroxychloroquine. For photosensitive cutaneous lupus, choose sun block, topical corticosteroids, and hydroxychloroquine. Hydroxychloroquine should be initiated and continued indefinitely in most patients to help prevent flares of SLE even in patients with quiescent disease. Patients taking hydroxychloroquine require annual routine ophthalmologic examinations. • Prescribe IV cyclophosphamide (or mycophenolate mofetil) and high-dose corticosteroids for proliferative glomerulonephritis. Manage any life-threatening disease such as lupus pneumonitis, inflammatory CNS disease, or severe cytopenia with high-dose corticosteroids and (usually) cyclophosphamide, azathioprine, or mycophenolate mofetil.

32. The discoid rash of lupus erythematosus consists of chronic, slowly progressive, scaly, infiltrative papules and plaques or atrophic red plaques on sun-exposed skin surfaces. Discoid lupus can be present in the absence of any other clinical feature of SLE.

33. Bright red, sharply demarcated plaques in a butterfly pattern that spares the nasolabial folds and areas beneath the nose and lower lip are associated with SLE.

34. Question 13 • A 52-year-old man is evaluated in the emergency department for a 2-week history of progressive fever and malaise with gradual onset of shortness of breath, pleuritic chest pain, myalgia, arthralgia, and rash. He reports no cough. He has a 15-year history of rheumatoid arthritis, which is well controlled with methotrexate and etanercept; his last flare was 1 year ago. Other medications are naproxen and folic acid. • On physical examination, temperature is 39.0 °C (102.2 °F), blood pressure is 148/94 mm Hg, pulse rate is 90/min, and respiration rate is 22/min. Cardiac examination is normal. Pulmonary examination reveals a left pleural friction rub. There is synovial thickening of the wrists and metacarpophalangeal and proximal interphalangeal joints bilaterally as well as small bilateral knee effusions. A nonblanching purpuric rash is noted over the distal lower extremities.

35. Laboratory studies: • Hemoglobin 9.8 g/dL (98 g/L) • Leukocyte count 2600/µL (2.6 × 109/L) • Platelet count 128,000/µL (128 × 109/L) • Erythrocyte sedimentation rate 86 mm/h • Urinalysis 1+ protein; 2-5 erythrocytes/hpf; 5-10 leukocytes/hpf • Chest radiograph reveals blunted costophrenic angles bilaterally without infiltrate. • Blood and urine culture results are pending.

36. Which of the following is the most appropriate diagnostic test to perform next? A Antinuclear antibody and anti–double- stranded DNA antibody assay B Bone marrow aspiration and biopsy C CT of the chest, abdomen, and pelvis D Rheumatoid factor and anti–cyclic citrullinated peptide antibody assay

37. Which of the following is the most appropriate diagnostic test to perform next? A Antinuclear antibody and anti–double- stranded DNA antibody assay B Bone marrow aspiration and biopsy C CT of the chest, abdomen, and pelvis D Rheumatoid factor and anti–cyclic citrullinated peptide antibody assay

38. Explanation • Testing for antinuclear antibodies (ANA), as well as anti–double-stranded DNA antibodies and complement levels, is indicated for this patient with suspected drug-induced lupus erythematosus (DILE) caused by the tumor necrosis factor (TNF)-α inhibitor etanercept. He has new-onset fever, arthralgia, myalgia, nonblanching purpuric rash, pleuritis, pancytopenia, and proteinuria with active urine sediment, all of which are suggestive of a clinical diagnosis of systemic lupus erythematosus (SLE). Although these findings might also be compatible with an infection, he has no focal symptoms or findings to suggest sepsis and has been appropriately tested with blood and urine cultures. • Most patients with DILE caused by TNF-α inhibitors have fever, rash, arthritis, and hematologic abnormalities in the presence of positive ANA as well as anti–double-stranded DNA antibodies. This clinical and serologic profile is in contrast to DILE induced by other medications, which is characterized by positive ANA, antihistone antibodies, and anti–single-stranded DNA antibodies. Nephritis is not common but has been reported in patients with DILE caused by TNF-α inhibitors.

39. Explanation • If DILE and infection are both ruled out, bone marrow aspiration and biopsy to evaluate for the presence of a primary hematologic diagnosis or CT of the chest, abdomen, and pelvis to evaluate for lymphadenopathy suggestive of underlying lymphoma would be indicated. • Testing of rheumatoid factor and anti–cyclic citrullinated peptide (CCP) antibodies is not appropriate because the patient has had a clear diagnosis of rheumatoid arthritis, and, even if a flare were present, rheumatoid factor and anti-CCP antibodies would not necessarily increase. Key Point • Drug-induced lupus erythematosus caused by tumor necrosis factor α inhibitors is characterized by fever, rash, arthritis, and hematologic abnormalities in the presence of positive antinuclear antibodies and anti–double-stranded DNA antibodies.

40. Question 14 A 36-year-old man is hospitalized for acute kidney injury and hypertension. He was given an intravenous dose of labetalol, and hemodialysis was initiated acutely to facilitate fluid and potassium management. He has a 5-year history of diffuse cutaneous systemic sclerosis. His only medication before hospitalization was omeprazole. On physical examination following dialysis, temperature is 36.6 °C (97.8 °F), blood pressure is 140/70 mm Hg, pulse rate is 70/min, and respiration rate is 18/min. Cardiac examination reveals regular rhythm without murmurs or extra sounds. Pulmonary auscultation reveals bibasilar crackles. Cutaneous examination reveals sclerodactyly of both hands as well as skin induration of the forearms and anterior chest; there are no digital ulcers or acrocyanosis.

41. Laboratory studies: Hematocrit 28% Leukocyte count 4900/µL (4.9 × 109/L) Platelet count 90,000/µL (90 × 109/L) Blood urea nitrogen 40 mg/dL (14.3 mmol/L) Serum creatinine 5.2 mg/dL (459.7 µmol/L) Lactate dehydrogenase 480 units/L Peripheral blood smear reveals several schistocytes. Kidney ultrasound reveals normal-sized kidneys and no hydronephrosis

42. Answer Choice Which of the following is the most appropriate treatment? A Bosentan B Lisinopril C Plasma exchange D Sildenafil

43. Answer Choice Which of the following is the most appropriate treatment? A Bosentan B Lisinopril C Plasma exchange D Sildenafil

44. Explanation Treatment with an ACE inhibitor such as lisinopril is indicated for this patient with scleroderma renal crisis (SRC) in the setting of diffuse cutaneous systemic sclerosis (dcSSc). SRC most commonly occurs in patients with dcSSc as a consequence of intimal proliferation and luminal thrombosis in the afferent renal arterioles, resulting in thrombotic microangiopathy with glomerular ischemia and high levels of renin. SRC is characterized by acute onset of hypertension, acute kidney injury, and microangiopathic hemolytic anemia; however, some patients with evolving SRC may be normotensive. Even in patients on dialysis, treatment with an ACE inhibitor is associated with improved outcomes in terms of kidney function and mortality compared with patients not receiving such therapy. For patients with this complication, prompt and aggressive treatment with an ACE inhibitor is essential to restore kidney function and optimally manage hypertension, even for patients who require dialysis and for whom blood pressure has been lowered with other antihypertensive agents. Bosentan is an endothelin receptor antagonist used to treat pulmonary hypertension or recurring digital ulcers in patients with systemic sclerosis and is not effective therapy for SRC.

45. Explanation Microangiopathic changes with thrombocytopenia can occur in patients with SRC; although plasma exchange has a therapeutic role in other microangiopathies associated with acute kidney injury such as hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, it does not have an established role in the management of SRC. Sildenafil, a phosphodiesterase inhibitor, is appropriate for patients with pulmonary hypertension or refractory Raynaud phenomenon symptoms but is not effective in the primary management of SRC. Key Point Prompt and aggressive treatment with an ACE inhibitor is essential to restore kidney function and manage hypertension associated with scleroderma renal crisis.

46. Systemic Sclerosis Diagnosis Systemic sclerosis (also known as scleroderma) is a disease of unknown cause characterized by microvascular injury and excessive connective tissue deposition. The presence of typical skin findings and one or more of the following features supports a diagnosis: • sclerodactyly • digital pitting • interstitial lung disease • Raynaud phenomenon • pulmonary hypertension • polyarticular arthritis • GERD • Pseudo-obstruction (small bowel) • malabsorption due to bacterial overgrowth • Systemic sclerosis is classified according to the degree of skin involvement.

47. Scleroderma renal crisis is characterized by hypertension, microangiopathy, hemolytic anemia and thrombocytopenia, proteinuria, and nonoliguric kidney failure. In addition, corticosteroid therapy is a risk factor and may be associated with normotensive renal crisis (acute kidney injury in the absence of hypertension). • Patients with systemic sclerosis also may develop an inflammatory, typically nonerosive arthritis. • The primary cause of morbidity and mortality in patients with systemic sclerosis is pulmonary disease. Screening tests include HRCT and pulmonary function tests (including DLCO) for interstitial lung disease and echocardiography for pulmonary hypertension.

48. Syndromes that can mimic systemic sclerosis: • Eosinophilic fasciitis: woody induration of the skin, sparing the hands and feet, and peripheral blood eosinophilia. Full-thickness skin biopsy establishes the diagnosis. • Mixed connective tissue disease: inflammatory myopathy, SLE features, arthritis, and scleroderma overlap with positive anti-RNP antibodies. • Idiopathic pulmonary fibrosis: restrictive lung disease but no Raynaud phenomenon, GI symptoms, or skin changes. Serologic tests for scleroderma-specific antibodies are negative.

50. Therapy • Therapies are for organ-specific manifestations; no overall disease-modifying therapy is available. • Use nifedipine, amlodipine, felodipine, sildenafil, and nitroglycerin paste to manage Raynaud phenomenon. Prescribe PPIs for GERD and promotility agents for gastric and intestinal dysmotility. Prescribe ACE inhibitors for scleroderma renal crisis regardless of the serum creatinine level and continue even in the setting of kidney failure. Bacterial overgrowth manifests as diarrhea and is managed with broad-spectrum antibiotics. Manage arthritis similarly to RA. Don't Be Tricked • Scleroderma is not managed with corticosteroids. Test Yourself • A 59-year-old woman has accelerated hypertension and chronic kidney disease. She has a history of Raynaud phenomenon. Blood pressure is 160/122 mm Hg. Her fingers appear tapered with very smooth skin and ulcers on the fingertips. Serum creatinine level is 5.4 mg/dL. • ANSWER: The patient is in scleroderma renal crisis. Prescribe an ACE inhibitor.