Disease-a-Month ] (2014) ]]]–]]]

Contents lists available at ScienceDirect

Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth

Clinical pearls in rheumatology Clem Michet, MD, Scott C. Litin, MD, John B. Bundrick, MD

Case 1 A 72-year-old man presents to your office with an 8-week history of proximal morning stiffness in his arms and legs. His wife brings him OTC ibuprofen before he tries to get up. She helps him dress, and by noon, he is ready to leave the house. He has lost 4 pounds due to decreased appetite. Sleep is disrupted by pain. No other systemic symptoms exist, and there are no symptoms of giant cell arteritis. His examination is notable for no fever, and he weighs 71 kg. He is unable to actively elevate his arms above his head. He needs help getting onto the exam table. He complains of pain when you passively rotate his shoulders and hips. There is no synovitis, and his pulses are normal as is the heart examination. ESR is 98 mm in 1 h. CRP is 49 mg/L (NL o 8.0 mg/L). Hemoglobin is 10.3 g/dl. His CCP antibody is negative. You make a diagnosis of polymyalgia rheumatica (PMR). What dose of prednisone would you prescribe as an appropriate initial therapy? A. B. C. D. E.

Prednisone Prednisone Prednisone Prednisone Prednisone

60 mg each AM 30 mg BID 15 mg each AM 10 mg each AM 40 mg each AM

Discussion Despite the recognition that prednisone is a reliable monotherapy for the majority of patients with PMR, there is still controversy regarding appropriate dosing for starting treatment. Excessive dosing will lead to more corticosteroid side effects and potentially delay the diagnosis of a serious systemic process masquerading as a polymyalgia syndrome. Under dosing will lead to a delay in resolution of the symptoms as well as frequent recurrences. Recent publications provide useful guidelines for managing this common illness. While we are still lacking a randomized controlled trial for managing PMR, a systematic review and new international guidelines give helpful interim advice. http://dx.doi.org/10.1016/j.disamonth.2014.04.008 0011-5029/& 2014 Mosby, Inc.. All rights reserved.

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Currently, prednisone 15 mg daily as a single AM dose is appropriate for treating PMR when there is no suspicion of giant cell arteritis. A dose of prednisone 20 mg daily would be an appropriate dose for larger men ( 4 78 kg). The degree of ESR or CRP elevation does not assist with the dosing decision. Symptoms should improve rapidly, and the C-reactive protein should be normal in 4 weeks. In situations where this is not the observed outcome, additional investigations and rheumatology consultation should be sought. The majority of PMR patients will require treatment for 1–3 years. Clinical pearl An appropriate starting dose of prednisone for polymyalgia rheumatica without giant cell arteritis is 15–20 mg daily as a single AM dose. Symptom and CRP response should be rapid. References 1. Dasgupta B, et al. BSR and BHPR guidelines for the management of polymyalgia rheumatica. Rheumatology. 2010;49:186–190. 2. Cimmino MA, Parodi M, Montecucco C, Caporali R. The correct dose of prednisone starting dose in polymyalgia rheumatica is related to body weight and not to disease severity. BMC Musculoskelet Disord. 2011;12:94. 3. Hernandez-Rodriquez J, et al. Treatment of polymyalgia rheumatica: a systemic review. Arch Intern Med. 2009;169:1839–1850. Case 2 A 37-year-old woman saw you last week for evaluation of an inflammatory polyarthritis involving her hands, forefeet, knees, and elbows. Symptoms began 3 months ago and are progressing. Her health is otherwise excellent. She stopped smoking 2 years ago. She has three school-aged children and works in an office. Her past medical history is significant only for tubal ligation. Your evaluation reveals synovitis in the elbows, wrists, MCPs, PIPs, and knees, and squeeze tenderness of her MTPs. Both the ESR and CRP are elevated, and she is anemic. She has a positive rheumatoid factor and CCP antibody. Radiographs reveal periarticular osteopenia in the MCPs and MTPs. The local rheumatology practice does not have a new patient opening for 2 months. What treatment would you recommend she start while waiting to see the rheumatologist? A. B. C. D.

Prescribe naproxen 500 mg BID and supplement with tramadol/acetaminophen Hydroxychloroquine 200 mg BID Prednisone 60 mg daily, tapered by 10 mg weekly until off Prednisone 60 mg daily tapered by 10 mg weekly, along with methotrexate 15 mg weekly and daily folic acid supplementation E. Sulfasalazine 500 mg BID

Discussion Recent landmark studies, the Finnish Fin-RACo and the Dutch BeSt trials, have reported longterm observational data comparing the results of initial monotherapy versus combined therapies for treating early rheumatoid arthritis. These studies demonstrated that aggressive initial treatment of rheumatoid arthritis using combinations of disease-modifying drugs results in sustained improvement in function and disease activity. Who should receive aggressive therapy? This patient is an example of the type of early RA that requires this approach—seropositive,

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systemic inflammatory response, and an active polyarthritis. What is the best aggressive approach? This issue remains controversial. Methotrexate, unless contraindicated, should be the foundation of therapy with a starting dose of 15 mg weekly. Adding prednisone is an appropriate combination therapy in early high-risk RA. The intention is to rapidly taper the corticosteroid while adjusting the methotrexate dose upward. If this strategy fails to induce remission, then in 3 months, additional disease-modifying drugs are added to the methotrexate. Options at that point include a TNF inhibitor, sulfasalazine with hydroxychloroquine, or leflunomide. Clinical pearl Seropositive rheumatoid arthritis requires initial aggressive therapy to inhibit disease progression and loss of function. Methotrexate is the foundation of treatment in early RA. Reference 1. Allaart CF, Huizinga TWJ. Treatment strategies in recent onset rheumatoid arthritis. Curr Opin Rheumatol. 2011;23:241–244. Case 3 A 70-year-old woman had been taking atorvastatin for 3 years until you stopped it 3 months ago. At that time, she was complaining about difficulty climbing stairs due to weakness. You found that her creatine kinase was 2654 U/L. TSH was normal, as was serologic testing for connective tissue disease with ANA and antibodies against extractable nuclear antigens. She was advised to stop the medication and expect that her weakness will improve. She returns now because the weakness has persisted. Examination confirms weakness on direct testing of the hip flexors. She is now unable to do a deep squat. Her neurologic examination is otherwise normal, including DTRs and Babinski. A repeat creatine kinase is 2200 U/L. The most likely explanation for this predicament would be A. B. C. D. E.

The The The She She

atorvastatin is not the cause of her problem atorvastatin unmasked an underlying metabolic myopathy atorvastatin may still be the etiology of her problem is a muscular dystrophy carrier has motor neuron disease

Discussion Myotoxicity is a well-recognized adverse effect of statin therapy. Severe toxicity defined by a creatine kinase 4 10xNL and symptoms requiring hospitalization are very rare. A good estimate for this severe risk is 0.4 per 10,000 person-years in first-time statin users. Benign myalgia and less significant creatine kinase elevations may occur in up to 20% of users. Myalgia alone may actually occur no more frequently than in individuals taking placebos in blinded trials. Statin myopathy is a class- and dose-effect phenomenon. Myopathy may also be genetically determined. A genome-wide association study revealed an association with a SNP in the SLCO1B1 gene on chromosome 12. The encoded protein regulates statin hepatic uptake. The mechanism of statin myopathy remains to be determined. This case represents a newly described form of persistent statin-related syndrome, an immune-mediated necrotizing myopathy. Described in 2010, the mechanism of this illness is related to the induction of autoantibodies against 3-hydroxy-3-methylgluraryl-coenzyme A reductase (HMGCR). The autoimmune process persists despite stopping statin therapy as there is

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upregulation of the autoantigen in regenerating muscle fibers. Diagnosis requires muscle biopsy, and these patients must be treated with immunosuppressant therapy to recover. Clinical pearl Statin therapy is capable of inducing an autoimmune response to HMGCR in a subset of patients. This syndrome should be considered in patients with a clinical myopathy who do not recover after statin therapy is discontinued. References 1. Garble-Esposito P, et al. Immune-mediated necrotizing myopathy associated with statins. Muscle Nerve. 2010;41:185–190. 2. Mammen AL, et al. Autoantibodies against hydroxy-3-methylgluraryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum. 2011;63:711–721. Case 4 A 57-year-old man visits you to establish ongoing care, as he just moved to your community. He comes in at this time primarily to get a refill of his prednisone for his Sjögren’s syndrome. Three years ago, he developed sudden swelling of his parotid and submandibular glands. Because of persistent swelling, he eventually saw an otolaryngologist who did a minor salivary gland lip biopsy and diagnosed Sjögren’s. He gave the patient a course of prednisone, and all the swelling remitted. Since then, the patient has continued to refill the prescription, taking 60 mg of prednisone daily for a month whenever the swelling returned. He estimates that he has taken prednisone about 6 times since the diagnosis. He denies symptoms of dry eyes or mouth. Your exam confirms mild swelling of his parotid and submandibular glands. He has puffy eye lids. There is a normal salivary pool beneath his tongue. His exam is otherwise unremarkable. You tell him that you were not aware that Sjögren’s syndrome responds to prednisone and you want to do more tests. What would be the best approach? A. B. C. D. E.

Request the previous biopsy slides and order a rheumatoid factor, ANA, and SSA antibody Request the previous biopsy slides, and order a chest x-ray and ACE level Request the previous biopsy slides and order IgG subclasses Carefully review his alcohol history, order a GGT, glucose, and lipid panel Discuss obtaining a HIV screening test

Discussion This case describes one of the presentations of the expanding spectrum of IgG4-related disease (IgG4-RD). This illness is characterized by lymphoplasmacytic infiltration of involved organs. Immunostaining reveals IgG4-positive plasma cells in the involved tissue. Serum IgG4 levels are frequently elevated. This syndrome was initially described in Japan, and investigators there have proposed preliminary criteria including diffuse or focal enlargement or mass lesions in one or more organs, elevated serum IgG4 4 135 mg/dl, and the appropriate histopathological findings including the IgG4 staining of plasma cells as well as fibrosis. The most widely recognized disorder in the IgG4-RD spectrum is autoimmune pancreatitis. However, many other familiar conditions may be part of the IgG4-RD spectrum. These include retroperitoneal fibrosis, Riedel’s thyroiditis, orbital pseudotumor, sclerosing mesenteritis, and many others. Treatment includes prednisone and rituximab in some cases.

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This patient suffers from “Mikulicz’s disease,” now understood to be part of the IgG4-RD disorders. Why is this not Sjögren’s syndrome? There is no sicca syndrome. The glandular swelling of Sjögren’s syndrome does not respond to prednisone. Malt lymphoma needs to be excluded. To confirm the clinical suspicion that he has IgG4-associated sialadenitis, a serum IgG4 level should be obtained, and the previous biopsy stained for IgG4. Clinical pearl The IgG4-RD spectrum of disorders represent yet another example of a “new” syndrome that we have all encountered but lacked the creative insight and clinical energy to identify; clinicians should become familiar with these disorders. References 1. Geyer JT, Deshpande V. IgG4-associated sialadenitis. Curr Opin Rheumatol. 2011;23:95–101. 2. Carruthers MN, Stone JH, Khosroshahi A. The latest on IgG4-RD: a rapidly emerging disease. Curr Opin Rheumatol. 2012;24:60–69. Case 5 A 60-year-old woman presents to urgent care for evaluation of her painful swollen right knee. She was diagnosed with seropositive rheumatoid arthritis 6 years ago and has been on a variety of medications. Methotrexate 20 mg weekly with prednisone 5 mg daily has been the base therapy for the past 3 years. Four months ago, etanercept (Enbrel) was added, and she has had a “great” response. Her knee suddenly swelled yesterday. There was no trauma. She comes in primarily for an analgesic prescription. Other medical problems include diabetes mellitus managed with diet and metformin, osteoporosis with alendronate, and hyperlipidemia treated with atorvastatin. She is afebrile and has otherwise normal vital signs. She has mild RA deformities in her wrists, but you see no active synovitis except in her right knee, which is moderately swollen and warm. It is tender to palpation. Her CBC is normal. The CRP is 62 mg/L (NL o 8.0 mg/L). You do not have any of the recent labs from her rheumatology office. The best approach would be to A. Prescribe hydrocodone/APAP, increase the prednisone to 20 mg daily, and ask her to call her rheumatologist on Monday B. Order radiograph of the knee, and if negative, get a MRI to look for a stress fracture C. Inject the knee with a glucocorticoid D. Aspirate the knee, and send the fluid for cell count, crystal exam, gram stain, and aerobic bacterial culture. Discuss admitting her to the hospital E. Take an extra dose of etanercept this weekend, and call her rheumatologist on Monday

Discussion Be afraid of the TNF inhibitors and respect their ability to mask infections. This is a typical case of Staphylococcus aureus septic arthritis in an immunosuppressed rheumatoid patient. With no fever and a normal white count, the clue here is a monoarticular flare of synovitis in a well-controlled RA patient. The only approach to this situation is to exclude a septic joint. The Gram stain might help making a decision, but with the elevated CRP and this presentation, strongly consider admission to the hospital with IV S. aureus coverage. In many communities, this should be coverage for MRSA. The greatest risk for septic arthritis in a RA patient treated with a TNF inhibitor is within the first months of starting therapy.

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Clinical pearl A monoarticular “flare” of RA is an infection until proven otherwise. Do not expect to see fever or leukocytosis in many of these cases. TNF inhibitor infection risk is highest the first few months of therapy. Reference 1. Galloway JB, et al. Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society of rheumatology Biologics Register. Ann Rheum Dis. 2011;70:1810–1814. Case 6 A 67-year-old man is referred to you by his nurse practitioner for a question of starting prednisone and arranging for a temporal artery biopsy. He came to see her yesterday complaining of myalgias and fatigue. He also mentioned that his left TMJ hurts while chewing. He has diabetes mellitus and has elected to self manage this problem by taking metformin and a fixed dose of insulin every morning. He eats whatever he wants and rarely checks his glucose level at home. Laboratory tests from yesterday revealed a random glucose 277 mg%, Hgb A1c 13.5%, a normal creatinine but elevated microalbumin, ESR 50, and a CRP 125.6 mg/L (NL o 8.0 mg/L). His blood pressure is normal, as is his vascular exam except for reduced pedal pulses. He can move his shoulders easily above his head without pain. As best as you can determine, the jaw pain is likely related to the joint as there is crepitus with active movement. The best approach at this point would be to A. Start prednisone 60 mg daily, increase his insulin, and arrange for a biopsy B. Hold off on the prednisone, add low-dose aspirin, and request a biopsy. Arrange for him to start working with the diabetes nurse C. Increase his insulin and begin a malignancy and infection workup D. Arrange for the diabetes nurse to see him today and repeat the inflammatory markers in 2 weeks E. Start prednisone 20 mg daily, increase his insulin, and arrange for a biopsy and the diabetes nurse

Discussion A characteristic clinical finding in patients with PMR is the inability to comfortably elevate their arms above their head. Although he does not feel well, you observe he has no problem with active shoulder motion. This man does not have true jaw claudication. So if you are not impressed that he has polymyalgia and giant cell arteritis, why does he have elevated acute phase reactants? While it is possible that his primary clinician has tumbled into an underlying systemic inflammatory disease, there is another more likely explanation to consider before embarking on a massive fruitless workup. Get the severe hyperglycemia under control, and recheck his labs in a couple of weeks. Uncontrolled diabetes mellitus and severe hyperglycemia lead to activation of monocytes and the release of proinflammatory cytokines, interleukin-6 (IL-6), and TNF via oxidative stress. Chronic CRP elevation in diabetes is associated with microalbuminuria and autonomic neuropathy. IL-6 is the primary cytokine for inducing the systemic inflammatory response in the liver with production of multiple serum protein abnormalities including elevation of the CRP and hyperfibrinogenemia, fibrinogen being the primary protein influencing the ESR. We now understand that the amount of CRP production in individuals is genetically determined.

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Clinical pearl Uncontrolled hyperglycemia will lead to proinflammatory cytokine release and an elevated CRP. Treatment reducing the blood glucose level should result in a rapid decline of the CRP if the diabetes is the etiology. References 1. Stentz FB, et al. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress and lipid peroxidation in patients with hyperglycemic crises. Diabetes. 2004;53:2079–2086. 2. Rhodes B, Furnrohr BG, Vyse TJ. C-reactive protein in rheumatology: biology and genetics. Nat Rheumatol. 2011;7:282–289. Case 7 A 62-year-old woman in your practice comes in to discuss what she can do about her osteoarthritic left knee. She is having increasing difficulties on stairs and walking through the mall. She states, “I don’t want to have surgery; my neighbor had a blood clot after knee surgery.” She is obese and takes medication for hyperlipidemia, diabetes, and hypertension. Trials of NSAIDs were abbreviated due to rises in her blood pressure. Periodic corticosteroid intra-articular injections have not helped, and her orthopedic surgeon gave her one series of hyaluronic viscosupplementation injection without benefit. She takes acetaminophen and tramadol. She brings in a news ad clipping about a local pain clinic that does platelet-enriched plasma joint injections for osteoarthritis. She states, “I’m desperate; I’ll try anything but surgery.” What would you consider? A. B. C. D. E.

Start regular dosing with hydrocodone and acetaminophen Discuss an attempt at weight loss and exercise Talk her into a total knee arthroplasty Give the platelet-enriched plasma injections a try Advise her that there are no remaining management options

Discussion While you are keeping your eyes open for new syndromes passing through your office, like IgG4-RD, the daily grind of our chronic disease patients continues. We need to give these patients our best advice while also protecting them from charlatans with medical degrees. We can agree that one should never talk a patient into an elective surgical procedure. It is guaranteed to not turn out well, and you know who will be blamed. Hydrocodone as the next option? Unlikely to improve functioning long term and the inevitable issues of tolerance arise. How about platelet-enriched plasma therapy? This is an increasingly marketed intervention by physicians who market hope not based on any scientific credible evidence of benefit. At $1000 a treatment and not covered by insurance, someone will benefit. Rest assured, it will not be your patient and her sore knee. In this case, it will be most beneficial to have a discussion with this patient about physical treatments. They will likely help her if she is willing to partner with you and take personal responsibility for managing her problem. Diet and exercise do help osteoarthritis of the knee. The goal to set with your patient is a 5% reduction in body weight over 12–18 months. Exercise should consist of both aerobic and resistance training. Set a goal of 3 exercise sessions weekly. Aerobic exercise should be a 15-min sessions with reaching a target of 50–75% of her predicted maximal heart rate. Resistance training should include 2 sets of 12 reps of leg extensions, leg curls, and heel raise and step up. Resistance can be provided

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initially by body weight and then by cuff ankle weights. Ideally, the patient should start this program with supervision at a gym or physical therapy. Dieting alone can also be successful, but a recent trial demonstrated that diet alone must be more aggressive, targeting a 410% loss of body weight. Clinical pearl Diet and exercise still can have a significant effect on symptomatic management for osteoarthritis of the knee. This is an often-neglected aspect of patient management. References 1. Hunter DJ, Neogi T, Hochberg MC. Quality of osteoarthritis management and the need for reform in the US. Arthritis Care Res. 2011;63:31–38. 2. Messier SP, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis. Arthritis Rheum. 2004;50:1501–1510. 3. Bliddal, H, et al. Weight loss as a treatment for knee osteoarthritis symptoms in obese patients: 1-year results from a randomized controlled trial. Ann Rheum Dis 2011; 70:1798-1803 Case 8 Most internists prescribe allopurinol for a patient who has had several attacks of gout over a year or for a person who presents with tophi. An evolving body of research indicates that earlier treatment may be reasonable in certain clinical contexts. According to this recent literature, initiation of allopurinol may be a reasonable consideration in all of the following patients with asymptomatic hyperuricemia except A. An obese adolescent who has several features of metabolic syndrome and a blood pressure of 140/95. B. A 62-year-old man with hypertensive nephrosclerosis and a creatinine of 1.8 mg/dl C. A 53-year-old man, ex-smoker with treated hyperlipidemia and hypertension who is being scheduled for a 3-vessel coronary bypass D. A 57-year-old man with treated hyperlipidemia, non-smoker, who was found to have carotid atherosclerosis by ultrasound during a “health fair screening” E. A 69-year-old woman with osteoarthritis of the wrists and hands and chondrocalcinosis

Discussion These are exciting times in the world of uric acid physiology. There has been a rebirth of interest in the direct role of hyperuricemia in vascular events. Hyperuricemia is associated with renal arteriolar hyperplasia, atherosclerotic lesion growth, increased platelet adhesiveness, and elevated inflammatory cytokines. Reactive oxygen species production is likely increased in patients overproducing uric acid. Although the standard recommendations for treating hyperuricemia include recurrent gout, tophaceous gout, or uric acid nephrolithiasis, recommendations may change over time and include all of the above scenarios. Early essential hypertension in adolescents is likely a uric acid-sensitive process due to renal effects of hyperuricemia. Treatment with allopurinol may be effective in lowering blood pressure in this group of individuals. Treatment of hyperuricemia has been demonstrated in a recent chronic kidney disease population to slow the deterioration of kidney function. Hyperuricemia is associated with poor outcome following coronary bypass surgery and raises the question of whether these patients should be treated. Long-term epidemiologic studies have demonstrated

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a direct association between uric acid levels and early coronary and carotid atherosclerotic lesions. In the future, the indications for allopurinol therapy may be expanded, and the old dictum of not treating “asymptomatic” hyperuricemia will be discarded. Clinical pearl The current recommendations for when to start uric acid-lowering therapy in persons with hyperuricemia may be changing. It may be time to think critically about ignoring symptomatic gout in your patients with chronic kidney disease, or atherosclerotic disease. Consider starting allopurinol earlier in these populations with intermittent gout. References 1. Feig DI, Solestsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension. J Am Med Assoc. 2008;300:924–932. 2. Goicoechea M, et al. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Clin J Am Soc Nephrol. 2010;5:1388–1393. 3. Hillis GS, et al. Uric acid levels and outcome from coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2009;138:200–205.

Answers: 1—C; 2—D; 3—C; 4—C; 5—D; 6—D; 7—B; and 8—E

Clinical pearls in rheumatology.

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