Arthritis

  

Points


Clinical

  

Pattern of joint or bursa involvement during past or present symptomatic episodes


Ankle or midfoot without first MTP joint


1


First MTP joint involved


2


Number of typical characteristics (reported or observed erythema overlying affected joint, can’t bear touch or pressure, difficulty walking and inability to use joint)


One characteristic


1


Two characteristics


2


Three characteristics


3


Time course of episodes (time to maximal pain <24 hours, resolution of symptoms in <14 days, complete resolution between symptomatic episodes)


One typical episode


1


Recurrent typical episodes


2


Clinical evidence of tophus


Present


4


Laboratory

  

Serum urate—ideally not on urate-lowering therapy and at least 4 weeks after the start of an acute flare


<4 mg/dL


−4


6–8 mg/dL


2


8–<10 mg/dL


3


≥10 mg/dL


4


Synovial fluid analysis of symptomatic joint or bursa


MSU negative


−2


Imaging

  

Double-contour sign on ultra sound or urate depositoin on dual-energy CT


Present


4


X-rays of hands and/or feet demonstrating at least 1 erosion


Present


4



Adapted from Neogi et al. [12]


aEntry criteria: at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa


bPresence of MSU crystals in the synovial fluid of a symptomatic joint or bursa, or in a tophus, is sufficient for classification of gout without applying this criteria




Treatment


Treatment of an acute gout attack focuses on reducing the inflammation associated with gout flares, whereas chronic treatment of gout centers around lowering serum urate levels. The ACR offers guidelines for treatment of acute gout attacks, prophylaxis against repeat flares, and therapies for chronic treatment [14, 15] (Fig. 15.1). In the setting of an acute gout flare, patients may be treated with either monotherapy or combination therapy (depending on the severity of the attack and number of joints involved) using non-steroidal anti-inflammatory drugs (NSAIDs), oral steroids, colchicine, and/or intra-articular steroid injections. The choice of an anti-inflammatory agent is based on safety (e.g., consideration of patient comorbidities) as well as physician and patient preference. NSAIDs and oral steroids should not be used in combination. When the aforementioned agents are ineffective or contraindicated, biologic agents that block IL-1β activity, most notably anakinra, may be considered, although these are not FDA approved. If the patient is already using urate-lowering agents, these should not be discontinued during the acute flare as the resultant rise in urate may exacerbate the attack.

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Fig. 15.1

American College of Rheumatology (ACR) guidelines for the management of gout. Summarized here are the ACR guidelines for treating gout, beginning with the management of acute flares and moving on to the indications for, and approaches to urate lowering. (For the complete guidelines, see Khanna et al [14, 15])


For patients with frequent attacks (>2/year), or who have had a single attack in the setting of chronic kidney disease or a history of tophi or renal stones, urate-lowering therapy (ULT) should be initiated. First-line options for ULT include the xanthine oxidase inhibitors allopurinol and febuxostat. A choice between these two agents may be made based on cost (allopurinol much cheaper), risk of potentially fatal allopurinol hypersensitivity syndrome (greatest among certain Asian populations who are HLA B58∗01-positive, requiring that these populations be checked for HLA type before starting allopurinol), and recent reports that use of allopurinol may be associated with reduced cardiovascular mortality relative to febuxostat [16]. The target serum urate level should be less than 6.0 mg/dL, or lower in the case of tophaceous gout (typically less than 5.0 mg/dL), or as needed to prevent attacks and resolve tophi. ULT should be started simultaneously with, or just after initiation of anti-inflammatory prophylactic colchicine or a low-dose NSAID (or low-dose steroids as a third-line agent), as ULT initiation has been found to paradoxically increase the risk of gout flares at the onset of therapy [17]. Prophylaxis is typically continued for at least 6–9 months. If both allopurinol and febuxostat are contraindicated or not tolerated by a particular patient, the uricosuric agent probenecid may be started instead. Probenecid or the alternative uricosuric lesinurad (not to be used as monotherapy) may also be “added on” to xanthine oxidase inhibitor therapy if a patient has had an inadequate response to treatment. Losartan and fenofibrate also have ULT potential and may be added on to a xanthine oxidase inhibitor, particularly if they are also indicated for hypertension or cardiovascular disease. Finally, the highly potent uricase pegloticase may be considered in patients with refractory disease, or with a significant tophus burden.


Calcium Crystal Diseases


Calcium Pyrophosphate Deposition Disease


Calcium pyrophosphate crystal deposition (CPPD) is a broad term used to describe the varying presentations associated with the formation and deposition of calcium pyrophosphate dihydrate (CPP) crystals. In many cases, CPPD is asymptomatic, but in some patients CPPD can provoke an acute inflammatory arthritis. In other cases, patients can develop a more chronic arthritis reminiscent of either osteoarthritis (non-inflammatory) or rheumatoid arthritis (inflammatory). The prevalence of CPPD varies from 7% to 10% in different studies [18]. Of these, a significantly smaller percentage will have symptomatic disease.


Risk Factors


CPPD is idiopathic in most cases, with no apparent underlying condition. However, several factors have been associated with an increased risk for crystal deposition. CPPD risk tends to increase with age, being most common among individuals over 80 years old [18]. Hyperparathyroidism raises the risk of CPPD approximately threefold above that of the general population [19]. Other conditions associated with increased CPPD risk include gout (~2.5 times more likely), osteoarthritis (~2 times more likely), rheumatoid arthritis (~2 times more likely), hemochromatosis (~2 times more likely), hypomagnesemia (~1.25 times more likely), and osteoporosis (~1.25 times more likely) [19]. In contrast, certain medications, including proton pump inhibitors, thiazide diuretics, and loop diuretics, have been associated with a decreased risk of CPPD. Other conditions that have been inversely associated with CPPD include alcohol and tobacco abuse disorders, coronary artery disease, congestive heart failure, diabetes, and hypertension [19].


Pathophysiology


CPP crystals are formed within the cartilage, as a result of the interaction of inorganic pyrophosphate with calcium ions. Inorganic pyrophosphate is a breakdown product of extracellular ATP. Although most ATP is generated within chondrocytes, it may be transported out into cartilage where ectonucleotidases enzymatically liberate pyrophosphate. Additionally, a membrane transport protein termed ANKH may directly secrete pyrophosphate from the chondrocytes into the extracellular milieu. Gain-of-function mutations of the ANKH protein have been seen in familial cases of CPPD, but ANKH up-regulation may also occur secondarily in the setting of cartilage damage [20]. Although CPPD crystals are formed from a combination of inorganic phosphate and calcium, the exact mechanism of crystal formation is not well understood.


Once CPPD crystals are liberated from the cartilage into the synovial fluid, they drive acute inflammation in a manner similar to that of MSU crystals. In vitro, CPPD and MSU crystals can be shown to have many similar effects, including activation of the NLRP3 inflammasome in macrophages [21].


Clinical Presentation


Most cases of CPPD are asymptomatic and are discovered incidentally when a radiograph of a joint shows CPPD deposition within the cartilage, the condition known as chondrocalcinosis. As noted earlier, however, CPPD may also present as an acute inflammatory arthritis, or as a chronic arthritis similar to osteoarthritis or rheumatoid arthritis.


Acute CPPD arthritis (colloquially known as pseudogout) usually presents as a rapid onset of mono- or oligoarticular pain but may rarely present with polyarticular involvement. The most common joint involved is the knee, followed by the wrist and the metacarpophalangeal joints [22]. In contrast to gout, bursal involvement is uncommon. Symptoms during an acute episode include pain, erythema, and swelling of the joint that occasionally spreads to the surrounding soft tissues [21]. Due to the inflammatory nature of the pain, patients may develop fevers, chills, and other constitutional symptoms. Occasionally, CPP crystals may deposit in the ligaments at the superior aspect of the dens in the cervical spine, which may intermittently cause acute pain (presumably relating to inflammatory flares) and may be seen on cervical computed tomography scans (crowned dens syndrome).


Symptoms of acute CPPD arthritis are similar to those of an acute gout attack. However, there are several notable features that may distinguish CPPD arthritis from a gout flare, including the fact that CPPD less commonly involves the first metatarsophalangeal joint. Acute CPPD arthritis is typically less severe than gout. On the other hand, whereas gout attacks usually resolve after a few days, acute CPPD arthritis may smolder for weeks to months if not adequately treated [21].


In contrast to acute CPPD arthritis, chronic CPPD arthritis may mimic osteoarthritis, with a mono- or polyarticular presentation. However, chronic CPPD arthritis generally affects different joints than those commonly affected in primary osteoarthritis, namely, the wrists, glenohumeral joints, metacarpophalangeal joints, the midfoot, or the hindfoot [2123]. In these cases, the presumption is that cartilage damage from CPPD leads to osteoarthritis in atypical locations [22]. On the other hand, the presence of established osteoarthritis appears to promote the risk for CPPD, including up-regulation of the ANKH protein in chondrocytes, suggesting that CPPD and OA can be reiterative processes. Patients with osteoarthritis as a phenotype of chronic CPPD arthritis may also develop acute flares, as well as severe articular destruction, out of proportion to that seen primary osteoarthritis. As noted above, in some cases, CPPD deposition may result in a smoldering polyarthritis similar to rheumatoid arthritis (pseudo-RA).


Diagnosis


As with gout, the gold standard for diagnosis of CPPD is identification of calcium pyrophosphate crystals within the synovial fluid of an affected joint. CPPD crystals are classically rhomboid-shaped, smaller than MSU crystals, and are weakly positively birefringent on polarized light microscopy [23]. They are often pale and may be missed without vigorous and persistent examination. As with gout, the presence of CPPD crystals does not preclude the simultaneous presence of other inflammatory arthritis, most commonly gout or joint infection [13].


Imaging of joints in CPPD often shows the presence of chondrocalcinosis. This can readily be seen on plain radiographs, computed tomography, and musculoskeletal ultrasound, where it presents as a hyperechoic dotted line within the cartilage, in contrast to the appearance of MSU, which is visible on ultrasound as a hyperechoic line along the surface of the cartilage (“double contour” sign) [21, 24].


Treatment


Acute CPPD arthritis is treated using many of the same anti-inflammatory medications as gout. In patients with mono-arthritis, intra-articular glucocorticoids are often an effective choice. In patients who have oligo- or polyarticular joint involvement, or who are not amenable to injections, treatment with oral colchicine at a daily dose of 0.6–1.2 mg, oral NSAIDs, or systemic glucocorticoids (oral, or intravenous) may be given [21]. As with gout, anti-IL-1β biologic therapy may be considered for refractory cases [25]. In contrast to gout, in which ULT can provide long-term management by preventing the formation of new crystals and promoting the dissolution of established ones, there are currently no medications available to remove or prevent the formation of CPP crystals, except perhaps in the rare cases of underlying metabolic diseases such as hyperparathyroidism. Thus, patients with frequent recurrent attacks may require chronic anti-inflammatory prophylaxis, most commonly with daily colchicine.


Similarly, there are no disease-modifying medications used in the treatment of primary chronic CPPD crystal arthritis. However, several studies report that use of intra-articular steroids, or the oral medications described, may provide pain relief and prevent recurrence [22]. As with acute CPPD arthritis, screening for and correcting underlying causes such as hyperparathyroidism may provide ameliorative opportunities, although such instances are rare.


Basic Calcium Phosphate


In clinical practice, basic calcium phosphate (BCP) crystals constitute three different types of calcium phosphate crystals, including carbonated-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate [22]. BCP crystals can cause two types of pathogenic syndromes affecting the musculoskeletal system, depending on where they deposit. If they infiltrate within the joint capsule, they may cause a severe destructive inflammatory arthritis. When found in the tissues around the joint, namely tendons, or bursae, they cause a calcific periarthritis. These presentations are not mutually exclusive, however. Rotator cuff calcification is common, with a prevalence of 2.7–7.3% in asymptomatic patients [26, 27].


Risk Factors


BCP crystal disease appears to be more common in women than men [28]. Risk factors that predispose to BCP crystal deposition include metabolic abnormalities, specifically elevated levels of circulating calcium or phosphate, calciphylaxis in end-stage renal disease, and familial hypophosphatasia (genetic deficiency in alkaline phosphatase activity leading to hyperphosphatemia) [29]. BCP crystal disease has also been described in patients with endocrinopathies including adult onset diabetes mellitus, hypothyroidism, and aberrant estrogen metabolism (menstrual disorders such as endometriosis, ovarian cysts, polycystic ovarian syndrome, or those with recurrent miscarriages) [30].


Pathophysiology


The formation of BCP crystals occurs in areas where there are elevated levels of extracellular calcium and phosphate along with conditions favorable to encourage mineralization of the crystals. When present, BCP crystals may promote production of matrix metalloproteinases and other substances associated with joint damage and erosion of connective tissue [31].


Clinical Presentation


BCP crystal deposition is often asymptomatic and discovered incidentally on x-rays. However, when BCP crystals infiltrate the soft tissues around a joint, they may cause calcific periarthritis, most commonly in the shoulder. Periarthritis is more common in women than men and usually occurs around or after age 50. The supraspinatus tendon is most frequently involved, followed by the infraspinatus tendon. The subscapularis and long biceps tendon are less frequently involved [32]. Other common locations for calcific periarthritis include the gluteus medius tendon and the reflected head of the rectus femoris [33]. More than one tendon may be involved. Symptoms included chronic pain along with self-limited flares of acute inflammatory pain. Calcification may cause tendon tears or adhesive capsulitis [32].


BCP-associated arthritis occurs when the crystals deposit within the joint capsule or cartilage [33]. In these cases an acute self-limiting arthritis may ensue, with edema, erythema, and joint tenderness, along with decreased joint motion. BCP infiltration in the joint capsule of the shoulder may rarely be associated with Milwaukee shoulder, a rapidly destructive arthritis most prevalent in elderly women [32]. As with other acute crystal diseases, systemic signs, including fevers and chills, may be present.


Diagnosis


A definitive diagnosis of BCP disease is made by identifying the crystals. However, because of their small size and relatively amorphous structure, BCP crystals are not birefringent and are invisible under polarizing light microscopy. Based on their calcium content, the alizarin red S stain may be used to identify BCP crystals under light microscopy, where they will resemble reddish-orange clumps. Unfortunately, alizarin red S staining is neither sensitive nor specific as a test for BCP crystals, and is uncommonly performed by hospital labs. Other calcium-sensitive dyes have been used along with flow cytometry to identify the crystals but are costlier and less available. Similarly, electron microscopy may be used but is not available at most centers.


Imaging using x-rays may show erosions, severe joint degeneration, and soft tissue calcifications, the presence of which are usually presumed to represent BCP deposition. MRI and ultrasonography may show tissue destruction and ligament damage, but these are not specific for BCP disease.


Treatment


For calcific tendonitis most patients are treated conservatively with oral NSAIDs or acetaminophen, along with physical therapy to improve function. For acute BCP arthritis NSAIDS, oral steroids and/or colchicine may be tried, but data supporting these strategies is limited. In patients with more severe pain, or who fail oral therapy, intra-articular glucocorticoids may be used. If pain is resistant to injections, in cases of severe joint damage from Milwaukee shoulder surgery may be needed, up to and including joint replacement. At present, there are no available pharmacologic options to prevent or resolve BCP crystals, although managing underlying metabolic defects is always recommended.


Calcium Oxalate


Calcium oxalate crystals are a rare cause of inflammatory arthritis. The underlying cause for calcium oxalate arthritis is oxalosis , most commonly diagnosed as hyperoxaluria [34]. Primary hyperoxalurias are a group of rare autosomal recessive diseases, with a prevalence of 0.8–2.9 in one million, that cause an abnormally increased conversion of glyoxylate to oxalate [35]. In contrast, secondary hyperoxaluria occurs due to increased intestinal absorption of dietary oxalate, most commonly as a consequence of diseases of fat malabsorption [36]. Oxalate is primarily excreted by the kidneys (raising the risk for oxalate kidney stones), but in both primary and secondary hyperoxaluria, the oxalate concentration exceeds the excretory capacity of the kidney, causing kidney failure and systemic buildup of oxalate, which may then deposit in various tissues of the body, including bones, tendons, cartilage, and joints. Oxalate arthritis is typically a symmetric, polyarticular disease with inflammatory joint effusions. The gold standard for diagnosis is microscopic identification of the crystals. Calcium oxalate crystals may be monohydrate or dihydrate. Monohydrate crystals are irregular squares or rods that look similar to CPP crystals, while the dihydrate crystals have a pathognomonic envelope-like or bipyramidal shape and are the most common ones seen. The crystals have variably positive birefringence and can also be stained with alizarin red S due to the calcium content. X-ray findings may show chondrocalcinosis, sclerosis, fractures, pseudofractures, subperiosteal resorption next to the oxalate deposits, and dense metaphyseal bands [34]. Treatment of the acute arthritis is similar to other inflammatory joint diseases with NSAIDs, colchicine, or steroids; treatment of hyperoxaluria requires dietary adjustment and management of the underlying cause , and in patients with primary hyperoxaluria, may require kidney and/or liver transplant [34].


Other Crystals


A number of other crystals can cause inflammation in joints. Perhaps most commonly seen, but uncommonly appreciated, are inflammatory reactions to intraarticular corticosteroid crystals . Most steroids are insoluble in lidocaine, and each forms their own unique and recognizable crystal structure. Injection of such steroids may therefore induce a transient acute inflammatory reaction, occurring within the first 24 hours and resolving with the dissolution of the crystals and the anti-inflammatory effect of the steroids themselves. Treatment is conservative, with NSAIDs and/or topical ice. Cholesterol crystals are characteristically reported in the joint or bursal fluid of individuals with rheumatoid arthritis, or occasionally other forms of inflammatory arthritis. Their presence is not typically associated with hyperlipidemia. Cholesterol crystals are negatively birefringent, plate-like, and notched. They are thought to have weak inflammatory potential; management addresses the primary underlying arthritis [37]. Lipid liquid crystals are positively birefringent lipid spherules that appear as Maltese crosses and stain positive with Sudan Black B. Their presence is associated with an acute inflammatory arthritis. Treatment with colchicine or NSAIDs has been reported to improve the arthritis [38].


Questions





  1. 1.

    A 59-year-old man presents for evaluation after his brother was hospitalized with an acute gout flare. The patient has not seen a doctor in 10 years but decided to come in because he is worried about his chances of developing a painful gout attack. He denies any past medical history and takes no medications other than an occasional aspirin for pain less than once a week. He actively smokes 0.5 packs of cigarettes daily and drinks 3–4 glasses of wine per week.


    Further workup demonstrates the following findings:



    • T 98.2 °F, BP 145/91 mm Hg, P 83/min and O2 saturation 100% on room air



    • Physical exam: negative for tophi.


    Laboratory studies:



    • AST 23 U/L (Reference range 0–40 U/L)



    • ALT 21 U/L (Reference range 0–40 U/L)



    • Alkaline phosphatase 75 U/L (Reference range 40–150 U/L)



    • Total bilirubin 0.3 mg/dL (Reference range 0.2–1.2 mg/dL)



    • Albumin 4.1 g/dL (Reference range 3.5–5.2 g/dL)



    • Blood urea nitrogen 31 mg/dL (Reference range 7–20 mg/dL)



    • Creatinine 1.8 mg/dL (Reference range 0.8–1.2 mg/dL)


    Which one of the following features of this patient’s case is most predictive for possible future development of gout?


    1. A.

      Aspirin use


       

    2. B.

      Chronic kidney disease


       

    3. C.

      Family history of gout in his brother


       

    4. D.

      Smoking history


       

    5. E.

      Wine intake


       

    Correct answer: B


    This patient’s creatinine suggests that he has chronic kidney disease (CKD) , probably secondary to hypertension, particularly since he has not had any medical follow-up in many years. CKD is considered an important risk factor for the development of gout, with studies demonstrating a 60% increase in gout risk for patients with chronic renal insufficiency.


    Low-dose aspirin use has been associated with decreased clearance of uric acid in the kidney. However, a study among healthy volunteers found no change in the renal clearance of urate after they were given a single dose of aspirin 100 mg. Given this patient’s sporadic use of aspirin, it is unlikely that his aspirin use confers a greater risk of gout flare than his renal disease. Thus, choice A is incorrect.


    Studies of gout heritability suggest that gout arises from multiple factors, including a combination of multiple different genes, as well as environmental contributors. A study from 2000 found a correlation of 0.19 for uric acid levels between siblings. Certain genetic polymorphisms have been found to increase risk for gout, particularly polymorphisms in the genes SCLA2 and ABCG2 encoding urate transporters in the kidney and gut, but the specific amount of risk conferred by these polymorphisms remains unclear. Because the impact of family history appears to be less potent than CKD, choice C is incorrect.


    Tobacco use has not been associated with a higher risk for developing gout. Indeed, some studies suggest a possible lower risk of gout in patients who smoke, for unclear reasons. ACR nevertheless strongly recommends smoking cessation for all patients. Choice D is therefore incorrect.


    While this patient does report regular alcohol use, a 2004 study utilizing the NHANES database did not find an increased risk for hyperuricemia among wine drinkers in the general population, as opposed to beer and liquor, both of which were associated with significantly increased serum uric acid levels. Other studies did find an association between wine drinking and increase risk for gout, but not at the level of wine consumption indicated here. Therefore Choice E is incorrect.


     

  2. 2.

    A 64-year-old Korean man presents for follow-up after experiencing an acute gout flare in his right 1st MTP joint during a recent hospitalization. Gout was confirmed by aspiration and microscopic examination for crystals, and he was treated with prednisone 30 mg with good response. He denies any history of prior gout flares. Today, he says he is feeling well, with minimal toe pain. Medical history is significant for chronic renal insufficiency, hypertension, coronary artery disease complicated by a myocardial infarction 1 year ago, and diabetes. Laboratory studies reveal the following:



    • Na 134 mmol/L (Reference range 134–146 mmol/L)



    • K 4.3 mmol/L (Reference range 3.6–5.2 mmol/L)



    • Cl 109 mmol/L (Reference range 98–108 mmol/L)



    • CO2 25 mmol/L (Reference range 22–29 mg/dL)



    • BUN 40 mg/dL (Reference range 7–20 mg/dL)



    • Cr 2.1 mg/dL (Reference range 0.8–1.2 mg/dL)



    • eGFR 38 ml/min/1.73m2 (Reference range > 60 mL/min/1.73m2)

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Oct 24, 2020 | Posted by in RHEUMATOLOGY | Comments Off on Arthritis
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