Anthony M. Reginato, PhD, MD

Over the past 2 decades, an increasing number of rheumatologists have progressively incorporated ultrasound (US) as an invaluable diagnostic and monitoring tool into their clinical and research practice.^1,2 This imaging modality has become an established aid incorporated into the clinical evaluation of periarticular and articular structures involved in the diagnosis of several rheumatic disorders.

Ultrasound is a safe, noninvasive, patient-friendly imaging modality with a lack of contraindications and free of ionizing radiation. It allows real-time evaluation with dynamic assessment in a multiplanar view, assessment of multiple targets, and lower cost compared with magnetic resonance imaging (MRI) or computerized tomography scan. Above all, for the rheumatologist, US provides real-time scanning of all peripheral joints as many times as is required at the time of consultation. It is of great advantage in the assessment of a wide spectrum of abnormalities in rheumatic diseases with the potential of point-of-care imaging modality in the clinical evaluation and management of the patient. It facilitates a direct correlation between imaging findings and clinical data that improves the approach to a wide range of rheumatic diseases, from acute to chronic inflammatory arthritis, crystalline arthropathies, osteoarthritis (OA), spondyloarthropathies (SpA), vasculitis, and soft tissue syndromes. In addition, US is a bedside tool for performing accurate and safe diagnostic arthrocentesis, injections, and synovial biopsies.^3,4

Recently, a gradual attempt has been made to incorporate US into rheumatology disease classification or diagnostic criteria for rheumatoid arthritis (RA), polymyalgia rheumatica, gout, calcium pyrophosphate deposition disease (CPPD), and Sjögren’s syndrome.^5-10 Furthermore, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have produced evidence and expert opinion-based recommendations on the use of US in the clinical management of rheumatic diseases.^10-12 This article highlights the most common applications of US for assessment and management of different rheumatic diseases frequently encountered at the VAMC rheumatology inpatient and outpatient clinical service.

Evaluation of Inflammatory Arthritis

In RA and any other inflammatory arthritis, US has been used for the detection of joint effusions, synovitis, bone erosions, and tendon and enthesis involvement.^11,12 Ultrasound B-mode and power Doppler (PD) techniques have demonstrated a consistent and relevant role in optimizing the diagnosis, assessing the inflammatory activity, monitoring response to therapy, and predicting the inflammatory arthritis outcomes (Figures 1-3).^10-12 Ultrasound provides real-time information about the status of the synovial membrane, tendons, cartilage, bursae, and cortical bones, allowing an accurate assessment of the degree of inflammatory process in periarticular and articular tissues. Also, US can provide details about the characteristics of the collected fluid (ie, effusion or synovial hypertrophy), which is fundamental for the correct interpretation of the pathologic joint and/or soft tissue processes. The inflammatory process can be assessed by using PD mode, which detects and quantifies the vascular changes in the pannus due to vasodilation and the increased blood flow characteristic of active inflammation.^13,14

The Outcomes Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) study group developed standardized sonopathologic definitions and scanning methods to be used in the daily rheumatologic practice and clinical trials (Table 1).¹⁵ Furthermore, it developed a semiquantitative scale to assess the degree of synovitis in US B-mode and PD mode (Table 2).¹⁵

The use of US to find subclinical synovitis in patients with RA considered to be in clinical remission is a new issue.¹⁶ Some reports have demonstrated progressive joint damage in these patients with evidence of active inflammation on PDUS despite clinical remission.^17,18 More prospective studies are required to provide a better understanding of the long-term effects of residual inflammation and the proper long-term treatment of these patients. Furthermore, the PD signal has been shown to be superior to the Disease Activity Score 28 (DAS-28) in evaluating disease activity, particularly in predicting joint damage.¹⁸

Ultrasound may be considered the gold standard imaging tool for the assessment of tendons in inflammatory arthritis and includes the detection of tenosynovitis and anatomical damage represented by the loss of the normal fibrillar echotexture and loss of definition of the tendon margins, which may occur in early disease.^19,20 Tenosynovitis of the extensor carpi ulnaris (ECU) detected by US has been shown to be an independent predictive factor of erosive joint damage, suggesting that ECU tenosynovitis represents a useful ultrasonographic landmark in the diagnosis of early RA.²¹

The availability of new nonbiologic and biologic therapies for inflammatory arthritis has raised the importance of identifying early changes, such as the detection of early erosions, which portend a poor long-term prognosis. The capability of US in identifying this lesion at an earlier stage compared with conventional radiography (CR) has allowed the early diagnosis and treatment of these patients before irreversible joint destruction occurs.²² In spite of all the supportive evidence of US utility in RA, it is not considered among the mandatory diagnostic criteria in the ACR/EULAR classification criteria for RA.⁵ Still, the addition of US findings to these criteria has increased the number of patients who fulfilled the 1987 ACR classification criteria for RA after 18 months of follow-up.²³ Despite extensive evidence of its utility in the diagnosis and monitoring of RA, further studies are still needed.

Spondyloarthritis

Similar to RA, SpA discloses sonographic findings of inflammatory arthritis; however, with more entheseal and tenosynovium involvement. Ultrasound has also been used in the early identification of characteristic changes of the skin and nail tissues, which can aid the global assessment of this heterogeneous disease, especially in psoriatic arthritis (PsA). The most common locations of enthesitis in SpA are the quadriceps and the Achilles enthesis.^24,25

Although US offers detailed imaging for the assessment of both tendons and enthesis, there is a lack of literature evaluating dactylitis. The OMERACT group recently released a composite measure of activity and severity of US dactylitis, which included newly defined elementary US lesions that may discern dactylitis of a digit.^26,27 Ultrasound has been compared with MRI in the detection of SpA-related synovitis of the hands and feet and has demonstrated competitive diagnostic sensitivity.²⁸ Ultrasound also shows higher sensitivity in detecting synovitis of the hands and feet compared with clinical examination and CR in PsA.^28,29 Unfortunately, there are no strongly validated US findings that can aid in the differential diagnosis of PsA against other chronic inflammatory arthritides. The presence of peritendinous extensor tendon inflammation was a highly specific sonographic feature of PsA, because it was present in 66% of metacarpophalangeal (MCP) joints as the only US sign of inflammation compared with patients with RA.³⁰

Another application of US is in the evaluation of subclinical inflammation at the enthesis in patients with a history of psoriasis without prior history of PsA.^27,31 In those patients with psoriatic nail changes, more subclinical enthesitis was found compared with patients with psoriasis without nail involvement.³² Furthermore, subclinical joint inflammation has also been described.³³ These findings suggest a possible predictive value in patients with psoriasis who should be monitored on a regular basis, because they are at risk of developing PsA.

Subclinical enthesitis by US imaging has been described in patients with recurrent anterior uveitis and inflammatory bowel disease.^34,35 In cases where SpA is suspected but diagnostic criteria are not fulfilled, the presence of one enthesis with increased PD signal highly predicts the eventual development of SpA.³⁶ Therefore, B-mode and PD evaluations of the entheses are critical in the identification of patients who are at an increased risk of developing SpA.³⁷ Treatment monitoring is performed by using a US scoring system in a follow-up evaluation of patients with PsA. Some of the scoring systems have evaluated changes in B-mode US lesions (enthesis and soft tissues, such as skin and nails), whereas others focus on changes in the PD signal.^37,38

The Five Targets Power Doppler for Psoriatic Disease PD scoring system comprises the assessment of PD signal in the joint, tendon with synovial sheath, enthesis, skin, and nails. Each of the targets is scored from 0 to 3 points, with a maximum of 15 total points. Some studies have shown that PDUS can provide valuable information in the evaluation of psoriatic plaques and onychopathy in patients with psoriasis and PsA.³⁹ The detection of a PD signal within the dermis and nail bed is equivalent to active inflammation in these sites.^39-41 However, further studies with larger cohorts proving inter- and intra-observer reliability are necessary to consolidate these findings and comfortably apply them in clinical practice.

Osteoarthritis

Increasingly US is studied for its validity and reliability in evaluating periarticular soft tissue and cartilage changes in knee OA. The associated US findings include a high prevalence of synovitis with a low prevalence of a PD signal, the presence of osteophytes, and joint space narrowing.^42,43 Increased PD signal, synovial hypertrophy, and joint effusion were observed in patients with radiographically erosive OA compared with those with radiographically nonerosive OA.⁴⁴

Bone erosions and inflammatory changes are also frequently detected by US in both erosive and nodal hand OA.⁴⁵ Compared with MRI, US has shown a good to excellent correlation in the assessment of osteophytes, bone erosions, synovitis, and tenosynovitis in erosive and hand nodal OA.⁴⁶ In comparison with CR, US has shown to have a higher sensitivity in the assessment of bony erosions, osteophytes, and space narrowing.⁴⁷ Ultrasound is able to detect changes in the earlier stages of cartilage erosion in OA, characterized by loss of the sharp contour and variations in the echogenicity of the cartilage matrix, asymmetric shrinkage, and ultimately the disappearance of the cartilaginous band, which is more evident in the later stages of OA.⁴⁵

Similar to RA management, US has been used to monitor disease activity and response to OA treatment. Patients who received intra-articular hyaluronic acid or intramuscular methylprednisolone for OA treatment were found to have a decrease of PD signal intensity and synovial effusion posttreatment.48 One could extrapolate these findings and conclude that US could be an additional tool for monitoring disease activity and assessing response to local and systemic treatments in OA.

Crystalline Arthropathies

Ultrasound application to crystal diseases facilitates the identification of microcrystalline deposits within the synovial membrane (joints), cartilage (both hyaline cartilage and fibrocartilage), and periarticular tissues (tendons, bursae, and soft tissues). Crystals appear as hyperechogenic spots of different sizes and shapes that can be seen in both articular and periarticular tissues.^49,50 The crystal deposition pattern on hyaline cartilage allows the differentiation between monosodium urate (MSU) and calcium pyrophosphate dehydrate (CPP) crystals. The MSU crystals are deposited at the chondrosynovial (or superficial) margin of the hyaline cartilage and described sonographically as the double contour sign in gout, whereas CPP crystals are deposited within the intermediate layer of the hyaline cartilage and are seen as hyperechoic spots frequently described as rosary beads on US.^6,49,50

Other important sites that can be evaluated to determine the presence of CPP crystals include the menisci, symphysis pubis, and triangular fibrocartilage at the wrists, hips, and shoulders. Recent EULAR recommendations have incorporated US as part of the diagnostic imaging modality for the diagnosis of CPPD and more recently for gout.^6,51 Tophi are seen as MSU precipitates deposited in the joint cavity, tendons, and/or periarticular tissues such as bursae. They can show different echogenic signal. Soft tophi can demonstrate high PD signal due to high vascularization. On the other hand, hard tophi are hyperechoic on B-mode due to the presence of calcification, which does not allow passage of US waves, creating postacoustic shadowing.⁸ Studies have evaluated the predictive role of US in evaluating patients with asymptomatic hyperuricemia without any prior history of crystal-related joint disease and found tophaceous deposits in the triceps and patellar and quadriceps tendons.^52-55 Studies have also looked at using US in the assessment of treatment response to serum uratelowering therapy in patients with gout.^56,57 These studies have noted an improvement in the double contour sign, hyperechoic spots, cloudy areas in the synovial fluid, and tophus diameter and size in those patients who achieved a treat-to-target with a serum uric acid level ≤ 6 mg/dL. Patients who did not reach this target had no changes in the gout US features.^56-57 Larger cohort studies are needed to confirm these findings.

An active inflammatory process can be determined by using a PD signal in the acute gout setting with increased vascularization; however, an increased PD signal can also be seen in septic arthritis or tenosynovitis, which sometimes can coexist with crystal-induced arthritis. Therefore, diagnostic arthrocentesis, Gram stain, and culture, as well as evaluation of crystals under polarized microscopy, are still recommended.

Therapeutic Interventions

Real-time visualization of the injection needle by US allows reliable placement of the needle tip in the tissue or cavity of interest. Multiple studies have shown the low accuracy of palpation-guided injection for reaching the site of interest.^58,59 Some studies have shown a higher response rate to US-guided injections compared with palpation-guided as well as a higher rate of successful aspirations and clinical outcomes. Meta-analyses have demonstrated improved treatment response with the use of US-guided procedures compared with blinded injections.^60,61 Ultrasound-guided interventions are performed in both peripheral and axial joints.⁶² The most common US-guided procedures at the VA rheumatology clinic include arthrocentesis and intra-articular corticosteroid injections of small and medium-sized joints, such as MCP joints, elbows, wrists, and ankles.

Conclusions

Ultrasound is becoming a relevant part of rheumatology practice and research and can be regarded as a feasible and effective imaging technique that can allow real-time recognition of early anatomical changes, provide careful guidance for aspiration, and monitor local and/or systemic treatment response at the joint, tendon, enthesis, nail, and skin levels. Ultrasound is a user-friendly imaging modality readily applied at the bedside and considered an extension of the rheumatologist's physical examination.

The success of US depends on the individual operator. For this reason, structured educational programs during fellowship training programs and an efficient competency assessment system would facilitate proper implementation of US in rheumatology practice as performed by some but not all institutions.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Over the past 2 decades, an increasing number of rheumatologists have progressively incorporated ultrasound (US) as an invaluable diagnostic and monitoring tool into their clinical and research practice.^1,2 This imaging modality has become an established aid incorporated into the clinical evaluation of periarticular and articular structures involved in the diagnosis of several rheumatic disorders.

Ultrasound is a safe, noninvasive, patient-friendly imaging modality with a lack of contraindications and free of ionizing radiation. It allows real-time evaluation with dynamic assessment in a multiplanar view, assessment of multiple targets, and lower cost compared with magnetic resonance imaging (MRI) or computerized tomography scan. Above all, for the rheumatologist, US provides real-time scanning of all peripheral joints as many times as is required at the time of consultation. It is of great advantage in the assessment of a wide spectrum of abnormalities in rheumatic diseases with the potential of point-of-care imaging modality in the clinical evaluation and management of the patient. It facilitates a direct correlation between imaging findings and clinical data that improves the approach to a wide range of rheumatic diseases, from acute to chronic inflammatory arthritis, crystalline arthropathies, osteoarthritis (OA), spondyloarthropathies (SpA), vasculitis, and soft tissue syndromes. In addition, US is a bedside tool for performing accurate and safe diagnostic arthrocentesis, injections, and synovial biopsies.^3,4

Recently, a gradual attempt has been made to incorporate US into rheumatology disease classification or diagnostic criteria for rheumatoid arthritis (RA), polymyalgia rheumatica, gout, calcium pyrophosphate deposition disease (CPPD), and Sjögren’s syndrome.^5-10 Furthermore, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have produced evidence and expert opinion-based recommendations on the use of US in the clinical management of rheumatic diseases.^10-12 This article highlights the most common applications of US for assessment and management of different rheumatic diseases frequently encountered at the VAMC rheumatology inpatient and outpatient clinical service.

Evaluation of Inflammatory Arthritis

In RA and any other inflammatory arthritis, US has been used for the detection of joint effusions, synovitis, bone erosions, and tendon and enthesis involvement.^11,12 Ultrasound B-mode and power Doppler (PD) techniques have demonstrated a consistent and relevant role in optimizing the diagnosis, assessing the inflammatory activity, monitoring response to therapy, and predicting the inflammatory arthritis outcomes (Figures 1-3).^10-12 Ultrasound provides real-time information about the status of the synovial membrane, tendons, cartilage, bursae, and cortical bones, allowing an accurate assessment of the degree of inflammatory process in periarticular and articular tissues. Also, US can provide details about the characteristics of the collected fluid (ie, effusion or synovial hypertrophy), which is fundamental for the correct interpretation of the pathologic joint and/or soft tissue processes. The inflammatory process can be assessed by using PD mode, which detects and quantifies the vascular changes in the pannus due to vasodilation and the increased blood flow characteristic of active inflammation.^13,14

The Outcomes Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) study group developed standardized sonopathologic definitions and scanning methods to be used in the daily rheumatologic practice and clinical trials (Table 1).¹⁵ Furthermore, it developed a semiquantitative scale to assess the degree of synovitis in US B-mode and PD mode (Table 2).¹⁵

The use of US to find subclinical synovitis in patients with RA considered to be in clinical remission is a new issue.¹⁶ Some reports have demonstrated progressive joint damage in these patients with evidence of active inflammation on PDUS despite clinical remission.^17,18 More prospective studies are required to provide a better understanding of the long-term effects of residual inflammation and the proper long-term treatment of these patients. Furthermore, the PD signal has been shown to be superior to the Disease Activity Score 28 (DAS-28) in evaluating disease activity, particularly in predicting joint damage.¹⁸

Ultrasound may be considered the gold standard imaging tool for the assessment of tendons in inflammatory arthritis and includes the detection of tenosynovitis and anatomical damage represented by the loss of the normal fibrillar echotexture and loss of definition of the tendon margins, which may occur in early disease.^19,20 Tenosynovitis of the extensor carpi ulnaris (ECU) detected by US has been shown to be an independent predictive factor of erosive joint damage, suggesting that ECU tenosynovitis represents a useful ultrasonographic landmark in the diagnosis of early RA.²¹

The availability of new nonbiologic and biologic therapies for inflammatory arthritis has raised the importance of identifying early changes, such as the detection of early erosions, which portend a poor long-term prognosis. The capability of US in identifying this lesion at an earlier stage compared with conventional radiography (CR) has allowed the early diagnosis and treatment of these patients before irreversible joint destruction occurs.²² In spite of all the supportive evidence of US utility in RA, it is not considered among the mandatory diagnostic criteria in the ACR/EULAR classification criteria for RA.⁵ Still, the addition of US findings to these criteria has increased the number of patients who fulfilled the 1987 ACR classification criteria for RA after 18 months of follow-up.²³ Despite extensive evidence of its utility in the diagnosis and monitoring of RA, further studies are still needed.

Spondyloarthritis

Similar to RA, SpA discloses sonographic findings of inflammatory arthritis; however, with more entheseal and tenosynovium involvement. Ultrasound has also been used in the early identification of characteristic changes of the skin and nail tissues, which can aid the global assessment of this heterogeneous disease, especially in psoriatic arthritis (PsA). The most common locations of enthesitis in SpA are the quadriceps and the Achilles enthesis.^24,25

Although US offers detailed imaging for the assessment of both tendons and enthesis, there is a lack of literature evaluating dactylitis. The OMERACT group recently released a composite measure of activity and severity of US dactylitis, which included newly defined elementary US lesions that may discern dactylitis of a digit.^26,27 Ultrasound has been compared with MRI in the detection of SpA-related synovitis of the hands and feet and has demonstrated competitive diagnostic sensitivity.²⁸ Ultrasound also shows higher sensitivity in detecting synovitis of the hands and feet compared with clinical examination and CR in PsA.^28,29 Unfortunately, there are no strongly validated US findings that can aid in the differential diagnosis of PsA against other chronic inflammatory arthritides. The presence of peritendinous extensor tendon inflammation was a highly specific sonographic feature of PsA, because it was present in 66% of metacarpophalangeal (MCP) joints as the only US sign of inflammation compared with patients with RA.³⁰

Another application of US is in the evaluation of subclinical inflammation at the enthesis in patients with a history of psoriasis without prior history of PsA.^27,31 In those patients with psoriatic nail changes, more subclinical enthesitis was found compared with patients with psoriasis without nail involvement.³² Furthermore, subclinical joint inflammation has also been described.³³ These findings suggest a possible predictive value in patients with psoriasis who should be monitored on a regular basis, because they are at risk of developing PsA.

Subclinical enthesitis by US imaging has been described in patients with recurrent anterior uveitis and inflammatory bowel disease.^34,35 In cases where SpA is suspected but diagnostic criteria are not fulfilled, the presence of one enthesis with increased PD signal highly predicts the eventual development of SpA.³⁶ Therefore, B-mode and PD evaluations of the entheses are critical in the identification of patients who are at an increased risk of developing SpA.³⁷ Treatment monitoring is performed by using a US scoring system in a follow-up evaluation of patients with PsA. Some of the scoring systems have evaluated changes in B-mode US lesions (enthesis and soft tissues, such as skin and nails), whereas others focus on changes in the PD signal.^37,38

The Five Targets Power Doppler for Psoriatic Disease PD scoring system comprises the assessment of PD signal in the joint, tendon with synovial sheath, enthesis, skin, and nails. Each of the targets is scored from 0 to 3 points, with a maximum of 15 total points. Some studies have shown that PDUS can provide valuable information in the evaluation of psoriatic plaques and onychopathy in patients with psoriasis and PsA.³⁹ The detection of a PD signal within the dermis and nail bed is equivalent to active inflammation in these sites.^39-41 However, further studies with larger cohorts proving inter- and intra-observer reliability are necessary to consolidate these findings and comfortably apply them in clinical practice.

Osteoarthritis

Increasingly US is studied for its validity and reliability in evaluating periarticular soft tissue and cartilage changes in knee OA. The associated US findings include a high prevalence of synovitis with a low prevalence of a PD signal, the presence of osteophytes, and joint space narrowing.^42,43 Increased PD signal, synovial hypertrophy, and joint effusion were observed in patients with radiographically erosive OA compared with those with radiographically nonerosive OA.⁴⁴

Bone erosions and inflammatory changes are also frequently detected by US in both erosive and nodal hand OA.⁴⁵ Compared with MRI, US has shown a good to excellent correlation in the assessment of osteophytes, bone erosions, synovitis, and tenosynovitis in erosive and hand nodal OA.⁴⁶ In comparison with CR, US has shown to have a higher sensitivity in the assessment of bony erosions, osteophytes, and space narrowing.⁴⁷ Ultrasound is able to detect changes in the earlier stages of cartilage erosion in OA, characterized by loss of the sharp contour and variations in the echogenicity of the cartilage matrix, asymmetric shrinkage, and ultimately the disappearance of the cartilaginous band, which is more evident in the later stages of OA.⁴⁵

Similar to RA management, US has been used to monitor disease activity and response to OA treatment. Patients who received intra-articular hyaluronic acid or intramuscular methylprednisolone for OA treatment were found to have a decrease of PD signal intensity and synovial effusion posttreatment.48 One could extrapolate these findings and conclude that US could be an additional tool for monitoring disease activity and assessing response to local and systemic treatments in OA.

Crystalline Arthropathies

Ultrasound application to crystal diseases facilitates the identification of microcrystalline deposits within the synovial membrane (joints), cartilage (both hyaline cartilage and fibrocartilage), and periarticular tissues (tendons, bursae, and soft tissues). Crystals appear as hyperechogenic spots of different sizes and shapes that can be seen in both articular and periarticular tissues.^49,50 The crystal deposition pattern on hyaline cartilage allows the differentiation between monosodium urate (MSU) and calcium pyrophosphate dehydrate (CPP) crystals. The MSU crystals are deposited at the chondrosynovial (or superficial) margin of the hyaline cartilage and described sonographically as the double contour sign in gout, whereas CPP crystals are deposited within the intermediate layer of the hyaline cartilage and are seen as hyperechoic spots frequently described as rosary beads on US.^6,49,50

Other important sites that can be evaluated to determine the presence of CPP crystals include the menisci, symphysis pubis, and triangular fibrocartilage at the wrists, hips, and shoulders. Recent EULAR recommendations have incorporated US as part of the diagnostic imaging modality for the diagnosis of CPPD and more recently for gout.^6,51 Tophi are seen as MSU precipitates deposited in the joint cavity, tendons, and/or periarticular tissues such as bursae. They can show different echogenic signal. Soft tophi can demonstrate high PD signal due to high vascularization. On the other hand, hard tophi are hyperechoic on B-mode due to the presence of calcification, which does not allow passage of US waves, creating postacoustic shadowing.⁸ Studies have evaluated the predictive role of US in evaluating patients with asymptomatic hyperuricemia without any prior history of crystal-related joint disease and found tophaceous deposits in the triceps and patellar and quadriceps tendons.^52-55 Studies have also looked at using US in the assessment of treatment response to serum uratelowering therapy in patients with gout.^56,57 These studies have noted an improvement in the double contour sign, hyperechoic spots, cloudy areas in the synovial fluid, and tophus diameter and size in those patients who achieved a treat-to-target with a serum uric acid level ≤ 6 mg/dL. Patients who did not reach this target had no changes in the gout US features.^56-57 Larger cohort studies are needed to confirm these findings.

An active inflammatory process can be determined by using a PD signal in the acute gout setting with increased vascularization; however, an increased PD signal can also be seen in septic arthritis or tenosynovitis, which sometimes can coexist with crystal-induced arthritis. Therefore, diagnostic arthrocentesis, Gram stain, and culture, as well as evaluation of crystals under polarized microscopy, are still recommended.

Therapeutic Interventions

Real-time visualization of the injection needle by US allows reliable placement of the needle tip in the tissue or cavity of interest. Multiple studies have shown the low accuracy of palpation-guided injection for reaching the site of interest.^58,59 Some studies have shown a higher response rate to US-guided injections compared with palpation-guided as well as a higher rate of successful aspirations and clinical outcomes. Meta-analyses have demonstrated improved treatment response with the use of US-guided procedures compared with blinded injections.^60,61 Ultrasound-guided interventions are performed in both peripheral and axial joints.⁶² The most common US-guided procedures at the VA rheumatology clinic include arthrocentesis and intra-articular corticosteroid injections of small and medium-sized joints, such as MCP joints, elbows, wrists, and ankles.

Conclusions

Ultrasound is becoming a relevant part of rheumatology practice and research and can be regarded as a feasible and effective imaging technique that can allow real-time recognition of early anatomical changes, provide careful guidance for aspiration, and monitor local and/or systemic treatment response at the joint, tendon, enthesis, nail, and skin levels. Ultrasound is a user-friendly imaging modality readily applied at the bedside and considered an extension of the rheumatologist's physical examination.

The success of US depends on the individual operator. For this reason, structured educational programs during fellowship training programs and an efficient competency assessment system would facilitate proper implementation of US in rheumatology practice as performed by some but not all institutions.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Over the past 2 decades, an increasing number of rheumatologists have progressively incorporated ultrasound (US) as an invaluable diagnostic and monitoring tool into their clinical and research practice.^1,2 This imaging modality has become an established aid incorporated into the clinical evaluation of periarticular and articular structures involved in the diagnosis of several rheumatic disorders.

Ultrasound is a safe, noninvasive, patient-friendly imaging modality with a lack of contraindications and free of ionizing radiation. It allows real-time evaluation with dynamic assessment in a multiplanar view, assessment of multiple targets, and lower cost compared with magnetic resonance imaging (MRI) or computerized tomography scan. Above all, for the rheumatologist, US provides real-time scanning of all peripheral joints as many times as is required at the time of consultation. It is of great advantage in the assessment of a wide spectrum of abnormalities in rheumatic diseases with the potential of point-of-care imaging modality in the clinical evaluation and management of the patient. It facilitates a direct correlation between imaging findings and clinical data that improves the approach to a wide range of rheumatic diseases, from acute to chronic inflammatory arthritis, crystalline arthropathies, osteoarthritis (OA), spondyloarthropathies (SpA), vasculitis, and soft tissue syndromes. In addition, US is a bedside tool for performing accurate and safe diagnostic arthrocentesis, injections, and synovial biopsies.^3,4

Recently, a gradual attempt has been made to incorporate US into rheumatology disease classification or diagnostic criteria for rheumatoid arthritis (RA), polymyalgia rheumatica, gout, calcium pyrophosphate deposition disease (CPPD), and Sjögren’s syndrome.^5-10 Furthermore, the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) have produced evidence and expert opinion-based recommendations on the use of US in the clinical management of rheumatic diseases.^10-12 This article highlights the most common applications of US for assessment and management of different rheumatic diseases frequently encountered at the VAMC rheumatology inpatient and outpatient clinical service.

Evaluation of Inflammatory Arthritis

In RA and any other inflammatory arthritis, US has been used for the detection of joint effusions, synovitis, bone erosions, and tendon and enthesis involvement.^11,12 Ultrasound B-mode and power Doppler (PD) techniques have demonstrated a consistent and relevant role in optimizing the diagnosis, assessing the inflammatory activity, monitoring response to therapy, and predicting the inflammatory arthritis outcomes (Figures 1-3).^10-12 Ultrasound provides real-time information about the status of the synovial membrane, tendons, cartilage, bursae, and cortical bones, allowing an accurate assessment of the degree of inflammatory process in periarticular and articular tissues. Also, US can provide details about the characteristics of the collected fluid (ie, effusion or synovial hypertrophy), which is fundamental for the correct interpretation of the pathologic joint and/or soft tissue processes. The inflammatory process can be assessed by using PD mode, which detects and quantifies the vascular changes in the pannus due to vasodilation and the increased blood flow characteristic of active inflammation.^13,14

The Outcomes Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) study group developed standardized sonopathologic definitions and scanning methods to be used in the daily rheumatologic practice and clinical trials (Table 1).¹⁵ Furthermore, it developed a semiquantitative scale to assess the degree of synovitis in US B-mode and PD mode (Table 2).¹⁵

The use of US to find subclinical synovitis in patients with RA considered to be in clinical remission is a new issue.¹⁶ Some reports have demonstrated progressive joint damage in these patients with evidence of active inflammation on PDUS despite clinical remission.^17,18 More prospective studies are required to provide a better understanding of the long-term effects of residual inflammation and the proper long-term treatment of these patients. Furthermore, the PD signal has been shown to be superior to the Disease Activity Score 28 (DAS-28) in evaluating disease activity, particularly in predicting joint damage.¹⁸

Ultrasound may be considered the gold standard imaging tool for the assessment of tendons in inflammatory arthritis and includes the detection of tenosynovitis and anatomical damage represented by the loss of the normal fibrillar echotexture and loss of definition of the tendon margins, which may occur in early disease.^19,20 Tenosynovitis of the extensor carpi ulnaris (ECU) detected by US has been shown to be an independent predictive factor of erosive joint damage, suggesting that ECU tenosynovitis represents a useful ultrasonographic landmark in the diagnosis of early RA.²¹

The availability of new nonbiologic and biologic therapies for inflammatory arthritis has raised the importance of identifying early changes, such as the detection of early erosions, which portend a poor long-term prognosis. The capability of US in identifying this lesion at an earlier stage compared with conventional radiography (CR) has allowed the early diagnosis and treatment of these patients before irreversible joint destruction occurs.²² In spite of all the supportive evidence of US utility in RA, it is not considered among the mandatory diagnostic criteria in the ACR/EULAR classification criteria for RA.⁵ Still, the addition of US findings to these criteria has increased the number of patients who fulfilled the 1987 ACR classification criteria for RA after 18 months of follow-up.²³ Despite extensive evidence of its utility in the diagnosis and monitoring of RA, further studies are still needed.

Spondyloarthritis

Similar to RA, SpA discloses sonographic findings of inflammatory arthritis; however, with more entheseal and tenosynovium involvement. Ultrasound has also been used in the early identification of characteristic changes of the skin and nail tissues, which can aid the global assessment of this heterogeneous disease, especially in psoriatic arthritis (PsA). The most common locations of enthesitis in SpA are the quadriceps and the Achilles enthesis.^24,25

Although US offers detailed imaging for the assessment of both tendons and enthesis, there is a lack of literature evaluating dactylitis. The OMERACT group recently released a composite measure of activity and severity of US dactylitis, which included newly defined elementary US lesions that may discern dactylitis of a digit.^26,27 Ultrasound has been compared with MRI in the detection of SpA-related synovitis of the hands and feet and has demonstrated competitive diagnostic sensitivity.²⁸ Ultrasound also shows higher sensitivity in detecting synovitis of the hands and feet compared with clinical examination and CR in PsA.^28,29 Unfortunately, there are no strongly validated US findings that can aid in the differential diagnosis of PsA against other chronic inflammatory arthritides. The presence of peritendinous extensor tendon inflammation was a highly specific sonographic feature of PsA, because it was present in 66% of metacarpophalangeal (MCP) joints as the only US sign of inflammation compared with patients with RA.³⁰

Another application of US is in the evaluation of subclinical inflammation at the enthesis in patients with a history of psoriasis without prior history of PsA.^27,31 In those patients with psoriatic nail changes, more subclinical enthesitis was found compared with patients with psoriasis without nail involvement.³² Furthermore, subclinical joint inflammation has also been described.³³ These findings suggest a possible predictive value in patients with psoriasis who should be monitored on a regular basis, because they are at risk of developing PsA.

Subclinical enthesitis by US imaging has been described in patients with recurrent anterior uveitis and inflammatory bowel disease.^34,35 In cases where SpA is suspected but diagnostic criteria are not fulfilled, the presence of one enthesis with increased PD signal highly predicts the eventual development of SpA.³⁶ Therefore, B-mode and PD evaluations of the entheses are critical in the identification of patients who are at an increased risk of developing SpA.³⁷ Treatment monitoring is performed by using a US scoring system in a follow-up evaluation of patients with PsA. Some of the scoring systems have evaluated changes in B-mode US lesions (enthesis and soft tissues, such as skin and nails), whereas others focus on changes in the PD signal.^37,38

The Five Targets Power Doppler for Psoriatic Disease PD scoring system comprises the assessment of PD signal in the joint, tendon with synovial sheath, enthesis, skin, and nails. Each of the targets is scored from 0 to 3 points, with a maximum of 15 total points. Some studies have shown that PDUS can provide valuable information in the evaluation of psoriatic plaques and onychopathy in patients with psoriasis and PsA.³⁹ The detection of a PD signal within the dermis and nail bed is equivalent to active inflammation in these sites.^39-41 However, further studies with larger cohorts proving inter- and intra-observer reliability are necessary to consolidate these findings and comfortably apply them in clinical practice.

Osteoarthritis

Increasingly US is studied for its validity and reliability in evaluating periarticular soft tissue and cartilage changes in knee OA. The associated US findings include a high prevalence of synovitis with a low prevalence of a PD signal, the presence of osteophytes, and joint space narrowing.^42,43 Increased PD signal, synovial hypertrophy, and joint effusion were observed in patients with radiographically erosive OA compared with those with radiographically nonerosive OA.⁴⁴

Bone erosions and inflammatory changes are also frequently detected by US in both erosive and nodal hand OA.⁴⁵ Compared with MRI, US has shown a good to excellent correlation in the assessment of osteophytes, bone erosions, synovitis, and tenosynovitis in erosive and hand nodal OA.⁴⁶ In comparison with CR, US has shown to have a higher sensitivity in the assessment of bony erosions, osteophytes, and space narrowing.⁴⁷ Ultrasound is able to detect changes in the earlier stages of cartilage erosion in OA, characterized by loss of the sharp contour and variations in the echogenicity of the cartilage matrix, asymmetric shrinkage, and ultimately the disappearance of the cartilaginous band, which is more evident in the later stages of OA.⁴⁵

Similar to RA management, US has been used to monitor disease activity and response to OA treatment. Patients who received intra-articular hyaluronic acid or intramuscular methylprednisolone for OA treatment were found to have a decrease of PD signal intensity and synovial effusion posttreatment.48 One could extrapolate these findings and conclude that US could be an additional tool for monitoring disease activity and assessing response to local and systemic treatments in OA.

Crystalline Arthropathies

Ultrasound application to crystal diseases facilitates the identification of microcrystalline deposits within the synovial membrane (joints), cartilage (both hyaline cartilage and fibrocartilage), and periarticular tissues (tendons, bursae, and soft tissues). Crystals appear as hyperechogenic spots of different sizes and shapes that can be seen in both articular and periarticular tissues.^49,50 The crystal deposition pattern on hyaline cartilage allows the differentiation between monosodium urate (MSU) and calcium pyrophosphate dehydrate (CPP) crystals. The MSU crystals are deposited at the chondrosynovial (or superficial) margin of the hyaline cartilage and described sonographically as the double contour sign in gout, whereas CPP crystals are deposited within the intermediate layer of the hyaline cartilage and are seen as hyperechoic spots frequently described as rosary beads on US.^6,49,50

Other important sites that can be evaluated to determine the presence of CPP crystals include the menisci, symphysis pubis, and triangular fibrocartilage at the wrists, hips, and shoulders. Recent EULAR recommendations have incorporated US as part of the diagnostic imaging modality for the diagnosis of CPPD and more recently for gout.^6,51 Tophi are seen as MSU precipitates deposited in the joint cavity, tendons, and/or periarticular tissues such as bursae. They can show different echogenic signal. Soft tophi can demonstrate high PD signal due to high vascularization. On the other hand, hard tophi are hyperechoic on B-mode due to the presence of calcification, which does not allow passage of US waves, creating postacoustic shadowing.⁸ Studies have evaluated the predictive role of US in evaluating patients with asymptomatic hyperuricemia without any prior history of crystal-related joint disease and found tophaceous deposits in the triceps and patellar and quadriceps tendons.^52-55 Studies have also looked at using US in the assessment of treatment response to serum uratelowering therapy in patients with gout.^56,57 These studies have noted an improvement in the double contour sign, hyperechoic spots, cloudy areas in the synovial fluid, and tophus diameter and size in those patients who achieved a treat-to-target with a serum uric acid level ≤ 6 mg/dL. Patients who did not reach this target had no changes in the gout US features.^56-57 Larger cohort studies are needed to confirm these findings.

An active inflammatory process can be determined by using a PD signal in the acute gout setting with increased vascularization; however, an increased PD signal can also be seen in septic arthritis or tenosynovitis, which sometimes can coexist with crystal-induced arthritis. Therefore, diagnostic arthrocentesis, Gram stain, and culture, as well as evaluation of crystals under polarized microscopy, are still recommended.

Therapeutic Interventions

Real-time visualization of the injection needle by US allows reliable placement of the needle tip in the tissue or cavity of interest. Multiple studies have shown the low accuracy of palpation-guided injection for reaching the site of interest.^58,59 Some studies have shown a higher response rate to US-guided injections compared with palpation-guided as well as a higher rate of successful aspirations and clinical outcomes. Meta-analyses have demonstrated improved treatment response with the use of US-guided procedures compared with blinded injections.^60,61 Ultrasound-guided interventions are performed in both peripheral and axial joints.⁶² The most common US-guided procedures at the VA rheumatology clinic include arthrocentesis and intra-articular corticosteroid injections of small and medium-sized joints, such as MCP joints, elbows, wrists, and ankles.

Conclusions

Ultrasound is becoming a relevant part of rheumatology practice and research and can be regarded as a feasible and effective imaging technique that can allow real-time recognition of early anatomical changes, provide careful guidance for aspiration, and monitor local and/or systemic treatment response at the joint, tendon, enthesis, nail, and skin levels. Ultrasound is a user-friendly imaging modality readily applied at the bedside and considered an extension of the rheumatologist's physical examination.

The success of US depends on the individual operator. For this reason, structured educational programs during fellowship training programs and an efficient competency assessment system would facilitate proper implementation of US in rheumatology practice as performed by some but not all institutions.

Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Calcium pyrophosphate (CPP) crystals may deposit in both articular tissues (predominantly hyaline cartilage and fibrocartilage) and periarticular soft tissues.^1,2 Calcium pyrophosphate deposition disease (CPPD) may be asymptomatic or be associated with a spectrum of clinical syndromes, including both acute and chronic inflammatory arthritis.²

The European League Against Rheumatism (EULAR) recently suggested changes in CPPD terminology.² According to the new EULAR classification, pseudogout, or CPPD, has been reclassified based on new key terms that include several of the previously described disease phenotypes: asymptomatic CPPD; acute CPP crystal arthritis (previously known as pseudogout); osteoarthritis (OA) with CPPD (previously, pseudo-OA); and the chronic CCP crystal inflammatory arthritis (previously, pseudorheumatoid arthritis). In similar fashion, chondrocalcinosis (CC) refers to calcification of the fibrocartilage and/or hyaline cartilage identified by imaging or histologic analysis. Although CC is most commonly seen in CPPD, it is not exclusive to this disease, as it can be seen in other crystal diseases (oxalosis, basic calcium phosphate [BCP]) and can appear as casual finding or coexist with OA.²

Clinical Manifestations

In clinical practice, CPPD may present with several phenotypic forms. In asymptomatic CPPD, CC is a common radiographic finding without clinical symptoms. Acute CPP arthritis always should be suspected in any patient aged > 65 years presenting with acute monoarticular or oligoarticular, migratory or additive, symmetrical, or polyarticular arthritis.³ Acute CCP arthritis is characterized by self-limited acute or subacute attacks of arthritis involving 1 or several extremity joints (knees, wrists, ankles; rarely affects large toe). Typically, the acute attacks last 7 to 10 days. Several unusual sites (eg, the hip joints, trochanteric bursa, and deep spinal joints) also may be affected. However, differences in pattern of joint involvement are insufficient to permit definitive diagnosis without demonstration of the specific crystal type in the inflammatory joint fluid.

Pseudogout attacks closely resemble gouty arthritis; CPPD presents as intermittent flares and often is asymptomatic between flares. Trauma, surgery, or severe medical illness frequently provokes attacks of monosodium urate (MSU) as well as acute CPP arthritis. Systemic findings, such as fever; leukocytosis with a left shift in the differential count; inflammatory markers, such as elevated sedimentation rate (ESR); or C-reactive protein, also can occur, resembling pyogenic arthritis, osteomyelitis, and/or systemic sepsis in the elderly patient.

Diagnosis must be confirmed with aspiration, Gram stain and cultures of the synovial fluid, and evaluation for the presence of CPP crystals under polarized light microscopy.² The diagnosis can be difficult to confirm secondary to the weakly birefringent nature of CPP crystals.⁴ Coexistence of MSU and CPP crystals in a single inflammatory effusion is neither uncommon nor unexplained given increased frequencies of both hyperuricemia/gout and CC among elderly patients.⁵

Chronic CPP crystal inflammatory arthritis may present as a chronic, symmetrical, bilateral, and deforming polyarthritis. It frequently affects the wrists and metacarpophalangeal joints and tendon sheaths. Chronic CPP may resemble rheumatoid arthritis (RA) and produce wrist tenosynovitis, which may manifest as carpal tunnel syndrome and/or cubital tunnel syndrome. Calcium pyrophosphate deposition disease should be on the differential diagnosis in the elderly patient presenting with a clinical picture that resembles “seronegative” RA, with morning stiffness, synovial thickening, localized edema, and restricted motion due to active inflammation or flexion contracture of the hands/wrist. It may present with prominent systemic features, such as leukocytosis, fevers, mental confusion, and inflammatory oligoarthritis or polyarthritis. The diagnosis of CPPD still may be possible even though the rheumatoid factor (RF) is positive, given the increasing likelihood of elevated RF in the older population. In this setting, aspiration of joint fluid and radiography will assist in clarification of the diagnosis. Furthermore, CPPD typically does not cause the type of erosive disease that is often seen in RA.

Calcium pyrophosphate deposition disease also can mimic polymyalgia rheumatica (PMR). A direct comparison of a cohort of patients with pseudo-PMR (PMR/CPPD) with actual PMR patients found that increased age at diagnosis, presence of knee osteoarthritis, tendinous calcifications, and ankle arthritis carried the highest predictive value in patients with CPPD presenting with PMR-like symptoms.⁶ However, the PMR/CPPD variant can be difficult to distinguish, because both conditions can have elevated systemic inflammatory markers, and both are steroid responsive.

Calcium pyrophosphate deposition disease involving a single joint can rarely lead to extensive destruction—as with neuropathic joints in the absence of any neurologic deficits—and is extremely debilitating. This presentation is not well understood and does not have good treatment alternatives. Calcium pyrophosphate crystals often are associated with manifestations of OA.^1,2 Indeed, up to 20% of OA joints have been found to be positive for CPP crystals in various studies. Given the extensive evidence supporting treatment of OA, usually they are treated in a similar fashion with good results. Occasionally, these will have unusual manifestations for typical OA, such as involvement of wrists and metacarpophalangeal joints; however, the presentation is often indolent like OA.

Calcium pyrophosphate crystal deposition involving the spine has been associated with a number of clinical manifestations. Spine stiffness, sometimes associated with bony ankylosis, can resemble ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. Such symptoms are seen more commonly in familial CPPD rather than in the elderly. However, crystal deposition in the ligamentum flavum at the cervical spine levels has been associated with a condition called crowned dens syndrome.⁷ Although mostly asymptomatic, it may be present with acute neck pain, fever, and an increased ESR, sometimes mimicking PMR or giant cell arteritis or neurologic symptoms. Similarly, CPP crystal deposition in the posterior longitudinal ligament at the lower levels of the spine may lead to spinal cord compression syndromes or symptoms of either acute nerve compression or chronic spinal stenosis.^8,9 Calcium pyrophosphate crystal deposition also can occur in other soft tissues, such as bursae, ligaments, and tendons and may be sufficient to cause local nerve compression, such as carpal or cubital tunnel syndrome.

Epidemiology

Radiographic surveys of the knees, hands, wrists, and pelvis and epidemiologic studies have demonstrated an age-related increase in the prevalence of CPPD: 15% prevalence in patients aged 65 to 74 years, 36% prevalence in patients aged 75 to 84 years, and 50% prevalence in patients aged > 84 years.¹⁰ In a recent radiographic study, 40% of patients with CPPD did not present with CC of the knee, and the study’s authors recommended additional radiographs of pelvis, wrists, or hands for accurate diagnosis of radiographic CC.¹¹

Diagnosis

Accurate diagnosis should be achieved on the basis of the clinical picture and demonstration of CPP crystals in synovial fluid or tissue by compensated polarized light microscopy (Figures 1A and 1B).² The sensitivity and specificity for CPP crystal detection has been shown to be 95.9% and 86.5%, respectively.¹² However, the CPP crystal is more readily identified by a rheumatologist rather than in a standard hospital laboratory, which misses 30% of CPP crystals.¹³

Findings of CC on radiograph strengthens a CPPD diagnosis, but its absence does not rule it out (Figure 2A).² More recently, the use of new imaging modalities, such as musculoskeletal ultrasound, provides the capacity to visualize crystal deposits within the joint structures, the hyaline cartilage, and/or fibrocartilage (Figure 2B and 2C).¹⁴ The presence of hyperechoic bands within the intermediate layer hyaline cartilage and hyperechoic spots in fibrocartilage are consistent with CPP crystal deposits.^2,14 The use of computed tomography is the gold standard imaging modality for the identification of CPPD of the spine.¹⁵ There is not enough evidence to support the use of magnetic resonance imaging in CPPD, but it may play a role in rare complications.²

Treatment

The EULAR recently defined new guidelines for the management of CPPD.¹⁶ Asymptomatic CPPD needs no treatment.In other CPPD phenotypes, the goals are to attempt prompt resolution of the acute synovitis, reduction in chronic damage, and management of associated conditions.In acute attacks, treatment modalities used in gout are often required; however, data for CPPD treatment are limited (Table). Treatment relies on the use of colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs), but toxicity and comorbidities in the elderly limit the usage of these drugs.

Given increased renal impairment, the loading dose of colchicine is not recommended.¹⁶ Colchicine has recently been shown to completely block crystal-induced maturation of IL-1β in vitro, indicating that the drug acts upstream of inflammasome activation.¹⁷ This is in addition to the well-known role of colchicine in inhibition of micro-tubule formation, which likely leads to prevention of cell migration, phagocytosis, and activation of inflammasome.^18-20

Intra-articular injection of corticosteroid is an efficient and well-tolerated treatment alternative for monoarticular CPP flares. Oral or parenteral corticosteroids are frequently used for polyarticular flares in particular for those patients in which NSAIDs and colchicine are contraindicated.¹⁶ Parenteral adrenocorticotropic hormone has been used in patients with congestive heart failure, renal insufficiency, gastrointestinal bleeding, or resistance to NSAIDs.²¹ For prophylaxis of acute CPP crystal arthritis, a low dose of oral NSAIDs, oral colchicine, or prednisone may be used with good results.¹⁶ In chronic CPP arthritis, continuous use of colchicine, NSAIDs, or low-dose prednisone is often appropriate. If these interventions are ineffective or contraindicated, using hydroxychloroquine (HCQ) and methotrexate (MTX) have been successfully used to control chronic CPP crystal inflammation.^22,23 Recent trials have raised questions about MTX, and further trials on HCQ usage are underway.²⁴ Biologic agents targeting IL-1 are not currently approved for the treatment of CPPD, but there are suggestions that it may be effective in refractory cases and induce rapid stable remissions after 3 days of therapy.²⁵

In contrast to gout, there is no specific target therapy for lowering CPP crystal load in the elderly. Crucial in the management of CPPD in the elderly is the search for associated diseases, such as hyperparathyroidism, hemochromatosis, hypomagnesemia, and hypophosphatemia, as well as avoidance of tacrolimus, which facilitates or causes CC.¹⁶ Correction of the underlying metabolic disorder, especially when undertaken early, may reduce the severity of CPPD. However, there is little evidence to suggest that treatment of associated disease results in resolution of CPPD—most famously, although therapeutic phlebotomy does not help in hemochromatosis for prevention of crystal disease, chelating agents do seem to be moderately effective.²⁶ Only oral administration of magnesium has shown a reduction in meniscal CC in a patient with CPPD arthropathy.²⁷ In addition, this was in the setting of familial hypomagnesemia associated CPPD. However, unlike uricosuric agents for gout, no pharmacologic treatments can prevent CPPD crystal formation and deposition in tissues.

Therapeutic Agents

Magnesium

Magnesium is a cofactor for the activity of pyrophosphatases that converts inorganic pyrophosphates (PPis) into orthophosphates. In addition, magnesium can increase the solubility of CPP crystals. Early detection and management of hypomagnesemia are recommended, because it occurs in patients who have well-defined conditions and situations: Gitelman syndrome, thiazide and loop diuretics use, tacrolimus use, familial forms of renal magnesium wasting or use of proton pump inhibitors, short bowel syndrome, and intestinal failure in patients receiving home parenteral nutrition. Long-term administration of magnesium in some patients with chronic hypomagnesemia decreased meniscal calcification.^27-29

Dietary Calcium

Epidemiologic studies showed a lower incidence of CC in Chinese subjects. The authors of the study speculate that this lower prevalence of CPPD could result from high levels of calcium found in the drinking water in Beijing, which may affect parathyroid hormone secretion.³⁰ Further studies are needed to confirm this hypothesis, as it could be a cheaper approach to pseudogout prevention.

Probenecid

Probenecid is an in vitro inhibitor of the transmembrane PPi transporter thought to possibly prevent extracellular PPi elaboration. However, this observation has not been confirmed by either case reports or clinical trials.³¹

Phosphocitrate

Phosphocitrate acts directly on preventing crystal deposition in tissues in CPPD as well as BCP based on in vitro evidence and mouse models.^32,33

Hyaluronan

An amelioration of pain and increased range of motion were observed in radiographic CC with OA.³⁴ However, it is associated with increased acute CPP arthritis.³⁵

Radiosynovectomy

In a double-blind study of 15 patients with symmetrical CPPD arthropathy, the knee that underwent intra-articular injection of yttrium-90 (5 mCi) plus steroid had less pain, stiffness, joint line tenderness, and effusion compared with the contralateral control knee injected with saline and steroids.³⁶

Precipitators of Acute Pseudogout

Diuretics are known to exacerbate gout, but they also can exacerbate pseudogout. A recent case-control study nested within a United Kingdom general practice database found that loop diuretics rather than hydrochlorothiazide was associated with increased risk of CPPD mediated primarily by magnesium reabsorption in the loop of Henle.²⁸ Chronic kidney disease associated with secondary and tertiary hyperparathyroidism increases calcium or PPi concentration, which leads to CPP-crystal deposition.

In addition, multiple case reports have described acute pseudogout caused by bisphosphonate administration for osteoporosis or Paget disease—more likely in the elderly population. Intravenous pamidronate, oral etidronate, and alendronate therapy have all been described in the elderly.³⁷ The overall mechanism behind this link is not completely understood, but bisphosphonates are structurally similar to PPi. Pseudogout attacks also have been described in neutropenic patients undergoing treatment with granulocyte-colony stimulating factor.³⁸ In addition to pharmaceutical exacerbation of pseudogout, surgical procedures and trauma can precipitate attacks. Joint lavage has been described to increase the incidence of pseudogout.³⁹ It was hypothesized that joint lavage with fluid induced “crystal shedding” from CPPD crystals imbedded in the joint tissue. Patients who underwent meniscectomy of the knee 20 years ago had a 20% incidence of CC in the knee that was operated compared with 4% CC in the contralateral nonoperated knee.⁴⁰ Overall, the surgery most linked with a pseudogout attack, however, is parathyroidectomy.⁴¹

Basic Calcium Phosphate Crystals

Basic calcium phosphate crystals are common but rarely diagnosed due to the cumbersome and expensive methods required to identify these crystals.⁴²

Basic calcium phosphate and CPPD crystals may coexist in synovial fluid. Similar to CPPD, BCP crystal disease is often concurrent with OA and can cause calcification of articular cartilage. Basic calcium phosphate is more common than CPP crystals with occurrence of 30% to 50% in OA synovial fluid.⁴² Additionally, BCP crystal disease has been linked to increased severity of OA. Basic calcium phosphate crystals in knee joints were found to have radiographically more severe arthritis with larger effusions.^44,45 Similarly, BCP crystals in OA synovial fluid correlated with higher Kellgreen-Lawrence grade scores by radiography.^42,46

It is currently believed that BCP crystals are continuously formed in the extracellular matrix, and their deposition is actively prevented by PPi present in the matrix.⁴⁷ Elevated PPi levels, on the other hand, favor the formation of CPP crystals.⁴⁸ The clinical upshot seems to be that although CPP crystals are almost universally intra-articular and released by chondrocytes, BCD crystals and deposits are more frequently present in soft tissues.

Acute Calcific Tendinitis

Typically, this type of tendinitis involves the shoulder joint and is extra-articular. Common treatments help, including NSAIDs, intra-articular steroids, ice, and rest. In addition, high-energy extracorporeal shock wave therapy has been shown to be effective when used with conscious sedation.^49,50 Needling or barbotage in association with lavage and steroid injections also is effective and has occasionally been shown to reduce the size of the calcium deposit as well, often in combination with IV drugs like ethylenediaminetetraacetic acid.^51-53

Acute calcific periarthritis of the hand presents similar to gout or pseudogout, affecting the wrist, usually in postmenopausal women.⁵⁴ Basic calcium phosphate crystals are aspirated from the joint, and periarticular crystals may be subtle. Local steroid injections are beneficial.Milwaukee shoulder syndrome is an arthropathy associated with BCP crystals in the joint fluid and results in extensive destruction of shoulder articular cartilage and surrounding tissues. It is commonly bilateral and occurs in elderly women more often than it does in men.⁵⁵ Aspiration of the shoulder joint typically reveals a serosanginous fluid. Fluid samples can be assessed for hydroxyapatite crystals by staining with alizarin red dye, which produces a characteristic “halo” or orange-red stain by light microscopy.⁴³ Surgical treatment of Milwaukee shoulder syndrome is difficult due to increased age of the population affected and the severity of the shoulder destruction. Usually a conservative approach of analgesics, recurrent shoulder aspirations, and steroid injections is the best treatment option.

Conclusions

Calcium-containing crystal-associated arthropathies are a complex array of entities that target the veteran elderly population with increasing frequency. Challenges still remain in the diagnosis, crystal identification, and treatment due to coexisting comorbid conditions and polypharmacy commonly seen in veterans. Overall morbidity associated with calcium-containing crystal-associated arthropathies and the coexisting osteoarthritis is great, and focused identification of the disease process with tailored treatment can achieve the goal of decreasing symptoms and improving quality of life.

Acknowledgements
This work was supported by grant P20GM104937 (A.M.R.).

Calcium pyrophosphate (CPP) crystals may deposit in both articular tissues (predominantly hyaline cartilage and fibrocartilage) and periarticular soft tissues.^1,2 Calcium pyrophosphate deposition disease (CPPD) may be asymptomatic or be associated with a spectrum of clinical syndromes, including both acute and chronic inflammatory arthritis.²

The European League Against Rheumatism (EULAR) recently suggested changes in CPPD terminology.² According to the new EULAR classification, pseudogout, or CPPD, has been reclassified based on new key terms that include several of the previously described disease phenotypes: asymptomatic CPPD; acute CPP crystal arthritis (previously known as pseudogout); osteoarthritis (OA) with CPPD (previously, pseudo-OA); and the chronic CCP crystal inflammatory arthritis (previously, pseudorheumatoid arthritis). In similar fashion, chondrocalcinosis (CC) refers to calcification of the fibrocartilage and/or hyaline cartilage identified by imaging or histologic analysis. Although CC is most commonly seen in CPPD, it is not exclusive to this disease, as it can be seen in other crystal diseases (oxalosis, basic calcium phosphate [BCP]) and can appear as casual finding or coexist with OA.²

Clinical Manifestations

In clinical practice, CPPD may present with several phenotypic forms. In asymptomatic CPPD, CC is a common radiographic finding without clinical symptoms. Acute CPP arthritis always should be suspected in any patient aged > 65 years presenting with acute monoarticular or oligoarticular, migratory or additive, symmetrical, or polyarticular arthritis.³ Acute CCP arthritis is characterized by self-limited acute or subacute attacks of arthritis involving 1 or several extremity joints (knees, wrists, ankles; rarely affects large toe). Typically, the acute attacks last 7 to 10 days. Several unusual sites (eg, the hip joints, trochanteric bursa, and deep spinal joints) also may be affected. However, differences in pattern of joint involvement are insufficient to permit definitive diagnosis without demonstration of the specific crystal type in the inflammatory joint fluid.

Pseudogout attacks closely resemble gouty arthritis; CPPD presents as intermittent flares and often is asymptomatic between flares. Trauma, surgery, or severe medical illness frequently provokes attacks of monosodium urate (MSU) as well as acute CPP arthritis. Systemic findings, such as fever; leukocytosis with a left shift in the differential count; inflammatory markers, such as elevated sedimentation rate (ESR); or C-reactive protein, also can occur, resembling pyogenic arthritis, osteomyelitis, and/or systemic sepsis in the elderly patient.

Diagnosis must be confirmed with aspiration, Gram stain and cultures of the synovial fluid, and evaluation for the presence of CPP crystals under polarized light microscopy.² The diagnosis can be difficult to confirm secondary to the weakly birefringent nature of CPP crystals.⁴ Coexistence of MSU and CPP crystals in a single inflammatory effusion is neither uncommon nor unexplained given increased frequencies of both hyperuricemia/gout and CC among elderly patients.⁵

Chronic CPP crystal inflammatory arthritis may present as a chronic, symmetrical, bilateral, and deforming polyarthritis. It frequently affects the wrists and metacarpophalangeal joints and tendon sheaths. Chronic CPP may resemble rheumatoid arthritis (RA) and produce wrist tenosynovitis, which may manifest as carpal tunnel syndrome and/or cubital tunnel syndrome. Calcium pyrophosphate deposition disease should be on the differential diagnosis in the elderly patient presenting with a clinical picture that resembles “seronegative” RA, with morning stiffness, synovial thickening, localized edema, and restricted motion due to active inflammation or flexion contracture of the hands/wrist. It may present with prominent systemic features, such as leukocytosis, fevers, mental confusion, and inflammatory oligoarthritis or polyarthritis. The diagnosis of CPPD still may be possible even though the rheumatoid factor (RF) is positive, given the increasing likelihood of elevated RF in the older population. In this setting, aspiration of joint fluid and radiography will assist in clarification of the diagnosis. Furthermore, CPPD typically does not cause the type of erosive disease that is often seen in RA.

Calcium pyrophosphate deposition disease also can mimic polymyalgia rheumatica (PMR). A direct comparison of a cohort of patients with pseudo-PMR (PMR/CPPD) with actual PMR patients found that increased age at diagnosis, presence of knee osteoarthritis, tendinous calcifications, and ankle arthritis carried the highest predictive value in patients with CPPD presenting with PMR-like symptoms.⁶ However, the PMR/CPPD variant can be difficult to distinguish, because both conditions can have elevated systemic inflammatory markers, and both are steroid responsive.

Calcium pyrophosphate deposition disease involving a single joint can rarely lead to extensive destruction—as with neuropathic joints in the absence of any neurologic deficits—and is extremely debilitating. This presentation is not well understood and does not have good treatment alternatives. Calcium pyrophosphate crystals often are associated with manifestations of OA.^1,2 Indeed, up to 20% of OA joints have been found to be positive for CPP crystals in various studies. Given the extensive evidence supporting treatment of OA, usually they are treated in a similar fashion with good results. Occasionally, these will have unusual manifestations for typical OA, such as involvement of wrists and metacarpophalangeal joints; however, the presentation is often indolent like OA.

Calcium pyrophosphate crystal deposition involving the spine has been associated with a number of clinical manifestations. Spine stiffness, sometimes associated with bony ankylosis, can resemble ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. Such symptoms are seen more commonly in familial CPPD rather than in the elderly. However, crystal deposition in the ligamentum flavum at the cervical spine levels has been associated with a condition called crowned dens syndrome.⁷ Although mostly asymptomatic, it may be present with acute neck pain, fever, and an increased ESR, sometimes mimicking PMR or giant cell arteritis or neurologic symptoms. Similarly, CPP crystal deposition in the posterior longitudinal ligament at the lower levels of the spine may lead to spinal cord compression syndromes or symptoms of either acute nerve compression or chronic spinal stenosis.^8,9 Calcium pyrophosphate crystal deposition also can occur in other soft tissues, such as bursae, ligaments, and tendons and may be sufficient to cause local nerve compression, such as carpal or cubital tunnel syndrome.

Epidemiology

Radiographic surveys of the knees, hands, wrists, and pelvis and epidemiologic studies have demonstrated an age-related increase in the prevalence of CPPD: 15% prevalence in patients aged 65 to 74 years, 36% prevalence in patients aged 75 to 84 years, and 50% prevalence in patients aged > 84 years.¹⁰ In a recent radiographic study, 40% of patients with CPPD did not present with CC of the knee, and the study’s authors recommended additional radiographs of pelvis, wrists, or hands for accurate diagnosis of radiographic CC.¹¹

Diagnosis

Accurate diagnosis should be achieved on the basis of the clinical picture and demonstration of CPP crystals in synovial fluid or tissue by compensated polarized light microscopy (Figures 1A and 1B).² The sensitivity and specificity for CPP crystal detection has been shown to be 95.9% and 86.5%, respectively.¹² However, the CPP crystal is more readily identified by a rheumatologist rather than in a standard hospital laboratory, which misses 30% of CPP crystals.¹³

Findings of CC on radiograph strengthens a CPPD diagnosis, but its absence does not rule it out (Figure 2A).² More recently, the use of new imaging modalities, such as musculoskeletal ultrasound, provides the capacity to visualize crystal deposits within the joint structures, the hyaline cartilage, and/or fibrocartilage (Figure 2B and 2C).¹⁴ The presence of hyperechoic bands within the intermediate layer hyaline cartilage and hyperechoic spots in fibrocartilage are consistent with CPP crystal deposits.^2,14 The use of computed tomography is the gold standard imaging modality for the identification of CPPD of the spine.¹⁵ There is not enough evidence to support the use of magnetic resonance imaging in CPPD, but it may play a role in rare complications.²

Treatment

The EULAR recently defined new guidelines for the management of CPPD.¹⁶ Asymptomatic CPPD needs no treatment.In other CPPD phenotypes, the goals are to attempt prompt resolution of the acute synovitis, reduction in chronic damage, and management of associated conditions.In acute attacks, treatment modalities used in gout are often required; however, data for CPPD treatment are limited (Table). Treatment relies on the use of colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs), but toxicity and comorbidities in the elderly limit the usage of these drugs.

Given increased renal impairment, the loading dose of colchicine is not recommended.¹⁶ Colchicine has recently been shown to completely block crystal-induced maturation of IL-1β in vitro, indicating that the drug acts upstream of inflammasome activation.¹⁷ This is in addition to the well-known role of colchicine in inhibition of micro-tubule formation, which likely leads to prevention of cell migration, phagocytosis, and activation of inflammasome.^18-20

Intra-articular injection of corticosteroid is an efficient and well-tolerated treatment alternative for monoarticular CPP flares. Oral or parenteral corticosteroids are frequently used for polyarticular flares in particular for those patients in which NSAIDs and colchicine are contraindicated.¹⁶ Parenteral adrenocorticotropic hormone has been used in patients with congestive heart failure, renal insufficiency, gastrointestinal bleeding, or resistance to NSAIDs.²¹ For prophylaxis of acute CPP crystal arthritis, a low dose of oral NSAIDs, oral colchicine, or prednisone may be used with good results.¹⁶ In chronic CPP arthritis, continuous use of colchicine, NSAIDs, or low-dose prednisone is often appropriate. If these interventions are ineffective or contraindicated, using hydroxychloroquine (HCQ) and methotrexate (MTX) have been successfully used to control chronic CPP crystal inflammation.^22,23 Recent trials have raised questions about MTX, and further trials on HCQ usage are underway.²⁴ Biologic agents targeting IL-1 are not currently approved for the treatment of CPPD, but there are suggestions that it may be effective in refractory cases and induce rapid stable remissions after 3 days of therapy.²⁵

In contrast to gout, there is no specific target therapy for lowering CPP crystal load in the elderly. Crucial in the management of CPPD in the elderly is the search for associated diseases, such as hyperparathyroidism, hemochromatosis, hypomagnesemia, and hypophosphatemia, as well as avoidance of tacrolimus, which facilitates or causes CC.¹⁶ Correction of the underlying metabolic disorder, especially when undertaken early, may reduce the severity of CPPD. However, there is little evidence to suggest that treatment of associated disease results in resolution of CPPD—most famously, although therapeutic phlebotomy does not help in hemochromatosis for prevention of crystal disease, chelating agents do seem to be moderately effective.²⁶ Only oral administration of magnesium has shown a reduction in meniscal CC in a patient with CPPD arthropathy.²⁷ In addition, this was in the setting of familial hypomagnesemia associated CPPD. However, unlike uricosuric agents for gout, no pharmacologic treatments can prevent CPPD crystal formation and deposition in tissues.

Therapeutic Agents

Magnesium

Magnesium is a cofactor for the activity of pyrophosphatases that converts inorganic pyrophosphates (PPis) into orthophosphates. In addition, magnesium can increase the solubility of CPP crystals. Early detection and management of hypomagnesemia are recommended, because it occurs in patients who have well-defined conditions and situations: Gitelman syndrome, thiazide and loop diuretics use, tacrolimus use, familial forms of renal magnesium wasting or use of proton pump inhibitors, short bowel syndrome, and intestinal failure in patients receiving home parenteral nutrition. Long-term administration of magnesium in some patients with chronic hypomagnesemia decreased meniscal calcification.^27-29

Dietary Calcium

Epidemiologic studies showed a lower incidence of CC in Chinese subjects. The authors of the study speculate that this lower prevalence of CPPD could result from high levels of calcium found in the drinking water in Beijing, which may affect parathyroid hormone secretion.³⁰ Further studies are needed to confirm this hypothesis, as it could be a cheaper approach to pseudogout prevention.

Probenecid

Probenecid is an in vitro inhibitor of the transmembrane PPi transporter thought to possibly prevent extracellular PPi elaboration. However, this observation has not been confirmed by either case reports or clinical trials.³¹

Phosphocitrate

Phosphocitrate acts directly on preventing crystal deposition in tissues in CPPD as well as BCP based on in vitro evidence and mouse models.^32,33

Hyaluronan

An amelioration of pain and increased range of motion were observed in radiographic CC with OA.³⁴ However, it is associated with increased acute CPP arthritis.³⁵

Radiosynovectomy

In a double-blind study of 15 patients with symmetrical CPPD arthropathy, the knee that underwent intra-articular injection of yttrium-90 (5 mCi) plus steroid had less pain, stiffness, joint line tenderness, and effusion compared with the contralateral control knee injected with saline and steroids.³⁶

Precipitators of Acute Pseudogout

Diuretics are known to exacerbate gout, but they also can exacerbate pseudogout. A recent case-control study nested within a United Kingdom general practice database found that loop diuretics rather than hydrochlorothiazide was associated with increased risk of CPPD mediated primarily by magnesium reabsorption in the loop of Henle.²⁸ Chronic kidney disease associated with secondary and tertiary hyperparathyroidism increases calcium or PPi concentration, which leads to CPP-crystal deposition.

In addition, multiple case reports have described acute pseudogout caused by bisphosphonate administration for osteoporosis or Paget disease—more likely in the elderly population. Intravenous pamidronate, oral etidronate, and alendronate therapy have all been described in the elderly.³⁷ The overall mechanism behind this link is not completely understood, but bisphosphonates are structurally similar to PPi. Pseudogout attacks also have been described in neutropenic patients undergoing treatment with granulocyte-colony stimulating factor.³⁸ In addition to pharmaceutical exacerbation of pseudogout, surgical procedures and trauma can precipitate attacks. Joint lavage has been described to increase the incidence of pseudogout.³⁹ It was hypothesized that joint lavage with fluid induced “crystal shedding” from CPPD crystals imbedded in the joint tissue. Patients who underwent meniscectomy of the knee 20 years ago had a 20% incidence of CC in the knee that was operated compared with 4% CC in the contralateral nonoperated knee.⁴⁰ Overall, the surgery most linked with a pseudogout attack, however, is parathyroidectomy.⁴¹

Basic Calcium Phosphate Crystals

Basic calcium phosphate crystals are common but rarely diagnosed due to the cumbersome and expensive methods required to identify these crystals.⁴²

Basic calcium phosphate and CPPD crystals may coexist in synovial fluid. Similar to CPPD, BCP crystal disease is often concurrent with OA and can cause calcification of articular cartilage. Basic calcium phosphate is more common than CPP crystals with occurrence of 30% to 50% in OA synovial fluid.⁴² Additionally, BCP crystal disease has been linked to increased severity of OA. Basic calcium phosphate crystals in knee joints were found to have radiographically more severe arthritis with larger effusions.^44,45 Similarly, BCP crystals in OA synovial fluid correlated with higher Kellgreen-Lawrence grade scores by radiography.^42,46

It is currently believed that BCP crystals are continuously formed in the extracellular matrix, and their deposition is actively prevented by PPi present in the matrix.⁴⁷ Elevated PPi levels, on the other hand, favor the formation of CPP crystals.⁴⁸ The clinical upshot seems to be that although CPP crystals are almost universally intra-articular and released by chondrocytes, BCD crystals and deposits are more frequently present in soft tissues.

Acute Calcific Tendinitis

Typically, this type of tendinitis involves the shoulder joint and is extra-articular. Common treatments help, including NSAIDs, intra-articular steroids, ice, and rest. In addition, high-energy extracorporeal shock wave therapy has been shown to be effective when used with conscious sedation.^49,50 Needling or barbotage in association with lavage and steroid injections also is effective and has occasionally been shown to reduce the size of the calcium deposit as well, often in combination with IV drugs like ethylenediaminetetraacetic acid.^51-53

Acute calcific periarthritis of the hand presents similar to gout or pseudogout, affecting the wrist, usually in postmenopausal women.⁵⁴ Basic calcium phosphate crystals are aspirated from the joint, and periarticular crystals may be subtle. Local steroid injections are beneficial.Milwaukee shoulder syndrome is an arthropathy associated with BCP crystals in the joint fluid and results in extensive destruction of shoulder articular cartilage and surrounding tissues. It is commonly bilateral and occurs in elderly women more often than it does in men.⁵⁵ Aspiration of the shoulder joint typically reveals a serosanginous fluid. Fluid samples can be assessed for hydroxyapatite crystals by staining with alizarin red dye, which produces a characteristic “halo” or orange-red stain by light microscopy.⁴³ Surgical treatment of Milwaukee shoulder syndrome is difficult due to increased age of the population affected and the severity of the shoulder destruction. Usually a conservative approach of analgesics, recurrent shoulder aspirations, and steroid injections is the best treatment option.

Conclusions

Calcium-containing crystal-associated arthropathies are a complex array of entities that target the veteran elderly population with increasing frequency. Challenges still remain in the diagnosis, crystal identification, and treatment due to coexisting comorbid conditions and polypharmacy commonly seen in veterans. Overall morbidity associated with calcium-containing crystal-associated arthropathies and the coexisting osteoarthritis is great, and focused identification of the disease process with tailored treatment can achieve the goal of decreasing symptoms and improving quality of life.

Acknowledgements
This work was supported by grant P20GM104937 (A.M.R.).

Calcium pyrophosphate (CPP) crystals may deposit in both articular tissues (predominantly hyaline cartilage and fibrocartilage) and periarticular soft tissues.^1,2 Calcium pyrophosphate deposition disease (CPPD) may be asymptomatic or be associated with a spectrum of clinical syndromes, including both acute and chronic inflammatory arthritis.²

The European League Against Rheumatism (EULAR) recently suggested changes in CPPD terminology.² According to the new EULAR classification, pseudogout, or CPPD, has been reclassified based on new key terms that include several of the previously described disease phenotypes: asymptomatic CPPD; acute CPP crystal arthritis (previously known as pseudogout); osteoarthritis (OA) with CPPD (previously, pseudo-OA); and the chronic CCP crystal inflammatory arthritis (previously, pseudorheumatoid arthritis). In similar fashion, chondrocalcinosis (CC) refers to calcification of the fibrocartilage and/or hyaline cartilage identified by imaging or histologic analysis. Although CC is most commonly seen in CPPD, it is not exclusive to this disease, as it can be seen in other crystal diseases (oxalosis, basic calcium phosphate [BCP]) and can appear as casual finding or coexist with OA.²

Clinical Manifestations

In clinical practice, CPPD may present with several phenotypic forms. In asymptomatic CPPD, CC is a common radiographic finding without clinical symptoms. Acute CPP arthritis always should be suspected in any patient aged > 65 years presenting with acute monoarticular or oligoarticular, migratory or additive, symmetrical, or polyarticular arthritis.³ Acute CCP arthritis is characterized by self-limited acute or subacute attacks of arthritis involving 1 or several extremity joints (knees, wrists, ankles; rarely affects large toe). Typically, the acute attacks last 7 to 10 days. Several unusual sites (eg, the hip joints, trochanteric bursa, and deep spinal joints) also may be affected. However, differences in pattern of joint involvement are insufficient to permit definitive diagnosis without demonstration of the specific crystal type in the inflammatory joint fluid.

Pseudogout attacks closely resemble gouty arthritis; CPPD presents as intermittent flares and often is asymptomatic between flares. Trauma, surgery, or severe medical illness frequently provokes attacks of monosodium urate (MSU) as well as acute CPP arthritis. Systemic findings, such as fever; leukocytosis with a left shift in the differential count; inflammatory markers, such as elevated sedimentation rate (ESR); or C-reactive protein, also can occur, resembling pyogenic arthritis, osteomyelitis, and/or systemic sepsis in the elderly patient.

Diagnosis must be confirmed with aspiration, Gram stain and cultures of the synovial fluid, and evaluation for the presence of CPP crystals under polarized light microscopy.² The diagnosis can be difficult to confirm secondary to the weakly birefringent nature of CPP crystals.⁴ Coexistence of MSU and CPP crystals in a single inflammatory effusion is neither uncommon nor unexplained given increased frequencies of both hyperuricemia/gout and CC among elderly patients.⁵

Chronic CPP crystal inflammatory arthritis may present as a chronic, symmetrical, bilateral, and deforming polyarthritis. It frequently affects the wrists and metacarpophalangeal joints and tendon sheaths. Chronic CPP may resemble rheumatoid arthritis (RA) and produce wrist tenosynovitis, which may manifest as carpal tunnel syndrome and/or cubital tunnel syndrome. Calcium pyrophosphate deposition disease should be on the differential diagnosis in the elderly patient presenting with a clinical picture that resembles “seronegative” RA, with morning stiffness, synovial thickening, localized edema, and restricted motion due to active inflammation or flexion contracture of the hands/wrist. It may present with prominent systemic features, such as leukocytosis, fevers, mental confusion, and inflammatory oligoarthritis or polyarthritis. The diagnosis of CPPD still may be possible even though the rheumatoid factor (RF) is positive, given the increasing likelihood of elevated RF in the older population. In this setting, aspiration of joint fluid and radiography will assist in clarification of the diagnosis. Furthermore, CPPD typically does not cause the type of erosive disease that is often seen in RA.

Calcium pyrophosphate deposition disease also can mimic polymyalgia rheumatica (PMR). A direct comparison of a cohort of patients with pseudo-PMR (PMR/CPPD) with actual PMR patients found that increased age at diagnosis, presence of knee osteoarthritis, tendinous calcifications, and ankle arthritis carried the highest predictive value in patients with CPPD presenting with PMR-like symptoms.⁶ However, the PMR/CPPD variant can be difficult to distinguish, because both conditions can have elevated systemic inflammatory markers, and both are steroid responsive.

Calcium pyrophosphate deposition disease involving a single joint can rarely lead to extensive destruction—as with neuropathic joints in the absence of any neurologic deficits—and is extremely debilitating. This presentation is not well understood and does not have good treatment alternatives. Calcium pyrophosphate crystals often are associated with manifestations of OA.^1,2 Indeed, up to 20% of OA joints have been found to be positive for CPP crystals in various studies. Given the extensive evidence supporting treatment of OA, usually they are treated in a similar fashion with good results. Occasionally, these will have unusual manifestations for typical OA, such as involvement of wrists and metacarpophalangeal joints; however, the presentation is often indolent like OA.

Calcium pyrophosphate crystal deposition involving the spine has been associated with a number of clinical manifestations. Spine stiffness, sometimes associated with bony ankylosis, can resemble ankylosing spondylitis or diffuse idiopathic skeletal hyperostosis. Such symptoms are seen more commonly in familial CPPD rather than in the elderly. However, crystal deposition in the ligamentum flavum at the cervical spine levels has been associated with a condition called crowned dens syndrome.⁷ Although mostly asymptomatic, it may be present with acute neck pain, fever, and an increased ESR, sometimes mimicking PMR or giant cell arteritis or neurologic symptoms. Similarly, CPP crystal deposition in the posterior longitudinal ligament at the lower levels of the spine may lead to spinal cord compression syndromes or symptoms of either acute nerve compression or chronic spinal stenosis.^8,9 Calcium pyrophosphate crystal deposition also can occur in other soft tissues, such as bursae, ligaments, and tendons and may be sufficient to cause local nerve compression, such as carpal or cubital tunnel syndrome.

Epidemiology

Radiographic surveys of the knees, hands, wrists, and pelvis and epidemiologic studies have demonstrated an age-related increase in the prevalence of CPPD: 15% prevalence in patients aged 65 to 74 years, 36% prevalence in patients aged 75 to 84 years, and 50% prevalence in patients aged > 84 years.¹⁰ In a recent radiographic study, 40% of patients with CPPD did not present with CC of the knee, and the study’s authors recommended additional radiographs of pelvis, wrists, or hands for accurate diagnosis of radiographic CC.¹¹

Diagnosis

Accurate diagnosis should be achieved on the basis of the clinical picture and demonstration of CPP crystals in synovial fluid or tissue by compensated polarized light microscopy (Figures 1A and 1B).² The sensitivity and specificity for CPP crystal detection has been shown to be 95.9% and 86.5%, respectively.¹² However, the CPP crystal is more readily identified by a rheumatologist rather than in a standard hospital laboratory, which misses 30% of CPP crystals.¹³

Findings of CC on radiograph strengthens a CPPD diagnosis, but its absence does not rule it out (Figure 2A).² More recently, the use of new imaging modalities, such as musculoskeletal ultrasound, provides the capacity to visualize crystal deposits within the joint structures, the hyaline cartilage, and/or fibrocartilage (Figure 2B and 2C).¹⁴ The presence of hyperechoic bands within the intermediate layer hyaline cartilage and hyperechoic spots in fibrocartilage are consistent with CPP crystal deposits.^2,14 The use of computed tomography is the gold standard imaging modality for the identification of CPPD of the spine.¹⁵ There is not enough evidence to support the use of magnetic resonance imaging in CPPD, but it may play a role in rare complications.²

Treatment

The EULAR recently defined new guidelines for the management of CPPD.¹⁶ Asymptomatic CPPD needs no treatment.In other CPPD phenotypes, the goals are to attempt prompt resolution of the acute synovitis, reduction in chronic damage, and management of associated conditions.In acute attacks, treatment modalities used in gout are often required; however, data for CPPD treatment are limited (Table). Treatment relies on the use of colchicine and nonsteroidal anti-inflammatory drugs (NSAIDs), but toxicity and comorbidities in the elderly limit the usage of these drugs.

Given increased renal impairment, the loading dose of colchicine is not recommended.¹⁶ Colchicine has recently been shown to completely block crystal-induced maturation of IL-1β in vitro, indicating that the drug acts upstream of inflammasome activation.¹⁷ This is in addition to the well-known role of colchicine in inhibition of micro-tubule formation, which likely leads to prevention of cell migration, phagocytosis, and activation of inflammasome.^18-20

Intra-articular injection of corticosteroid is an efficient and well-tolerated treatment alternative for monoarticular CPP flares. Oral or parenteral corticosteroids are frequently used for polyarticular flares in particular for those patients in which NSAIDs and colchicine are contraindicated.¹⁶ Parenteral adrenocorticotropic hormone has been used in patients with congestive heart failure, renal insufficiency, gastrointestinal bleeding, or resistance to NSAIDs.²¹ For prophylaxis of acute CPP crystal arthritis, a low dose of oral NSAIDs, oral colchicine, or prednisone may be used with good results.¹⁶ In chronic CPP arthritis, continuous use of colchicine, NSAIDs, or low-dose prednisone is often appropriate. If these interventions are ineffective or contraindicated, using hydroxychloroquine (HCQ) and methotrexate (MTX) have been successfully used to control chronic CPP crystal inflammation.^22,23 Recent trials have raised questions about MTX, and further trials on HCQ usage are underway.²⁴ Biologic agents targeting IL-1 are not currently approved for the treatment of CPPD, but there are suggestions that it may be effective in refractory cases and induce rapid stable remissions after 3 days of therapy.²⁵

In contrast to gout, there is no specific target therapy for lowering CPP crystal load in the elderly. Crucial in the management of CPPD in the elderly is the search for associated diseases, such as hyperparathyroidism, hemochromatosis, hypomagnesemia, and hypophosphatemia, as well as avoidance of tacrolimus, which facilitates or causes CC.¹⁶ Correction of the underlying metabolic disorder, especially when undertaken early, may reduce the severity of CPPD. However, there is little evidence to suggest that treatment of associated disease results in resolution of CPPD—most famously, although therapeutic phlebotomy does not help in hemochromatosis for prevention of crystal disease, chelating agents do seem to be moderately effective.²⁶ Only oral administration of magnesium has shown a reduction in meniscal CC in a patient with CPPD arthropathy.²⁷ In addition, this was in the setting of familial hypomagnesemia associated CPPD. However, unlike uricosuric agents for gout, no pharmacologic treatments can prevent CPPD crystal formation and deposition in tissues.

Therapeutic Agents

Magnesium

Magnesium is a cofactor for the activity of pyrophosphatases that converts inorganic pyrophosphates (PPis) into orthophosphates. In addition, magnesium can increase the solubility of CPP crystals. Early detection and management of hypomagnesemia are recommended, because it occurs in patients who have well-defined conditions and situations: Gitelman syndrome, thiazide and loop diuretics use, tacrolimus use, familial forms of renal magnesium wasting or use of proton pump inhibitors, short bowel syndrome, and intestinal failure in patients receiving home parenteral nutrition. Long-term administration of magnesium in some patients with chronic hypomagnesemia decreased meniscal calcification.^27-29

Dietary Calcium

Epidemiologic studies showed a lower incidence of CC in Chinese subjects. The authors of the study speculate that this lower prevalence of CPPD could result from high levels of calcium found in the drinking water in Beijing, which may affect parathyroid hormone secretion.³⁰ Further studies are needed to confirm this hypothesis, as it could be a cheaper approach to pseudogout prevention.

Probenecid

Probenecid is an in vitro inhibitor of the transmembrane PPi transporter thought to possibly prevent extracellular PPi elaboration. However, this observation has not been confirmed by either case reports or clinical trials.³¹

Phosphocitrate

Phosphocitrate acts directly on preventing crystal deposition in tissues in CPPD as well as BCP based on in vitro evidence and mouse models.^32,33

Hyaluronan

An amelioration of pain and increased range of motion were observed in radiographic CC with OA.³⁴ However, it is associated with increased acute CPP arthritis.³⁵

Radiosynovectomy

In a double-blind study of 15 patients with symmetrical CPPD arthropathy, the knee that underwent intra-articular injection of yttrium-90 (5 mCi) plus steroid had less pain, stiffness, joint line tenderness, and effusion compared with the contralateral control knee injected with saline and steroids.³⁶

Precipitators of Acute Pseudogout

Diuretics are known to exacerbate gout, but they also can exacerbate pseudogout. A recent case-control study nested within a United Kingdom general practice database found that loop diuretics rather than hydrochlorothiazide was associated with increased risk of CPPD mediated primarily by magnesium reabsorption in the loop of Henle.²⁸ Chronic kidney disease associated with secondary and tertiary hyperparathyroidism increases calcium or PPi concentration, which leads to CPP-crystal deposition.

In addition, multiple case reports have described acute pseudogout caused by bisphosphonate administration for osteoporosis or Paget disease—more likely in the elderly population. Intravenous pamidronate, oral etidronate, and alendronate therapy have all been described in the elderly.³⁷ The overall mechanism behind this link is not completely understood, but bisphosphonates are structurally similar to PPi. Pseudogout attacks also have been described in neutropenic patients undergoing treatment with granulocyte-colony stimulating factor.³⁸ In addition to pharmaceutical exacerbation of pseudogout, surgical procedures and trauma can precipitate attacks. Joint lavage has been described to increase the incidence of pseudogout.³⁹ It was hypothesized that joint lavage with fluid induced “crystal shedding” from CPPD crystals imbedded in the joint tissue. Patients who underwent meniscectomy of the knee 20 years ago had a 20% incidence of CC in the knee that was operated compared with 4% CC in the contralateral nonoperated knee.⁴⁰ Overall, the surgery most linked with a pseudogout attack, however, is parathyroidectomy.⁴¹

Basic Calcium Phosphate Crystals

Basic calcium phosphate crystals are common but rarely diagnosed due to the cumbersome and expensive methods required to identify these crystals.⁴²

Basic calcium phosphate and CPPD crystals may coexist in synovial fluid. Similar to CPPD, BCP crystal disease is often concurrent with OA and can cause calcification of articular cartilage. Basic calcium phosphate is more common than CPP crystals with occurrence of 30% to 50% in OA synovial fluid.⁴² Additionally, BCP crystal disease has been linked to increased severity of OA. Basic calcium phosphate crystals in knee joints were found to have radiographically more severe arthritis with larger effusions.^44,45 Similarly, BCP crystals in OA synovial fluid correlated with higher Kellgreen-Lawrence grade scores by radiography.^42,46

It is currently believed that BCP crystals are continuously formed in the extracellular matrix, and their deposition is actively prevented by PPi present in the matrix.⁴⁷ Elevated PPi levels, on the other hand, favor the formation of CPP crystals.⁴⁸ The clinical upshot seems to be that although CPP crystals are almost universally intra-articular and released by chondrocytes, BCD crystals and deposits are more frequently present in soft tissues.

Acute Calcific Tendinitis

Typically, this type of tendinitis involves the shoulder joint and is extra-articular. Common treatments help, including NSAIDs, intra-articular steroids, ice, and rest. In addition, high-energy extracorporeal shock wave therapy has been shown to be effective when used with conscious sedation.^49,50 Needling or barbotage in association with lavage and steroid injections also is effective and has occasionally been shown to reduce the size of the calcium deposit as well, often in combination with IV drugs like ethylenediaminetetraacetic acid.^51-53

Acute calcific periarthritis of the hand presents similar to gout or pseudogout, affecting the wrist, usually in postmenopausal women.⁵⁴ Basic calcium phosphate crystals are aspirated from the joint, and periarticular crystals may be subtle. Local steroid injections are beneficial.Milwaukee shoulder syndrome is an arthropathy associated with BCP crystals in the joint fluid and results in extensive destruction of shoulder articular cartilage and surrounding tissues. It is commonly bilateral and occurs in elderly women more often than it does in men.⁵⁵ Aspiration of the shoulder joint typically reveals a serosanginous fluid. Fluid samples can be assessed for hydroxyapatite crystals by staining with alizarin red dye, which produces a characteristic “halo” or orange-red stain by light microscopy.⁴³ Surgical treatment of Milwaukee shoulder syndrome is difficult due to increased age of the population affected and the severity of the shoulder destruction. Usually a conservative approach of analgesics, recurrent shoulder aspirations, and steroid injections is the best treatment option.

Conclusions

Calcium-containing crystal-associated arthropathies are a complex array of entities that target the veteran elderly population with increasing frequency. Challenges still remain in the diagnosis, crystal identification, and treatment due to coexisting comorbid conditions and polypharmacy commonly seen in veterans. Overall morbidity associated with calcium-containing crystal-associated arthropathies and the coexisting osteoarthritis is great, and focused identification of the disease process with tailored treatment can achieve the goal of decreasing symptoms and improving quality of life.

Acknowledgements
This work was supported by grant P20GM104937 (A.M.R.).