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Crystal Arthropathies

  • Eleftherios Pelechas
  • Evripidis Kaltsonoudis
  • Paraskevi V. Voulgari
  • Alexandros A. Drosos
Chapter
  • 1.3k Downloads

Abstract

Crystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints which lead to joint destruction and soft tissue disturbances (swelling, redness, masses etc.). Clinical presentations of the different types of crystal arthropathies are often characteristic enough to differentiate them from each other, but mistakes can be made, leading to delayed or incorrect management. Gout is the most common form of crystal arthropathies. First identified by the Egyptians in 2640 BC and later by Hippocrates in the 5th century BC, who referred to as “the unwalkable disease”. Throughout history, gout has been associated with rich foods and excessive alcohol consumption and has been referred to as the “disease of kings”. Calcium pyrophosphate dihydrate disease (CPPD/pseudogout) and basic calcium phosphate (BCP/hydroxyapatite) are the two other forms of crystal arthropathies.

12.1 Introduction

Crystal arthropathies are a group of joint disorders due to deposition of crystals in and around joints which lead to joint destruction and soft tissue disturbances (swelling, redness, masses etc.). Clinical presentations of the different types of crystal arthropathies are often characteristic enough to differentiate them from each other, but mistakes can be made, leading to delayed or incorrect management. Gout is the most common form of crystal arthropathies. First identified by the Egyptians in 2640 BC and later by Hippocrates in the 5th century BC, who referred to as “the unwalkable disease”. Throughout history, gout has been associated with rich foods and excessive alcohol consumption and has been referred to as the “disease of kings”. Calcium pyrophosphate dihydrate disease (CPPD/pseudogout) and basic calcium phosphate (BCP/hydroxyapatite) are the two other forms of crystal arthropathies.

12.2 Epidemiology

Gout is the most common form of inflammatory arthritis. The reported prevalence of gout worldwide ranges from 0.1% to approximately 10%, and the incidence from 0.3 to 6 cases per 1000 person-years. Both prevalence and incidence is highly variable across various regions of the world. Developed countries show a higher prevalence than developing countries. Major risk factors for gout include hyperuricaemia, genetics, dietary factors, medications, comorbidities and exposure to lead.

Pseudogout needs the identification of CPPD crystals in joint fluid or articular tissue in order to make a diagnosis. Because joint aspiration or biopsy is impractical in population studies, presence of radiographic chondrocalcinosis often has been used in epidemiologic and clinical investigations to study CPPD disease. The prevalence of radiographic chondrocalcinosis in the knee joints varies from less than 4% in those under age 70–27% in those over 85. Mean age at presentation is between sixth and seventh decades of life. Female to male ratio is 2–3:1. Most studies agree that the prevalence of radiographic chondrocalcinosis increases with age.

BCP deposition is usually asymptomatic but can potentially lead to destructive arthropathy. The epidemiology of BCP crystal deposition is poorly understood. Although periarticular BCP crystal deposits occurs at all ages and in both sexes, intra-articular BCP crystal deposition tends to associate with increasing age and OA.

12.3 Aetiopathogenesis

Gout is the result of the pathogenic effect of monosodium urate (MSU) crystals in the joints and soft tissue. Uric acid comes from the metabolism of purine nucleotides. Purine metabolism leads to inosine then hypoxanthine. Hypoxanthine is metabolised to xanthine, which is metabolised to uric acid. The enzyme xanthine oxidase catalyzes the last two steps and is the major site for pharmacologic intervention by allopurinol. If the body is unable to metabolise urate, hyperuricaemia develops. As urate levels increase, crystals develop and precipitate into the joint leading to arthritis. Urate crystals activate monocytes and macrophages which try to clear the crystals by phagocytosis. This leads to the release of proinflammatory cytokines and chemokines triggering a cascade of acute inflammatory reaction. An additional proposed mechanism involves the role of an inflammasome and interleukin (IL)-1 in the pathogenesis of inflammation induced by MSU and CPPD. Pathogenesis of BCP is complex. It can be secondary to intracellular calcium increase, leading to the activation of calcium-dependent pathways.

12.4 Classification Criteria

The 2015 American College of Rheumatology / European League Against Rheumatism (ACR/EULAR) classification criteria for gout are the latest ones. The entry criterion is at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa. Presence of MSU crystals in a symptomatic joint or bursa or tophus is a sufficient criterion. There are also clinical, laboratory and imaging criteria. The entry criterion must be met. If sufficient criterion is met, patient is classified as having gout without applying other criteria. If not, a score ≥8 is required to classify as gout. If serum urate <4 mg/dL a score of −4 points is applied; if serum urate ≥4–6 mg/dL the score is 0 points; if ≥6–8 mg/dL the score is 2; if ≥8–10 mg/dL the score is 3; if >10 mg/dL then the score is 4. If polarizing microscopy of synovial fluid from a symptomatic joint or bursa by a trained examiner fails to show MSU crystals, then −2 points. If synovial fluid was not assessed, the score is 0. If imaging evidence of urate deposition in symptomatic joint or bursa or gout-related joint damage, the score is 4; if absent or not done, the score is 0.

12.5 Signs and Symptoms

Gout is clinically manifested as acute inflammation of the involved joint or soft tissue. In general, gout includes joint swelling in both the lower and upper extremities with a predilection to the first metatarsophalangeal (MTP) joint (podagra). Any peripheral joint can be involved (feet, ankles, knees, hands, wrists, elbows). Acute gout can also occur in the bursae, such as the olecranon or prepatellar bursae, where it causes bursitis. Tendons, such as the Achilles tendon can also be involved. Systemic manifestations such as fever and malaise may develop. The arthritis in acute gout usually manifests as asymmetric monoarticular or oligoarticular inflammation. Without treatment it may last for 3–10 days, and resolves spontaneously, but when the attacks occur more frequently, they tend to last longer and do not resolve completely leading to chronic gouty arthropathy. Chronic arthropathy eventually leads to erosions and joint destruction.

CPPD encompasses a variety of clinical manifestations. It may be asymptomatic, but it may mimic gout (pseudogout), rheumatoid arthritis (RA) (pseudo-rheumatoid arthritis), and OA (pseudo-OA). The knee is the most commonly affected joint, followed by the wrist. Acute podagra involving the 1st MTP joint is rare. In contrast to the brief attacks of acute gouty arthritis that last only some days, acute attacks of CPPD disease may last for weeks to months. It is important to remember that CPPD disease can be a presenting sign of hyperparathyroidism, hypophosphatasaemia or other metabolic disorders. Thus, an appropriate screening is indicated, especially in patients younger than 60 years of age who present with CPPD symptoms. Similar to gout, CPPD disease can manifest with systemic features such as fever and malaise, especially in the elderly. The acute attacks can involve one or multiple joints.

BCP crystals are mainly responsible for acute periarthritis that involves all possible tendon or capsular sites. The most affected site is the shoulder. The formed calcifications can be unfragmented and dense, with a round shape, at the asymptomatic phase. When they start to be fragmented the inflammation starts provoking pain and even limited range of motion (ROM) of the affected joint.

12.6 Diagnostic Modalities

Synovial fluid analysis is considered the technical standard for evaluating patients with gout or acute CPPD arthritis not only as a diagnostic procedure but also to rule out septic arthritis. The collected fluid needs to be processed by Gram stain, culture, and microscopic examination. The white blood cell count is useful to estimate the degree of inflammation. Under polarized light, MSU crystals are strongly negative birefringent and have a needle-shape, whereas CPPD crystals are weakly birefringent and have a rhomboid shape. BCP crystals are not detectable by light polarized microscopy. Alizarin red staining can provide information on BCP crystals.

Laboratory tests such as serum urate levels, acute phase reactants, serum creatinine, full blood count (FBC) and liver function tests (LFTs) are useful for evaluating other comorbid diseases or to monitor and adjust the dose of urate-lowering therapy. Of note, serum urate levels are not helpful indicators during acute gouty attacks because they can fluctuate from low to high. Measuring a 24 h collection of urine urate is a very useful test to identify patients who overproduce urate. BCP disease may present with no laboratory abnormalities.

Imaging studies:

a high-end musculoskeletal ultrasound (MSUS) equipment can detect crystal depositions before they can be seen on plain x-rays. MSUS is a not invasive, safe, easily accessible and a well-accepted imaging technique by the patient. In gout, MSUS can be useful for the diagnosis and management from the initial manifestations of the disease in comparison with other imaging modalities. Specific signs in gout are the double contour sign, aggregates and tophi. The double contour sign is defined as an abnormal hyperechoic band over the superficial margin of the hyaline cartilage (HC). As non-specific findings, inflammatory abnormalities (joint effusion and synovial hypertrophy) and structural lesions (such as bone erosions) can be detected.

Gout – radiographic findings: Urate crystal deposits in tissues with poor blood supply such as cartilage, tendon, sheaths, bursae etc. Acute attacks occur at the night when the blood supply of the body is decreased and the body temperature is low. Both these factors facilitate urate crystal precipitation. Only 45% of patients with gout manifest radiographic bone changes and then only 6–8 years after the first attack. The radiographic changes indicate the chronicity of the disease process.

Gouty arthritis has several characteristic radiographic features. Erosions, which are usually sharply marginated, are initially periarticular in location and are later seen to extent into the joint. An overhanging edge of erosion is a frequent identifying feature. Usually, there is a striking lack of osteoporosis, a feature helpful in differentiating this condition from RA. The reason of this is that acute gouty attack is short in duration to allow the development of the periarticular osteoporosis so often seen in RA patients. Other radiographic features of chronicity in gout attack is punched-out erosions with sclerotic borders. Chronic tophaceous arthritis is created by the deposition of urate crystals in soft tissues. Tophi are dense tissue masses usually found in the periarticular area along the extensor surface of the bone. Urate crystals are not radio-opaque. However, calcium may precipitate with the urate crystals to varying degrees, creating variation in the density of tophi.

CPPD has characteristic findings on plain x-rays. Conventional radiographs provide important evidence for the diagnosis of CPPD disease and may assist to differentiate CPPD from other types of arthritis. Although chondrocalcinosis is the radiographic finding that is most closely aligned with CPPD disease, other radiographic findings may assist to differentiate primary OA from CPPD. These include: hook-like osteophytes involving the metacarpophalangeal (MCP) joints, annulus fibrosus calcification, disc degeneration with vacuum phaenomenon and subchondral erosions, and vacuum phaenomenon of the sacroiliac joints as far as it concerns the axial skeleton. Other radiographic features include radio-carpal or patello-femoral narrowing of the joint space with cysts formation and subchondral collapse. Chondrocalcinosis is seen in the knees, the wrists, and other joints such as intervertebral discs and symphysis pubis.

Hydroxyapatite deposition disease: the radiographic findings are the following: Periarticular calcification (a. early deposition in linear and poorly defined, often blending with the soft tissue, b. with time the calcifications become denser, homogeneous, well-delineated and circular).

Soft tissue swelling, with occasional reactive sclerosis. Single-joint distribution. Occasionally multiple joints. Distribution in shoulders, hip, wrists, elbow, and neck in decreasing order of frequency. Finally, in crystal arthropathies, other imaging modalities are used when indicated such as computed tomography (CT) and magnetic resonance imaging (MRI).

12.7 Management

The main concern in the acute attacks of crystal arthropathies is to reduce inflammation and pain, and also to prevent future joint erosions and flares. Treatment depends on the clinical presentation and findings. Non-steroidal anti-inflammatory drugs (NSAIDs), colchicine, corticosteroids (CS), interleukin (IL)-1 inhibitors and urate-lowering drugs can be used depending on the clinical presentation.

Fig. 12.1

Gout – acute arthritis

Acute arthritis in gout, typically affects the first MTP and it is called podagra. Figure 12.1a depicts a patient with gout. It was the first attack, with mild to moderate erythema of the 1st MTP, mild oedema and tenderness on palpation. Figure 12.1b, shows a patient with recurrent attacks. There is a dusky, shiny erythema overlying swollen 1st MTP joint. This patient was unable to weight bear due to excruciating pain even in mild movements of his foot. He was a heavy drinker and was not taking any medicines for gout prophylaxis. In Fig. 12.1c and d another example of an acute episode of gout is shown with the corresponding plain radiograph. Note the bone erosions and cyst formation affecting the 1st and 5th MTP joints (white arrows) and the swelling of the soft tissue around the 1st MTP joint (white arrowheads). Occasionally, ankle, other toes, knees or fingers (Fig. 12.1e) are affected (black arrowheads).

Fig. 12.2

Chronic tophaceous gout

Tophaceous gout is a chronic form of gout. For reasons that remain unclear, not all gouty patients present with acute arthritis as the first sign. In Fig. 12.2ac, tophi have been developed on the fingers of those patients (white arrows). Tophi, are usually painless, hard deposits of uric acid that can appear virtually at any joint. Tophaceous deposits can be distinguished from calcinosis by their radiological appearance. Calcinotic deposits are more radio-opaque than tophaceous and are often described as giving a “halo” effect (see below – Fig. 12.5a). Other, less common affected sites are the elbows. In Fig. 12.2d and e, there is a patient with chronic gouty olecranon bursitis bilaterally. Gout may be presented for the first time as an acute olecranon bursitis. In order to set a correct diagnosis, the clinician should aspirate a sample for analysis. MSU crystals ingested by polymorphonuclear leucocytes under the microscope, will confirm the diagnosis. Renal function test should always be investigated in such patients.

Fig. 12.3

Acute and chronic features of gout

A patient with chronic manifestations of gout should be on lifelong treatment for the prevention of recurrences. This patient has a large tophus on the 1st MTP (white arrowhead) as well as two smaller on the distal interphalangeal joint (DIP) of the second toe of the foot (black arrowheads). He discontinued the treatment on his own and developed de novo an acute gout flare of the 1st MTP.

Fig. 12.4

Severe cases of tophaceous gout

In the above figures, patients are suffering from longstanding tophaceous gout. Nodular masses of uric acid crystals (tophi) are deposited in various soft tissue areas of the body. Large tophi can easily be seen in Fig. 12.4ad, which can lead to disastrous effects of the affected joints. In Fig. 12.4d some tophi have been ulcerated. Figure 12.4e shows a patient with an ulcerating tophus associated with chronic gouty arthritis of the DIP joint of the middle finger. Patients with tophaceous gout rarely develop ulcers, but when they do occur, these ulcers are difficult to treat. IL-1 inhibitors are used in refractory chronic tophaceous cases.

Fig. 12.5

Radiographic findings in gout

In the acute setting of the first gout arthritis there may not be present any radiographic findings. Erosions may appear after years, usually 6-8 years after the initial attack. The feet and hands are commonly affected in an asymmetric pattern. Tophaceous deposits can be distinguished from calcinosis by their radiological appearance (Fig. 12.5ad). They are less radio-opaque than calcinotic deposits and are often described as giving a “halo” effect (white arrowheads – Fig. 12.5a). Punched-out erosions (or mouse bitten) are very typical for patients with gout (white arrows – Fig. 12.5b, c). As the erosion develops, the edges of the cortex can be remodeled in an outward fashion, creating an overhanging edge (yellow arrows – Fig. 12.5a, b). Intra-osseous lesions are another finding consisting of intra-osseous tophus with or without calcification that tend to expand (yellow arrowhead). In contrast to RA, there is no periarticular osteopenia. Of note is that such erosions are rare findings in the shoulders. Figure 12.5d shows tophaceous deposits in the acromioclavicular joint (yellow arrowhead).

Fig. 12.6

Imaging findings in gout: elbow, knees

Elbows are frequently affected but usually the soft tissue is involved by the presence of swelling of the olecranon bursae (see Figs. 12.2d, e). Gout must always be considered in patients with unilateral olecranon bursitis. If bilateral, gout is usually the diagnosis. If the adjacent bone is involved, it may be either erosive or proliferative. In Fig. 12.6a, punched-out erosions with sclerotic borders involving the humeral condyles are seen (white arrowheads). Of note, the tophaceous deposit in the olecranon bursa (white arrow). MSUS (Fig. 12.6b) depicts olecranon bursitis in longitudinal view with a fluid filled bursa (*) and tophaceous deposits (yellow arrows).

Figure 12.6c shows the knee of a patient with the characteristic ultrasonographic finding “double-contour sign” (yellow arrowheads) in a transverse MSUS image of the suprapatellar knee joint. Two parallel hyperechoic contours on either side of the hypoechoic HC are clearly seen. The lower echogenic contour (yellow arrowheads) represents the femoral cortex, while the upper echogenic contour (red arrowheads) represents uric acid crystals accumulating on the surface of the hypoechoic HC.

In Fig. 12.6d, the knees of a patient with chronic tophaceous gout. Punched-out erosions of the femoral and tibial condyles are seen (blue arrowheads) with scattered periarticular tophaceous deposits (blue arrows).

Figure 12.6a and d are rare cases of gout patients without receiving the appropriate treatment.

Fig. 12.7

Calcium pyrophosphate dehydrate crystal deposition disease

CPPD is observed more frequently with increasing age. Examination of the joint fluid reveals rhomboidal, weakly positively birefringent intra- and extracellular crystals of calcium pyrophosphate whereas in gout the joint fluid reveals needle-shaped, strongly negatively birefringent crystals of monosodium urate.

Figure 12.6a shows a patient 73-years old with a CPPD attack. The term chondrocalcinosis should be reserved for the radiological appearance of calcification of articular cartilage. There is marked redness and swelling of the right foot and the patient could not weight bear.

The typical clinical picture mimics acute urate gout, although it usually affects the wrist, knee or ankle. In Fig. 12.7b and c, there is chronic deposition of calcium pyrophosphate in the fibrocartilaginous menisci (white arrows) and in the HC. MSUS is a very useful imaging modality that helps identifying those deposits (Fig. 12.7d – blue arrows), because the HC of the knees is normally completely anechoic. Another site is the symphysis pubis (Fig. 12.7e – yellow circle). CPPD in the symphysis pubis is not a common finding.

Fig. 12.8

Calcification of the hyaline cartilage

CPPD in the HC produces a fine line of calcification parallel to the surface of the bone as seen in Fig. 12.8a and b (humeral head – white arrowheads).

The knee joint is commonly affected. After the knee, the wrist is the second most commonly affected joint, with deposits usually appearing in the triangular ligament.

About 5% of patients with widespread chondrocalcinosis have a chronic inflammatory arthritis which mimics RA.

In younger patients who demonstrate symptomatic or even asymptomatic chondrocalcinosis on x-rays, associated diseases such as hyperparathyroidism, haemochromatosis or hypothyroidism should be excluded.

Fig. 12.9

Hydroxyapatite crystal deposition disease (HADD)

HADD is a disease with peri- and intra-articular deposition of hydroxyapatite or BCP crystals (yellow rectangles). Early deposition appears as a linear and poorly defined calcification often blending with the soft tissue (Fig. 12.9a), but by the time the depositions become as those in Fig. 12.9bd. In the latter figures, there are well circumscribed, amorphous calcifications not containing trabeculae adjacent to the greater trochanter of the left femur and the greater tubercle of the right humerus respectively. This condition is very common and causes severe pain and functional disability of the affected joint. Figure 12.9e shows calcifications of the supraspinatus as seen by the use of MSUS (white arrows).

Fig. 12.10

Crowned dens syndrome

The “crowned” dens syndrome is the result of crystal deposition in the cruciform and alar ligaments surrounding the dens. It is a rare form of calcium crystal deposits and often presents with recurrent neck pain, stiffness of neck, increased inflammatory markers and fever. The typical image appears as a radiopaque “crown” around the odontoid process which is a curvilinear calcification of the transverse ligament of the atlas. In this CT scan you can notice the crystal deposition surrounding the dens (white arrows). This patient was admitted to the hospital due to localised pain at the back of the neck with neck stiffness and elevated inflammatory markers.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Eleftherios Pelechas
    • 1
  • Evripidis Kaltsonoudis
    • 1
  • Paraskevi V. Voulgari
    • 1
  • Alexandros A. Drosos
    • 1
  1. 1.Rheumatology Clinic - Department of Internal MedicineUniversity of IoanninaIoanninaGreece

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