Calcific Periarthritis

Calcific scapulohumeral periarthritis was first described in 1870 and radiographic demonstration of periarticular shoulder calcifications was accomplished by 1907. Initially these calcifications were thought to have arisen in the subdeltoid bursa but were subsequently demonstrated to occur chiefly in the supraspinatus tendon or the shoulder joint capsule. Years later in 1938, further descriptions of calcific periarthritis of the shoulder heralded a revival of interest in the syndrome and also the recognition of periarticular calcifications at other sites. Another generation later in 1966, it was recognized that the calcific material consisted primarily of HA. This paved the way for the development of the theory that the pathogenic mechanism of calcifying tendonitis is a unique disorder of the musculotendinous junction involving primary tendon necrosis leading to secondary calcification. Subsequently, aggregated clumps of what have become known as BCP crystals and their various crystalline structures, chemical compositions, and physical properties have been further defined using various ultrastructural and microanalytical techniques. These modern tools include standard microscopy with staining, electron microscopy, x-ray diffraction, atomic force microscopy, Raman and Fourier transformation infrared spectroscopy, radioactive assays, and some novel developments involving tetracycline binding and modified paramagnetic beads. These developments have enhanced our understanding of the bioactive nature of BCP crystals and have led to a renewed interest in their pathogenic potential.

Intraarticular BCP Crystal Disease

Robert Adams, the famed nineteenth-century Irish surgeon, in what he termed “chronic rheumatic arthritis of the shoulder” in 1857, is credited with the earliest description of the pathologic consequences and anatomic structural damage due to intraarticular BCP crystal deposition. In 1934, Codman reported what he called a “subacromial space hygroma” in a middle-aged woman who presented with recurrent shoulder joint effusions, absent rotator cuff, cartilaginous bodies attached to the synovial tissue, and severe destructive glenohumeral arthritis. These clinical descriptions were made without the benefit of modern radiologic investigations or diagnostic tests and were primarily based on direct visualization during operative surgery or at postmortem examination. This condition has subsequently been known by many different names. In the French literature, the terms les caries séniles hémorragique de l’épaule and l’arthropathie destructrice rapide de l’épaule have been used, and in the English literature, terms such as “cuff-tear arthropathy” appear. Common to all of these descriptions is the preponderance of elderly female patients with primary involvement of the shoulder joint.

The identification of BCP crystal deposition in articular cartilage (both hyaline and meniscal) and its association with joint disease is a much more recent discovery. Electron microscopic evaluation of synovial fluid led to the first description in 1976 of BCP crystal aggregates in patients with OA, albeit that the presence of solid deposits of BCP crystals in knee menisci had been noted 10 years previously in a report detailing pathologic postmortem findings. This finding that clumps of BCP crystals are present in the synovial fluid of patients with degenerative joint disease was later confirmed by others. In a seminal paper, Dan McCarty’s group described a large joint destructive arthropathy, most commonly affecting the shoulder joint and mostly seen in elderly women, and called it “Milwaukee shoulder.” They noted the presence of large quantities of BCP crystals and collagenase in the synovial fluid, and they hypothesized that the BCP crystals played a major causal role in the associated joint destruction. Subsequently, others noted that many large joints could be involved and terms such as apatite-associated destructive arthritis and idiopathic destructive arthritis of the shoulder were added to the list of names. BCP crystals were also described in the joint fluids of a few patients with acute synovitis and other forms of arthropathy.

Calcific Periarthritis

Juxtaarticular BCP crystal deposits are often asymptomatic and are most commonly discovered as an incidental finding on plain film radiography. One large scale study of approximately 12,000 shoulder joints of white collar workers published in 1941 reported a prevalence of approximately 3% of calcific shoulder deposits in a predominantly Caucasian population, of which only slightly more than one third were associated with clinical problems. Interestingly, the prevalence was highest (about 20%) in the younger cohort (31 to 40 years of age), with a clear female predominance. No comparable epidemiologic data have been reported subsequently, although a number of smaller pathologic and radiographic studies have documented the relatively high frequency of periarticular calcification. In contrast to intraarticular BCP crystal deposition, calcific periarthritis has been reported in children as young as 3 years old but appears to be relatively uncommon in the elderly. This suggests that many of the calcific deposits seen in young adults must disappear spontaneously. However, there remains a paucity of hard epidemiologic data related to this relatively common phenomenon.

Periarticular BCP Deposition

Juxtaarticular BCP crystal deposition may occur in bursae, tendons, ligaments, joint capsules, and soft tissues. These periarticular crystal deposits are often asymptomatic but are also associated with a number of clinical syndromes. The most well-recognized presentation is that of acute calcific periarthritis. This is an acute inflammatory syndrome mainly affecting the shoulder but it can occur in association with almost any joint. The vast majority of cases present spontaneously with a sudden onset, and if there is a history of trauma, it is usually mild and related to overuse. Presenting features include all the cardinal signs of acute inflammation. Patients complain of sudden onset of severe pain followed by local swelling, heat, and erythema of the overlying skin. The pain is exacerbated by both active and passive movement of the joint, and there is extreme local tenderness. When the shoulder is affected, the pain is usually felt in the subacromial region with radiation distally, and there is marked rotator cuff tenderness. Both glenohumeral and scapulothoracic movements are voluntarily restricted due to pain. As symptoms typically take up to 3 weeks to resolve, the lack of shoulder mobilization may lead to the development of a “frozen shoulder.”

The syndrome of calcific periarthritis is thought to arise following rupture of a previously quiescent calcific deposit into the adjacent soft tissue or bursa, thus initiating an acute inflammatory reaction. However, it remains unclear why this rupture occurs as most cases arise spontaneously in the absence of any clear precipitant. When the shoulder joint is affected, this rupture of crystalline material (arising most commonly from the supraspinatus tendon) often induces an intense inflammatory reaction involving the subacromial bursa. The dense radiographic appearance of calcium deposits with well-defined borders seen in asymptomatic individuals before an attack is in contrast to often blurred and poorly defined calcification on plain film radiographic imaging during an acute attack ( Fig. 22-1 ). Consequently, patients presenting with suspected calcific periarthritis may require further imaging during an acute episode. Figure 22-2 illustrates the contemporaneous CT images in the sagittal ( Fig. 22-2 , A ) and axial ( Fig. 22-2 , B ) planes of the same shoulder joint depicted in the plain radiograph of Figure 22-1 , with a much clearer delineation of the size, location, and extent of the calcific deposit in the supraspinatus tendon. While the shoulder joint is by far the most commonly affected site, other large peripheral joints such as the hip, knee, elbow, wrist, and ankle may also be affected. The smaller peripheral joints of the hands and feet are rarely involved, apart from the first metatarsophalangeal joint of the foot (which may simulate an attack of gout in an otherwise healthy young woman), a condition known as “hydroxyapatite pseudopodagra,” which is characterized by amorphous calcium crystal deposition in periarticular tendons, bursae, and ligaments. Acute neck pain attributed to calcifications surrounding the odontoid process has been described and called the “crowned dens” syndrome. These calcifications appear to be composed of apatite or calcium pyrophosphate dihydrate (CPPD), or a combination of both, although analytical data of the exact biochemical nature of these calcified deposits are limited.

Plain film radiograph (AP view) of the right shoulder in a patient with clinical calcific periarthritis. Note the blurred hyperintensity close to the insertion of the supraspinatus tendon ( arrow ), most likely representing a calcific deposit within the supraspinatus tendon.

A, CT scan (sagittal view) of the same shoulder shown in Figure 22-1 with a much clearer depiction of the ruptured calcific deposit within the supraspinatus tendon anterior to the humeral head. B, CT scan (axial view) of the shoulder in Figure 22-1 depicting a large ruptured calcific deposit anterior to the humeral head.

Some patients with multifocal deposits develop symptoms simultaneously at several different sites. This can cause significant diagnostic confusion as the presentation mimics an autoimmune seronegative polyarthritis. There are also reports of calcific periarthritis occurring in families, although no particular inheritance pattern or specific genetic loci have been identified.

Calcific deposits in periarticular tissues may also be associated with chronic pain syndromes. However, as calcific deposits are a common finding in the shoulder area, it is difficult to say what contribution, if any, they make to chronic shoulder pain in the absence of an acute inflammatory reaction. In some patients, recurrent attacks of acute calcific periarthritis result in significant damage to the musculotendinous junctions of the rotator cuff and thus lead to the development of chronic rotator cuff arthropathy.

Secondary BCP Crystal Deposition

Clinically significant periarticular BCP crystal deposition may also occur in association with chronic renal failure and hyperparathyroidism (with or without renal failure) and in the systemic autoimmune diseases of scleroderma and dermatomyositis. A number of secondary forms of BCP crystal–associated arthropathies have been described. BCP crystal deposits have been reported in the joints and periarticular tissues of renal failure patients, mostly when undergoing dialysis. Renal failure predisposes to virtually all forms of crystal deposition including monosodium urate (MSU), CPPD, calcium oxalate, and aluminum phosphate, in addition to BCP. Chronic end-stage renal failure requiring dialysis is therefore associated with several different crystal arthropathies, most commonly manifesting as gout (MSU) or pseudogout (CPPD). These conditions are extensively reviewed in Chapter 23 of this book, and the reader is referred here for a more detailed discussion of the increasingly important contribution of end-stage renal failure to joint pathology.

It is only when these conditions and infection have been excluded that BCP crystal deposition is considered in the diagnosis of an acute monoarthritis in a dialysis-dependent patient.

Tumoral calcinosis is a rare condition characterized by the progressive deposition of calcified masses in cutaneous and subcutaneous tissue. It is typically associated with chronic renal failure and either secondary or tertiary hyperparathyroidism. A rare inherited form of familial tumoral calcinosis is characterized by markedly elevated plasma phosphate levels, normal or elevated serum 1,25-dihydroxyvitamin D levels, and severe ectopic calcifications in various different sites. Mutations in both fibroblast growth factor-23 and GALNT3, which encodes a glycosyltransferase responsible for initiating mucin-type O -glycosylation, have been found in this condition. A dreaded and often lethal complication of chronic dialysis that is also associated with elevated phosphate and calcium levels is calciphylaxis. This condition is characterized by nodular subcutaneous and intradermal calcification with painful tissue necrosis often leading to ulceration, secondary infection, and high mortality rates.

BCP deposition is also associated with systemic autoimmune connective tissue disease, in particular scleroderma and dermatomyositis. Following dermatomyositis in childhood, massive sheets of fascial calcification can occur. In scleroderma, the deposits are usually subcutaneous and are associated with the CREST syndrome, although they may also be seen in mixed connective tissue disease. However, in some patients there is extensive subcutaneous calcification known as calcinosis cutis, which may occur in isolation without any other major features of the disease.

A recognized iatrogenic cause of BCP crystal deposition is associated with the intraarticular injection of triamcinolone hexacetonide. This can sometimes lead to the formation of periarticular calcifications along the injection tract, which may become apparent months after the injection and are gradually resorbed over a period of months to years. Finally, major trauma resulting in significant neurologic damage (brain, spinal cord, or peripheral nerve) is sometimes followed by massive heterotopic ossification in periarticular tissues and may drastically limit patients’ functional rehabilitation.

Intraarticular BCP Crystal Deposition

Articular cartilage calcification due to BCP crystal deposition (composed mainly of HA) and clumps of BCP crystal aggregates in synovial fluid are associated with specific clinical entities.

Milwaukee Shoulder

A particular type of large joint destructive arthropathy mainly affecting elderly women with a predilection for the shoulder joint and associated with the presence of abundant BCP crystalline material, rotator cuff tears, and marked cartilage degeneration was described by Dan McCarty’s group. This entity has been termed Milwaukee shoulder syndrome, cuff tear arthropathy, or apatite-associated destructive arthritis. The clinical presentation of this condition typically involves a history of chronic pain, swelling, decreased joint mobility, and gross impairment of function. Patients are nearly always over 70 years old, and approximately 90% are women. The dominant side is most often the presenting problem, although more than half of those affected have objective evidence of bilateral involvement. The pain may be mild but is usually most apparent at night and on joint use. There is often total disruption of the rotator cuff apparatus, manifested by upward migration of the humeral head on plain film radiography ( Fig. 22-3 ). Extensive damage to the periarticular soft tissues as well as to cartilage and subchondral bone on both sides of the joint may also occur ( Fig. 22-4 ). There is reduced active range of motion in all planes, and examination of passive movement usually reveals pronounced joint instability. Crepitation and pain may be noted, especially when the humerus is grated passively against the glenoid. Joint effusion is typically present and may be massive, extending into the subdeltoid region. Aspiration of affected shoulder joints typically yields large volumes (more than 100 ml) of serosanguinous synovial fluid containing relatively low numbers of mononuclear leukocytes. Rupture of the effusion can lead to a massive extravasation of blood and synovial fluid into the surrounding tissues. Although the shoulder predominates, knees, hips, elbows, and other joints may be involved.

Plain film radiograph of the right shoulder in a patient with rotator cuff rupture. Note the upward migration of the humeral head and close approximation to the degenerative acromion process.

Plain film radiograph of the left shoulder in a patient with “Milwaukee shoulder” syndrome. Note the sclerotic changes in the subchondral bone on both sides of the glenohumeral joint ( arrow ). Also, there is extensive damage to the articular surface of the humeral head.

The natural history of the condition is unclear, but many cases seem to enter spontaneous stable remission after 1 or 2 years, with a reduction of symptoms, decreased joint effusions, and no further radiographic changes. However, if sufficient damage to articular surfaces and periarticular structures has occurred, particularly if associated with joint instability, functional rehabilitation is severely curtailed and joint replacement surgery is sometimes the only viable therapeutic option ( Fig. 22-5 ).

Plain film radiograph of the same joint depicted in Figure 22-4 , following left shoulder hemiarthroplasty.

Acute Synovitis

Episodic attacks of acute monoarthritis associated with intraarticular BCP crystals in relatively young individuals, mainly affecting the knee joint, and resembling gout have been described. These attacks appear to be rare and the diagnosis is difficult to establish, mainly due to the lack of readily available methods of accurately detecting BCP crystals. Occasionally, crystals from a periarticular deposit can rupture into the joint itself, causing acute synovitis. This only occurs where there is a direct connection between the site affected by the calcific rupture and the joint space itself, and it is most commonly seen in elderly individuals when the subacromial bursa also communicates with the glenohumeral joint.

Chronic Monoarthritis

A chronic, sometimes erosive monoarthritis has also been linked with intraarticular BCP crystals. BCP crystals have been particularly implicated in finger joint arthropathies, including erosive or inflammatory forms of OA. However, this appears to be a very rare phenomenon and the exact contribution of BCP crystals to the pathogenesis of these types of conditions remains unclear.

Osteoarthritis

OA is the leading cause of joint disease in humans. Its complex pathogenesis remains poorly understood but appears multifactorial. OA is slowly progressive and involves all components of the joint, including bone, cartilage, meniscus, and synovium. No specific therapy has been identified to reverse or retard the consequences of OA. Therefore, joint replacement surgery is often ultimately the only therapeutic option.

Calcification of articular cartilage (both hyaline and meniscal) is a well-recognized feature of OA, and current evidence suggests that it contributes directly to joint degeneration. Calcium-containing crystals are found in more than 60% of synovial fluid samples from unselected OA patients at knee arthroplasty. Although ample in vitro evidence demonstrates the potent biologic effects of calcium-containing crystals, controversy exists as to whether these crystals play a causal role or are merely a consequence of the joint damage seen in OA.

CPPD and BCP are the two most common forms of calcium crystals found in articular cartilage. Their presence is associated with a number of clinical manifestations. For example, CPPD crystals cause acute attacks of articular pseudogout, and the presence of intraarticular BCP crystals correlates strongly with the severity of radiographic OA. Both types of crystals are found in OA, but data on the distribution and frequency of BCP crystals vary considerably, mainly due to the lack of simple and reliable methods of detection. Furthermore, the precise source of these crystals is unclear. Recent work by Fuerst et al. clearly demonstrates that BCP is the predominant crystal type in OA hyaline articular cartilage and that chondrocytes derived from OA hyaline cartilage produce BCP crystals in vitro. This suggests that cartilage mineralization with BCP crystals by chondrocytes is part of the disease process in OA.

While meniscal degeneration and calcification are key features of OA knee joints, few studies have investigated the potential role of OA meniscal cells in the pathogenesis of OA. In addressing this neglected area, recent work by Sun et al. offers novel insights into the pathogenesis of meniscal calcification in OA knee joints. Therefore, both meniscal calcification (mediated by meniscal cells) and hyaline calcification (mediated by chondrocytes derived from OA hyaline cartilage) are potentially important contributory factors in the pathogenesis of OA and are discussed in detail later, along with their clinical implications.

Imaging

Plain radiographs are a simple and cost-effective tool in the detection of periarticular calcific deposition. These deposits are usually visualized in the rotator cuff, typically a few centimeters proximal to the supraspinatus insertion or sometimes within the subacromial bursa. Conventional anteroposterior and lateral films are usually sufficient, but special views, with internal or external rotation of the shoulder, may be necessary to detect retrohumeral deposits. Other imaging modalities such as arthrography may be used to confirm the diagnosis of rotator cuff rupture, and computed tomography (CT) or magnetic resonance imaging (MRI) may be useful in demonstrating small, less radiopaque crystal deposition and other subtle inflammatory changes in the adjacent soft tissues but are rarely necessary in arriving at the diagnosis of calcific periathritis. Imaging of the contralateral joint should also be carried out, as bilateral calcification is common. Similarly, radiographs of other asymptomatic sites (hips, knees, wrists) will sometimes reveal multiple calcific deposits. It should be remembered that these deposits are often reabsorbed during acute attacks of pericalcific arthritis, only to reappear subsequently.

Heterotopic ossification can sometimes look like periarticular calcification, but these generally contain a trabecular pattern, unlike calcific deposits of BCP crystals. CPPD rarely deposits in periarticular tendons and nearly always manifests as linear deposits of chondrocalcinosis within intraarticular cartilage. This is in contrast to intraarticular BCP crystal deposits, which are rarely visible with any of the aforementioned imaging tools. This is largely due to the fact that individual aggregates of BCP crystals, within cartilage or synovial fluid, are generally tiny and therefore beyond the current limits of detection of conventional radiographic imaging.

Radiographic features of the Milwaukee shoulder syndrome typically involve evidence of rotator cuff rupture (upward migration of the humeral head); degenerative changes of the humeral head, acromioclavicular joint, glenoid, and scapula; and cystic degeneration of the humeral tuberosities, and pseudoarthrosis formation between the humeral head and acromion process is common. MRI is often used to further define these marked anatomic changes.

Serologic Testing

As gout and pseudogout are the main differential diagnoses for BCP-related joint disease, serum urate, renal function, and hematinics are often tested. BCP crystal deposition usually occurs in the absence of any detectable metabolic abnormality, but calcium and phosphate levels should always be checked. Recent evidence indicates that high serum phosphate levels seem more likely to predispose to BCP crystal deposition than abnormalities of calcium alone.

BCP Crystals in Synovial Fluid

Aspiration of bursae involved in acute calcific periarthritis often reveals a creamy mixture of calcific and inflammatory matter that resembles chalky toothpaste. In cases of suspected intraarticular BCP crystal deposition, the synovial fluid findings may vary. Gout (negatively birefringent needle-shaped MSU crystals) and pseudogout (positively birefringent rhomboid-shaped CPPD crystals) are generally excluded using compensated polarized light microscopic analysis of a fresh synovial fluid sample. Infection is ruled out by the absence of any organisms and few, if any, pus cells. Fluid from patients with large joint destructive arthropathy is frequently blood stained with low numbers of white cells (predominantly monocytes) and is usually quite viscous.

In light of the emerging pathogenic role of BCP crystals in OA, the identification of these crystals from the synovial fluid of patients with intraarticular pathology is now of much greater importance. Synovial fluid acts as both a lubricant and a source of biochemical nutrients to the relatively avascular articular surfaces. It is a viscous ultrafiltrate of plasma with a high glycoprotein and hyaluronic acid content, and its complex biologic matrix presents significant analytical challenges. BCP crystals are mainly composed of HA, with smaller amounts of its precursors (octacalcium phosphate and tricalcium phosphate). Individual crystals are typically less than 1 μm (20 to 100 nm), and they aggregate in OA synovial fluid to form clumps (5 to 20 μm), which appear as amorphous-looking globules that are nonbirefringent in polarized light. Thus, their presence in joints is often unrecognized.