Basic calcium phosphate (BCP) crystal arthritis, including Milwaukee shoulder syndrome

INTRODUCTION — Basic calcium phosphate (BCP)-associated musculoskeletal syndromes can be organized into two categories, arthritis associated with BCP crystals and calcific periarthritis. Osteoarthritis (OA) associated with BCP crystals is the most common form of arthritis associated with these crystals, and Milwaukee shoulder syndrome (MSS) is a characteristic syndrome in which BCP crystals play a prominent role. The predominant mineral type in BCP-associated musculoskeletal pathology is carbonated hydroxyapatite [1].

An overview of the clinical manifestations, diagnosis, and treatment of BCP-associated arthritis will be presented here. An overview of BCP-associated calcific periarthritis, calcific tendinopathy of the shoulder, and the pathogenesis of OA are discussed in detail separately. (See "Basic calcium phosphate (BCP) crystal-associated calcific periarthritis (tendinopathy)" and "Calcific tendinopathy of the shoulder" and "Pathogenesis of osteoarthritis".)

DEFINITION AND DISEASE SPECTRUM

BCP crystals — The predominant mineral type in basic calcium phosphate (BCP)-associated musculoskeletal pathology is carbonated hydroxyapatite, although the term "basic calcium phosphate" refers to a trio of submicron-sized calcium phosphate crystals [1]. These include partially carbonate-substituted hydroxyapatite, octacalcium phosphate, and tricalcium phosphate (whitlockite). The terms "calcium phosphate" and "hydroxyapatite" are often used synonymously with the more accurate term "basic calcium phosphate." BCP crystals are similar in composition to both the normal mineral found in bones and teeth and the pathologic mineral found in atherosclerotic plaques and calcinosis cutis.

BCP-associated arthritis — Intraarticular BCP crystals have been recognized since the 1970s, initially in the synovial fluid of patients with osteoarthritis (OA) and subsequently in other conditions [2,3]. A subset of patients with a unique clinical presentation of noninflammatory, shoulder-predominant, OA-like arthritis associated with BCP crystals has been termed Milwaukee shoulder syndrome (MSS), although OA is the clinical syndrome that remains most closely linked with intraarticular BCP crystals [4].

OA with BCP crystals and MSS likely represent points on the same spectrum of disease pathogenesis rather than different syndromes. In addition to these conditions, there are case reports of BCP-associated arthritis in patients with autoimmune inflammatory processes and in the setting of end-stage kidney disease (ESKD).

Other common BCP-associated musculoskeletal syndromes are BCP-associated calcific periarthritis and calcific tendinopathy of the shoulder, which are described in detail elsewhere. (See "Basic calcium phosphate (BCP) crystal-associated calcific periarthritis (tendinopathy)" and "Calcific tendinopathy of the shoulder".)

PATHOGENESIS AND RISK FACTORS — The causes of pathologic basic calcium phosphate (BCP) crystal formation are not fully understood [5]. BCP mineral formation often occurs at sites of local tissue damage associated with injury or inflammation. Once formed, BCP crystals can produce symptoms and mediate tissue damage by several mechanisms, including the induction of a vigorous inflammatory response, biomechanical disruption, and by direct interactions with connective tissue cells, producing destructive cytokines and prostaglandins in the absence of inflammation [6-10].

Severe radiographic damage and the presence of articular calcium pyrophosphate (CPP) crystals are risk factors for BCP crystals in patients with osteoarthritis (OA). A history of shoulder trauma or heavy use, along with increased age, are associated with Milwaukee shoulder syndrome (MSS). (See 'Osteoarthritis with BCP crystals' below and 'Milwaukee shoulder syndrome' below.)

The average age of the largest collection of reported cases of MSS was 72 years, and most were female [11]. Approximately one-third of these patients described some trauma to the affected shoulder, while others had occupations involving heavy use of the shoulders or a history of crutch walking and/or wheelchair use. Calcium pyrophosphate crystal deposition (CPPD) disease has some clinical overlap with MSS, but whether these patients are clinically different from those with BCP crystals alone is not known.

The absence of widely available clinical tests to accurately detect articular BCP crystals has slowed progress in understanding their roles in OA and other settings in which they occur, and relatively little is known about the factors that specifically initiate symptomatic arthritis associated with the crystals. The pathogenesis of BCP crystal disease is reviewed in more detail separately. (See "Basic calcium phosphate (BCP) crystal-associated calcific periarthritis (tendinopathy)", section on 'Pathogenesis of BCP-associated musculoskeletal syndromes'.)

CLINICAL PRESENTATION — Basic calcium phosphate (BCP) crystals are associated with arthritis in several syndromes and clinical settings, including osteoarthritis (OA) with BCP crystals and Milwaukee shoulder syndrome (MSS). BCP crystal arthritis can also occur in a subset of patients with systemic rheumatic ("connective tissue") diseases, in patients with calcium pyrophosphate deposition (CPPD) disease, and in patients with end-stage kidney disease (ESKD). (See 'Osteoarthritis with BCP crystals' below and 'Milwaukee shoulder syndrome' below and 'Other conditions associated with intraarticular BCP crystals' below.)

Osteoarthritis with BCP crystals — BCP crystals are common components of advanced large-joint OA. Patients with OA and intraarticular BCP crystals are generally clinically indistinguishable from those with typical OA, although the presence of BCP crystals is postulated to predict rapid progression to end-stage disease [12]. The clinical manifestations of OA are described in detail separately. (See "Clinical manifestations and diagnosis of osteoarthritis" and "Clinical manifestations and diagnosis of osteoarthritis", section on 'Hip' and "Pathogenesis of osteoarthritis", section on 'Aging'.)

There are no population-based studies of this association, due to the absence of a widely available clinical test for articular BCP crystals. Two studies of synovial fluids sampled at the time of knee joint replacement for OA demonstrated that approximately 50 percent contained BCP crystals [13,14]. Histologic studies confirm the high prevalence of BCP crystal deposits in OA tissues, with 100 percent of end-stage hip and knee joints showing BCP crystal deposition at the time of joint replacement [15,16]. Routine laboratory studies are generally normal in patients with OA with and without BCP crystals. It is not known whether the modest elevations in C-reactive protein (CRP) observed in OA correlate with the presence of BCP crystals [17].

Milwaukee shoulder syndrome — MSS is a chronic syndrome of shoulder arthritis, which presents with chronic shoulder pain and loss of function. It occurs in older adult patients, especially women, and is often associated with large but noninflammatory shoulder effusions [4,11].

The largest reported case series involved 30 patients. A compilation of published reports included 72 patients with MSS [18].

In the largest reported case series, which involved 30 patients, 80 percent were women; the mean age was 72 years, ranging from 50 to 90 years of age [11]. Observations from one compilation of published reports of MSS that included a total of 72 patients found that MSS tended to be worse on the patient's dominant side but was bilateral in 64 percent of the patients [18]. Severe degenerative arthritis of the knee, with an atypical pattern of lateral-compartment-predominant involvement, was present in 53 percent of the MSS patients, and 7 percent had hip involvement. The elbow may also be affected [19].

Physical examination may show a large cool glenohumeral joint effusion, crepitation, and joint instability. Sinus tracts and capsular ruptures with large chest wall ecchymoses have been described.

Routine laboratory studies are generally normal, while elevated inflammatory markers, including erythrocyte sedimentation rate (ESR), are described in some case reports of MSS [20].

Involved shoulder joints eventually demonstrate a classic radiographic appearance characterized by severe joint destruction, cartilage loss, and extensive rotator cuff damage. However, not all of these features may be present in early disease (image 1). (See 'Imaging' below.)

Other conditions associated with intraarticular BCP crystals

●Systemic rheumatic ("connective tissue") diseases – Intraarticular BCP crystal deposition has been described in case reports affecting patients with myositis and in other settings in which calcinosis is sometimes expected to occur but is typically not articular, such as systemic sclerosis (scleroderma) [3,21]. Joint aspiration may show milky fluid with low-grade inflammation. Some patients have periarticular calcification as well as intraarticular involvement (image 2).

●CPPD – Calcium pyrophosphate (CPP) crystals frequently coexist with BCP crystals. In one study of knee synovial fluids from patients undergoing knee arthroplasty for degenerative arthritis, 11 percent of fluids had only CPP crystals, while 19 percent had both CPP and BCP crystals [13]. In the original MSS series, 8 out of 30 patients also had concurrent CPP crystals in synovial fluid samples [11]. The clinical significance of this finding is uncertain.

●Chronic kidney disease – Among the many factors contributing to musculoskeletal symptoms in patients with ESKD, there are scattered case reports of intraarticular BCP crystals in patients with erosive arthritis and ESKD [22]. The role of BCP crystals in erosive arthritis in ESKD remains unclear and requires further study.

SYNOVIAL FLUID ANALYSIS AND CRYSTAL IDENTIFICATION

●Routine synovial fluid analysis – The white blood cell count in the synovial fluid is typically less than 1000 cells/mm³. The fluid may be blood-tinged. A careful examination for calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals using compensated polarizing light microscopy should be negative. Basic calcium phosphate (BCP) crystals may accompany CPP or MSU crystals, but the clinical significance of BCP crystals in these cases is uncertain. BCP crystals are not visible on plain polarizing light microscopy. Synovial fluid cell counts are not different from patients with typical osteoarthritis (OA) [23]. (See "Clinical manifestations and diagnosis of osteoarthritis", section on 'Synovial fluid'.)

●Alizarin red S staining for calcium-containing crystals – Alizarin red S staining can identify calcium-containing crystals in synovial fluid with ordinary light microscopy. BCP aggregates appear as orange-red clumps in stained synovial fluid. Unfortunately, alizarin red S staining is neither sensitive nor specific for BCP crystals. In one study of synovial fluid samples from patients with OA who were strongly positive on alizarin red S staining, only 50 percent contained crystals by transmission electron microscopy [24]. CPP crystals also stain positive with alizarin red S and can be indistinguishable from BCP crystals [24].

●BCP crystal identification – Specialized testing can accurately identify BCP crystals in synovial fluid from affected patients but is not routinely available in clinical practice [25]. (See 'Alizarin red S staining and BCP crystal identification' below.)

IMAGING

●Conventional plain radiography in osteoarthritis (OA) with basic calcium phosphate (BCP) crystals demonstrates typical changes of severe OA. (See "Clinical manifestations and diagnosis of osteoarthritis", section on 'Imaging'.)

●In Milwaukee shoulder syndrome (MSS), characteristic radiographic features include marked glenohumeral joint degeneration and soft tissue calcifications (image 1). Rotator cuff destruction is manifest by a "high-riding" humeral head. Bony destruction of the coracoid process and acromion are often noted. The humeral neck may also show erosions. Chondrocalcinosis is rarely observed as damage to the articular cartilage is typically extensive.

Advanced imaging, including magnetic resonance imaging (MRI), can reveal the extent of the tendon and ligament damage that almost always accompanies MSS [26]. Ultrasonography can demonstrate tissue destruction and the presence of large effusions.

PATHOLOGY — In osteoarthritis (OA), calcific deposits can be identified in hyaline cartilage, fibrocartilage, and synovium. Tissue histopathology from patients with Milwaukee shoulder syndrome (MSS) demonstrates synovial hypertrophy and embedded basic calcium phosphate (BCP) crystals in the synovium, accompanied by fibrin deposition and occasional giant cells. An inflammatory infiltrate is typically absent from the synovial tissues [27].

DIAGNOSIS

Diagnosis and diagnostic evaluation — The diagnosis of basic calcium phosphate (BCP) crystal-associated arthritis is based upon the presence of characteristic clinical features of joint swelling and pain, with routine synovial fluid analysis that excludes inflammation and other crystals as the cause of the findings, and plain radiographic imaging showing substantial joint injury. (See 'Clinical presentation' above and 'Synovial fluid analysis and crystal identification' above and 'Imaging' above.)

Examination of the synovial fluid is essential to this diagnosis. The white blood cell count in the fluid should be less than 1000 cells/mm³. The fluid may be blood-tinged. A careful examination for calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals using compensated polarizing light microscopy should be negative.

Thus, we identify the major clinical syndromes of BCP crystal-associated arthritis based upon their clinical features and routine synovial fluid analysis:

●Osteoarthritis with BCP crystals – The diagnosis of OA with BCP crystals is made by obtaining a clinical history consistent with noninflammatory arthritis in large joints. These patients have subacute or chronic pain in one or more large joints, which is worse with activity, increases as the day progresses, and is not associated with prolonged (>30 minutes) morning stiffness. The presence of intraarticular BCP crystals may be suspected when there is an unusually rapid pace of progression or very aggressive joint and soft tissue destruction. The diagnosis is further supported by the presence of noninflammatory synovial fluids without visible MSU or CPP crystals.

●Milwaukee shoulder syndrome – MSS is diagnosed based upon a clinical history of severe noninflammatory shoulder arthritis and an examination that often shows large effusions and shoulder instability. The diagnosis is further supported by synovial fluid aspirates showing cell counts of <1000 cells/mm³ and no MSU or CPP crystals. Radiographs can provide additional validation by demonstrating large effusions, massive rotator cuff damage, and extensive cartilage loss and bony changes.

These diagnoses can be further supported by the identification of BCP crystals with alizarin red S staining of synovial fluid, if sufficient expertise in such staining and appropriate reagents are available (see 'Alizarin red S' below). This would be most helpful in patients with unusually aggressive or rapidly progressive osteoarthritis (OA), particularly in the shoulder. Ideally, analytic techniques to identify the chemical composition of crystals, such as spectroscopy or x-ray diffraction, could be employed to confirm the diagnosis, but these techniques are generally not available in routine clinical practice. (See 'Other techniques' below.)

Alizarin red S staining and BCP crystal identification

Alizarin red S — Alizarin red S staining can be used to identify calcium-containing crystals [24]. This procedure requires a drop of freshly diluted and filtered (using a 0.45 micron microfilter) 2% alizarin red S mixed on a slide with a drop of synovial fluid and examined with ordinary light microscopy. BCP aggregates appear as orange-red clumps. This test should be interpreted with caution as both false negatives and false positives are common [28]. It cannot differentiate between BCP and CPP crystals.

Other techniques — A number of testing techniques, none of which are routinely available for clinical use, can be used to more specifically identify BCP crystals. As examples, BCP crystals can be definitively identified in clinical samples with techniques such as Fourier-transform infrared spectroscopy, Raman spectroscopy, and transmission electron microscopy; however, these technologies are not widely available for clinical use. Other measures may also be effective to identify BCP crystals. Some clinical laboratories are willing to analyze particulates from synovial fluid with equipment used to identify kidney stone composition. In addition, methods to detect BCP crystals based upon radioactive bisphosphate-binding or calcium-binding fluorescent dyes, with or without flow cytometry, have been described but have not been validated for clinical use [25]. Some evidence has suggested that dual-energy computed tomography (CT) scanning may ultimately be capable of differentiating CPP crystal deposits from those of BCP crystals [29]. Further work in this area may result in better diagnostic tools for BCP-associated musculoskeletal syndromes.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of osteoarthritis (OA) with basic calcium phosphate (BCP) crystals and Milwaukee shoulder syndrome (MSS) includes posttraumatic or postinflammatory OA, calcium pyrophosphate deposition (CPPD) disease, and gout, as well as other less common syndromes causing joint pain and dysfunction, often without a prominent inflammatory component. The following conditions are included in the differential diagnosis of BCP crystal-associated arthritis:

●CPPD disease and gout – Like other crystal-related forms of arthritis, BCP-associated arthritis can cause significant joint swelling and pain. CPPD disease and gout can be distinguished from BCP arthritis by the presence of characteristic calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals, respectively, which are seen in these other disorders on examination of the synovial fluid with compensated polarizing light microscopy. Differences in the acuity of presentation and the degree of inflammation may help differentiate between these syndromes.

MSS usually presents with symptoms and signs that evolve over months or years, while acute CPP crystal arthritis and gout more often present with rapid onset of symptoms. Synovial fluid analysis in acute gout and acute CPP crystal arthritis demonstrates inflammatory cell counts, while cell counts in joints from patients with MSS are in the noninflammatory range. More chronic presentations of CPPD involving the shoulder may be more difficult to differentiate from MSS, and a careful search for synovial fluid CPP crystals would be needed to distinguish between these two syndromes. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease" and "Clinical manifestations and diagnosis of gout".)

●Hemochromatosis and acromegaly – Other causes of noninflammatory arthritis in joints not typically involved in OA, such as the shoulder, should prompt a search for alternative diagnoses. Hemochromatosis and acromegaly may mimic BCP-associated arthritis in these respects but can generally be distinguished by their pattern of articular involvement, including typical involvement in the hand, and extraarticular clinical characteristics. In addition, these conditions typically affect younger patients. (See "Arthritis and bone disease associated with hereditary hemochromatosis" and "Rheumatologic manifestations of acromegaly".)

●Tenosynovial giant cell tumor – Tenosynovial giant cell tumor (TGCT, formerly termed localized pigmented villonodular synovitis) of the shoulder shares features with MSS, including prominent joint swelling, but is usually unilateral and can be differentiated by synovial fluid analysis and synovial or bone biopsy. Radiographic changes in TGCT are usually distinct from those of MSS; however, a patient with concurrent TGCT and MSS has been described [30]. (See "Treatment for tenosynovial giant cell tumor and other benign neoplasms affecting soft tissue and bone", section on 'Tenosynovial giant cell tumor' and "Radiologic evaluation of knee tumors in adults", section on 'Tenosynovial giant cell tumor'.)

●Neuropathic joint disease – Neuropathic ("Charcot") arthropathy can also mimic MSS as both may cause large-joint effusions and marked bone destruction, but it is accompanied by significant sensory nerve dysfunction in the affected distribution. (See "Diabetic neuroarthropathy".)

●Rotator cuff arthropathy – Rotator cuff arthropathy is a poorly defined syndrome in which degenerative arthritis occurs after rotator cuff insufficiency. The clinical presentation of rotator cuff arthropathy may overlap with MSS in that these patients may have pain, loss of motion, crepitus, and small effusions. They should lack the large-joint effusions and destructive radiographic findings characteristic of MSS. (See "Evaluation of the adult with shoulder complaints" and "Clinical manifestations and diagnosis of osteoarthritis", section on 'Shoulder'.)

●Amyloid arthropathy – Amyloid arthropathy often affects shoulders, like MSS, but can be differentiated from MSS by Congo red staining of amyloid in synovial fluid or synovial tissue. Unlike MSS, amyloid arthropathy can be quite inflammatory. In addition, the appearance on radiography is typically distinct from MSS. Amyloid arthropathy causes well-defined bone cysts, and there is preservation of the joint space until late in the course. (See "Musculoskeletal manifestations of amyloidosis".)

●Stickler syndrome – Congenital abnormalities resulting in widespread severe OA, such as Stickler syndrome, often occur in patients younger than those typically affected by BCP-related disease. Patients with Stickler syndrome can be distinguished by their other clinical characteristics, including cleft palate, micrognathia, midface hypoplasia, retinal detachment, hearing loss, and late-onset spondyloarthropathy. (See "Skeletal dysplasias: Specific disorders", section on 'Stickler syndrome'.)

MANAGEMENT — Management of basic calcium phosphate (BCP) crystal-associated arthritis depends upon the clinical syndrome. In most patients with osteoarthritis (OA), the presence of BCP crystals does not affect treatment. The recognition of their likely role in causing joint damage does help guide the approach to therapy in patients with Milwaukee shoulder syndrome (MSS). (See 'Osteoarthritis with BCP crystals' below and 'Milwaukee shoulder syndrome' below and 'Other disorders' below.)

Osteoarthritis with BCP crystals — In patients with OA found to have BCP crystals in the synovial fluid, we use the same treatment approach as in OA without BCP crystals. The treatment of OA is described in detail separately. (See "Overview of the management of osteoarthritis".)

Very limited evidence suggests that colchicine, as used for prophylaxis against acute attacks of gout or acute calcium pyrophosphate (CPP) crystal arthritis, may be useful in patients with OA and BCP crystals. We view this as an investigational therapy, and further studies are necessary before colchicine can be advised for OA.

There is one randomized trial, involving only 36 patients, that demonstrated a small benefit for colchicine in patients with typical knee OA [31]. This five-month study used an oral colchicine dose of 0.5 mg twice daily, along with a nonsteroidal antiinflammatory drug (NSAID), and showed that 57.9 percent of the group treated with colchicine achieved 30 percent improvement in Western Ontario and McMaster Universities Osteoarthritis (WOMAC) scores compared with 23.5 percent of the controls. Diarrhea and abdominal pain were more common in the colchicine cohort.

Milwaukee shoulder syndrome — Our primary management goal is symptom relief, which involves the use of local intraarticular interventions and, if needed, orally administered analgesics (eg, acetaminophen) or NSAIDs. Retaining and improving shoulder function through physical therapy is also important. In the absence of pain, no intervention may be necessary.

The patients described in the original cohort were treated with joint aspiration, tidal lavage, and intraarticular glucocorticoids with variable outcomes [4,11,32]. Our treatment approach is based upon case reports, case series, and clinical experience [4,18,32-34]. There have not been any randomized trials performed to evaluate or compare potential therapies for MSS.

We take the following approach:

●All patients – All patients should be referred for physical therapy with the goals of retaining and improving shoulder range of motion.

●Absence of pain – In patients without pain, we generally do not pursue any therapeutic intervention other than physical therapy.

●Mild pain – In patients with mild pain that does not impair physical function, we suggest oral nonopioid analgesics or NSAIDs. We prefer acetaminophen (eg, 500 to 1000 mg up to three times daily) or an NSAID (eg, naproxen 250 to 500 mg twice daily or ibuprofen 400 to 600 mg four times daily or 800 mg two to three times daily), using the lowest dose and for the shortest time necessary to provide symptom relief. NSAIDs should be avoided or used with particular care in older adults and in patients with increased risk of gastrointestinal, cardiovascular, or renal disease, as in patients with OA. (See "Overview of the management of osteoarthritis", section on 'Pharmacologic therapy'.)

●Moderate to severe pain – In patients with considerable pain (eg, that impairs sleep and physical function), we suggest joint aspiration and intraarticular glucocorticoid injections, with 40 to 60 mg of triamcinolone acetonide. This intervention may need to be repeated every two to three months in some patients. Most patients respond to aspiration and intraarticular glucocorticoid injections with improvement lasting for a period of weeks to months. However, some patients exhibit an inadequate response, with rapid recurrence of pain and reaccumulation of the effusion within days of the injection. For patients who don't respond to glucocorticoid injections, we generally do not perform injections more than twice, as responses to additional injections are unlikely; however, some patients still respond to repeated aspiration without injection. (See "Joint aspiration or injection in adults: Technique and indications" and "Joint aspiration or injection in adults: Complications".)

●Inadequate response to joint injection – In patients with an inadequate response to pain medication and intraarticular glucocorticoids, we perform tidal lavage if oral analgesics are inadequate. Tidal lavage is usually performed under ultrasound guidance, with insertion of a 14-gauge intravenous catheter into the joint space, through which 1500 to 2000 mL of sterile saline are injected and aspirated, typically over a period of approximately 15 to 30 minutes. This is then followed by injection of intraarticular glucocorticoid [33].

●Other therapies – Other therapies may be tried in patients unresponsive to these measures. There are reports of improvement with injections of commercially available hyaluronan preparations [18]. There is a single case report of a good response to oral colchicine and NSAIDs [34]. Tidal lavage followed by intraarticular glucocorticoids and tranexamic acid (an antifibrinolytic drug) was reported to produce a sustained response in 4 out of 10 patients with MSS [33]. As with many therapies, this was more efficacious in patients with less advanced disease.

●Recurrent symptoms – Effective treatments should be repeated when pain recurs.

●Resistant to intraarticular and systemic medications – Shoulder joint replacement is an effective intervention in MSS but needs to be performed before there is complete destruction of the rotator cuff. Joint replacement should be reserved for patients with refractory pain deemed appropriate for this procedure [35]. Frailty, the presence of serious comorbidities, and/or major rotator cuff insufficiency are common reasons to avoid shoulder replacement in these patients.

Other disorders — There are very little data other than case reports to guide management of BCP crystal arthritis associated with other conditions, such as end-stage kidney disease (ESKD), systemic sclerosis (scleroderma) or inflammatory myositis, and other crystal disorders:

●Calcific arthritis in the setting of ESKD is managed by reducing calcium and phosphate levels. If traditional therapies fail, systemic administration of sodium thiosulfate may be useful in this setting, based on case reports [36]. (See "Calciphylaxis (calcific uremic arteriolopathy)", section on 'Treatment of calcium, phosphorus, and parathyroid hormone abnormalities'.)

●In the setting of inflammatory disease such as myositis or scleroderma, management of the inflammatory disease may help reduce intraarticular calcifications. Surgical removal of cutaneous calcific deposits has been helpful in cases of subcutaneous calcinosis in scleroderma based on case reports [37] but has not been reported in BCP-associated arthritis in patients with connective tissue diseases. (See "Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults" and "Initial treatment of dermatomyositis and polymyositis in adults" and "Management of refractory cutaneous dermatomyositis in adults", section on 'Calcinosis cutis'.)

●When BCP arthritis coexists with calcium pyrophosphate deposition (CPPD) disease, we manage patients as if they had CPPD alone. (See "Treatment of calcium pyrophosphate crystal deposition (CPPD) disease".)

PROGNOSIS — The prognoses of osteoarthritis (OA) with basic calcium phosphate (BCP) crystals and Milwaukee shoulder syndrome (MSS) are not well studied. However, anecdotal evidence suggests that, while pain may regress, large effusions and poor function persist despite therapy.

Joint replacement for BCP-associated OA of the knee or hip may produce longstanding reduction in pain, and there is no evidence that these interventions are less effective in OA with BCP crystals than they are in patients with OA without BCP crystals. Shoulder joint replacement for selected patients with MSS may also result in long-term improvement.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gout and other crystal disorders".)

SUMMARY AND RECOMMENDATIONS

●Basic calcium phosphate (BCP) mineral formation often occurs at sites of local tissue damage associated with injury or inflammation. Once formed, BCP crystals can produce symptoms and mediate tissue damage by induction of an inflammatory response, biomechanical disruption, and by inducing the local production of destructive cytokines and prostaglandins in the absence of inflammation. (See 'Pathogenesis and risk factors' above.)

●BCP crystals are associated with arthritis in several syndromes and clinical settings, including osteoarthritis (OA) with BCP crystals and Milwaukee shoulder syndrome (MSS). BCP crystal arthritis can also occur in a subset of patients with systemic rheumatic diseases, in patients with calcium pyrophosphate deposition (CPPD) disease, and in patients with end-stage kidney disease (ESKD). (See 'Clinical presentation' above.)

●BCP crystals are common components of advanced large-joint OA. Patients with OA and intraarticular BCP crystals are generally clinically indistinguishable from those with typical OA, although the presence of BCP crystals may predict rapid progression to end-stage disease. (See 'Osteoarthritis with BCP crystals' above.)

●MSS is a chronic syndrome of shoulder arthritis, which typically presents in older adult patients, especially women, with chronic shoulder pain, loss of function, and often with large but noninflammatory shoulder effusions. Radiographs of involved joints eventually demonstrate a characteristic severe joint destruction, cartilage loss, and extensive rotator cuff damage. (See 'Milwaukee shoulder syndrome' above.)

●The synovial fluid white blood cell count in OA and MSS is typically less than 1000 cells/mm³, the fluid may be blood-tinged, and calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals are typically not seen on compensated polarizing light microscopy. BCP crystals are not visible on plain polarizing light microscopy. Alizarin red S staining can identify calcium-containing crystals, including both BCP and CPP, in synovial fluid with ordinary light microscopy. Testing to identify BCP crystals in synovial fluid from affected patients is not routinely available in clinical practice. (See 'Synovial fluid analysis and crystal identification' above.)

●The diagnosis of OA with BCP crystals is made in a patient with a clinical history consistent with noninflammatory arthritis in large joints, especially when there is an unusually rapid pace of progression or very aggressive joint and soft tissue destruction. The diagnosis is further supported by the presence of noninflammatory synovial fluids without visible MSU or CPP crystals. (See 'Diagnosis' above.)

●MSS is diagnosed based upon a clinical history of severe noninflammatory shoulder arthritis and an examination that often shows large effusions and shoulder instability. The diagnosis is further supported by synovial fluid aspirates showing cell counts of <1000 cells/mm³ and no MSU or CPP crystals. Radiographs can provide additional validation by demonstrating large effusions, massive rotator cuff damage, and extensive cartilage loss and bony changes. (See 'Diagnosis' above.)

●The differential diagnosis of BCP crystal arthritis includes posttraumatic or postinflammatory OA, CPPD disease, and gout, as well as other less common syndromes causing joint pain and dysfunction, often without a prominent inflammatory component. (See 'Differential diagnosis' above.)

●In patients with OA found to have BCP crystals in the synovial fluid, we use the same treatment approach as in OA without BCP crystals. (See 'Osteoarthritis with BCP crystals' above and "Overview of the management of osteoarthritis".)

●Management of patients with MSS involves the following (see 'Milwaukee shoulder syndrome' above):

•The treatment goal for patients with MSS is symptom relief, and patients without pain generally do not require treatment other than physical therapy, which all patients with MSS should receive to retain and improve shoulder range of motion.

•In patients with mild pain that does not impair physical function, we suggest oral nonopioid analgesics or nonsteroidal antiinflammatory drugs (NSAIDs). We use acetaminophen (eg, 500 to 1000 mg up to three times daily) or an NSAID (eg, naproxen, 250 to 500 mg twice daily, or ibuprofen, 400 to 600 mg four times daily or 800 mg two to three times daily), using the lowest dose and for the shortest time necessary to provide symptom relief.

•In patients with pain that impairs sleep and physical function, we suggest joint aspiration and intraarticular glucocorticoid injection. We use triamcinolone acetonide (40 to 60 mg), which may need to be repeated every two to three months in some patients.

•In patients with an inadequate response to pain medication and intraarticular glucocorticoids, we perform tidal lavage. This is performed under ultrasound guidance, with 1500 to 2000 mL of sterile saline injected and aspirated, followed by injection of intraarticular glucocorticoid. Shoulder joint replacement is an effective intervention in MSS but needs to be performed before there is complete destruction of the rotator cuff.