Recent Advances In Management Of Crystal Arthropathies Biology Essay

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The crystal arthropathies are a heterogenous group of disorder which are associated with crystal deposition leading to arthritis. The Monosodium urate monohydrate (MSU) crystal deposition is the most important Crystal arthropathy which leads to development of clinical syndrome of gout. The other important crystal related disease includes calcium pyrophosphate dehydrate (CPPD) and Basic calcium phosphate (BCP) or hydroxyapatite deposition disease. In past two decades there has been marked increase in the prevalence of gout which may have multi-factorial causes. The first and foremost is the increase in life expectancy of the general population due to optimized treatment of the chronic diseases of heart, lung, liver and kidney and the second major cause may be due to sedentary lifestyle of individuals with obesity, metabolic syndrome and alcohol playing major role. Recently there has been major advance in diagnosis of gout with development of Dual Energy Computed Tomography (DECT) which may detect and confirm the MSU crystal without aspiration of synovial fluid. The novel xanthine Oxidase inhibitor febuxostat is now available in India and can be used as alternative to allopurinol in chronic kidney disease as well as in allopurinol failed or intolerant cases. The recombinant uricase enzyme, rasburicase and pegloticase as well as anakinra are in the final stages of approval with some encouraging results in phase 2 and phase 3 trials.


The Crystal arthropathies are the group of disorders secondary to the crystal deposition in joints and others tissues and organs. These intra-articular crystals, which can be intrinsic (i.e. uric acid) or extrinsic (i.e. foreign bodies) and they may lead to tissue inflammation and joint damage by virtue of their biochemical and biomechanical properties. The synovial fluid examination for the crystals by polarizing light was first performed in 1961 by McCarty and Hollander and the subsequent application of other crystallography techniques like electron micrography and x-ray diffraction studies have helped to identify most of the pathogenic crystals, which were previously thought to be due to gout. The monosodium urate (MSU) crystal deposition is the most important crystal arthropathy which leads to development of clinical syndrome of gout. The other important crystal related disease includes calcium pyrophosphate dehydrate (CPPD) and basic calcium phosphate (BCP) or hydroxyapatite deposition disease. The various other crystals which may be found in the synovial fluids are given in Table 1. The polarizing light microscopy alone can identify most of them except for hydroxyapatite crystals.

There is recent upsurge in the prevalence of gout for past couple of decades; this may be due to multiple factors like increase in life expectancy due to control and optimum treatment of other diseases (i.e. chronic kidney disease, Heart failure, chronic obstructive lung disease and malignancies). The role of modern lifestyle and obesity may also play important role in hyperuricemia and gout. Recently there have been positive advances in the field of diagnosis and management of gout after many decades. The state of the art imaging modality like Dual Energy CT and the recent increase in the armamentarium of hypouricemic drugs like febuxostat, rasburicase and pegloticase has fuelled new interest in gout management.

The CPPD disease is mainly a disease of advanced age and is commonly associated with radiological and pathological cartilage calcification, also called chondrocalcinosis. They may present as acute pseudogout to asymptomatic chondrocalcinosis. The secondary causes of CPPD diseases should be evaluated if chondrocalcinosis is seen before the age of 55 yrs. The other causes of crystal arthropathies are uncommon.


The gout is a metabolic disease whose description has been there since ancient times of Babylon. The evidence of disease has been also found in early skeletal remains and mummies of Egypt. One of the best descriptions of the disease was found with Hippocrates [1]. The term gout is derived from the Latin 'gutta', which means a drop. In the 13th century, it was thought that gout resulted from a drop of evil humour affecting a vulnerable joint [2]. In past the gout was considered to be the disease of kings and was incorrectly thought to be due to overindulgence of alcohol and food which only the rich can afford. Now it is well understood that anyone can be affected with this disease as the various other factor interact to manifest as gout.

EPIDEMIOLOGY: In the past few decades gout prevalence has almost doubled in the united states as well as other countries and more so in older age group of > 65 yrs of age [3]. The overall prevalence is of 5-28 /1000 in males and 1-6 / 1000 in females. Gout is uncommon in pre-menopausal females due to uricosuric effect of estrogens, the male: female ratio is 2-7:1. There is some major geographic differences in the prevalence of gout, the China, South-east Asia region including India and Maori individuals of New Zealand are found to be having high prevalence (10-15%) compared to Caucasian of west in whom the prevalence is found to be only 1%. This wide difference may be due to high meat protein and decreased dairy product in diet. The largest and most widely quoted Framingham study reported the incidence of gout to be 36% over 12 years in patients with uric acid levels >8mg%. In India there are very few and small studies, Chopra et al found the prevalence of gout to be of 0.12% in 746 pt surveyed in rural village of Pune [4].

H K Choi and colleagues have demonstrated that several features of western diets (high intakes of meat, seafood, fructose-sweetened beverages and beer) are linked with development of gout in middle-aged men, whereas high intakes of low-fat dairy products, coffee and ascorbate are linked with reduced rates of disease development in the same population [5].

AETIOPATHOGENESIS of GOUT: During the evolution, humans lost the activity of uricase enzyme which metabolizes the purine metabolic end product uric acid to a highly water-soluble form allantoin. Uric acid is weak acid and is sparingly soluble in un-ionized form( in urine) and in ionized form in extracellular body fluid, therefore in presence of supersaturated solutions (hyperuricemia) these uric acid get crystallizes and get deposits in tissue leading to gout.

Hyperuricemia and gout can be classified as primary hyperuricemia when the cause of hyperuricemia is not secondary to another acquired disorder (kidney disease or major inborn error of metabolism like Lesch Nyan syndrome). The Table 2 shows the various common causes of primary and secondary hyperuricemia.

In acute gout, MSU crystals liberated from tissue deposits promote an inflammatory cascade that involves complement activation and release of multiple inflammatory cytokines, which culminates in acute but self- limited neutrophilic inflammation [6]. This leads to activation of toll like receptors 2 & 4 and mononuclear phagocytes to the site. The phagocytic cells release cytokines to activate proteosome, oxygen free radicals, cryopyrin and caspase 1as well as IL1Beta leading to acute inflammation at the involved joint. The other cytokines involved in inflammation includes tumour necrosis factor, Il-6, CXC-chemokine ligand (CXCl1 and CXCl8) [7].

CLINICAL FEATURES: The clinical features of hyperuricemia and Gout can be divided into asymptomatic hyperuricemia and clinical gout. The clinical gout can be sub-divided into three stages: acute gouty arthritis, intericritical gout and chronic tophaceous gout.

Asymptomatic hyperuricemia: the term is applied to the state at which the serum urate levels are abnormally high but the symptoms of gout have not occurred yet. According to epidemiological surveys the arbitrary definition of hyperuricemia is serum urate levels > 6 mg/dl in females and > 7 mg/dl in males. The prevalence of asymptomatic hyperuricemia is found to be 5% to 8% and somewhat higher prevalence has been found in South East Asia region [8]. Although only 15% of all patients with hyperuricemia develop gout, the risk increases to 30%-50%, if their serum uric acid concentration >10 mg/dl. There is still no conclusive evidence that the asymptomatic hyperuricemia itself can lead to renal deterioration. In a prospective cohort study for over 15 years only 4.9% annual incidence of gout was reported in individual with uric acid of >9mg% and only 0.55 for urate level of 7-8.9 mg/dL.[9]. Fessel et al in his study concluded that there is no clinical importance with respect to renal outcome until the serum uric acid rises above 13 mg% in males and 10 mg% in females [10].

Considering there is no proven literature to recommend treatment of asymptomatic hyperuricemia, it is still not advisable to do treat such patients. One should also consider the adverse effects of urate lowering drugs like allopurinol which can lead to fatal adverse drug reactions which are more commonly observed in asymptomatic gout patients.

Acute gouty arthritis: the first episode of acute gouty arthritis usually occurs in one joint and subsequent attacks can be of polyarticular in nature. The first metatarsophalangeal joint of big toe also known as podagra is often involved, but tarsal joints, ankle, and knee are also commonly affected. The acute gouty arthritis frequently begins in the middle of the night with dramatic joint pain, swelling, redness as well as tenderness, so that it may mimic a cellulitis. The attacks usually subside spontaneously within 3-10 days and most patients have complete resolution till they suffer subsequent attack. The attacks are usually precipitated by dehydration, alcohol, acute stress, trauma or dietary excess of protein (animal).

Intercritical gout: Patients of gout may undergo intercritical period after their first episode of acute gout and before second or subsequent attack of gout. Usually the second attack of gout do occurs within 2 years in untreated patient. The diagnosis can be made by taking history of the previous episode and aspirating MSU crystals from the knee joint or any previously or presently inflamed joint. In a study, the demonstration of crystals in previously non-inflamed and inflamed knee joint on urate lowering medication was found to be 22% and 50% respectively [11].

Chronic tophaceous gout: After many years (average 11.2 yrs) with repeated attacks of acute gout patient develops chronic tophaceous gout (Figure 1a and 1b). It is characterized by the identifiable deposition of solid urate crystals (tophi) in connective tissue and articular surface. It usually leads to asymmetric polyarthitis but sometime it may be difficult to differentiate it from polyarticular rheumatoid arthritis. The sites of predilection of tophi are helix of ear, olecranon, prepatellar bursae, ulnar surface of forearm, Achilles tendon and finger pads.

Tophaceous gout is often associated with early age of onset, long duration of active and untreated disease, alcohol and diuretic use as well as other iatrogenic cause like cyclosporine use in renal transplant patients.


Light and compensated polarized microscopy: If possible the acute or chronically inflamed joint or tophi should be aspirated and examined under compensated polarized microscopy for confirmation of intracellular and extracellular MSU crystals which appears negatively birefringent by polarized microscopy. If clinical picture is atypical the synovial fluid should also be evaluated with gram stain to rule out infection and other crystal diseases. The synovial fluid is usually cloudy and cell count is elevated from 2000-60,000 /micro L. The compensated polarized microscopy is the cornerstone of the investigation for the diagnosis of gout. This consists of a red compensator which is marked by an arrow to denote its axis, when the crystals are aligned with the axis the colour of the crystals is noted. The MSU crystals are needle shaped and negative birefringent, therefore appear yellow when placed with axis of compensator. The CPPD crystals are weakly positive birefringent therefore appears blue, when they are placed along the axis. The pneumonic for CPPD crystal to remember is ABC- Aligned Blue Calcium.

Radiology and DECT: The Typical radiological finding of gout includes asymmetrical soft tissue swelling around the joint. The articular tophi can produce soft tissue densities that occasionally get calcified. The typical bony erosion in gout appears "punched out" with sclerotic margins and overhanging edges, sometime termed "rat bite" erosions (Figure 2). The joint space is typically preserved without any peri-artcular osteopenia.

Dual Energy Computed Tomography (DECT): The DECT scanner which uses two x-ray tubes is recently approved in United States for evaluation of gout as well as other organs like heart lung etc. The principal behind the new technique is that, the degree of attenuation of incident x-rays depends on the atomic number "Z" of the material and the energy spectrum to which it is exposed. Therefore by measuring the difference in attenuation using two different energy spectra, the composition of a material can be determined by exploiting the x-ray energy dependent attenuation of different materials. The DECT has been shown to accurately differentiate uric acid kidney stones (Figure 3a) from stones of various other materials such as calcium oxalate, cysteine, or struvite as well as uric acid deposits in gout vs. calcium deposits in chondrocalcinosis of Calcium pyrophosphate deposition disease (CPPD). The DECT has been successfully used in diagnosis of MSU crystals of gout in the joint as well as in subcutaneous tophi without even aspirating the crystals (Figure 3b). Its clinical use is also been extended to monitor the MSU crystal load after urate lowering therapy, especially after rapid acting pegloticase and anakinra (IL1 antagonist) therapy. This investigation once becomes available in general circulation may again revolutionize the management of gout, as the need for invasive and difficult to aspire synovial fluid examination will be history, which revolutionized the diagnosis of gout and other crystal arthropathies in sixties when the polarized microscopy was first used. The drawbacks of the investigations are its high price, high dose of ionized radiation exposure, and limited availability at present as well as non standardized methods.

DIAGNOSIS: The gout is a systemic metabolic disease in which tissue deposition of monosodium urate (MSU) crystals occurs secondary to hyperuricemia, resulting in one or more of the following manifestations of acute arthritis, chronic arthritis, tophaceous deposition of uric acid crystals in joints, cartilage, bone or skin, gouty nephropathy or nephrolithiasis. The definitive diagnosis of gout can only be made with demonstration of MSU crystals in aspirated synovial fluid by compensated polarized microscopy. There are different clinical criteria's for diagnosis of gout proposed by different investigators which includes American college of rheumatology (ACR), Rome criteria and New York criteria, but the ACR criteria is commonly used. The ACR preliminary criterion for diagnosis of Gout was first given by Wallace et al in 1977 [12]. The criteria consist of 11 clinical criteria and patient fulfilling 6 or more criteria are considered to be having gout (Table 3). Although in recent studies it has been seen that ACR criteria is having sensitivity of 70% to 80% only, but this can still be useful in cases in which definite diagnosis could not be made due to non availability or failure to get synovial fluid analysis done for MSU crystals.


The management of gout can be divided into acute gout treatment and chronic gout management for hyperuricemia.

Acute gout Management: The acute gouty patient's presents with acute monoarthritis or polyarthritis, therefore the mainstay of treatment consists of optimum pain relief and suppression of the active inflammation. The drugs which have been used and found to be effective are non steroidal anti-inflammatory drugs (NSAIDS), colchicines and corticosteroid (prednisolone). In recent reports the anakinra (IL1 rec antagonist) has been used successfully in acute gouty arthritis. The commonly used drugs are prednisolone 35 mg daily for 5 days or the naproxen 500 mg twice daily for 5 days; both have been demonstrated to be comparable in efficacy and tolerance in a acute gout treatment [13]. In a recent trial Prednisolone (6 doses of 30 mg over 5 days) was also comparable in efficacy to indomethacin and was better tolerated in acute gout [14]. European League Against Rheumatism (EULAR) expert consensus guidelines for oral colchicine in acute gout are for a maximum of three colchicine 0.5 mg tablets per 24 hour period [15]. This low dose is associated with less side effects and comparable efficacy compared to high dose colchicines in which colchicine is given as 1.2 mg followed by 0.6 mg every hour for 6 hours with a total dose of 4.8 mg.

Anakinra: It is a recombinant human interlukin 1(IL1) receptor antagonist. It is already approved for refractory rheumatoid arthritis since Nov 2001 by food and drug administration (FDA). It has been successfully used in acute gouty arthritis as steroid or NSAIDS sparing agents, in patients in whom they are contraindicated or intolerant [16]. Anakinra is used as 100 mg subcutaneous injection once daily for three days in acute gout. There are very few case reports about its successful use in chronic gout as well but at present this drug is not approved for acute or chronic gout by FDA.

Chronic gout Management: Hypouricemic and Uricosuric drugs


Allopurinol is the first line hypouricemic drug and is the most commonly used drug in chronic gout as well as for resolution of gouty tophi. It acts by inhibiting the enzyme xanthine oxidase. The allopurinol is usually started at the dose of 300mg / day and is approved by FDA to be used up to the maximum dose of 800mg/day, which is rarely used in clinical practice due to poor tolerance and poor patient compliance. Recent EULAR consensus guidelines have reinforced FDA dosing guidelines for allopurinol in patients with preserved renal function [17], specifically to initiate allopurinol at 100 mg daily, and then to increase the dose by 100 mg every 1 to 4 weeks until a target serum urate level (<6 mg/dL) is achieved or the maximum appropriate allopurinol dose is reached. The major side effect of allopurinol is skin rash in up to 2% of patients, while severe hypersensitivity reaction which usually occurs early in the therapy is seen in 0.1%-0.4% only but has a very high case fatality of up to 50%. The reaction is common in pt. with CKD or on thiazide. In recent studies HLA-B58 has been reported to be a risk factor for severe cutaneous adverse reactions to allopurinol (Stevens-Johnson syndrome or toxic epidermal necrolysis) in individuals of European, Han Chinese, and Japanese ancestry. The prevalence of HLA-B58 is only 1-2 % in US and Europe while in Asia and China it has been found to be very high, up to 85% of general population is positive to HLA-B58.


Febuxostat is a novel xanthine oxidase inhibitor which is recently approved by USA and Europe as second line hypouricemic drug in patients of gout. It is also available in Indian market for past few months. Its main indication is allopurinol refractory or intolerant patients, chronic kidney disease stage 3 or more and in patients with a history of urolithiasis with difficult to maintain hydration and lastly the patients with uric acid overproduction.

Febuxostat is a selective inhibitor of xanthine oxidase, the drug sitting in the access channel to the molybdenum-pterin active site of the enzyme. Febuxostat does not have a purine-like backbone, unlike allopurinol and oxypurinol (Figure 4). Significantly, Febuxostat is primarily metabolized by oxidation and glucuronidation in the liver and renal elimination plays a minor role in febuxostat pharmacokinetics, as opposed to allopurinol pharmacology. Febuxostat also does not directly regulate pyrimidine metabolism and it is not reincorporated into nucleotides, in contrast to allopurinol, where such properties have the potential to contribute to certain drug toxicities [18].

Febuxostat is available in three strengths, 40mg, 80mg and 120 mg. The starting dose is of 40 mg daily, followed by dose increase to 80 mg/ 120 mg daily if serum urate is not normalized after at least 2 weeks. Side effects of febuxostat include rash in <2% of subjects and elevation of hepatic enzymes. The other side effects include diarrhoea, and arthralgia may also occur. The side effects compared to allopurinol is less and allopurinol associated severe hypersensitivity reaction are not reported till date. The potential for major drug interactions with azathioprine, 6-mercaptopurine and theophylline persists with it also as it is due to xanthine oxidase inhibition [19].


Probenecid is the most commonly used uricosuric agents in gout; it enhances renal uric acid excretion, primarily by inhibiting urate anion re-absorption by proximal renal tubule epithelial cells. Moreover, uricosuric therapy can provide additive effects when used in combination with xanthine oxidase inhibitors. Probenecid and other uricosuric agents like fenofibrate, losartan and benzparone increase the risk of urolithiasis in acid urine, which is common in gout and metabolic syndrome, due to defective bicarbonate renal output, mediated by insulin resistance [20]. Probenecid is completely absorbed from the intestine and has biologic half life of 6-12 hours. It is usually started at dose of 250 mg BID and can be gradually increased up to a maximum dose of 3 gm/day. The drawback of probenecid includes it's twice to thrice a day dosing, in-effectiveness at creatinine clearance <50ml/min and significant drug interactions with a number of drugs therefore should avoided in patients who are on multiple drugs. It is contraindicated in patients with renal calculi therefore it is used only as adjunctive agents to hypouricemic agents by most of rheumatologists.

Diet therapy and life style modification:

Choi HK has recommends overall health benefits and risk considerations before embarking on dietary restrictions in patient's of gout as these patients also have metabolic syndrome and are at increased future risk of cardiovascular disease (CVD) and mortality. The weight reduction with daily exercise and limiting intake of red meat and sugary beverages would help reduce uric acid levels, the risk of gout, insulin resistance, and co morbidities. Heavy drinking should be avoided, whereas moderate drinking, sweet fruits, and seafood intake, particularly oily fish, should be tailored to the individual, considering their anticipated health benefits against CVD. Dairy products, vegetables, nuts, legumes, fruits (less sugary ones), and whole grains are healthy choices for the co morbidities of gout and may also help prevent gout by reducing insulin resistance. Coffee and vitamin C supplementation could be considered as preventive measures as these can lower urate levels, as well as the risk of gout and some of its co morbidities [21]. Dietary purines such as guanosine, which is readily absorbed from beer, promote uric acid overproduction, as do certain disorders of increased cell turnover. Moderate intake of purine-rich vegetables or protein makes food palatable is not associated with an increased risk of gout.

Uricase Therapy:

Uricase enzyme activity is absent in humans and higher primates. It is thought to be lost in evolution by natural selection. Uricase enzyme oxidatively degrades uric acid to highly soluble allantoin. There are major advances in the development this enzyme by genetic engineering and trials are underway to exploit its use in management of gout. The rasburicase and pegloticase are the two recent discovery and phase 2 and 3 trails are already underway, although these are still not approved for the use in gout.

Rasburicase: is a fungal enzyme with uricase like activity. It has been approved by FDA for single course therapy for tumor lysis syndrome in paediatrics population. It is used as off label pilot study in severe, chronic gout. Unfortunately, rasburicase is both highly antigenic and has a plasma half-life of 18 to 24 hours. Efficacy, tolerability, and sustainability of rasburicase treatment beyond 6 to 12 months appear to be poor for treatment of refractory hyperuricemia in gout [22].

Pegloticase: is a recombinant porcine-baboon uricase. The uricase enzyme is PEGylated to reduce immunogenicity as well as to increase the circulating half life of the drug. In recent phase 3 trials it has been used for sustained refractory hyperuricemia of chronic tophaceous gout. The results to date indicate that intravenous PEGylated uricase treatment has the potential to rapidly decrease the pool size of miscible urate, and also to de-bulk tophi in weeks to months rather than the months to years as seen to date with therapy with xanthine oxidase inhibitors at conventional doses. Pegloticase is given as 8mg IV infusion every 2 week with premedication with acetaminophen, and hydrocortisone (200 mg) to limit the infusion reaction which is very frequent. Infusion reactions were moderate to severe in approximately 8% to 11% of subjects, and include flushing, urticaria, and hypotension, and, by undefined mechanisms, non-cardiac chest pain or muscle cramping [23]. Anaphylaxis was uncommon (approximately 2%) in the phase 3 pegloticase study. Glucose 6 phosphate deficiency is a contraindication for uricase therapy as it may lead to meth-hemoglobinemia and haemolysis (< 1%) in these patients. Pegloticase therapy has been found to be associated with antibody formation and this may lead to poor response and increased infusion reaction.

In a recent phase 3 trial the pegloticase was found to be very effective with 42% of patients reached the target serum uric acid level of < 6mg % and 40 % had complete resolution of tophi within 6months of treatment. One major finding was the frequent acute gout flares( up to 80%) in first few months of pegloticase therapy [24].

At present scenario the rapid acting uricase therapy is still in experimental stage and there is an urgent need for formulating a consensus guideline on uricase therapy. Few expert rheumatologists are of the opinion that this biologic should be used for a short finite period as induction therapy in gout and it should be followed by the conventional xanthine oxidase inhibitors for maintenance. The Table 4 proposes a basic algorithm for management of gout including the pegloticase therapy (experimental basis in severe refractory gout)


CPPD deposition disease is a metabolic arthropathy with the typical hallmark of formation of CPPD crystals in articular hyaline and fibro cartilage. These crystals can produce inflammatory reaction like arthritis or the structural destructive pyrophosphate arthropathy. The term chondrocalcinosis (CC) is also used interchangeably used for CPPD disease (Figure 5), although CC can also occur with other crystal deposition disease like Calcium hydroxyapatite deposition disease.

Epidemiology: The prevalence of CPPD disease increases with age and in the largest epidemiological survey of the general population in Framingham study the radiological CC is found in up to 30% of patient in 9th decade [25]. The incidence of CPPD disease before the 5th decade of life is uncommon except in some hereditary causes. Therefore whenever there is radiological finding of CPPD disease in a patient with age < 55 yrs of age, the secondary causes of CPPD disease should be evaluated in depth. The secondary causes of CPPD disease include primary hyperparathyroidism, haemochromatosis, haemosiderosis, hypo-phosphatasia, hypomagnesaemia, amyloidosis, hypothyroidism, ochronosis, wilson's disease, CKD, etc.

Clinical features: The CPPD disease has been classified by various investigators in past, but the two most common presentation of the disease includes acute synovitis (pseudogout) and chronic pyrophosphate arthropathy. The other uncommon presentations can tendinitis, tenosynovitis, bursitis, axial presentation or atypical arthropathy.

Pseudogout: The classic presentation is in the form of acute monoarthritis in an elderly. The most common joint involved is knee, but it can present in any joint in including 1st metatarsophalangeal joint. The typical attack develops rapidly within 6-24 hours with sign of inflammation, swelling similar to gout and usually last for 1-3 weeks. The development is spontaneous, but sometime there may a trigger in the form of local trauma, medical illness, parathyroid surgery, joint injection or rarely blood transfusion or hypothyroid treatment.

Chronic pyrophosphate arthropathy: The usual presentation in the arthritis of large and medium sized joints in an elderly person. The knee remains the most common and severely affected joint but 2nd and 3rd metacarpophalageal (MCP) as well as wrist elbow, ankles are also involves frequently. There may be early morning stiffness and sometime pseudogout attack may superimpose on the chronic arthropathy. On examination osteoarthritic changes are predominant in the joint with varying amount of synovitis. At times it becomes difficult to differentiate from rheumatoid arthritis. Therefore, sometime it is also called pseudo-rheumatoid presentation of CPPD disease.

Diagnosis: The diagnosis of CPPD disease is usually suspected in a case of CC. The diagnosis can be confirmed as definitive if the synovial fluid identification is positive for CPPD crystal disease and radiological evidence of calcification is also identified. The diagnosis is also said to be definitive if the crystals are confirmed by x- ray diffraction, chemical or electron microscopy. The diagnosis is said to be probable if only radiological evidence is present [26].

Management: Currently there is no treatment available to reduce the CPPD crystal deposition in the joint; the treatment is basically symptomatic for acute synovitis of pseudogout with NSAIDS and intra-articular steroids. The acute triggering event should be treated as well as patient with secondary metabolic cause s should be treated accordingly, i.e. hypo magnesia correction.

Chronic arthropathy patients should be managed in the line of osteoarthritis by education, symptomatic treatment and muscle strengthening exercises. Short term benefit can be achieved with local intra articular steroid injection in mono-oligoarthropathy. In few studies the control of chronic synovitis was found to be achieved by radiosynovectomy as well as in other studies with oral magnesium and hydroxychloroquine.


Deposition of hydroxyapatite and BCP crystals in and around the joint can have myriad presentation from completely asymptomatic peri-articular deposits to acute calcific arthritis and sometime may lead to destructive arthropathy. "Milwaukee shoulder knee" syndrome is a type of severe hydroxyapatite deposition disease. The diagnosis of BCP disease is by radiography and synovial fluid analysis. The radiographic demonstration of periartcular calcification is highly diagnostic, but sometime CT or MRI of the joints is needed to confirm the calcific deposits. The synovial fluid analysis of crystal can be confirmatory but due to small size and need for special technique like transmission electron-microscopy may be needed. No specific therapy for the BCP disease is available at present.