Update on Calcium Pyrophosphate Deposition A

Update on calcium pyrophosphate deposition A. Abhishek, M. Doherty

Academic Rheumatology, University of ABSTRACT Introduction Nottingham, Nottingham, U.K. Calcium pyrophosphate crystal depo- Calcium pyrophosphate (CPP) crystal Abhishek Abhishek, MRCP, PhD sition (CPPD) associates with age- deposition (CPPD) occurs mainly in Michael Doherty, MD, FRCP ing, osteoarthritis (OA), uncommon the elderly, can present with acute CPP Please address correspondence to: Dr. A. metabolic diseases, mutations and crystal arthritis or chronic arthropathy Abhishek, A21, Academic Rheumatology, polymorphisms in the ankylosis hu- with structural changes of osteoarthri- Clinical Sciences Building, University of man gene (ANKH). CPPD is frequently tis (OA), or may be asymptomatic, Nottingham, Nottingham NG5 1PB, UK. polyarticular, occurs due to a general- E-mail: Abhishek.abhishek@nottingham. presenting as an incidental finding of ac.uk ised articular predisposition, and the chondrocalcinosis (CC) on imaging Received and accepted on June 29, 2016. association between CPPD and OA is studies (1, 2). Several diverse presenta- joint specific, for example CPPD- as tions e.g. pseudo-rheumatoid, pseudo- Clin Exp Rheumatol 2016; 34 (Suppl. 98): S00-S00. sociates with knee OA, but not with polymyalgia rheumatica, pseudo-anky- hip OA. Other recently identified -as losing spondylitis etc. were attributed © Copyright Clinical and Experimental Rheumatology 2016. sociations include knee malalignment to CPPD in the 1960s and 1970s (3). (knee CC), low cortical BMD and soft- These presentations were supported Key words: calcium pyrophosphate tissue calcification. CPPD is generally by hospital based case series, with no crystal deposition (CPPD), ankylosis asymptomatic. A recent study reported clear evidence for causality, resulting human gene (ANKH), ageing, osteo- that knees with OA plus CC at the index in a potentially confusing and com- arthritis joint, or at distant joints (in absence of plex phenotypic classification. A -Eu index joint CC), were more likely to ropean League Against Rheumatism have attrition. (EULAR) task force has recommended CPPD can cause acute CPP crystal simpler terminology in order to stand- arthritis, chronic CPP crystal inflam- ardise the terminology and classifica- matory arthritis, and is frequently pre- tion of CPPD (Table I) (4). sent in joints with OA. Joint aspiration CPPD is common, and the prevalence remains the gold standard for diagnos- depends on the joints surveyed. In plain ing CPPD, although other promising radiographic surveys, CC, a surrogate techniques are emerging. Patients with for CPPD in epidemiologic studies, polyarticular or young onset CPPD affects 7.0-8.1% knees, 10.0-10.4% should be screened for underlying met- knees plus either hand/wrist or hip/ abolic abnormalities, however, such symphysis pubis respectively (5-7). It testing can be unrewarding. was the 4th most prevalent musculo- The treatment of CPPD is sympto- skeletal condition in an Italian popula- matic. Acute CPP crystal arthritis is tion survey with a prevalence of 0.42% treated with rest, local application of (8). CPPD predominantly affects the ice-packs, joint aspiration, colchicine knees, but wrists, hips, and symphysis and/or intra-articular corticosteroid pubis CC may occur in the absence of injection (once infection is excluded). knee CC (9). Colchicine, low-dose corticosteroids, hydroxychloroquine and radiosynovec- Risk factors tomy are recommended for the treat- Both ageing and OA independently as- ment of chronic or recurrent acute CPP sociate with CPPD (6, 7). The associa- crystal arthritis. Recent RCTs did not tion between OA and CC may be joint confirm any benefit from methotrexate, specific as knee, wrist, scapho-trape- and although there is increasing inter- zoid joint, and metacarpophalangeal est in the use of anti-IL1 agents for joint (MCPJ) OA associates with CC acute or chronic CPP crystal arthritis, (10-13), but hip OA does not associate their efficacy has not been formally ex- with hip CC or with CC at distant joints amined. Unlike gout, currently there (5, 14). CPPD can rarely be inherited as are no treatments to eliminate CPP a monogenic autosomal dominant dis- Competing interests: none declared. crystal deposits. ease, generally due to mutations in the

1 Update on calcium pyrophosphate deposition / A. Abhishek & M. Doherty

ANKH (ankylosis human) gene, or oth- Table I. Classification of calcium pyrophosphate crystal deposition (CPPD)(4). er genes such as the procollagen type Asymptomatic CPPD: CPPD with no apparent clinical consequence 2, CCAL1 and osteoprotegerin genes OA with CPPD: CPPD in a joint that also shows structural changes of OA, on imaging or histological (15). Even apparently sporadic CPPD examination (previously “pseudo-OA”). As with OA without CPPD, this can be symptomatic or has a genetic component, and associ- asymptomatic. ates with the -4bp G to A polymorphism Acute CPP crystal arthritis: acute onset, self-limiting painful synovitis with CPPD (previously in the 5’-UTR of ANKH, and this asso- “pseudogout”) ciation is independent of age, sex, body Chronic CPP crystal inflammatory arthritis: chronic inflammatory arthritis associated with CPPD mass index and OA (16, 17). (previously “pseudo-rheumatoid arthritis”) Metabolic disease associations of (OA: osteoarthritis). CPPD include haemochromatosis (18), hyperparathyroidism (19, 20), hypomagnesemia (21) and hypophos- phatasia (22). Other diseases such as diabetes mellitus and hypothyroidism do not associate with CPPD once ad- justed for age (22, 23). Haemochro- matosis is the only metabolic disease associated with CPPD that results in structural arthropathy, and this commonly affects the knees, wrists, hips, MCPJs, and ankles (18, 24). CC associates with local joint insult e.g. meniscectomy (25), self-reported varus knee malalignment in young adult life (26), low cortical bone mineral density (27), gout (28) but not hy- peruricemia (29), and associates negatively with rheumatoid arthritis (RA) (pooled OR (95%CI) 0.18 (0.08-0.41)) (4). The latter observation is supported mechanistically by the subnormal levels of inorganic pyrophosphate (PPi) in the synovial fluid of patients with RA Fig. 1. Extracellular pyrophosphate (PPi) metabolism. AMP: adenosine monophosphate, ATP: adeno- (30). OA, hyperparathyroidism, chron- sine triphosphate, ANKH: ankylosis human, TNAP: alkaline phosphatase, Ca: calcium, CPP: calcium ic kidney disease (CKD) 5, and loop pyrophosphate, Mg: magnesium, Pi: phosphate, PC1: plasma cell glycoprotein 1 (belongs to the ENPP/ diuretic use associate with acute CPP PDNP family). Similar processes take place on the enzyme rich articular cartilage vesicles, and matrix crystal arthritis independent of age and vesicles. sex (31). from the breakdown of nucleoside to AMP and PPi by plasma cell mem- Pathogenesis triphosphates (NTPs). Despite a turn- brane bound phosphodiesterase nucleo- CPP crystals form extracellularly in over of several kilograms/day, PPi tide pyrophosphatase (PDNP) enzyme vivo (32), and their formation requires concentrations are maintained at low plasma cell membrane glycoprotein 1 sufficient extracellular PPi (ePPi), cal- levels by ubiquitous pyrophosphatase (PC-1) or by the export of intracellular cium, and a cartilage matrix that facili- enzymes. Patients with CPPD have PPi by the multi-pass transmembrane tates crystal nucleation and growth. Of high synovial fluid PPi levels, and the ankylosis human protein (ANKH) (15, these, PPi concentration is best stud- plasma and urinary concentrations are 16, 38) (Fig. 1). ied, and promotes CPP crystal forma- normal, which strongly supports lo- PC-1 has a greater contribution to ePPi tion over other types of calcium crys- cal production as the main contribu- than ANKH (39, 40). Gain in func- tals e.g. BCP crystals (33). PPi inhibits tor to a high ePPi (34, 35). Compared tion mutations and polymorphisms in abnormal BCP related calcification in to normal knees, elevated synovial ANKH result in elevated ePPi (fre- the vasculature, saliva, and the urinary fluid PPi concentrations are reported quently quantified as low iPPi) and tract, and is used as an industrial water in OA ± CPPD, hyperparathyroidism, CPPD (15, 16). Apart from PPi, ANKH softener. hypomagnesaemia, and haemochro- also exports ATP which may be broken PPi and CPPD PPi is not absorbed di- matosis (30, 34, 36, 37). Extracellular down to ePPi (41). The amount of ex- rectly from the gastrointestinal tract, PPi (ePPi) is derived either from local tracellular ATP, which determines the but is derived entirely endogenously production by the breakdown of ATP concentration of ePPi, and whether

2 Update on calcium pyrophosphate deposition / A. Abhishek & M. Doherty

CPP or BCP crystals are formed, de- duction (55). IL-1β then orchestrates milial CPPD which may either present pends on mechanical loading, metabol- the release of other cytokines such as as part of a premature dysplastic OA ic cell activity, cell division and injury TNF-α (55). They also activate the toll phenotype, or be the only manifesta- (34, 42, 43). like receptors (56). CPP crystals induce tion presenting with recurrent episodes a neutrophilic inflammatory response of acute CPP crystal arthritis (15, 63). Regulation of ePPi predominantly due to their preferential Most instances are inherited in an au- The concentration of ePPi is regulat- induction of IL-8 (and not macrophage tosomal dominant manner (15). Other ed by several growth factors and cy- inflammatory protein-1α), and inhibi- rare manifestations include spinal tokines such as TGF-β, IL-1β and IGF- tion of neutrophil apoptosis (57, 58). CPPD presenting as crowned-dens syn- I. TGF-β promotes PC-1, ANKH, carti- Cells that phagocytose CPP crystals drome or with acute localized mening- lage intermediate layer protein (CILP) respond with increased metabolic ac- ism and/or myelo-radiculopathy, and and transglutaminase activity and tivity, and the release of myelo-perox- tophaceous CPPD (“tumoral”) CPPD down regulates TNAP activity, thus idase, IL-1β, IL-8, IL-6 and neutrophil which usually presents as slow grow- increasing ePPi levels (15). IGF-1 and extracellular traps which can damage ing painless lumps, and most common- inflammatory cytokines such as IL-1β bystander cells (59, 60). The inflamma- ly occurs at the temporo-mandibular have the opposite effect to TGF-β re- tory potential of CPP crystals depends joint (64). sulting in lower ePPi levels. on their size, type, surface charge, pro- The differential diagnosis of acute CPP Pi and PPi levels are inter-related via tein coating, with negatively charged crystal arthritis includes gout, joint in- complex biofeedback mechanism. small M-CPP crystals with protein and fection (which may rarely co-exist), For example, the TGF-β induced in- immunoglobulin coating being more and rarer crystal deposition dieases. crease in ANKH expression increases inflammatory (51). Chronic CPP-crys- In older patients, however, a marked the expression of PiT‑1 resulting in tal induced tissue damage is less well inflammatory component, polyarthri- high intracellular Pi levels which then understood, though postulated mecha- tis with metacarpophalangeal joint stimulates TNAP activity, thereby low- nisms include increased matrix metal- involvement and modest elevation of ering ePPi concentration (44). Type loproteinase expression, NO release, ESR may lead to consideration of RA 2 transglutaminase, factor XIIIa, and persistent synovial inflammation, -al or polymyalgia rheumatica. osteopontin also promote CPP crystal tered cell metabolism, prostaglandin formation (45-49). E2 release, altered osteoblast activity Investigations (56) and mechanical shear (61, 62). The definite diagnosis of CPPD- re CPP crystal formation quires synovial fluid examination and The formation of CPP crystal in vivo ap- Clinical features identification of CPP crystals. The aspi- pears restricted to higher primates, and Acute CPP crystal arthritis develops rated synovial fluid in acute CPP crys- occurs principally in fibro- and hyaline over a few hours, with pain, stiffness, tal arthritis is often turbid, can be blood articular cartilage, or in areas of chon- erythema and swelling, and is usually stained, and has reduced viscosity. The droid metaplasia in the synovium (50). maximal within a day of onset. Fever white cell (WBC) count is elevated, Of the twelve known crystallographic and confusion may be present. Acute averages >19,000/mm3 with over 76% forms of CPP crystals only the rod-like attacks are self-limiting and usually polymorphonuclear cells (65). The monoclinic (M-) or squat triclinic (T-) resolve within 1 to 3 weeks. Although synovial fluid WBC count is also ele- forms are deposited in vivo (51). Histo- any joint can be affected, acute attacks vated in the intercritical period (mean: logic studies suggest that CPP crystals occur most commonly in knees and 301 cells/μl (95% CI: 217 - 386)), with form initially in pericellular locations, then wrists. Most episodes of acute >80% WBCs being mononuclear (66). usually in the collagenous matrix in CPP crystal arthritis develop sponta- The WBC count and % polymorpho- the midzone of fibro- and hyaline- ar neously, but several provoking factors nuclear cells are significantly higher ticular cartilage that is depleted of pro- such as intercurrent illness are impli- in OA synovial fluid positive for CPP teoglycan and rich in Sudan-positive cated. crystals than those without CPP crys- lipid granules (32). They form close tals (65). Examination of fresh syno- to metabolically active hypertrophic Chronic arthropathy vial fluid is ideal, but if not possible, chondrocytes that are rich in iPPi and Chronic arthropathy most commonly the synovial fluid may be stored at o4 C readily release ATP (52). presents as OA with CPPD. Some pa- or at a stable room temperature of 20oC tients present with chronic oligoar- for up to 3 days without any significant CPP crystal induced inflammation thritis or polyarthritis with more overt reduction in crystal count (67). Low Crystal shedding is the preferred mech inflammatory symptoms and signs and speed centrifugation and examination anism to explain the occurrence of CPP occasional systemic upset (with elevat- of the aspirate from base of the tube crystals within synovial fluid (53, 54). ed inflammatory markers) and -addi can increase the diagnostic yield (65). CPP crystals induce inflammation by tional episodes of superimposed acute CPP crystals can be present intracellu- their effects on the NALP-3 inflam- crystal synovitis. larly in both actively inflamed and in- masome which results in IL-1β pro- Uncommon presentations include fa- tercritical joints (66). CPP crystals are

3 Update on calcium pyrophosphate deposition / A. Abhishek & M. Doherty

Fig. 2. Chondrocalcinosis affecting both the medial and lateral knee menisci (left panel), triangular and distal radioulnar joint (middle panel, bottom image), and intracapsular calcification and chondrocalcinosis affecting the middle metacarpophalangeal joint (middle panel, top image). Structural radiographic change in knees with chondrocalcinosis (right panel) - note osteophytes, joint space narrowing and subchondral sclerosis in the medial tibio-femoral joint. less readily identified than monosodi- a very young age. Genotyping for mu- does not modify the phenotype of OA um urate crystals (68), and lack of con- tations and polymorphisms, especially (7, 77, 78), while another study report- sistency between different observers in in the ANKH gene may be carried out ed an association with knee attrition identifying CPP crystals is a potential in those with a family history of pre- (79). Thus, further research is required problem, though training improves mature CPPD if there is no evidence of to identify the structural changes that the levels of inter-observer agreement an associated metabolic predisposing can be attributed to CPPD plus OA. (69). A recent study has demonstrated condition. that a small inexpensive point of care Treatment Raman spectroscope device can detect Imaging Asymptomatic CPPD (chondrocalci- CPP crystals with a greater sensitivity Plain radiography, ultrasonography, nosis) does not require any treatment, than polarized light microscopy (70). and computerised tomography (CT) although screening for underlying Once CPPD is confirmed, considera- can be used to identify CPPD (Fig. metabolic predispositions may be war- tion should be given to the need for 2). Magnetic resonance imaging has ranted. Other manifestations of CPPD further investigations to determine if low sensitivity for detecting CPPD should be managed to provide opti- an underlying metabolic predisposi- (72). Ultrasonography has excellent mum symptom control. tion is present. Metabolic disease pre- specificity (96.4%), good sensitivity disposition to CPPD is uncomomon, (86.7%), a positive predictive value of Acute CPP crystal arthritis and routine screening of all patients 92% and a negative predictive value The treatment of acute CPP crystal ar- with CPPD is unrewarding. Neverthe- of 93% for detecting CPPD compared thritis includes joint aspiration and less, screening tests are warranted in to synovial fluid examination (73) and intra-articular injection of slow-release those with early-onset CPPD (young- is reported to perform better than CT intermediate-acting corticosteroids once er than 55 years), florid polyarticular (74). However, ultrasonography may infection is excluded, or colchicine 0.5 CC, clinical presentation with recur- not be able to detect CPPD in joints or 0.6 mg bd or tds (this may also pre- rent acute attacks, or additional clini- with acute CPP crystal arthritis, and vent recurrent acute attacks (80)). An cal clues that suggest an underlying further research is needed to compare NSAID plus a proton pump inhibi- metabolic abnormality (71). After the the diagnostic performance of ultra- tor are another option if there are no age of 55 years the presence of hyper- sonography and joint aspiration in de- contraindications. However, in a pre- parathyroidism should be looked for in tecting CPPD (75). CPPD appears as dominantly elderly population a short all patients with CPPD because both single or multiple hyperechoic deposits course of systemic corticosteroids are conditions are more common in this or as thin hyperechoic bands parallel to preferable to an NSAID or colchicine age group (22, 71). Testing for iron the surface of hyaline cartilage on ul- (once infection has been excluded as a overload is especially relevant in those trasonography (76). trigger) and produce a more rapid relief with chondrocalcinosis and an atypical CPPD associates with OA, and modi- (81). Adrenocorticotrophic hormone distribution of early onset OA. Tests fies the distribution of OA with greater (ACTH) may be an effective alterna- for rarer diseases e.g. acromegaly or involvement of lateral tibio-femoral tive, and a recent retrospective case se- Wilson’s disease associated with CPPD joints, MCPJs, and trapezio-scaphoid ries reported a dramatic response, with are only warranted if there are clinical joints (10, 77). Some studies report- attenuation of signs of inflammation features suggestive of these conditions ing an association with osteophytosis within 24 hours in 13 of 14 patients or in those with polyarticular CPPD at while other studies suggest that CPPD with mono-articular acute CPP crystal

4 Update on calcium pyrophosphate deposition / A. Abhishek & M. Doherty arthritis who were given a single intra- controlled cross-over trial (n=26) did in Italian subjects from northeastern Italy. muscular injection of 1 mg (100 units) not report any statistically significant The Pro.V.A. (PROgetto Veneto Anziani) study. Clin Exp Rheumatol 2009; 27: 981-4. of synthetic depot ACTH as sole thera- improvement with methotrexate (maxi- 6. FELSON DT, ANDERSON JJ, NAIMARK A, py, with one patient requiring a second mum dose 15 mg/week) in chronic CPP KANNEL W, MEENAN RF: The prevalence of injection the following day (82). inflammatory arthritis who had an un- chondrocalcinosis in the elderly and its asso- Anakinra (IL-1 receptor antagonist) satisfactory response or were contrain- ciation with knee osteoarthritis: the Framing- ham Study. J Rheumatol 1989; 16: 1241-5. has been used in the treatment (100 dicated to oral NSAID or low-dose 7. NEAME RL, CARR AJ, MUIR K, DOHERTY M: mg/day for 3 days) and prophylaxis of glucocorticoids (92). Therefore, over- UK community prevalence of knee chon- polyarticular acute CPP crystal arthri- all there is no convincing evidence to drocalcinosis: evidence that correlation with osteoarthritis is through a shared association tis unresponsive to oral corticosteroids recommend methotrexate in the treat- with osteophyte. Ann Rheum Dis 2003; 62: (83). In a case-series of patients with ment of recurrent acute or chronic CPP 513-8. predominantly refractory polyarticu- crystal inflammatory arthritis. Other 8. SALAFFI F, DE ANGELIS R, GRASSI W: Prev- lar acute CPP crystal arthritis 14/16 treatment options like anakinra, and ra- alence of musculoskeletal conditions in an Italian population sample: results of a re- patients reported a good or partial im- diosynovectomy, may be used. gional community-based study. I. The MAP- provement on day four after receiving PING study. Clin Exp Rheumatol 2005; 23: anakinra injections (100 mg/day for 3 Crystal dissolution 819-28. days) (84). Some patients continued Once deposited, CPP crystals cannot 9. ABHISHEK A, DOHERTY S, MACIEWICZ R, MUIR K, ZHANG W, DOHERTY M: Chondroc- Anakinra for longer duration, up to six be safely dissolved in vivo (93). Phos- alcinosis is common in the absence of knee in- months, and more than a third of pa- phocitrate inhibits the deposition and volvement. Arthritis Res Ther 2012; 14: R205. tients had a relapse when Anakinra was growth of CPP crystals in vitro (94) 10. SANMARTI R, KANTEREWICZ E, PLADE- stopped. and polyphosphates dissolve synthetic VALL M, PANELLA D, TARRADELLAS JB, GOMEZ JM: Analysis of the association be- OA with CPPD should be managed as CPP crystals and CPP crystals from hu- tween chondrocalcinosis and osteoarthritis: OA without CPPD. Some patients with man menisci without cell damage (95), a community based study. 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PETER A, SIMMEN BR, BRUHLMANN P, complicated OA, without an increase MICHEL BA, STUCKI G: Osteoarthritis of the Chronic CPP crystal inflammatory in the risk of prosthetic failure (96, 97). scaphoidtrapezium joint: an early sign of calcium pyrophosphate dihydrate disease. Clin arthritis Treatment of underlying metabolic dis- Rheumatol 2001; 20: 20-4. Reccommended pharmacotherapy for eases that predispose to CPPD is appro- 14. ABHISHEK A, DOHERTY S, MACIEWICZ R, chronic CPP crystal arthritis includes priate, however, other than possibly for MUIR K, ZHANG W, DOHERTY M: Evidence oral NSAIDs or low dose corticos- correction of hypomagnesaemia, such of a systemic predisposition to chondrocalcinosis and association between chondroc- teroids (both based on expert opinion treatment does not appear to influence alcinosis and osteoarthritis at distant joints: and clinical experience), colchicine, the outcome of CPP crystal-associated a cross-sectional study. 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