Calcium Pyrophosphate Deposition Disease: EULAR Recommendations Thomas Bardin Lariboisière Hospital Centre Viggo Petersen Paris Diderot University Paris France
Calcium pyrophosphae dihydrate crystals deposit in the mid zone of articular cartilage and in fibrocartilage Grassi
D. McCarty
EULAR Recommendations on Terminology New Calcium pyrophosphate (CPP) crystals CPP deposition (CPPD) Chondrocalcinosis Clinical presentations: Asymptomatic CPPD Acute CPP crystal arthritis OA with CPPD Chronic CPP crystal inflammatory arthritis (others – rare)
Old calcium pyrophosphate dihydrate
(CPPD) crystals CPPD crystal deposition diseases chondrocalcinosis
lanthanic CPPD pseudogout pseudo-OA pseudo-RA (other pseudo-syndromes) Hollander JL Bulletin on the Rheumatic Diseases 1961;12:263-4 McCarty DJ Annals of Internal Medicine 1962;56:711-37 McCarty DJ Arthritis & Rheumatism 1976;19:Suppl-85
EULAR Recommendations on Diagnosis Definitive diagnosis of CPPD is by identification of characteristic CPP crystals (parallelepipedic, predominantly intracellular crystals with absent or weak positive birefringence) in synovial fluid, or occasionally biopsied tissue.
LOE: Ib Sensitivity: 0.95 (0.92 - 1.00) Specificity: 0.86 (0.80 - 0.93) LR: 7.09 (4.27 - 11.76) SOR: 94 (90 – 97) Crystals can be found in asyptomatic joints Swan A et al ARD 2002;61:493-8 Lumbreras B et al ARD 2005;64:612-5
E Pascual
EULAR Recommendations on Diagnosis
Radiographic CC supports the diagnosis of CPPD, but absence does not exclude it.
EULAR Recommendations on Diagnosis Ultrasonography can demonstrate CPPD in peripheral joints, appearing typically as thin hyperechoic bands within hyaline cartilage and hyperechoic sparkling spots in fibrocartilage. Both sensitivity and specificity appear excellent and possibly better than those of conventional X-rays.
LOE: IIb Sensitivity: 0.87 (0.69 - 1.04) Specificity:0.96 (0.90 - 1.03) LR: 24.2 (3.51 - 168.01) SOR: 78 (70 – 87)
Filippou G et al Journal of Emergency Medicine 2007;32:23-6
Ultrasonography versus radiography Ann Rheum Dis 2005;64:638–640.
2005
11 patients withcrystal-proven CPPD
11 patients: US (+)
9 patients X ray(+).
2 negative X rays: triangular ligament and fibrocartilage
Exemple: US + / X ray -
Echo: type II Ligament triangulaire du carpe
2007
EULAR Recommendations for CPPD Management
2. For acute CPP crystal arthritis optimal and safe treatment comprises application of ice or cool packs, temporary rest, joint aspiration and intra-articular injection of long acting gluco-corticosteroid. For many patients these approaches alone may be sufficient.
LOE • Non pharmacological treatment : IV • Joint aspiration/steroid injection : IV SOR (95%CI): 95 (92, 98)
EULAR Recommendations for CPPD Management 3. Both oral NSAID (with gastroprotective therapy if indicated) and low dose oral colchicine (eg 0.5 mg up to 3 to 4 times per day with or without an initial dose of 1 mg) are effective systemic treatments for acute CPP crystal arthritis, although their use is commonly limited by toxicity and comorbidity, especially in the elderly.
LOE: Efficacy:IIb Toxicity: Ib SOR (95%CI): 79 (66, 91)
EULAR Recommendations for CPPD Management
4. A short tapering course of oral GC, or parenteral GC or ACTH, may be effective for acute CPP crystal arthritis that is not amenable to intra-articular GC injection and are alternatives to colchicine and/or NSAID.
LOE: • Parenteral corticosteroid: IIa • ACTH: III SOR (95%CI): 87 (76, 97)
Management of acute pseudogout • Corticosteroids may appear safer than NSAIDs or colchicine in the elderly : – Systemic administration(Werlen et al. Rev Rhum1996; Roane et al. J Rheumatol 1997)
– ACTH (Ritter et al. J Rheumatol 1994) – Intrarticular route +++ after excluding septic arthritis allows synovial fluid aspiration and analysis
EULAR Recommendations for CPPD Management 5. Prophylaxis against frequent recurrent acute CPP crystal arthritis can be achieved with low dose oral colchicine (e.g. 0.5 to 1 mg daily) or low dose oral NSAID (with gastroprotective therapy if indicated).
LOE: • Cochicine : IIb • NSAIDs : IV SOR (95%CI): 81 (70, 92)
EULAR Recommendations for CPPD Management
6. The management objectives and treatment options for OA patients with CPPD are the same as those without CPPD.
•
LOE: Ia
•
SOR (95%CI): 84 (74, 94)
CPPD and OA # management of OA Destructive arthropathies total joint prosthesis Intra articular hyaluronic acid injections or joint lavage may trigger acute pseudogout attacks Bradley A&R 2OO2 Pasquetti ARD 2004
Maillefert Rev Rhum 1997 Luzard A&R 1998 Ali Am J Med 1999 Dosla A&R 1999 Punzi A&R 2000 Romera A&R 2002 …..
EULAR Recommendations for CPPD Management
7. For chronic CPP crystal inflammatory arthritis, pharmacological options to consider are oral NSAID (plus gastroprotective therapy if indicated), colchicine (0.5 -1.0 mg daily), low dose corticosteroid, methotrexate and hydroxychloroquine.
LOE: • colchicine Ib • Hydroxychloroquine: Ib, • Methotrexate: III • NSAIDs and corticosteroid: IV SOR (95%CI): 79 (67, 91)
Methotrexate and chronic CPPD deposition disease Chollet-Janin et al. Arthritis Rheum 2007;56: 688-692 • • • • •
Five patients 54 to 90 years old MTX 10 à 15 mg/week during 6 to 81 months Subjective patient assessment very favorable Improvement took 1 to 3 months Decrease of pain, n° of painfull and swollen joints, acute attack frequency • Methotrexate stop : recurence
EULAR Rome: intermediary analysis of RCT negative
Effect of intra-articular Ytrium-90 on chronic pyrophosphate Arthropathy of the knee. Doherty and Dieppe. Lancet 1981
15
patients with bilateral chronic pyrophosphate arthropathy of the knee One knee: 90 Y + steroid Other knee: saline + steroid Blinded assesment up to 6 months
Anti-cytokine therapy
Role of IL1 in a mouse model of CPPD crystal-mediated peritonitis
Martinon et al. Nature 2006
Anticytokine therapy and chronic pyrophosphate inflammatory arthritis Anti TNF α agents : little data One RA patient developed pseudogout attacks during etanercept trx Josefina JCR 2007
Anakinra : one case report Mc Gonagle Arthritis Rheum 2008
EULAR Recommendations for CPPD Management 8. If detected, associated conditions such as primary hyperparathyroidism, haemochromatosis or hypomagnesemia should be managed as appropriate.
LOE: IV SOR (95%CI): 89 (81, 98)
CPP Crystal Deposition
Hyperparathyroidism Hemochromatosis Hypomagnesemia Gout …..
Associated with trauma, including surgery
30 Prevalence of CC (%)
Hereditary Sporadic (aging) Associated with metabolic disease
25 20 Men
15
Women
10 5 0 <65
65-
70-
75-
80-
85-
Age (years)
Utsinger PD et al Arthritis & Rheumatism 1975;18:485-91
Etiological therapy of CPPD crystal deposits Management of etiological disorders such as primary hyperparathyroidism or hemochromatosis are beleived to have little influence on the outcome of CPPD crystal deposition disease Parathyroidectomy (or bisphosphonate therapy) can trigger acute attacks
EULAR Recommendations for CPPD Management 9. Currently no treatment is known to modify CPP crystal formation or dissolution and no treatment is recommended for asymptomatic CPPD.
LOE: IV SOR (95%CI): 90 (83, 97)
Pathophysiology of CPP deposition Early findings PPi concentration is normal in the blood but increased in synovial fluid Ca x PPi product is increased in cartilage Cell membrane are impermeable to passive transfert of Ppi Ppi can be generetad in the milieu of cartilage culture
ATP
ATP
AMP + PPi
Extracellular PPi metabolism
NTP- PPH
ATP
PPi
PPi
Pase Alc P + P
Ho et al (2000) : Discovery of the ANK gene ANK mutation is responsible for the ank/ank phenotype ank is a membrane transporter of PPi Inactivationg mutation result in a decrease of extracellular PPi and apatite deposition
Normal mice
Ank/ank mice
ANK mutations in familial CPPD
Activating mutations induce extra cellular PPi in the cartilage and results in CPPD
ATP
ATP
AMP + PPi
ANK and Extracellular metabolismPPi
NTP- PPH
ATP
PPi
PPi ANK
Pase Alc P + P
ANK : a therapeutic target?
Magnesium and CPPD crystal deposition Ca
PPi Alkaline Phatase
CPPD
-
+ Magnesium P + P
Double blind, placebo-controlled trial of magnesium carbonate in chronic pyrophosphate arthropathy
Doherty M, Dieppe PA. Ann Rheum Dis 1983; S1: 106-7
38 patients (without hypomanesemia) 30 mEq Mg/d or placebo Regular follow-up during 6 months Improvement significant (p<0.05) for pain and objective assessment No change in radiographs
Improvement of chondrocalcinosis in one Barter’syndrome patient after long term Mg supplementation
TJ Smilde et al. J Rheumatol 1994; 21: 1515-9
EULAR Recommendations for CPPD Management Conclusion
• 9 key recommendations were developed based on clinical expertise and best available evidence • Research evidence for treatment of CPPD is sparse : only four RCTs have been identified. • Recommendations are supported mainly by expert opinion and evidence extrapolated from data relating to gout. • Drug toxicity needs to be balanced against efficacy, especially in the elderly • Further clinical trials in CPPD (a very common inflammatory arthritis) are needed