Journal Club Presentation

Journal club presentation Presenter: Dr Spoorthy Chair person: Dr Prabhakar Antibodies to cyclic citrullinated protein and erythrocyte sedimentation rate predict hand bone loss in patients with rheumatoid arthritis of short duration: a longitudinal study Journal: Arthritis Research &

Rheumatoid arthritis • Rheumatoid arthritis (RA) is a chronic multisystem disease • characteristic feature- persistent inflammatory synovitis, usually involving peripheral joints in a symmetric distribution. • hallmark of the disease -synovial inflammation , cartilage damage and bone erosions , subsequent changes in joint integrity.

Epidemiology • • • • •

Most common autoimmune disease Affects ~1%(0.8) of the world’s population In pt’s <60… 3-5:1 female predominance 4th 5th decade.. 80% betwn -35y-50y genetic predisposition- HLA-DR4 (DR 1*0401 ) This association is particularly strong for individuals who develop RA associated with antibodies to cyclic citrullinated polypeptides (CCP).

ETIOLOGY • Unknown • Response to infectious agents in a genetically suscetible host • mycoplasma,cmv, parvo, rubella

pathogenesis • Microvascular injury , increase in synovial lining

cells • Autoimmune inflammatory destruction of the synovium • AKA – pannus – A proliferative mass of inflammatory vascularized tissue • Can erode into bone and cartilage • Aided by local generation of metalloproteinases

• As the process continues, the synovium becomes edematous and protrudes into the joint cavity as villous

projections.

• cytokines IL-1 and TNF play an important role by stimulating the cells of the pannus to produce collagenase and other neutral proteases

Pathogenesis • The inflammation in RA causes a shift in the bone metabolism towards increased osteoclast mediated bone turn-over

RA Classification criteria – 1987 American College of Rheumatology 1. Morning stiffness in and around the joints lasting at least 1 hour 2. At least 3 joint areas simultaneously have had soft tissue swelling or fluid (PIP, MCP, wrist, elbow, knee, ankle, and MTP) 3. At least 1 area swollen (as defined above) in a wrist, MCP, or PIP joint 4. Symmetical involvement of the same joint areas (as defined in 2) 5. Subcutaneous nodules over bony prominences, extensor surfaces, or in juxta-articular regions 6. Postive serum Rheumatoid Factor 7. Radiographic changes typical of rheumatoid arthritis on hand and wrist radiographs (must include erosions or unequivocal bony decalcification) Need 4 of 7 for Diagnosis

Characteristic changes of the hand include radial deviation at the wrist with ulnar deviation of the digits, often with palmar subluxation of the proximal phalanges ("Z" deformity) • (2) hyperextension of the proximal interphalangeal joints, with compensatory flexion of the distal interphalangeal joints (swan-neck deformity) • (3) flexion contracture of the proximal interphalangeal joints and extension of the distal interphalangeal joints (boutonnière deformity); • (4) hyperextension of the first interphalangeal joint and flexion of the first metacarpophalangeal joint with a consequent loss of thumb mobility and pinch. •

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Imaging Techniques • X-Rays -Measurements of localised bone involvement in RA can be performed by digital X-ray radiogrammetry (DXR), which gives an estimate of cortical hand bone mineral density (DXR-BMD) • Dexa Scans- dual energy x-ray absorptiometry, may be useful in

detecting early bone loss in rheumatoid arthritis (2 - 27 months after onset).

• Ultrasound. power Doppler ultrasonography (PDUS) or

quantitative ultrasound (QUS). PDUS -monitoring inflammatory activity in the joint. QUS, which is used for osteoporosis, can detect bone loss in fingers, a good indicator of early RA.

The inflammation in RA causes a shift in the bone metabolism towards increased osteoclast mediated bone turnover.

• The dysregulation causes reduced bone mass which is known as an early feature in RA patients, visualised as juxtaarticular bone demineralisation on radiographs. • Quantification of this localised bone loss has been proposed as an outcome measure in early RA.

Laboratory tests • • • • •

Acute phase reactants:ESR & CRP Autoantibodies:RF (usually IgM) ANA Anti-CCP (cyclic citrullinated peptide) Anaemia: normocytic normochromic

Rheumatoid Factor (RF) • RF test is approximately 65%75% sensitive for the diagnosis • The presence of RF, even in high titers or large amounts, is not specific for RA

Conditions Assoc. with (+) Tests for Rheumatoid Factor • • • • •

Rheumatologic Diseases Rheumatoid arthritis (~70%) Sjögren’s syndrome (~90%) Lupus (~20%) Cryoglobulinemia syndrome (90%)

• • •

Lung Diseases Interstitial fibrosis Silicosis

• • • • •

Infections Hepatitis C virus Acute viral infections Endocarditis Tuberculosis

• • • •

Miscellaneous Sarcoidosis Malignancies Aging

Anti-CCP • There are other RA-associated auto-Abs known to be specific for rheumatoid arthritis – Perinuclear factor – Antikeratin antibodies

• They are not widely used due to technical difficulties with their detection

Anti-CCP • The epitopes of the antigens (target of Ab’s) are arginyl residues • These are converted “citrullinated” by an enzyme to citrulline (an amino acid). The enzyme is called PAD14. • These citrullinated epitopes are recognized by other RA-assoc. Ab’s

Anti-CCP • Citrullinated peptides have been synthesized as Ag’s for diagnostic immunoassays • ELISA – Wells coated w/ cyclic citrullinated peptides – Exposed to RA pt’s serum – Colorimetric response in Ag-Ab binding

Anti-CCP • Anti-CCP antibodies are locally produced in inflamed joints • Anti-CCP antibody is present before symptoms develop, therefore, • Frequently (+) early in the course of RA when the diagnosis may be uncertain. • Unlike RF, anti-CCP is not associated with Hep C infection

Prognosis • Presence of CCP antibodies is associated with development of erosive arthritis. • The presence of anti-CCP in high titer has important prognostic implications • Anti-CCP helps in predicting which RA patients will have persistent disease, and erosive disease

• • • • • • • •

Features correlated with a greater likelihood of developing joint abnormalities or disabilities

>20 inflamed joints, a markedly elevated ESR, radiographic evidence of bone erosions rheumatoid nodules, high titers of serum rheumatoid factor anti-CCP antibodies the presence of functional disability advanced age at onset,

contd • the presence of comorbid conditions, • low socioeconomic status or educational level, • the presence of HLA-DR 1*0401 or -DR *0404.

Algorithm for the medical management of rheumatoid arthritis

Introduction of the study •

Disease course of RA is heterogeneous and about one third of RA patients do not experience joint damage.

•

Early intervention with disease-modifying antirheumatic drugs (DMARDs) which inhibit joint damage, is accepted as a cornerstone in the treatment strategy of RA

• The identification of patients prone to bone involvement is important at an early stage of the disease in order to individually tailor the RA treatment and optimise disease outcome

objective • A longitudinal study to examine if serological markers also predict hand bone mineral density (BMD) loss in patients with RA of short disease duration.

Methods • 163 patients with RA of short disease duration (2.4 years) were included and followed longitudinally. • Antibodies to cyclic citrullinated protein (anti-CCP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analysed from baseline blood-samples. •

CONTD. • Hand BMD was measured by digital X-ray radiogrammetry (DXR) based on hand and wrist radiographs obtained at baseline and 1, 2 and 5-year follow-up.

EURIDISS (European Research on Incapacitating Disease and Social Support) study, a Norwegian arm of the cohort was followed longitudinally. At inclusion in 1992,238 patients aged from 20 to 70 years, with a clinical diagnosis of RA and disease duration of less than 4 years were included . out of these 163 were included in the cohort.

Baseline assessment • • • • •

Blood samples Medical history health assessment questionnaire (HAQ). conventional, bilateral hand and wrist radiographs were taken at baseline and one, two and five-year follow-up

Treatment given • The percentages of patients who were treated with DMARDs/ prednisolone at • baseline 53.8/26.3 • one 46.9/28.1 • two 50.6/29.4 • Five 54.9/37.5,

Lab analysis used • Crp • Esr • Anti ccp- . Values above 25 U/ml were considered positive • IgA and IgM rheumatoid factor (RF)ELISA technique, positive cut-off at 25 U/ml • BMD was measured by DXR

• The DXR software automatically recognises the regions of interest(metacarps two to four) and measures the cortical thickness, bone width, and bone porosity118 times per cm..

Statistical analysis • Dxr-bmd changes calculated as a percentage difference betwn follow up and baseline.. • Prediction of Loss in cortical hand bone was defined as a negative change in DXR-BMD exceeding the LSC. • Least significant change being 0.79% individual differences from baseline to one yr, one to two and two to five yrs.. • This correlated with clinical cutoffs of increased values of serological markers .

Statistical analysis. Contd.. ESR CRP IGA RF IGM RF ANTI-CCP

• • • • •

>20MM/HR >10MG/DL >25U/ML >25U/ML >25U/ML

Associations were explored by linear regression analysis and multivariate regression analysis

Results-% of patients with loss in cortical bone loss At one yr of follow up

66.7%

At second yr

77.3%

At fifth yr

89.1%

Change in DXR-BMD • • • •

1 TO 2 YRS – -1.46% 2 TO 5YRS-3.81%

YOUNGER OLDER WOMEN(<4 WOMEN 0YRS) 1YR-2.32

-1.15

2YR-3.39

-1.73

5YR-7.45

-3.88

Associations between baseline serological biomarkers and Change in DXR-BMD(ODDS RATIO) 2YR

5 YR

ANTI CCP>25 2.2

2.6

4.9

ESR

3.5

1YR

4.5

REDNISOLO NE USE AGE

4.7 1

SEX-FEMALE 1

1

1.1

0.5

0.9

RESULTS CONTD.. • Anti-CCP was a consistent and independent predictor of cortical hand bone loss during the five-year follow-up period in multivariate logistic regression analyses. • Elevated baseline ESR was independently predictive of one- and two-year cortical hand bone loss. • Two-year cortical hand bone loss was also predicted by prednisolone use

Weaknesses of the study • A lack of available data on important factors that influence the bone mineral density. There were no available data on use of vitamin-D, calcium supplements, hormone replacement therapy or anti-resorptive treatment. • There were no available specifications on the different DMARDs used during the five-year period. • The menopausal status of the patients was not known.

Weakness contd… • Another weakness of this study was that DXA-BMD measurements were not performed. • The observed cortical bone loss could neither be validated against the measured gold standard DXA-BMD, • Nor could the observed predictors be validated against trabecular bone loss.

CONCLUSIONS • In this study THEY confirm that RF and CRP are associated with DXR-BMD. • In addition they show that elevated levels of anti-CCP and ESR are independent predictors of DXR-BMD loss. • These common predictors support that erosions and focal bone loss have a common cellular mechanism.

conclusions • The results of these analyses implies that a hypothetical forty year old female RA patient with • elevated levels of ESR and anti-CCP would at one-year follow-up have a predicted DXRBMD loss of 4.2% and • an odds of 6.4 for cortical hand bone loss, compared to a similar patient with normal levels of ESR and anti-CCP

• findings support that elevated levels of anti-CCP and ESR are important markers that have potential impact on the disease course and should have impact on considerations about treatment strategies in RA patients. • Further, this observation adds support to the hypothesis of similar mechanisms being involved in hand bone loss and erosive disease.

• • • • • • • • • • • • • • • • •

References 1. Goldring SR: Pathogenesis of bone and cartilage destruction in rheumatoid arthritis. Rheumatology (Oxford) 2003, 42 Suppl 2:ii11-ii16. 2. Schett G, Hayer S, Zwerina J, Redlich K, Smolen JS: Mechanisms of Disease: the link between RANKL and arthritic bone disease. Nat Clin Pract Rheumatol 2005, 1:47-54. 3. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988, 31:315-324. 4. Hoff M, Haugeberg G, Kvien TK: Hand bone loss as an outcome measure in established rheumatoid arthritis: 2-year observational study comparing cortical and total bone loss. Arthritis Res Ther 2007, 9:R81. 5. Jørgensen JT, Andersen PB, Rosholm A, Bjarnason NH: Digital X-ray radiogrammetry: a new appendicular bone densitometric method with high precision. Clin Physiol 2000, 20:330-335. der Heijde D, Landewe R, Kvien TK: High anti-cyclic citrullinated peptide levels

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6. Rosholm A, Hyldstrup L, Backsgaard L, Grunkin M, Thodberg HH: Estimation of bone mineral density by digital X-ray radiogrammetry: theoretical background and clinical testing. Osteoporos Int 2001, 12:961-969. 7. Finckh A, Liang M, Van Herckenrode C, De Pablo P: Long-term impact of early treatment on radiographic progression in rheumatoid arthritis: A metaanalysis. Arthritis Rheum 2006, 55:864-872. 8. Quinn MA, Conaghan PG, Emery P: The therapeutic approach of early intervention for rheumatoid arthritis: what is the evidence?*. Rheumatology (Oxford) 2001. 9. Syversen SW, Gaarder PI, Goll GL, Ødegård S, Haavardsholm EA, Mowinckel P, van

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The association of anti-CCP antibodies with disease activity in rheumatoid arthritis Münevver Serdaroğlu, 1 Haşim Çakırbay,1 Orhan Değer,2 Sevil Cengiz,2 and Sibel Kul3 1Physical Therapy and Rehabilitation, Karadeniz Technical University, Trabzon, Turkey 2Biochemistry Department, Karadeniz Technical University, Trabzon, Turkey 3Radiology Department, Karadeniz Technical University, Trabzon, Turkey Münevver Serdaroğlu, Phone: +90-462-3775426, Fax: +90-5054828581, Email: [email protected]. Corresponding author. Received July 17, 2007; Accepted March 16, 2008.