Early Inflammatory arthritis Dr Charlie Filer Consultant Rheumatologist Stepping Hill Hospital

Objectives Understand what is meant by the term EIA and the importance of identifying patients Understand the challenges in identifying these patients Gain a clear understanding of the symptoms and simple clinical signs that can help identify which patients to refer Gain an understanding of the important investigations to complete and the interpretation of the results when you suspect a patient to have EIA Gain an understanding of the EIA clinic and an overview of the management of these patients Know how and when to refer these patients to rheumatology

What is meant by EIA? Term used to identify patients who may be at high risk of developing Rheumatoid Arthritis (RA) and whom may not meet diagnostic criteria for the condition as yet Not all patients with EIA will develop RA Resolve spontaneously Definite alternative inflammatory arthropathy Remain undifferentiated

What is RA? A systemic inflammatory disease characterized by synovial proliferation that leads to joint destruction, cartilage loss, progressive deformities and serious functional disability It affects approximately 1% of the population It is more common in women F:M 3:1 Commonly presents between 30-60 yrs Associated with autoantibodies Rheumatoid Factor (RF) Anticyclic citrullinated peptides (Anti-CCP)

What is RA? 50% of patients are disabled within 10 years of the onset of disease. Severe disease is associated with premature mortality-cardiac disease Joint erosions occur in 67% of patients within 2 years of disease onset. Erosions occur as early as four months after disease onset. Erosions predict a poor functional outcome

RA and Cardiovascular disease Women with RA have a 2-3 fold higher risk of myocardial infarction, even in the absence of traditional coronary risk factors OR for MI 1.47 for RA patients 7.12 for RA and diagnosed hyperlipidaemia

RA and Osteoporosis Two-fold increase in osteoporosis in patients with RA compared to individuals of the same age and sex who do not have RA. Risk factors Disease-related risk factors inflammation, disease duration, immobility, disability and high dose corticosteroid use Traditional risk factors female, increasing age, a postmenopausal state, family history of osteoporosis, being underweight, inadequate physical activity, cigarette smoking, high alcohol intake

Risk Factors for RA Largely unknown Genetics – 21-65% risk Shared epitope amino acid substitutions at positions 67-74 of the HLA-DRB1 molecule PTPN22 Environmental – 41% risk Smoking Peridontal disease - Porphyromonas gingivalis

Smoking and RA Current smokers, ex-smokers, and ever-smokers of both sexes have an increased risk for seropositive RA odds ratio 1.7 - 1.9 Not a risk for seronegative RA Duration of smoking Risk only if smoked ⩾20 years, Risk if smoking of 6–9 cigarettes/day Risk increases with increasing cumulative dose of smoking Smoking cessation Risk remains for up to 10–19 years after smoking cessation.

Smoking and RA Risk to offspring of Seropositve RA patient 1 in 10 risk of developing RA 1 in 4 risk of developing RA if they smoke

Seropositive Seronegative  Relative risk (RR) for development of rheumatoid arthritis (RA) in current smokers (with different numbers of copies (0–2) of the shared epitope (SE) of HLA-DR) compared with never smokers. Seropositive  Relative risk (RR) for development of rheumatoid arthritis (RA) in current smokers (with different numbers of copies (0–2) of the shared epitope (SE) of HLA-DR) compared with never smokers. (A) RR for seropositive RA and (B) RR for seronegative RA. These graphs are schematic representations of the original data from a case–control study of RA reported in reference 9. Seronegative L Klareskog et al. Ann Rheum Dis 2004;63:ii28-ii31 ©2004 by BMJ Publishing Group Ltd and European League Against Rheumatism

Gene-Environment interaction in RA

Diagnosis of RA 2010 ACR/EULAR Classification criteria for RA

RA pattern of joint involvement

Diagnosis of RA 2010 ACR/EULAR Classification criteria for RA

Serology: Rheumatoid Factor(RF) Antibody directed against the Fc portion of IgG RA patients 50-70% RF-positive at disease onset Approximately 80% become RF-positive over the course of their disease Sensitivity (70%) specificity (70%) Can be positive in other conditions and normal people Associated with poorer prognosis if positive in RA patients

Serology: Rheumatoid Factor(RF) Positive in other disease Positive in Normal people Viral/Bacterial infections Hepatitis C TB Neoplasms Chronic diseases – hepatic/pulmonary Autoimmune conditions Sjogrens SLE Cryoglobulinaemia 20-60 yrs: 2-4% 60-70 yrs: 5% > 70 yrs: 10-25%

Serology: Anti-cyclic citrullinated peptide antibody (Anti-CCP) Anti-CCP antibodies are directed against citrullinated proteins Citrullination results from the post-translational modification (ie. not encoded in the original protein) of the amino acid arginine to citrulline by the enzyme peptidyl arginine deiminase  Anti-CCP assays recognize a number of citullinated proteins

Serology: Anti-cyclic citrullinated peptide antibody (Anti-CCP) Highly specific for RA (98%) Positive in 70% RA patients Positve in 33% RA patients who are RF negative Can be seen years prior to RA onset and rarely develop after onset, suggesting that they are not just a consequence of inflammation.  Associated with a more severe disease course and lower chance of drug-free remission Diagnostic accuracy as good in early disease as in established RA Rarely documented in other diseases May also be useful in differentiating RA from other disorders with articular symptoms plus RF positivity (hepatitis C etc)

Diagnosis of RA 2010 ACR/EULAR Classification criteria for RA Elevated levels of CRP and ESR in patients with RA suggest heightened disease activity. However, elevations may also be due to other inflammatory conditions. Normal CRP and ESR results indicate relatively low disease activity. In patients with discordant CRP and ESR results, CRP levels may be the more reliable marker of RA disease activity.37 Recent evidence suggests that CRP levels during early RA may be predictive of long-term (10-year) disease progression.26 duration of symtpoms can also help todetermine the likelihood of RA, if symtoms progress beyond 6 weeks this is more likely whereas viral/bacterial causes of polyarthritis are most likely to resolve

Treatments NSAIDs Prednisolone/IM kenalog/depomedrone DMARDs Biologics Methotrexate PO/s/c, Leflunomide, sulphasalazine, Hydroxychloroquine IM Myocrisin Biologics Anti-TNF – Adalimumab, Certolizumab, Etanercept, Golimumab Anti- IL-6 - Tocilizumab Anti-B cell - Rituximab Anti-CTLA-4/B7 - Abatacept

Disease Activity/Response to treatment: DAS28 score The DAS28 is a measure of disease activity in rheumatoid arthritis (RA). DAS stands for 'disease activity score' and the number 28 refers to the 28 joints that are examined in this assessment DAS28 score >5.1 =high disease activity 3.2-5.1 = moderate disease activity 2.6-3.2= low disease activity <2.6 = remission

Why is diagnosing EIA important?

Why is diagnosing EIA important? Early Treatment: Over the last 15 years, unequivocal evidence has emerged that early aggressive treatment: Improves symptoms Reduces damage Reduces complications Improves mortality … and is cost-effective There is some evidence of a “window of opportunity” for treatment… … and the process may potentially be reversed

Early versus delayed treatment 8-9 month delay in treatment from symptom onset worsens long term outcomes Treating to target significantly improves outcomes The median lag to the initiation of disease-modifying treatment was 15 days in the early treatment group and 123 days in the delayed treatment group. There was less radiologic joint damage after 2 years in the early treatment group (median Sharp score, 3.5; 95% confidence interval [CI]: 1 to 7) compared with the delayed treatment group (median Sharp score, 10; 95% CI: 5 to 15; P <0.05). The median area under the curve of the 2-year disease activity score was lower in the early treatment group (64 units; 95% CI: 59 to 69 units) compared with the delayed treatment group (73 units; 95% CI: 69 to 77 units; P = 0.002)

Early versus delayed treatment

Early Diagnosis Therefore it is crucially important to recognise synovitis and refer early Encompassed in NICE RA Management guidelines 2009 New “Best Practice Tariff” for inflammatory arthritis reflects this But…..this is not always easy…..

DIAGNOSTIC DELAY Patients accrue joint damage Diagnostic uncertainty GP Referral to Rheumatology Patient’s Symptoms Rheumatology appointment DMARD GP appointment Patients accrue joint damage Diagnostic uncertainty

Diagnostic difficulties Easily missed rheumatological conditions presenting with joint pain Easily missed conditions Common reasons for delay or misdiagnosis Early inflammatory arthritis: rheumatoid arthritis May present initially with joint pain and/or fatigue with no examination findings Early inflammatory arthritis: psoriatic arthritis May have only one area affected with subtle findings, e.g. dactylitis (sausage toe or finger), or periarticular inflammation such as enthesitis, e.g. presenting with Achilles pain Connective tissue disease Symptoms may be non-specific, including fatigue and arthralgia Gout: acute Marked overlying joint erythema often confused with cellulitis Gout: chronic Gouty tophi on hands in the elderly easily confused with signs of osteoarthritis such as Heberden’s nodes Polymyalgia rheumatica May present with shoulder or hip pain initially leading to other diagnoses such as soft tissue problems or frozen shoulder Patients often present to gps with symptoms rather than diseases. A number of musculoskeletal condtions can prove difficult to diagnose for a gp for exaple

Clinical Scenarios

Scenario 1 Female, 75 yrs Pain in PIPs and DIPs most fingers of both hands EMS 30 mins, limiting ADLs Mother had an ‘arthritis’ – unclear as to what type RF 16 (Normal <8) Anti-CCP 1.0 (Normal <10) CRP 11 (Normal <10) Likely OA

Scenario 2 Female 30 yrs 4 week history of arthralgia MCPs, PIPs, Wrists, Knees, ankles Not marked swelling noticed EMS 1 hour, Eased with activity Unwell, marked fatigue Initially a vague rash to face – now settled RF 64 (normal <8) Anti-CCP 14 (Normal <10) CRP 24 (normal <10) ESR 27 (normal <19) FBC normal ?EIA ?viral polyarthritis ??Connective tissue disease

Scenario 3 Male, 35 yrs Lumbar back pain EMS 1 hour, eased with activity but can also be worsened at the end of a work day (manual job) No other joints affected No history of psoriasis, colitis, iritis No musculoskeletal family history RF 32 (normal <8) ESR 18 (normal <19) CRP 9 (normal <10) Not EIA ?spondyloarthropathy/ ?mechanical

When to consider EIA in a patient with joint pain? The History:

When to consider EIA in a patient with joint pain? The History: Family history of RA Social history Smoking

When to consider EIA in a patient with joint pain When to consider EIA in a patient with joint pain? Pattern of joint involvement :

When to consider EIA in a patient with joint pain? Joint Swelling: History Examination Potentially present as a symptom Can be an unreliable symptom and obviously needs correlation with examination Squidgy/boggy swelling in the right joint distribution Opposed to firm bony swelling of OA Can be difficult to elicit/not obviously present in early RA Those with a raised BMI have ‘puffy’ joints making eliciting synovitis difficult

Joint Examination Joint tenderness Joint vs Tendon Erythema Elicited when pressing to allow examiners nail bed to whiten RA distribution Joint vs Tendon Eg ulnar styloid Erythema Lacking in RA Marked erythema seen in alternative diagnosis Crystal Septic

Examination MCP/MTP Squeeze test: subclinical/subtle synovitis It is well recognised that synovitis can be difficult to detect by examination alone, and new imaging techniques now pick up ‘subclinical’ synovitis in a number of patients with normal examination findings. The squeeze test is a useful clinical test to determine subtle synovitis that is not palpable and can be performed at the metacarpophalangeal (MCP) or metatarsophalangeal (MTP) joints as shown in Figure 2. Tenderness elicited with a gentle squeeze is suggestive of synovitis.

Investigations to consider CRP ESR Rheumatoid Factor Anti Cyclic Citrullinated Peptide (anti CCP) FBC/U+E/Bone/LFTs Additional considerations depending on the above – CK/TFTs/ANA/virology

Imaging: X-rays (particularly hands and feet) Not always diagnostically useful in early disease Important for a baseline assessment for erosions Early signs may be: Soft tissue swelling Periarticular osteopenia Rule out erosions which can occur in asymptomatic joints (particularly the feet) Alternative pathology – chondrocalcinosis in pseudogout, OA

Traps for the unwary Rheumatoid arthritis may be associated with: A normal Rheumatoid factor Only very subtle joint swelling Normal inflammatory markers Normal x-rays Fibromyalgia may be associated with: Early morning stiffness A perception of peripheral joint swelling Peripheral joint tenderness

EIA Clinics A number of rheumatology departments will now have such a clinic To allow patients suspected of having EIA to be seen, diagnosed and commenced on treatment in the critical period of their diseases

EIA Clinic – New Patients Patients triaged according to information on GP referral Those suspected of having possible EIA features given clinic appointment <3 weeks from when the referral was received in SHH Those with a definite diagnosis of EIA commenced on DMARDs Those with unclear diagnosis referred for more sensitive diagnostic radiology: Patients with normal bloods but suggestive symptoms Patients with positive immunology/raised inflammatory markers but little clinically to find/not overly suggestive symptoms

New diagnostic techniques Ultrasound Increased sensitivity in detecting synovitis than clinical examination Detects bone lesions before erosions are evident on x-ray Dynamic, will hopefully be available in the clinic MRI Provides detailed information regarding synovitis and erosions Not readily available Expensive

EIA patients Follow up Frequent over initial 12 months from diagnosis Aim for patients to be in remission/low disease activity Assessed by disease activity score for RA (DAS28) Rapid escalation of DMARDs/combination DMARDs instigated Steroids used liberally in the initially stages – IM kenalog/depomedrone, reducing courses of oral Prednisolone Biologics as per NICE guidance/GMMMG guidance

When to refer to the EIA clinic If the referral criteria is met If a patient has inflammatory sounding joint symptoms, in the joint distribution for RA even if blood tests are normal and no joint swelling Anti-ccp positive with musculoskeletal symptoms, even if no joint swelling Rheumatoid factor positive with inflammatory sounding joint symptoms in the appropriate joints lasting longer than 4-6 weeks

Summary EIA term used to allow early identification of patients with potentially RA RA is associated with significant morbity and mortality Smoking is an important modifiable risk factor Treating RA early has a significant benefit on long term outcomes Suspecting EIA is not always easy but there are certain features and the history and examination that will make you suspect this more If concerned a patient has EIA they should be referred urgently to an EIA clinic for assessment If any doubts speak to us!

Thank you Any questions?