1. Early Inflammatory arthritis
Dr Charlie Filer
Consultant Rheumatologist
Stepping Hill Hospital

2. 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

3. 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

4. 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 yrs
Associated with autoantibodies
Rheumatoid Factor (RF)
Anticyclic citrullinated peptides (Anti-CCP)

5. 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

8. 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

9. 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

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

11. Smoking and RA
Current smokers, ex-smokers, and ever-smokers of both sexes have an increased risk for seropositive RA
odds ratio
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.

12. 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

13. 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

14. Gene-Environment interaction in RA

15. Diagnosis of RA 2010 ACR/EULAR Classification criteria for RA

16. RA pattern of joint involvement

18. Diagnosis of RA 2010 ACR/EULAR Classification criteria for RA

19. 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

20. 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%

21. 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

22. 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)

23. 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

24. 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

25. 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
= moderate disease activity
= low disease activity
<2.6 = remission

26. Why is diagnosing EIA important?

27. 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

28. 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)

29. Early versus delayed treatment

30. 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…..

31. 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

32. 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

33. Clinical Scenarios

34. 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

35. 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

36. 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

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

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

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

40. 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

41. 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

42. 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.

43. 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

44. 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

45. 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

46. 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

48. 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

49. 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

50. 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

51. 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

52. 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!

53. Thank you
Any questions?