Undifferentiated Arthritis Guide

Undifferentiated Arthritis

Ahmed Fathi Blasi
MSc Rheumatology, P.M & Rehab.

Definition
Undifferentiated Connective Tissue Disease

people who have symptoms and certain lab
test results that look like a systemic autoimmune
disorder or connective tissue disease. But they
don't have enough of such characteristics to meet
the diagnosis for a well-defined connective tissue

disease.

Definition
Early Arthritis patients that cannot be
classified according to EULAR/ACR criteria and in
whom the arthritis is not septic or reactive in

origin have per exclusion an Undifferentiated
Arthritis (UA).

EARLY R.A
Early

ArthritisUA

Other
Diagnosis

The criteria were formulated by experts based on
characteristics of patients with long-standing RA

(mean disease duration of 8 years)

Harrison BJ, Symmons DP, Barrett EM, Silman AJ. Th e performance of the 1987 ARA classifi cation criteria for rheumatoid arthritis in a population based
cohort of patients with early infl ammatory polyarthritis. American Rheumatism Association. J Rheumatol 1998;25(12): 2324–2330.

PRE-DISEASE PROCESSES
A number of abnormalities have been observed
in pre-disease samples that can be distinguished in

the onset of autoantibodies, the onset of an

inflammatory response, and the onset of lipid
abnormalities.

MID-1970 S
ACPA

In studies from Finland from the 1970s, it was

already identified that autoantibodies are present
before disease onset.
Aho K, Heliovaara M, Maatela J, et al. Rheumatoid factors antedating clinical rheumatoid arthritis. J Rheumatol 1991;18: 1282–1284.
Aho K, von Essen R, Kurki P, et al. Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process. J Rheumatol
1993;20:1278–1281.

A T H E RO S C L E RO T I C

EVENTS

Recent-onset RA is associated with dyslipidemia.
Patients who later developed rheumatoid arthritis

had a considerably more atherogenic lipid profile at
least 10 years before onset of symptoms.
Georgiadis AN, Papavasiliou EC, Lourida ES, et al. Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis: eff ect of early
treatment—a prospective, controlled study. Arthritis Res Th er 2006;8(3):R82.

In the early phases of RA, only 13% of the
patients have erosive disease. Additionally, erosions

often initially present in the small joints of the feet
and appear in the small joints of the hands at a later
point in the disease course.
Van der Heijde DM, van Leeuwen MA, van Riel PL. Radiographic progression on radiographs of hands and feet during the fi rst
3 years of rheumatoid arthritis measured according to Sharp’s method (van der Heijde modifi cation). J Rheumatol 1995;22(9): 1792–1796.
Symmons DP, Silman AJ. Th e Norfolk Arthritis Register (NOAR). Clin Exp Rheumatol 2003;21(5 Suppl 31):S94–S99.

 Rheumatoid nodules are very rare in the early
phases of RA

 Rheumatoid factor is present in only 50% of the
patients with early RA.

Quinn MA, Green MJ, Marzo-Ortega H, et al. Prognostic factors in a large cohort of patients with early undiff erentiated infl ammatory arthritis after application
of a structured management protocol. Arthritis Rheum 2003;48(11):3039–3045.

Patients fulfill the criteria for at least 6 weeks, a
disease duration of less than 6 weeks is by definition

impossible in case of early RA.

This indicates that at present a set of criteria is
needed that applies to early Undifferentiated

Arthritis and that differentiate the UA patients that
will progress to RA from those that will have a more
benign disease course.

The syndrome RA can now be identified
in

ACPA-positive & ACPA-negative
disease.

Van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, et al. Autoantibodies to cyclic citrullinated peptides predict progression to
rheumatoid arthritis in patients with undiff erentiated arthritis: A prospective cohort study. Arthritis Rheum 2004;50(3):709–715.

This

applies

to

UA

as

well

with

a different disease course in these two

syndromes with a much higher chance to

develop RA in the ACPA-positive UA
patients.
Van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, et al. Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients
with undiff erentiated arthritis: A prospective cohort study. Arthritis Rheum 2004;50(3):709–715.

The Natural Disease Course of Patients

with Early Arthritis and UA
Rheumatoid Arthritis

Differentiated
Persistent undifferentiated
Arthritis
EARLY
ARTHRITIS

30-50%

26%

arthritis

Other diagnoses

Undifferentiated
Arthritis
Remission

16%
35-54%
26-55%

• Reported percentages differ among early arthritis cohorts,
which explains why the total may add to more than 100%.

• The duration of symptoms are of importance for the

outcome of the patient group. In other words UA
from recent onset (several weeks) has a different
natural course than an arthritis that after 1 year of
follow-up

is

still

undifferentiated arthritis).

unclassified

(persistent

• The reported rates of spontaneous remission in

patients with UA are importantly different from those
in RA.
• Where as remission was achieved in 40% to 55% of
the patients with recent-onset undifferentiated
arthritis.
Harrison BJ, Symmons DP, Brennan P, et al. Natural remission in inflammatory polyarthritis: Issues of definition and prediction. Br J
Rheumatol 1996;35(11):1096–1100.
Linn-Rasker SP, Allaart CF, Kloppenburg M, et al. Sustained remission in a cohort of patients with RA: Association with absence of IgMrheumatoid factor and absence of anti-CCP antibodies. Int J Adv Rheumatol 2004:2(4):4–6.
Van der Helm-van Mil AH, Dieude P, Schonkeren JJ, et al. No association between tumour necrosis factor receptor type 2 gene
polymorphism and rheumatoid arthritis severity: A comparison of the extremes of phenotypes. Rheumatology (Oxford) 2004;43(10): 1232–
1234.

• The remission rate in RA is less than 10% to 15%.

• Apparently, the chance to achieve a natural
remission becomes smaller when the disease
process is more mature.
• This supports the notion that chronicity might be
more easily reversed in the UA phase.

Harrison BJ, Symmons DP, Brennan P, et al. Natural remission in inflammatory polyarthritis: Issues of definition and prediction. Br J Rheumatol 1996;35(11):1096–1100.
Linn-Rasker SP, Allaart CF, Kloppenburg M, et al. Sustained remission in a cohort of patients with RA: Association with absence of IgM-rheumatoid factor and absence of anti-CCP antibodies.
Int J Adv Rheumatol 2004:2(4):4–6.
Van der Helm-van Mil AH, Dieude P, Schonkeren JJ, et al. No association between tumour necrosis factor receptor type 2 gene polymorphism and rheumatoid arthritis severity: A comparison
of the extremes of phenotypes. Rheumatology (Oxford) 2004;43(10): 1232–1234.

Important Points
• UA has a variable disease course.

• Disease-modifying antirheumatic drug (DMARD)
therapy is potentially toxic.
•

only the UA patients that have a high probability of
developing RA are preferentially treated with
DMARDs.

Predicting Progression
from
Undifferentiated Arthritis
to
Rheumatoid Arthritis

The construction
of a prediction rule
• Initial attempts to define such prognostic criteria
have been made.
• This

model

predicts

disease

persistency

development of erosions.

Visser H, le Cessie S, Vos K, et al. How to diagnose rheumatoid arthritis early: A prediction model for persistent (erosive) arthritis. Arthritis
Rheum 2002;46(2):357–365

and

The construction
of a prediction rule
• Form Used to Calculate Prediction Score in Points
for Individual Patients with Undifferentiated Arthritis

Van der Helm-van Mil AH, le Cessie S, van Dongen H, et al. A rule to predict disease outcome in patients with recent-onset undifferentiated
arthritis to guide individual treatment decisions. Arthritis Rheum 2007;56(2):433–440.

Age in years

Gender

Multiply by 0.02

If female

1 point

Distribution of involved joints

If small joints in hands/feet

0.5 point

If symmetric

0.5 point

If upper extremities

1 point

If upper and lower extremities

1.5 points

Length of VAS morning stiffness
(range 0–100 mm)

If 26–90 mm

1 point

If > 90 mm

2 points

Number of tender joints
If 4–10

0.5 point

If ≥ 11

1 point

Number of swollen joints
If 4–10

0.5 point

If ≥ 11

1 point

C-reactive protein level (mg/L)
If 5–50
0.5 point
If ≥ 51
1.5 points

Positive rheumatoid factor
If yes
1 point

Positive anti-CCP antibodies (ACPA)
If yes
2 points

Total Score

• Age
• gender

Total Score
•

Distribution of
involved joints.

•

Morning stiffness
severity

•

Number of tender

and swollen joints.

Total Score
• C-reactive proteins
• Rheumatoid factor
• Anti-CCP antibodies

Presentation Patterns of ACPA positive
Versus ACPA negative Disease

Question

of

whether

anti-CCP

positive

and

negative RA are different disease entities with
distinct clinical characteristics ?

Presentation Patterns of ACPA positive
Versus ACPA negative Disease
• After 4 years of follow-up, patients with ACPA had

more swollen joints and more severe radiologic
destruction.
• In conclusion, the phenotype of RA patients with or
without ACPA is similar with respect to clinical
presentation but differs with respect to disease
course.

Van der Helm-van Mil AH, Verpoort KN, Breedveld FC, et al. Antibodies to citrullinated proteins and diff erences in clinical progression of rheumatoid arthritis.
Arthritis Res Th er 2005;7(5): R949–R958.

Outcomes of Treatment
in Undifferentiated Arthritis

Van Gaalen F, Ioan-Facsinay A, Huizinga TW, et al. Th e devil in the details: Th e emerging role of anticitrulline autoimmunity in
rheumatoid arthritis. J Immunol 2005;175(9):5575–5580.
Van Dongen H, van Aken J, Lard LR, et al. Effi cacy of methotrexate treatment in patients with probable rheumatoid arthritis: A doubleblind,
randomized, placebo-controlled trial. Arthritis Rheum 2007; 56(5):1424–1432.

• In a double-blind clinical trial, patients were
randomized for treatment
Methotrexate

Placebo
18 month

Progression
towards RA

Level of joint
destruction



• A significantly lower number of MTX-treated UA
patients had progressed to RA compared to the
placebo-treated patients.


• In addition, the UA patients that were treated with
methotrexate had a significantly lower level of

radiologic joint destruction, indicating a less
severe disease course.


• After the cessation of methotrexate at 18 months,
the difference in the number of patients who

developed RA remained statistically significant but
the difference became smaller.


• This suggests that in some patients methotrexate
had hampered the progression of the disease, but

had not been able to totally stop the underlying
pathophysiologic mechanisms.


Age in years

Multiply by 0.02

Gender

If female

1 point

Distribution of involved joints
If small joints in hands/feet
If symmetric
If upper extremities
If upper and lower extremities

0.5 point
0.5 point
1 point
1.5 points

Length of VAS morning stiffness
(range 0–100 mm)
If 26–90 mm
If > 90 mm

1 point
2 points

Number of tender joints

Number of swollen joints

If 4–10
If ≥ 11

If 4–10
If ≥ 11

0.5 point
1 point

C-reactive protein level (mg/L)
If 5–50
0.5 point
If ≥ 51
1.5 points
Positive anti-CCP antibodies
If yes
2 points

0.5 point
1 point
Positive rheumatoid factor
If yes
1 point

Revision ?
 Radiology
 Sex
 Family

History
 Morning Stiffness

Early diagnosis, Early referral to a specialist,
Early aggressive therapy

2- The concept of early initiation of more
aggressive therapy is important because
irreversible joint damage develops within

the first 3 month after disease onset.

Take Home Message
Early diagnosis, early referral to a specialist

and

early

aggressive

therapy(window

of

opportunity, i.e. within the first 3 month of
diagnosis), will delay or prevent the risk of bone
erosions, joint destruction, deformity; which may
improve patient’s survival and increase the
number of years that patients enjoy a better
quality of life.

Undifferentiated Arthritis Guide

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