Rheumatoid Factor Revisited

 

 

Article By

Ashish Rodricks

Bento Rui Mascarenhas

 

 

Abstract :

Despite improved understanding of mechanisms of disease, there is no gold standard for the diagnosis of autoimmune  diseases. A clinician therefore  needs to use a set of criteria for the diagnosis of an autoimmune disease. This article deals with the methods of detection of rheumatoid factor including more accurate methods like nephelometry, it’s interpretation and clinical significance. A clinician should have this knowledge for the appropriate diagnosis and treatment of patients with arthritis.

 

 

Introduction :

Rheumatoid factor (RF) has been the most widely used test for a number of years in the evaluation of patients with arthritis. In recent years, an improved understanding of pathophysiology of rheumatoid arthritis has led to inclusion of the newer, anti-CCP antibody test in the revised criteria for diagnosis of the disease. However, rheumatoid  factor has not yet been excluded. Therefore,  RF still remains an important  tool  in  the  hands  of a  clinician, especially in resource limited settings, considering the higher cost of anti-CCP antibody testing. the abbreviation RA factor is a misnomer and it should always be referred to as Rheumatoid Factor or RF.

Autoantibodies  are  a characteristic  feature of autoimmune  rheumatic diseases, directly against highly specific targets. These originate from B cells which recognise self antigens as foreign. This immune  dysregulation  occurs  in  genetically predisposed  individuals  who  are  exposed to infection or other insults such as cell derived micro particles[1].

However, mere presence of autoantibodies is not synonymous with autoimmune diseases as these can be observed in otherwise healthy individuals. Autoantibodies in the presence of characteristic clinical features helps in the diagnosis of autoimmune disease. In the absence of a gold standard for the diagnosis of rheumatological diseases, they are best used as part of a diagnostic panel rather than as a marker indicating one particular disease[2].

Many autoimmune diseases are associated with a specific autoantibody  at significantly high titres compared  to  the  level present  in  individuals without that particular disease. Thus, interpretation of a test report requires an understanding of the cut off value for a particular antibody. The upper  limit of an  antibody  level which is present  in  not  more  than  5% of the normal population is fixed as the cut off level of an autoantibody for that specific disease.

Rheumatoid  factors (RF) are  autoantibodies directed against Fc portion of human immunoglobulin and may be of IgM, IgG and IgA isotypes. (Figure 1)

TC- Jul 2016 - 001 - Role of Rheumatoid factor in pathogenesis

Methods of Detection :

(1) Tests to detect RF by passive haemagglutination were initially described by Rose and Waaler (1940). This  detects anti-Rabbit  IgG and  is expressed as a ratio (e.g. >1:16 is positive).

(2) RF latex agglutination test detects anti-Human IgG and results are expressed as IU/ml (>20 IU is positive). The reciprocal of highest dilution of the  serum  which is able to  agglutinate IgG coated latex particles is expressed as titre. The titre can be converted to International  units ( I U )  by  multiplying the titre with the conversion factor provided in the kit. For e.g. if the highest dilution is 1/20, the titre is 20 and if the conversion factor is 8, then the RF level is calculated as 20×8=160 IU. There is a reference preparation  (WHO 1066) and most methods are calibrated against this standard[3].

(3) ELISA detects class specific IgG, IgA and IgM antibodies and these are not routinely required. IgM RF is the  one  currently  measured  in commercial laboratories.

(4)  Turbidimetry  and  Nephelometry  :  These methods  measure  the  rate  of  formation  of immune complexes in solution. These are more widely used because of  speed,  accuracy and automation. These  can be used to measure RF, CRP, ASO, C3 and C4 levels. (Figure 2 & 3)

TC- Jul 2016 - 002 - Turbidimetry

TC- Jul 2016 - 003 - Nephelometry

 

Turbidimetry measures a decrease in intensity of light as it passes through a solution of particles. Whereas, nephelometry  measures light energy scattered towards a detector – not in direct path of transmitted light but placed at 60⁰-70⁰ angle from incident  light. The amount  of light scattered  is proportional  to  concentration  of antigen  or antibody in solution. Since the amount  of  light scattered  is greater than  transmitted  light  in  a turbid suspension, nephelometry is more sensitive than  turbidimetry  with a detection  limit of 10 µg/ml, while with turbidimetry it is 20-30 µg/ml. This  is superior to other techniques as it is able to detect changes in absolute levels at earlier stages and has a low inter assay co-efficient of variance[4].

RF has a sensitivity of 70-80% at a titre more than 20 IU, but specificity is poor. Therefore,  a positive or negative result neither confirms nor excludes rheumatoid arthritis. RF is also found in 1-5% of healthy population and higher in elderly people (3-25%) without rheumatic disease. When present in this population, RF is found in low-moderate titre (1:40-1:160). There are a number of conditions in which RF may be falsely positive. (Table 1 & 2)

TC- Jul 2016 - 004 - Table 1 - Association of RF with condtions other than Rheumatoid arthritis

TC- Jul 2016 - 005 - Table 2 - False positive Rheumatoid Factor in Infections

There is a huge variation between methods used for detection and quantification of autoantibodies. Do not  assume that  results will be interchangeable between laboratories. Hence, interpretation  of results must be made in the background of clinical presentation :

  1. If RF positive along with characteristic clinical presentation, the positive predictive value is about 80%. This includes patients with symmetrical polyarthralgia or polyarthritis involving small joints,  prominent  morning stiffness or sicca symptoms[5].
  2. In early inflammatory arthritis, the presence of RF predicts a future diagnosis of rheumatoid arthritis with a positive odds ratio of approximately 30[5]. These patients require aggressive therapy, because presence of RF early in the course of disease is associated with erosion and extra-articular features.
  3. If RF is negative consistently in a patient presenting with typical clinical features of rheumatoid arthritis, then other serological markers (anti-CCP antibody) are to be tested for early intervention. RF may be negative in 20-50% of patients with rheumatoid arthritis[5].
  4. If RF is positive in patients without typical features, other causes of RF positivity are to be ruled out[3].

 

Clinical Case Study :

A 50-year-old lady presents with asymmetrical, inflammatory polyarthritis since 2 years. There is no history of low back pain or systemic symptoms. She gives a history of treatment for psoriasis since 1 year and there are no lesions presently. There is clinical synovitis of bilateral metacarpophalangeal joints, right wrist, both knees and left ankle joint. There is sausage shaped swelling of 2nd/3rd proximal interphalangeal  joints  of right  hand  and  distal interphalangeal joint of left 4th   toe(dactylitis) as shown in (Figure 4). Her Rheumatoid  factor is positive 414 IU .

 

TC- Jul 2016 - 006 - Dactylitis in psoriatic arthritis

 

 

Therefore,  this RF is falsely positive in  psoriatic arthritis and the patient may be  inappropriately diagnosed and treated as rheumatoid arthritis. A proper history of asymmetrical arthritis with or without  low  back  pain  and  uveitis should  be sought. A careful examination for psoriatic skin lesions (especially hidden areas), nail changes and sacroilitis is essential. Clinicians need to be aware of the fact that arthritis can precede the onset of skin lesions in  about  15-20% of patients  with psoriatic arthritis by years.

 

CLINICAL SIGNIFICANCE OF RHEUMATOID FACTOR  :

 

(1) There is a  correlation  between higher  RF concent rat ions  and  systemic  symptoms, vasculitis and more severe forms of the disease.

(2) Despite low sensitivity, RF has  value as a screening test for polyarthralgias. Anti-CCP testing helps because of its specificity of 90%.

(3) Higher  titres  of RF have higher  positive predictive value for Rheumatoid arthritis.

(4) RF is positive in  75-95% of patients  with Sjogren’s syndrome, which may or may not be associated with RA. Therefore,  these  patients are invariably labelled and treated as Rheumatoid  arthritis  unless high  index  of clinical suspicion.

 

 

IMPORTANT LEARNING POINTS :

 

(1) Rheumatoid factor shows no correlation with disease activity. Therefore, need not be repeated every time the patient is followed up.

(2) The clinician should be aware of the laboratory method  used for testing and  always ask for titres. Laboratories should be accredited and participate in external quality assurance schemes.

(3) If laboratory results are completely inconsistent with the clinical findings, request anti-CCP test.

TC- Jul 2016 - 007 - Writers Art pg 08

 

 

References :

  1. Rao URK. Manual of Rheumatology. 4th edition. Indian Rheumatology Association. 2014.
  2. Sheldon J. Laboratory testing in autoimmune rheumatic diseases. Best Practice and Research Clinical Rheumatology. 2004. Vol.18, No.3. 249-269.
  3. Roberts-Thomson PJ, McEvoy R, Langhans T, Bradley J. Routine quantification of Rheumatoid factor by rate nephelometry. Ann Rheum Dis. June 1985, 44(6):379-383.
  4. Symposium on Laboratory Diagnosis of Autoimmune  Diseases, IRACON December 2011.
  5. Shmerling RH, Wener MH, Romain P. Origin and utility of measurement of rheumatoid factors, www.uptodate.com Jan-Feb 2016.