Dr Fahim Khan examines rheumatic disease
Rheumatoid factor (RF) has long been known to be typical (though not pathognomonic) of rheumatoid arthritis (RA) and associated with severe disease. Rheumatoid factor became part of the classification criteria of RA almost 50 years ago.
RFs are autoantibodies directed against the Fc portion of immunoglobulin (Ig), most commonly IgM against IgG. RF is detected in the majority of patients with established disease and constitutes one of the American College of Rheumatology (ACR) classifications. The RF, as initially described by Waaler and Rose in 1940 and as currently measured in clinical practice, is an IgM RF, although other immunoglobulin types, including IgG and IgA, have been described.
Pima Indians
RFs are found in 75-80 per cent of RA patients at some time during the course of their disease. In some populations, such as Pima Indians, there is a higher incidence of arthritis and RFs. RFs have been found in up to 4 per cent of young, healthy individuals.
It is also common in elderly individuals without rheumatic disease, ranging from 3-25 per cent. When present, RF is typically found in low to moderate titer (1:40 to 1:160) in individuals with no demonstrable rheumatic or inflammatory disease. A high correlation for RF has been noted among identical twins with RA, suggesting that genetic factors influence both RF function and disease development.
New studies support its usefulness in diagnosis; it is included (along with the duration of symptoms, duration of morning stiffness, arthritis in three or more joint groups, metatarsophalangeal tenderness, and anti-CCP antibodies) in a scoring system developed to differentiate persistent arthritis from transient arthritis, and erosive arthritis.
RF is a major predictor of bone damage as assessed by radiographs. Patients with a positive RF were 2.5 times more likely to have rapid progression of Sharp/van der Heidje scores over one year follow-up than those who were seronegative for RF.
It has a prognostic role in RA, as patients with poly-articular symmetrical arthritis who have a persistently positive test for RF are likely to have more erosions of bones and joints, more extra-articular manifestations and worse function. RFs are Ig reactive against epitopes on the Fc portion of IgG. The role of RF in the pathogenesis and perpetuation of RA or other rheumatic diseases is unknown. The origin of RF is incompletely understood.
The production of RFs results in part from the help provided from a specific subset of T cells to rheumatoid factor precursor B cells. Since T cells reactive with autologous IgG have not been identified in patients with RA, it is likely that these T cells react with antigen(s), and then bind to specific B lymphocytes, which proliferate.
One such putative antigen is p205, a protein of unknown function that is present in synovium and synovial fluid. It has been reported to be a very effective stimulator of T-cells of patients with pathogenesis.
The p205 possesses sequences of peptides with a high degree of similarity to those of the third and fourth constant regions of the heavy chain of immunoglobulin.
The helper T cells are probably CD4+/CD45RA-/CD45RO+/CD45RB (dim)/CD27- cells. Such cells are terminally differentiated, produce little IL-2, and presumably have differentiated in synovium in response to recurrent stimulation by arthritogenic peptides.
Normal human lymphoid tissue commonly possesses B lymphocytes with RF expression on the cell surface. However, RF is not routinely detectable in the circulation in the absence of an antigenic stimulus.
Modified IgG could be a stimulus to RF production and could be an important component of RA pathogenesis; this concept is supported by studies that observed an association of RF and more severe RA with auto-antibodies to advanced glycated end product-damaged IgG or agalactosyl Ig.
X-ray showing rheumatism of the knees
Costimulation of B cells, perhaps mediated by toll-like receptors (TLRs), may allow B cells with low affinity receptors for IgG to become activated. TLRs are components of the innate immune system, and they provide signals after engaging various bacterial and viral products.
Other studies on the origin of RF have shown that CD14-positive cells (monocytes) from the bone marrow stimulate RF-producing B cells. Synovial fluid RF may be produced by synovium-derived CD20-negative, CD38-positive plasma cells. Other studies on the origin of RF have shown that CD14-positive cells (monocytes) from the bone marrow stimulate RF-producing B cells.
Lattice-like complexes
Another factor that amplifies the inflammatory potential of RFs is the propensity for IgG RF to self-associate into large, lattice-like complexes. These complexes can be found in all tissues of the rheumatoid joint, and may help concentrate additional material within this structure.
As an example, within the superficial layers of articular cartilage in rheumatoid joints are rheumatoid factors-IgG complexes, antibodies against native and denatured type II cartilage collagen, and activated components of complement.
In RF-negative patients with RA, B cells capable of RF production are fewer in number and less responsive to T cell help than in RF-positive patients with RA.
In one study, for example, the frequency of RF+: IgM+ B cells was increased more than 50-fold in seropositive patients (7-20 per cent of IgM+ B cells versus well under 1 per cent in normal); patients with sero-negative RA had intermediate values (1.5 per cent to 6 per cent of IgM+ B cells).
IgG and IgA RFs are occasionally present in patients with RA in the absence of IgM RF. Measurement of these non-IgM RFs is not widely available. However, they may be of prognostic value, since there is evidence suggesting that IgG, IgA, and 7S IgM RFs are associated with more severe disease.
The function of RF is poorly understood. Possible functions include:
- Binding and processing of antigens embedded in immune complexes;
- Presentation of antigens to T lymphocytes in the presence of HLA molecules;
- Immune tolerance;
- Amplification of the humoral response to bacterial or parasitic infection.
RF test and rheumatoid titre
Testing for RF is primarily used for the diagnosis of RA; however, RF may also be present in other rheumatic diseases and chronic infections.
The RF test is considered the basic screen and hallmark for the autoimmune disorders, i.e. inflammatory arthritis. RF is considered an early marker since its presence is linked with an increased risk of developing RA in people with mild arthritic symptoms.
The presence of RF can be detected by a variety of techniques such as agglutination of IgG-sensitised sheep red cells or bentonite or latex particles coated with human IgG, radioimmunoassay, enzyme-linked immunosorbent assay (ELISA) or nephelometry. Measurement of RF is not standardised in many laboratories (leading to problems with false positive results) and no technique has clear advantage over others.
RF currently measured in clinical practice is an IgM RF, although other immunoglobulin types, including IgG and IgA, have been described. Autoantibodies in RA are useful both for diagnosis and prognosis. In the Norfolk Arthritis Register Study, patients with a RF titer of greater than 1:160 (latex) were 2.3 times more likely to have worsening of their Larsen scores over five years than those who were seronegative.
Radiographic damage
Finally, patients with a positive rheumatoid factor were 3.3 times more likely to develop severe radiographic damage over 12 years than were those who were seronegative. Measurement of the RF titer is generally inexpensive. However, the cost per true-positive result may be high if the test is ordered in patients with a low disease prevalence.
High RF titers (e.g., >50 IU/ml) discriminate well between RA and other types of inflammatory arthritis. As an example, in prospective follow-up of an inception cohort of 200 patients with inflammatory joint disease of less than three months’ duration, the finding of a high RF titer was associated with a sensitivity of 96 per cent for RA.
RFs have been found in up to 4 per cent of young, healthy individuals. The reported incidence may be higher in elderly subjects without rheumatic disease, ranging from 3-25 per cent. Part of this wide range may be explained by a higher incidence of RF among the chronically ill elderly as compared to healthy older patients. When present, RF is typically found in low to moderate titer (1:40 to 1:160) in individuals with no demonstrable rheumatic or inflammatory disease.
Associated clinical disorders
RF may also be present in other rheumatic diseases and chronic infections. A positive RF test can be found in rheumatic disorders, non-rheumatic disorders and healthy subjects.
Rheumatic disorders:
- Rheumatoid arthritis 26-60%
- Sjögren’s syndrome 75-95%
- Mixed connective tissue
- disease 50-60%
- Mixed cryoglobulinemia (types II and III) 40-100%
- Systemic lupus erythematosus (SLE) 15-35%
- Polymyositis/dermatomyositis 5-10%
- Primary biliary cirrhosis 40-70%
Non-rheumatic disorders:
Included in this group are indolent or chronic infection, such as bacterial endocarditis or hepatitis B or C virus infection. Studies have demonstrated that hepatitis C infection, especially when accompanied by cryoglobulinemia, is associated with a positive RF in 54-76 per cent of cases.
Other infections with a positive RF include tuberculosis, syphilis, leprosy, viral infections (rubella, mumps, influenza and HIV), parasitic diseases (Chagas disease, leishmaniasis, onchocerciasis, schistosomiasis), inflammatory or fibrosing pulmonary disorders (SLE, systemic sclerosis, sarcoidosis, silicosis, asbestosis) and malignancy (leukaemia, colon carcinoma).
Prognostic and predictive value
RF-positive patients with RA may experience more aggressive and erosive joint disease and extra-articular manifestations than those who are RF-negative.
The presence or absence of RF may have some value in predicting response to treatment. As an example, the anti-CD20, B cell depleting monoclonal antibody rituximab may be less effective for patients with sero-negative than for those with seropositive RA. Rheumatoid nodules and vasculitis occur almost exclusively in sero-positive patients.
Radiographic progression may be more rapid among patients with a positive RF at initial evaluation. Assays for autoantibodies and acute phase reactants are helpful in the early diagnosis of RA. The most reliable early predictors of both chronic and erosive disease are the presence of RF and anti-CCP antibodies.
RF testing also has modest positive predictive value among unselected patients presenting with arthralgia and arthritis. In patients with undifferentiated inflammatory arthritis, the presence of RF was somewhat helpful in predicting the ultimate diagnosis of RA, although not as predictive as duration of symptoms for more than 12 weeks.
On the other hand, the negative predictive value of the RF (the likelihood of not having disease if the RF is negative) appears to be relatively high. The negative predictive value for RA and for any rheumatic disease was 89 per cent and 85 per cent, respectively. It is important to appreciate that the value of a negative test depends upon the clinical setting.
Summary
Measurement of RF has little value as a screening test to diagnose or exclude rheumatic disease in either healthy populations or those with arthralgias. Healthy individuals should not be tested for RF. Similarly we should not be using the RF as a diagnostic test in patients who have arthralgias but no other symptoms or signs of a rheumatic disease.
The test should also be evaluated in the same clinical setting in which it is planned to be used. The studies of Sieper et al and Mandl et al remind us that diagnostic tests are most useful when applied in clinical situations in which the disease in question is reasonably likely to be present and unhelpful when the likelihood of disease is very low. Higher titers of RF have higher positive predictive value for RA.
Although, in aggregate, seropositive disease and higher titers of RF are associated with more severe RA, measurement of RF has limited prognostic value in the individual patient with RA.
The titer of RF should be considered when analysing its utility. The higher the titer, the greater the likelihood that the patient has rheumatic disease. There are, however, frequent exceptions to this rule, particularly among patients with one of the chronic inflammatory disorders as mentioned earlier.
Most asymptomatic persons with a positive RF do not progress to RA or SLE; as a result, measurement of RF is a poor screening test for future rheumatic disease.
Testing for the combination of anti-CCP antibodies and IgM RF may be better for excluding the diagnosis of RA than is achievable by testing for either antibody alone. Among patients with early oligo- or polyarthritis, anti-CCP testing appears to be of predictive value in the IgM-RF negative subgroup.
RF is detected in the setting of various rheumatic diseases, infections, other inflammatory diseases and in some healthy people.
The RF has a higher positive predictive value if ordered more selectively in patients with a modest or higher chance of having an RF-associated rheumatic disease such as RA or Sjögren’s syndrome. Included in this group are patients with prominent morning stiffness, sicca symptoms, or arthralgia or arthritis in a rheumatoid distribution (i.e., symmetric polyarthritis involving small joints).
RFs are found in 75-80 per cent of RA patients at some time during the course of their disease. High titer IgM RF is relatively specific for the diagnosis of RA in the context of a chronic polyarthritis, and was for decades the sole serologic criterion widely used in the diagnosis of RA. It has little predictive value in the general population; however, since the overall disease prevalence is relatively low. RF also occurs in other diseases.
RF may have some prognostic value with regard to disease manifestations and activity, and the severity of joint erosions. Seropositive RA (i.e. RA associated with a positive RF test) is often associated with more aggressive joint disease, and is more commonly complicated by extra-articular manifestations than seronegative RA. There is currently no clear consensus regarding the indications for ordering RF testing.
The overall utility of this test may be historically overestimated and the pre-test probability of RF-associated disease as well as confounding inflammatory disorders should be considered.
RF should not be used as a diagnostic test in patients who have arthralgias but no other symptoms or signs of a rheumatic disease. Repeat testing of RF may be useful if a patient’s diagnosis remains uncertain. Higher titers of RF have higher positive predictive value for RA. Seropositive disease and higher titers of RF are associated with more severe RA, measurement of RF has limited prognostic value in the individual patient with RA.
References on request.
- Dr Fahim Khan is a Consultant Rheumatologist at Aut Even Hospital, Kilkenny; Ballinderry Clinic, Mullingar; and St Joseph’s Private Hospital, Sligo.
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