Early signs of rheumatism, rheumatoid factors and CCP antibodies

Pain and stiffness of the finger and toe joints are early signs of rheumatoid arthritis. Rheumatoid factors and the CCP antibody value are often determined for diagnosis.

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Rheumatoid arthritis is an autoimmune disease in which chronic inflammation in the joints is manifested. In order to effectively treat rheumatoid arthritis, rapid diagnosis is important. Studies show that permanent damage and sequelae can be prevented if treatment is initiated early. Ideally, this should be done within three months of the first signs of illness.

This article describes early signs of rheumatoid arthritis and explains rheumatoid factors and the CCP value as laboratory diagnostic tools.

What are early signs of rheumatoid arthritis?

Early signs of rheumatoid arthritis are often one-sided pain in individual finger and toe joints. In rare cases, large joints (e.g. knee joints) can also be affected. The joints swell and are difficult to move in the morning. It is also known as morning stiffness.

These signs may indicate early rheumatoid arthritis if

  • The joint swelling is soft (not hardened), occurs in more than two joints and does not subside after six weeks
  • The affected joints are symmetrical, i.e. the same finger joints of the right and left hands are affected, for example
  • The morning stiffness lasts longer than 60 minutes and it is not possible to close the fist during this time.

Inflammation often spreads across several joints in the first few weeks and months. Rarely, rheumatoid nodules may also form on the forearms or fingers.

How is rheumatoid arthritis diagnosed?

If early symptoms occur, it is advisable to see a doctor quickly. In addition to typical symptoms, other factors play a role in the diagnosis of rheumatoid arthritis.

Blood tests are usually carried out to confirm the diagnosis, which detect inflammation. Analyzed are frequently

  • General inflammation levels such as blood subsidence and CRP levels
  • rheumatoid factors, and
  • antibodies against so-called cyclic citrullinated peptides (CCP, ACPA).

Ultrasound or other imaging techniques, such as X-rays or MRI, can help confirm the diagnosis and assess the severity. A genetic predisposition (rheumatoid arthritis in the family) is also surveyed.

Rheumatoid factors

Rheumatoid arthritis is an autoimmune disease in which the immune system mistakenly targets the body's own structures. To do this, the immune system sends antibodies.

Antibodies are proteins that are found in blood and other body fluids. Their actual main task is to protect the body from 'invaders' such as bacteria, viruses, fungi or pollutants. In autoimmune diseases, however, the immune system also targets the body's own healthy structures.

What is the rheumatoid factor?

Rheumatoid factor (RF) is an antibody that is directed against the immunoglobulin G (IgG) of other antibodies.

Like all other antibodies, rheumatoid factors are divided into different classes. These include

  • immunoglobulin M (IgM),
  • immunoglobulin A (IgA) and
  • immunoglobulin G (IgG).

As a rule, the proven rheumatoid factors belong to the IgM class (Rf-IgM or RhF-IgM).

The rheumatoid factor is one of several parameters that can be used for diagnosis. Further investigations are usually carried out, as the rheumatoid factor can also indicate other rheumatic diseases.

What do rheumatoid factors say?

Rheumatoid factors are an important criterion for diagnosing rheumatoid arthritis. They are among the classification criteria.

If the rheumatoid factor is elevated, a rheumatic disease may be present. However, an elevated rheumatoid factor alone is not sufficient to diagnose rheumatoid arthritis. A negative rheumatoid factor also does not rule out rheumatoid arthritis.

In addition to diagnosis, rheumatoid factors can also provide information about the course of the disease. Studies suggest that, in particular, high rheumatoid factor levels of the class IgA (Rf-IgA) and/or IgG (Rf-IgG) are associated with more severe forms of rheumatoid arthritis. In severe cases, the joint infection is more pronounced and the disease progresses more quickly [1]. In 70-80% of cases, IgM antibodies are detectable which are not associated with a severe course [5].

When are rheumatoid factors elevated?

Rheumatoid factors may indicate rheumatoid arthritis, but may also be elevated in other rheumatic and non-rheumatic diseases.

Rheumatoid Factor and Rheumatoid Arthritis

Studies show that the rheumatoid factor is elevated in 50% of patients at the onset of the disease. As rheumatoid arthritis progresses, the rheumatoid factor is increased in 70-80% of patients. It is then referred to as seropositive rheumatoid arthritis. Conversely, patients may also have rheumatoid arthritis without the rheumatoid factor being positive. In this case, we speak of seronegative rheumatoid arthritis.

rheumatoid factor and other rheumatic diseases

The rheumatoid factor can be positive not only in rheumatoid arthritis. The rheumatoid factor may also be increased in other rheumatic and non-rheumatic diseases.

The rheumatoid factor is also positive in percentages for the following rheumatic diseases:

  • 50-100% for cryoglobulinemia type II, which is a form of vascular inflammation that occurs as a result of deposits of immune complexes in the small vessels
  • 55-95% SJÖGREN syndromeAn autoimmune connective tissue disorder, which includes dry eyes
  • 50-60% mixed collagenosis (MCTC) A disease with symptoms of various autoimmune connective tissue diseases (e.g. systemic lupus erythematosus, scleroderma and polymyositis as well as Raynaud's syndrome)
  • 20-30% scleroderma (systemic sclerosis) An autoimmune disease associated with hardened connective tissue
  • 15-35% Systemic lupus erythematodesystemic autoimmune disease of the skin, vascular connective tissue and organs
  • 10-15% juvenile chronic arthritis
  • 5-26% polymyositis

The rheumatoid factor can also be positive in people who suffer from non-rheumatic diseases. The same goes for healthy people. Around 1-4% of adults under 60 years of age have a positive rheumatoid factor without showing symptoms. For adults over 60 years of age, this proportion is 5-12%.

Rheumatoid factors are among the classification criteria for rheumatoid arthritis. In combination with symptoms and medical history, the rheumatoid factor may be indicative of rheumatic diseases. However, the rheumatoid factor usually represents only one parameter that is used for diagnosis.

Cyclic citrullinated peptide (CCP)

Cyclic citrullinated peptide (English cyclic citrullinated peptide, CCP) is a protein. Rheumatoid arthritis produces antibodies against CCPs because the body regards them as foreign. These antibodies against CCPs are called CCP antibodies (CCPAK, CCP AK) or, more rarely, anti-CCP antibodies or ACPA.

CCP antibodies were discovered in the 1970s. While rheumatoid factors may also be elevated in other diseases, CCP antibodies are very specific for rheumatoid arthritis. Increased levels of CCP antibodies in the blood can therefore be a clear sign of rheumatoid arthritis.

CCP antibodies may be elevated up to 10 years before the onset of rheumatoid arthritis. They therefore also serve as an early indicator.

When are CCP values elevated?

Elevated CCP antibody levels are a strong sign of early rheumatoid arthritis.

The sensitivity of CCPAK is 55-80% [8], the specificity is 88-98% [9].

In scientific terminology, sensitivity means that an examination reliably recognizes sick patients as ill. The specificity of an investigation indicates how reliable this examination considers healthy patients to be healthy.

This means that CCP antibodies are primarily detectable in the blood of rheumatoid arthritis. They are therefore considered a reliable marker for rheumatoid arthritis [10].

If CCPAK values are negative, rheumatoid arthritis cannot be ruled out.

Understanding laboratory values

To make a diagnosis, body fluids are often examined. To do this, these body fluids are removed and sent to a laboratory. To diagnose rheumatoid arthritis, the laboratory tests your blood for inflammation levels, rheumatoid factors, and CCP antibodies.

For this purpose, laboratories use various methods and measurement variables to diagnose rheumatism in the laboratory. Each method is based on scientific studies and is based on defined standard values or reference intervals.

In order to understand rheumatoid factors and CCP values or CCP antibody values, it is important to know the standard values of the method used. These are also always stated on the findings report that your doctor receives from the laboratory. If you would like to understand your blood values, ask your doctor for the laboratory results and it is best to address questions directly.

Swollen joints and morning stiffness are among early symptoms of rheumatoid arthritis. In order to reduce the risk of restrictions and sequelae, it is important to see a doctor quickly. Blood tests are usually carried out for the diagnosis. In laboratory diagnostics, in addition to general inflammation levels (blood subsidence, CRP), rheumatoid factors and CCP antibodies are also determined, with which a diagnosis can be made.

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[2] Aletaha D et al. Rheumatoid arthritis classification criteria: at the American College of Rheumatology/ European League against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62:2569 —81.

[3] Conrad K, Schoessler W, Hiepe F. Autoantibodies in systemic autoimmune disorders. PABST 2012

[4] Sakthiswary, R. et al.: IgA Rheumatoid Factor as a Serological Predictor of Poor Response to Tumour Necrosis Factor α Inhibitors in Rheumatoid Arthritis, International Journal of Rheumatic Diseases, Volume 17, Issue 8, November 2014, p.872-7

[5] IMD Labor Berlin: Rheumatoid Factors — Classification Criteria for Rheumatoid Arthritis retrieved on 29.05.2024 at https://www.imd-berlin.de/fachinformationen/diagnostikinformationen/rheumatoide-arthritis-rheumafaktoren-klassifikationskriterium-fuer-die-rheumatoide-arthritis

[6] Austrian public health portal. CCP antibodies. Retrieved on 29.05.24 at https://www.gesundheit.gv.at/labor/laborwerte/autoimmun/ccp-antikoerper-ccpak1.html

[7] van Venrooij, W., van Beers, J. & Pruijn, G. Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol 7, 391—398 (2011). https://doi.org/10.1038/nrrheum.2011.76

[8] B. Vander Cruyssen, I. Peene, T. Cantaert, I.E.A. Hoffman, L. De Rycke, E.M. Veys, F. De Keyser, Anti-Citrullinated Protein/Peptide Antibodies (ACPA) in Rheumatoid Arthritis: Specificity and Relation with Rheumatoid Factor, Autoimmunity Reviews, Volume 4, Issue 7, 2005, pages 468-474, ISSN 1568-9972, https://doi.org/10.1016/j.autrev.2005.04.018.

[9] Liu J, Gao J, Wu Z, Mi L, Li N, Wang Y, Peng X, Xu K, Wu F, Zhang L. Anti-citrullinated protein antibody generation, pathogenesis, clinical application, and prospects. Front Med (Lausanne). 2022 Jan 12; 8:802934. doi: 10.3389/fmed.2021.802934. PMID: 35096892; PMCID: PMC8791387.

[10] Toes RE, van der Woude D. ACPA (anti-citrullinated protein antibodies) and rheumatoid arthritis. Acta Reumatol Port (2011) 36:205 —7.