Antibodies to cyclic citrullinated peptide (ACCP)

Rheumatoid arthritis

(RA) is a systemic autoimmune inflammatory disease of the connective tissue of the joints. Pathological processes lead to the development of irreversible changes. One or more joints may be affected. As a rule, the small joints of the hands and feet are affected, as well as the knees, elbows, jaws, hips and joints of the cervical spine.

As the disease progresses, the joints lose their mobility and the patient’s quality of life decreases. What makes the situation worse is that the cause of the disease has not yet been established. It is not yet possible to stop the process. In total, up to 1% of the world's population is affected by rheumatoid arthritis, of which 3/4 are women. The average age of onset of the disease is 40 years. The disease manifests itself during periods of severe emotional stress, under the influence of unfavorable environmental conditions, after trauma, or infection. RA is characterized by early disability in 70% of cases. The main causes of death are infectious complications and renal failure.

tests

Causes of rheumatoid arthritis

Currently, there is no reliable data on the causes of the disease. There are several most likely versions supported by most of the medical community. The most popular of them is that RA is caused by several factors present in the patient’s medical history at the same time.

• Genetic predisposition to autoimmune disorders.
• Presence of MHC class II antigen (noted in most patients).
• Infectious agents: paramyxoviruses, hepatoviruses, retroviruses.
• The presence of antibody titers to the Epstein-Barr virus (found in 80% of patients).

Thus, the risk of developing rheumatoid arthritis is higher in women aged 35 - 40 years and older. Increases the chances of having close relatives with a similar diagnosis, as well as previous diseases such as measles, hepatitis B, lichen, herpes, mumps.

Any changes in the immune system, which begin an attack on one’s own connective tissue, can activate the pathological process. Among the triggering factors are frequent hypothermia, hyperinsolation (sunstroke), prolonged intoxication, viral and bacterial infections. May be affected by medications, disruption of the endocrine glands, long-term stress and depression.

Antibodies to cyclic citrullinated peptide (ACCP)

What are anti-cyclic citrullinated peptide (CCP) antibodies?

ACCPs are autoantibodies that interact with synthetic peptides containing an atypical amino acid - citrulline.

The discovery of citrulline-containing autoantigens characteristic of rheumatoid arthritis has become one of the most important recent developments in rheumatology in the field of serological diagnosis. Citrulline is not a standard amino acid included in proteins during their synthesis; it is formed as a result of subsequent modification of arginine. The process of citrullination is observed during natural physiological and pathological processes and plays a role in the processes of cell differentiation and apoptosis. Citrullinated antigens were discovered during the search for antigenic targets of antikeratin antibodies, a specific marker of rheumatoid arthritis. It was found that anti-keratin antibodies recognize only citrullinated forms of the filaggrin protein, which is part of keratin. Among the possible inducers of the formation of antibodies to citrullinated peptides in the mechanism of development of rheumatoid arthritis, citrullinated fibrin, which accumulates in large quantities in the inflamed synovium, is considered. Citrullinated vimentin is also classified as a citrullinated antigen of synovial tissue. During the development of methods for determining antibodies to citrullinated antigens, it was proven that the use of synthetic cyclic forms of citrullinated peptides provides greater test sensitivity compared to the use of linear peptides.

Antibodies to cyclic citrullinated peptide are extremely specific for rheumatoid arthritis and are detected very early in the disease.

The main characteristic of one of the most common autoimmune diseases, rheumatoid arthritis, is inflammation of the joint, leading to joint damage and loss of function. On average, a patient sees a rheumatologist after 21 months of illness, before which he consults doctors of other specialties. By this point, 60% of patients develop irreversible joint damage, i.e. The best time for therapy has passed. Diagnosis is complicated by the fact that in the early stages clinical signs are nonspecific: weakness, fatigue, apathy, depression, night sweats, increased sensitivity to weather changes, morning stiffness and joint pain, muscle tension. Early diagnosis of RA and immediate initiation of appropriate treatment are very important to prevent complete joint damage.

Early diagnosis of RA has become particularly important in recent years due to a change in treatment strategy, which involves the early administration of active therapy.

It is the determination of ACCP that makes it possible to diagnose rheumatoid arthritis in the early stages even before the appearance of clinical signs characteristic of this disease,

The importance of this test is determined by:

• the appearance of antibodies to cyclic citrullinated peptide in the blood serum 1 year before the onset of the disease (its sensitivity at the early stage of the disease reaches 75%);
• sufficient specificity for rheumatoid arthritis (75–90%);
• determination of ACCP in patients seronegative for rheumatoid factor;
• used to predict the development of rheumatoid arthritis - a high titer of ACCP is associated with a more severe course of the disease (in particular, with more rapid progression of erosion)

Specificity of the ACCP test in diagnosing RA in combination:

• ACCP + ESR is 95%,
• ACCP + RF is 91%,
• ACCP + CRP is 97%,
• ACCP + polyarticular pain – 95%,
• ACCP + morning stiffness – 99%.

This test is not suitable for monitoring the effectiveness of treatment, since the use of most basic and symptomatic drugs does not result in a significant decrease in the level of antibodies.

Limitations - Interference

Patients treated with high doses of biotin (>5 mg/day) should be sampled no sooner than 8 hours after the last biotin administration. The results of the ACCP test may be false-negative in patients with hypergammaglobulinemia: the results obtained in these patients cannot be used for diagnostic purposes. Patients treated with mouse monoclonal antibodies for therapeutic or diagnostic purposes may experience erroneous results. In some cases, extremely high titers of antibodies to streptavidin may occur, which may affect the test results.

Indications for the purpose of analysis

• Differential diagnosis of rheumatoid arthritis in the absence of clinical and radiological signs in the earliest stages of disease development.
• Choosing treatment tactics for rheumatoid arthritis

When can there be an increase in the level of ACCP?

• rheumatoid arthritis
• in some cases of other connective tissue diseases, especially SLE (systemic lupus erythematosus).

Development of rheumatoid arthritis

When exposed to one or more factors in the body, an inadequate response of the immune system is triggered. Defender cells - lymphocytes stop diagnosing and destroying foreign microorganisms, their own healthy cells become their target. Substances are produced that cause erosive and destructive damage to the synovial membrane of the joints.

RA moves through the following stages:

• Synovitis. Cells of tissue origin (synoviocytes) begin to perform the function of macrophages, i.e., digest the remains of dead cells and foreign particles. As a result, pro-inflammatory cytokines are produced, causing activation of T-helper cells - cells that stimulate enhanced immune function.
• Osteoporosis. Reduced bone density is caused by activated macrophages and monocytes through the production of proinflammatory cytokines, including IL-1. This cytokine activates osteoclasts, which dissolve and destroy mineral compounds and collagen.
• The composition of blood and synovial fluid changes. The level of plasma cells producing immunoglobulins increases. The concentration of IgM and IgG to the altered Fc region of IgG increases (rheumatoid factors).
• Proliferative stage. At this time, pathological processes cause damage to cartilage tissue and bones. Capillaries of synovial tissue proliferate. Synoviocytes lead to the formation of pannus, an aggressive granulation tissue prone to tumor-like growth with invasion into cartilage and the articular part of the bone.

The last, proliferative stage is characterized by the formation of erosions. Without treatment, these processes can occur several months after the onset of the disease. Increased angiogenesis promotes the germination of blood vessels into cartilage and the penetration of bacteria deep into the cartilage tissue.

Classification

According to ICD-10, the disease is systematized into the following groups:

1. Seropositive RA:

• Felty's syndrome.
• RA with involvement of other organs and systems.
• Unspecified forms.

2. Youth RA.

3. Other RAs:

• Seronegative type.
• Still's disease.
• Rheumatoid bursitis.
• Rheumatoid nodule.
• Other specified and unspecified arthritis.

According to clinical manifestations, the disease is divided into the primary stage (less than 6 months have passed since the onset of the disease), early (from 6 months to a year), advanced (from 1 year) and late (more than 2 years). Rheumatoid arthritis is distinguished by the degree of loss of functionality, immunological factors, disease activity, and instrumental characteristics.

For doctors, immunological characteristics are of greatest importance. The presence of rheumatoid factor in the blood or the presence of anti-CCP (seropositive and seronegative RA). The results of tests that reveal these values ​​allow you to correctly plan therapy.

Preparing for the analysis of ACDC and conducting the study

In order to obtain test results that correspond to reality, the patient is advised to follow the following rules:

• Since the analysis is done on an empty stomach, the last meal should be 8-12 hours before blood sampling;
• You are not allowed to drink liquids during the day;
• On the day of collection of biological material, you should not smoke;
• On the eve of the study, do not drink alcohol.

To conduct the test, the nurse draws blood from a vein, observing the rules of asepsis and antisepsis. Serum is extracted from it and used for analysis. When conducting the study, the cytofluometry method is used: the serum is illuminated with a laser. The nature of the beam scattering allows us to determine the content of ACCP in the serum.

Decoding helps the rheumatologist create an effective treatment plan. At the end of therapy, doctors prescribe a repeat test, the results of which must correspond to the norm. If this does not happen, treatment is continued until the result is positive.

In order to undergo examination if you have signs of rheumatoid arthritis, call the contact center of the Yusupov Hospital at any time of the day, regardless of the day of the week. You will be scheduled for an appointment with a rheumatologist at a time convenient for you. After the examination, the doctor will prescribe a comprehensive examination. Analysis for ACCP for rheumatoid arthritis is included in the diagnostic program.

Symptoms

The initial stage of the disease has virtually no obvious symptoms. Over time, slight stiffness appears in the affected joints. As a rule, it occurs in the morning, as the secretion of glucocorticoids decreases. It is difficult for the patient to move, movements are inhibited. Sometimes you need help getting up. But after 30 minutes - an hour everything returns to normal. The clinic can be rolled out over several months or even years, gradually intensifying.

Primary symptoms also include:

• periodic joint pain;
• loss of appetite;
• increased fatigue.

Second stage

characterized by rapid cell division and thickening of the synovial membrane. There is symmetrical swelling of the joints, the skin in the affected areas has an increased temperature. Sudden pain is also observed, intensifying with active movement. To complete the process, they need the same amount of rest time that was spent moving.

Third stage

― active phase of inflammation involving cartilage and bones. The affected joints begin to deform, which leads to increased pain and loss of motor function.

Rheumatoid arthritis often has concomitant joint diseases, and vague symptoms make differential diagnosis difficult. Among the most beneficial combinations are rheumatism, osteoarthritis and other systemic pathologies of connective tissue. The only specific manifestation of rheumatoid arthritis can be called nodules, so-called subcutaneous formations on the extensor surface. They can be detected by palpation.

Extra-articular manifestations of RA

Pathological processes caused by rheumatoid arthritis that occur outside the joints occur in a third of patients. These symptoms also complicate diagnosis and influence the choice of treatment tactics. Among them:

• Cutaneous vasculitis (ulcerative-necrotic, livedoangiitis, infarction of the nail bed).
• Sjogren's syndrome (damage to the salivary and lacrimal glands).
• Eye lesions (scleritis - inflammation of the deep layer of the eye, episcleritis - inflammation of the connective tissue of the eye).
• Interstitial lung disease (inflammation of the alveoli, pulmonary capillaries and other tissues).

As a result of inflammation accompanying rheumatoid arthritis, pathologies of the cardiovascular, respiratory, and nervous systems may occur. The most serious complication is AA amyloidosis, which causes kidney failure.

Separately, it is worth highlighting various associated diseases that are not directly caused, but are associated with RA. These are coronary heart disease, thromboembolism, anemia, psychoneurological disorders, among which depression deserves attention. Like any other autoimmune disease with chronic inflammation, rheumatoid arthritis affects psychological well-being. The patient is recommended to undergo psychological courses and a comprehensive, comprehensive examination.

Diagnostics

First of all, the doctor studies the clinical criteria for rheumatoid arthritis. The disease should be suspected in patients with symmetrical polyarthritis. Damage to the wrist, II and III metacarpophalangeal joints is important. It is necessary to exclude hepatitis C. Pay attention to the presence or absence of changes in skin color in inflamed joints, the presence of deformities of the limbs, tenosynovitis of the flexors or extensors of the fingers. Diagnostics also includes laboratory and instrumental results.

Laboratory research

The tasks of the laboratory include blood tests for RF, anti-CCP, ESR, and CRP. The most progressive analysis is the titer of antibodies to ACCP, anti-CCP, anti-CCP.

• RF - analysis for antibodies to human gamma globulin is detected in 70% of RA patients. However, the indicator is not critical, since titers can be detected in other viral diseases and connective tissue pathologies. An RF test confirms rheumatoid arthritis in combination with a positive ACCP test.
• ACCP is a test with high sensitivity reaching 86%. In combination with the RF titer, it indicates RA. However, it is necessary to exclude hepatitis C, since ACCP and RF titer may occur with this viral infection.

Additional tests include a biochemical blood test to determine the activity of inflammation. A general blood test to detect anemia, an immunological test to determine the presence of rheumatoid factor (IgM antibodies).

Instrumental diagnostics

• X-ray examination. In the first months of the disease, radiography can only show soft tissue swelling. Marginal erosions, osteoporosis, and narrowing of the joint space are detected by the end of the first year of the disease or later.
• Magnetic resonance imaging. The most informative research method at the moment. It allows you to identify early signs of inflammation, detect erosions and lesions of the subchondral bone.
• Examination of synovial fluid. The procedure is carried out for exudative changes in the joints, to differentiate RA from arthritis of another nature. Cloudiness and yellowish color of the synovial fluid indicate the development of rheumatoid arthritis. The leukocyte count increases to 50,000/µl.

When making a diagnosis, it is important to exclude similar diseases: microcrystalline arthritis, sarcoidosis, reactive and psoriatic arthritis, systemic lupus erythematosus, osteoarthritis and other diseases.

Normal ACCP for rheumatoid arthritis

Analysis for ACCP in rheumatoid arthritis is done for the purpose of early diagnosis of the disease. It shows the amount of antibodies to cyclic citrullinated peptide in the blood serum. The study is carried out using the enzyme-linked immunosorbent assay method. The unit of measurement is the number of units per milliliter (U/ml).

An ACCP level of less than 4 U/ml is considered negative. An indicator equal to or greater than four units per milliliter is positive. ACCP, compared with other markers of rheumatoid arthritis that may be present in healthy people, has the following advantages with similar clinical sensitivity:

• Significantly higher specificity;
• Positive predictive value;
• Diagnostic accuracy.

Antibodies to cyclic citrullinated peptide can be detected in 30% of patients with seronegative rheumatoid factor-negative rheumatoid arthritis. The test is used in the early diagnosis of arthritis and for the purpose of prognosis of recently developed rheumatoid arthritis; ACCP is more associated with progression and erosive arthritis than rheumatoid factor. The ADDC is not used to monitor process activity. Rheumatologists at the Yusupov Hospital evaluate the test results in conjunction with the history of the disease and clinical observations, including instrumental examination data

Treatment

Therapy is aimed at containing the progression of the disease, reducing inflammation and preventing joint deformation and loss of functionality. The following medications are prescribed:

• Non-steroidal anti-inflammatory substances. They reduce pain to some extent and slow down the progression of RA. May include inhibitors and blockers for IL-1, IL-6, TNF-alpha. They do not block the development of erosion and disease, therefore they are used as aids.
• Glucocorticoids. Prescribed in combination with anti-inflammatory drugs. Allows you to control the development of severe monoarticular and oligoarticular symptoms. Not used on a regular basis, as they often cause unpleasant metabolic effects.
• Basic drugs. Essential medications that can significantly slow the progression of arthritis. Courses of treatment range from several weeks to several months. The drugs differ in chemical composition and pharmacology. They are combined with each other to select the optimal treatment with the greatest effect. According to statistics, ⅔ of patients who completed the course experience significant improvement, more than half of them achieve complete remission. However, you should be aware of the toxicity of these drugs. The doctor and patient must weigh all the risks and conduct regular monitoring of the patient’s condition.

Thus, the main treatment includes basic drugs, especially methotrexate, biological antagonist drugs, and immunomodulatory drugs. Other methods of auxiliary therapy include physiotherapeutic procedures, therapeutic exercises, and a balanced combination of physical activity and rest. Quitting alcohol and smoking can prolong the patient's life. Joint curvature can be corrected through surgical correction.

Forecast

Rheumatoid arthritis shortens a person's life expectancy for a number of reasons. The risk of heart disease doubles. This is caused by the presence of chronic inflammation. The situation can be aggravated by concomitant pathologies, for example, diabetes, obesity, alcoholism.

With the development of AA amyloidosis, despite treatment, the average life expectancy of the patient is about 10 years from the onset of the disease. Without therapy, the period is estimated at several years. A common cause of death is kidney failure. On average, RA shortens life by 3 to 7 years due to the high risk of infections and gastrointestinal bleeding.

Drug therapy is also not perfect. It can cause concomitant diseases and become one of the factors in the development of malignant neoplasms. Criteria for poor prognosis include:

• early (up to 4 months) x-ray changes in joints;
• persistent increase in erythrocyte sedimentation rate;
• constant involvement of new joints;
• carriage of HLA-DR4 antigens.

About 10% of patients are doomed to severe disability with loss of self-care skills. Rheumatoid arthritis is most severe in women, smokers, and Caucasians.

Advantages of the laboratories of JSC "SZTsDM"

At the laboratory terminals of the Northwestern Center for Evidence-Based Medicine, you can take tests to diagnose rheumatoid arthritis and other autoimmune diseases. Among the advantages of SZTsDM JSC:

• New modern equipment,
• Qualified and friendly staff,
• Quick availability of results and convenient ways to obtain them.

Laboratories are located in Pskov, Veliky Novgorod, Kaliningrad, St. Petersburg and other cities of the Leningrad region. You can take tests at any of them without being tied to residence or registration.

Anticyclic citrulline-containing peptide antibodies, IgG, are a heterogeneous group of IgG autoantibodies that recognize antigenic determinants of filaggrin and other proteins containing the atypical amino acid citrulline.

Synonyms Russian

ACCP, anti-CCP-AT, anti-CCP, anti-SCP.

English synonyms

Anti-CCP, cyclic citrullinated peptide antibody, Anti-citrullinated protein antibody, Ig G; Soft-CCP, AntiCCP Antibody, Anticitrullinated Protein/Peptide Antibody (ACPA).

Research method

Electrochemiluminescent immunoassay (ECLIA).

Determination range: 7 - 500 U/ml.

Units

U/ml (unit per milliliter).

What biomaterial can be used for research?

Venous blood.

How to properly prepare for research?

Do not smoke for 30 minutes before the test.

General information about the study

Antibodies to cyclic citrulline-containing peptide, IgG, are currently one of the most informative markers of early rheumatoid arthritis. ACCPs belong predominantly to the IgG class and are found in the blood at the earliest stages of rheumatoid arthritis (1-2 years before the onset of the first symptoms).

Rheumatoid arthritis is the most common chronic autoimmune disease, characterized by damage to peripheral joints with the development of erosive and destructive changes in them and a wide range of extra-articular manifestations. A characteristic sign of rheumatoid arthritis is symmetrical damage to the joints of the hands, feet, wrists, elbows, shoulders, knees and ankles. There is pain, swelling, redness of the skin over the affected joints, limitation of movements and, as a result, dysfunction of the joints. One of the important symptoms of rheumatoid arthritis is morning stiffness in the joints lasting more than one hour. Progressive inflammation of the joints leads to a significant limitation of their mobility with the development of articular abnormalities.

Initially, when joints are affected in the form of arthritis, there is a need for differential diagnosis. In this case, it is necessary to pay attention to the typical signs of rheumatoid arthritis, the development of an erosive process in the joints of the hands, rheumatoid factor and especially antibodies to CCP. Rheumatoid factor is not specific enough and can be detected in other autoimmune diseases and chronic infections, while antibodies to cyclic citrulline-containing peptide have a higher specificity (98%) and diagnostic value for the detection of rheumatoid arthritis. The test also allows you to differentiate between erosive and non-erosive forms of the disease. Patients with elevated levels of antibodies to CCP experience a greater degree of joint cartilage damage compared to patients whose blood does not contain these antibodies. This can be used to predict the rate of joint destruction at the stage of early rheumatoid arthritis, which allows us to consider the detection of ACCP as one of the factors for the unfavorable prognosis of this disease. Joint determination of rheumatoid factor and ACCP allows diagnosing rheumatoid arthritis at an early stage, prescribing therapy in a timely manner and preventing severe destructive changes in the joints.

What is the research used for?

• To diagnose rheumatoid arthritis at a very early stage (duration of disease
• For the diagnosis of seronegative forms of rheumatoid arthritis (when the test for rheumatoid factor is negative).
• For the differential diagnosis of rheumatoid arthritis and other autoimmune diseases with articular syndrome.
• To assess the risk of developing joint destruction in patients with early rheumatoid arthritis.

When is the study scheduled?

• In some rheumatic diseases, articular syndrome occurs (pain, swelling in the joints, morning stiffness, local redness of the skin), which can complicate the correct diagnosis, especially in the early stages of the disease. In this case, the analysis helps to carry out differential diagnosis, since it has high specificity (up to 98%) and sensitivity (up to 70%) for detecting rheumatoid arthritis even in the earliest stages of the disease, when only a few symptoms are present.
• When planning treatment for rheumatoid arthritis. Patients in whose blood ACCP are detected are characterized by a more aggressive course of the disease with rapid progression of erosions in the joints, therefore, in the early stages of the disease, it is necessary to prescribe adequate therapy to prevent the development of irreversible changes in the joints (deformations, ankylosis).

What do the results mean?

Reference values: 0 - 17 U/ml.

Causes of elevated ACCP levels

• Rheumatoid arthritis.
• Juvenile idiopathic arthritis.
• Some connective tissue diseases (systemic lupus erythematosus, systemic scleroderma, Sjogren's syndrome).
• Systemic vasculitis (Wegener's granulomatosis).
• Autoimmune thyroiditis.

What can influence the result?

In patients with hypergamma globulinemia, the test result may be falsely negative.