Sunday, November 27, 2022

What Is Seronegative Rheumatoid Arthritis

Can Seropositive Change To Seronegative And Vice Versa

Rheumatoid Arthritis | What is seronegative rheumatoid arthritis?

In the RA literature, viewpoints differ on the possibility of seroconversion, that is seronegative becoming positive or vice versa. Some indicate that seropositive can convert to negative during treatment, while reviews of studies seem to indicate that seroconversion from positive to negative is rare. Its also rare for someone who is seronegative to become positive.

Can Seronegative Ra Turn Into Seropositive Ra

Previously, researchers thought it was likely that seronegative RA could turn into seropositive RA over time. However, a recent study that followed people with seronegative RA over 10 years found that only about 3 percent developed seropositive RA. Since the long-term outcomes were so varied, the researchers have suggested that seronegative RA may not even be considered a single disease.5

Autoantibodies In Relation To Ra Risk Factors

Classical RA risk factors HLA-DRB1 SE, PTPN22 polymorphism, and cigarette smoking are known to associate with the anti-CCP2-positive subset of RA . In addition, we and others have shown associations between SE and the presence of ACPA in anti-CCP2-negative RA. Here we can confirm an association between SE and ACPA+/anti-CCP2 RA, while there was no significant association between SE and the presence of RF or other autoantibodies in anti-CCP2-negative RA . Smoking, on the other hand, did not associate with ACPA, or other autoantibodies, but showed a significant association with RF in anti-CCP2-negative RA. PTPN22 polymorphism associated significantly with all anti-CCP2-negative RA subsets, irrespective of autoantibody status .

Table 2 Associations between autoantibodies and risk factors, in anti-CCP2 RA

Based on these data, we proceeded to investigate associations between SE and individual ACPA fine-specificities further, as well as associations between smoking and different RF isotypes, in both anti-CCP2-positive and anti-CCP2-negative RA subsets.

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Direct Or Competitive Elisa Assays

Fifteen sera from seronegative RA patients were used to obtain specific IgG antibodies directed against the RA-peptide and against an irrelevant peptide. These affinity-purified anti-RA-peptide Abs were able to bind the RA-peptide in a direct ELISA test , while the anti-irrelevant-peptide Abs did not have this ability. Furthermore, RA-peptide was able to inhibit direct binding of purified anti-RA-peptide Abs. Such inhibition was not present using the irrelevant control peptide .

Antibodies directed against the other peptides were obtained from the same sera of 15 seronegative RA patients . We investigated the ability of these affinity-purified IgG antibodies to bind to their specific peptides and to cross-react with the other peptides in ELISA assays, using different concentrations of anti-peptide antibodies .

All the purified antibodies bind their specific peptide with high affinity and in a dose dependent manner, whereas antibodies against the irrelevant peptide do not show similar behavior .

Anti-CTLA-4 peptide purified antibodies displayed a lower affinity binding to PYK2/FADK2, BANK-1 and LIPRIN-1 peptides, even when we used different concentrations of antibodies. Moreover, anti-CTLA-4 and anti-RA-peptide purified antibodies showed a similar binding to CTLA-4 peptide while the other Abs displayed a lower recognition of this peptide . We supposed that these differences in affinity binding derive from the differences in the sequence homology, as shown in Figure 3A.

A Wide Variety Of Conditions Can Present As Inflammatory Arthritis

Seronegative RA: Symptoms, diagnosis, and treatment

The other difficulty is the wide differential diagnosis of polyarthritis . A good history and physical examination combined with a few simple laboratory or radiological investigations should help in excluding most of the conditions that mimic RA. In our patients, the following need to be considered:

  • Postviral arthritisParvovirus arthritis should be considered, since she may have encountered the virus at her school. However, against this diagnosis are the duration of joint symptoms , the fact that she did not have fever, rash or sore throat and the negative parvovirus serology

  • Seronegative spondyloarthritisIn this condition one would expect features such as psoriasis, inflammatory bowel disease or inflammatory back pain and a family history of similar disorders. However, a small proportion of patients with psoriatic arthritis do get arthritis before skin lesions appear.

Box 2Conditions that can present as polyarthritis and mimic RA

Postviral arthritise.g. parvovirus, mumps, rubella, hepatitis B and C

Seronegative spondyloarthritise.g. psoriatic arthritis, inflammatory bowel disease

Connective tissue diseasese.g. systemic lupus erythematosus, scleroderma, vasculitis

Osteoarthritis

Crystal arthritise.g. polyarticular gout, pseudogout

Miscellaneouse.g. sarcoidosis, thyroid disease, infective endocarditis, malignant disease

Box 3Investigations that may help in diagnosing common underlying causes of polyarthritis

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Does This Affect The Medications That Will Work For Me

Whilst the efficacy of most medications for RA is not affected by whether someone is seropositive or seronegative, evidence suggests that patients who are seronegative for both RF and anti-CCP do not respond as well to rituximab as patients who are seropositive for one or both.

  • Rheumatoid arthritis is an auto-immune disease, meaning that the symptoms such as pain and inflammation are caused by the immune system attacking the joints.

Information

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Use Of Random Peptide Library And Elisa Test

A dodecamer random peptide library was used to identify possible relevant autoantigens in seronegative RA. An IgG pool derived from the first cohort of 50 patients with seronegative RA was used to screen the peptide library, while a pool of IgGs from 25 healthy donors was used for the pre-screening step . Finally, a set of 17 putative peptides was used to evaluate the binding of individual patients sera

We also analyzed the sera of 25 seropositive RA patients and found that 64% of them recognized the RA-peptide . Statistically significant differences were found in the binding to RA-peptide between the seronegative RA patients and healthy donors sera or between the seropositive RA and healthy donors , but not between seronegative and seropositive patients .

The potential diagnostic value of anti-RA-peptide antibodies in either seronegative or seropositive RA patients was assessed by a receiver operating characteristic curve. The area below the ROC curve was 0.9244 between anti-peptide Abs of seronegative RA patients and healthy donors and 0.8840 between anti-peptide Abs of seropositive RA patients and healthy donors . No significant difference was found in ROC curve between the seronegative and seropositive RA .

In order to validate the binding specificity of RA-peptide, a second study sample of seronegative RA patients was analyzed, as well as a group of patients with other immune-mediated diseases,like SA, PsA, and SSc .

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Additional File : Supplementary Table 6

Associations between different ACPA fine-specificities and HLA-DRB1 SE, in anti-CCP2-positive and anti-CCP2-negative RA. Odds ratios with 95% confidence intervals are shown for associations between HLA-DRB1 SE and presence/absence of 19 different ACPA fine-specificities, in anti-CCP2-positive and -negative RA: p-values indicate differences in ORs between ACPA fine-specificity-positive and -negative subsets in the anti-CCP2-positive subset.

Seronegative Ra: What Are The Symptoms Of Seronegative Ra

Diagnosis & Treatment Delay in Seronegative Rheumatoid Arthritis

Seronegative rheumatoid arthritis is the diagnosis of rheumatoid arthritis without the presence of certain antibodies in the patients blood. It is one of two main types of rheumatoid arthritis diagnoses.

In most cases of rheumatoid arthritis, the patient tests positive for rheumatoid factor and/or anti-citrullinated peptides antibodies. These indicate that the patient is seropositive and that they possess the antibodies that cause an attack on joints and lead to inflammation. These patients tend to have a more severe disease course with more joint deformities, x-ray damage, disability and inflammation outside of the joints.

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Seropositive And Seronegative Rheumatoid Arthritis

Not so long ago, different types of rheumatoid arthritis were not recognized. When rheumatoid arthritis was diagnosed, it was always treated in the same way.

As research progressed, some experts began to see rheumatoid arthritis as a group of diseases.

Within this group, genetic differences between individuals affect the features, symptoms, and triggers of the disease.

These differences may be able to help doctors improve treatments for rheumatoid arthritis, and in some cases, even prevent the disease altogether.

The difference that researchers currently know the most about is between seropositive and seronegative rheumatoid arthritis.

What Differences Are There Between People That Are Seropositive And Seronegative

As well as seropositive patients having a greater likelihood of developing a more serious disease, they are also more likely to have extra-articular complications than those who are seronegative.Patients seronegative for RF and anti-CCP may have a different form of inflammatory arthritis, for example, psoriasis-related arthritis or a spondyloarthropathy.

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Connect With Others Who Understand

On myRAteam, youll have access to the social network for people living with RA and their loved ones. Here, more than 146,000 members come together to ask questions, give advice, and share their stories with others who understand life with RA.

Are you living with seronegative RA? Start the conversation in the comments below or by posting on myRAteam.

How Is Seronegative Rheumatoid Arthritis Diagnosed

The Diverse Fate of Seronegative Rheumatoid Arthritis

Once the blood tests rule out the presence of RF and anti-CPPs in the patient, it becomes more difficult to achieve a rheumatoid arthritis diagnosis. However, it does happen. Just as having the presence of antibodies doesnt necessarily solidify a seropositive rheumatoid arthritis diagnosis, the absence of antibodies doesnt necessarily rule out a rheumatoid arthritis diagnosis.

If a patient exhibits strong symptoms of rheumatoid arthritis , x-rays can be performed to further examine the symptoms. If the x-ray results indicate bone and cartilage erosion and damage, then a rheumatoid arthritis diagnosis can be made.

Testing for levels of inflammation in a patients joints also helps to support a rheumatoid arthritis diagnosis in seronegative patients. Here are some important criteria doctors follow when diagnosing seronegative rheumatoid arthritis:

  • Negative antibody blood test results
  • Symmetrical symptoms
  • Polyarthritic symptoms, meaning multiple joints are affected
  • Condition is inflammatory

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What Is Seropositive/seronegative

The blood test that is ordered by the doctor in order to help establish the diagnosis of rheumatoid arthritis is looking for the presence of two proteins in the blood. One of them is called rheumatoid factor . This is a very old but tried and tested investigation that was first introduced into rheumatology in the 1940s. The other test is called anti-CCP and is more recent. Anti-CCP is more sensitive than RF and may appear much earlier in the course of RA.

Presence Of Rf In Anti

In the present study, we have also analysed RF isotypes IgM, IgG, and IgA in EIRA, and all RF isotypes were detected in the anti-CCP2-negative subset, with IgM RF present in 23.8%, IgG RF in 17.4%, and IgA RF in 10.6% . Higher frequencies were detected in anti-CCP2-positive RA: 89.6% , 75% , and 56.8% . IgM RF levels were higher in anti-CCP2-positive, compared to anti-CCP2-negative patients, while no differences were observed for IgG and IgA RF levels . Co-occurrence of at least two RF isotypes was 47% among RF+/anti-CCP2 patients, and all three isotypes were present in 25% the corresponding figures for RF+/anti-CCP2+ patients were 83% and 53%, respectively . Co-occurrence of RF isotypes was rare among RF-positive controls, and RF levels were significantly lower than in patients.

Fig. 2

Autoantibody data in anti-CCP2-positive RA, anti-CCP2-negative RA, and controls. a Prevalence of IgM, IgG, and IgA RF. b Median IgM, IgG, and IgA RF levels among RF-positive individuals asterisks indicate significantly lower IgM, IgG, and IgA RF levels in controls compared to RA patients . c Co-occurrence of different RF isotypes among RF-positive individuals, in anti-CCP2-positive RA , anti-CCP2-negative RA , and controls . d Prevalence of different autoantibody groups . e Co-occurrence of different autoantibody groups among autoantibody-positive individuals, in anti-CCP2-positive RA , anti-CCP2-negative RA , and controls

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How Is Seronegative Ra Diagnosed

RA that does not cause high levels of anti-CCP or RF is called seronegative RA. Seronegative RA can be difficult to diagnose because doctors cannot rely on a blood test. Symptoms can be an important part of the diagnosing process. Symptoms that may be a sign of seronegative RA include:3

If a person has these symptoms but their blood test did not show high antibody levels, a doctor may recommend imaging tests. X-rays, MRIs, and ultrasounds may show inflamed or damaged joints, which is a sign of RA.4

Without positive blood tests, it may be difficult for your doctor to diagnose you with RA. Other inflammatory conditions, such as viral infections or gout, can cause similar symptoms. Also, other types of arthritis, like spondyloarthritis, do not cause high levels of RF and anti-CCP, and would show a seronegative test. This can cause people with seronegative RA to wait longer for a diagnosis, as compared to those with seropositive RA.1

Delay In Accurate Information

Seronegative Rheumatoid Arthritis Pain Solved with Functional Medicine – #LifeAtOptimal

Any time I see any doc other than my rheumatologist or GP I get treated as though my RA is all in my head. Darlyne

Unfortunately, the information that anti-CCP should be the basis for determining seronegative RA has not yet moved past beyond the field of rheumatology. If aware of the concept of seronegative RA, most doctors still understand this as being related to the RF test. In addition, many doctors dont know that its possible to have RA if the RF is negative.

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Associations Of Od With Clinical And Laboratory Parameters And Od Quartile Distribution Of Ra Patients Taking Or Not Corticosteroid Therapy

Within the group of seronegative RA patients there was no difference in O.D. values between females and males or between subjects with or without joint erosions . There was no correlation between O.D. levels and age at enrollment, age at diagnosis, disease duration, ESR, CRP, DAS28, tender and swollen joint counts . There was no difference in O.D. values among patients receiving different disease modifying anti-rheumatic drugs , while treatment with corticosteroids was associated with lower O.D. levels .

Finally, we stratified the whole study sample according the O.D. quartile distribution. Considering the potential influence of corticosteroid therapy, these analyses were performed in subgroups of subjects taking or not corticosteroids . As expected, healthy donors were strictly prevalent in the lowest quartile while seropositive RA or seronegative RA patients were more frequent in the higher quartiles in both the subgroups. A progressive increase of prevalence of RA+/RA- patients by increasing O.D. values, from the lowest to the highest quartile, was particularly evident among subjects not taking corticosteroids , while the trend although significant appeared milder in those taking corticosteroids .

Clinical And Laboratory Features And Treatment Of Ra Patients

The main clinical features, biochemical characteristics and treatment of all seronegative RA patients included in the study are summarized in Table 1. Supplementary Table 1 shows the data related to patients with seropositive RA, used as control. The RA patients were predominantly female and the gender percentage in the two seronegative RA groups were equally balanced.

Table 1 Clinical and laboratory features and treatment of seronegative rheumatoid arthritis patients from the Perugia and Verona cohorts.

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How Do Doctors Diagnose Seronegative Ra

People who dont test positive for the presence of RF and anti-CCP can still be diagnosed with rheumatoid arthritis based on their symptoms, a physical exam of their joints, and imaging tests that can show patterns of cartilage and bone deterioration.

Interestingly, some people who initially test seronegative develop those RF and anti-CCP antibodies later. Among people with more established RA, the percentage of seropositive patients rises to 80 to 85 percent, says Konstantinos Loupasakis, MD, rheumatologist with MedStar Washington Hospital Center.

But most people with seronegative RA never develop antibodies and become seropositive.

Because doctors feel less confident diagnosing RA without positive blood tests, theyll need to rule out other conditions like viral infections, gout, or spondyloarthritis , says Dr. Loupasakis.

We want to be very careful that we are not missing something, says Dr. Loupasakis. There are diseases that can camouflage as rheumatoid arthritis, and might be something else.

This may help explain why research shows that people with seronegative RA often take longer to get diagnosed and to start treatment than people with seropositive RA, according to study presented at the 2017 annual meeting of the American College of Rheumatology.

Seronegative Vs Seropositive Ra: Are There Other Differences

What is Seronegative Arthritis? Why is termed as a Fatal Condition?

Past studies seemed to indicate that seropositive RA patients had a worse prognosis and more severe disease progression than seronegative RA patients, according to MedPage Today. This has created a certain stigma around seronegative RA that it is a less severe disease and perhaps even requires less aggressive treatment.

However, the thinking here is changing based on newer research. For example, a Dutch study found that seronegative RA patients had significantly greater disease activity and worse functional ability than seropositive patients on the other hand, seropositive patients had greater joint damage.

A Canadian study found that measures of RA disease activity was higher in seronegative patients than in seropositive patients when the study began. Both seronegative and seropositive patients received similar treatment. When measured again after two years, the seronegative RA patients had a significantly greater improvement in several measures of disease activity and less erosion than those with seropositive disease.

Part of the problem may be the delay in diagnosis. Because people with seronegative RA take longer to get diagnosed and start disease-modifying medication, they may be missing a crucial window to prevent progression and enter remission.

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How Being Seronegative Affects Ra

As with people who are seropositive, RA isnt predictable for those who are seronegative. But because it can be harder to diagnose seronegative RA, it can take longer to get treated for it. That delay might make it less likely that youll go into remission, which is when you have very few signs of the disease.

People who start treatment within the first 2 years of symptoms are more likely to go into remission than those who dont.

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