PREVALENCE OF Anti-CCP POSITIVITY AND SUBCLINICAL SIGNS OF INFLAMMATION IN PATIENTS WITH NEW ONSET OF NON-SPECIFIC MUSCULOSKELETAL SYMPTOMS (PANORA)

• ClinicalTrials.gov Identifier: NCT03267147
• Recruitment Status: Completed
• First Posted: August 30, 2017
• Last Update Posted: March 2, 2022
• Sponsor: Fraunhofer Institute for Molecular Biology and Applied Ecology
• Collaborators: Bristol-Myers Squibb; Goethe University
• Information provided by (Responsible Party): Dr. Frank Behrens, Fraunhofer Institute for Molecular Biology and Applied Ecology

Study Description

Brief Summary:

Non-interventional, prospective, observational study to assess the relative risk of anti-CCP positive patients to develop (subclinical) signs of inflammation in accordance with early Rheumatoid Arthritis (RA) in a population without pre-classified RA but new1 onset of non-specific musculoskeletal (MSK) symptoms in general practices in Germany and subsequent 36 months follow-up by rheumatologists

Condition or disease	Intervention/treatment
Rheumatoid Arthritis	Other: no intervention is given

Detailed Description:

Studies of early arthritis cohorts have shown that a large number of early arthritis patients cannot be accurately diagnosed at their first visit, and hence are often referred as undifferentiated arthritis patients. If patients are found to be anti-CCP(+) when referred to the clinician, however, more than 90% develop RA within 3 years - in contrast to only 30% of the anti-CCP(-) patients. The presence of anti-CCP antibodies in undifferentiated arthritis therefore accurately predicts development of RA. Anti-CCP antibodies are very specific for RA, and they are produced at significant level very early in disease. The specificity of anti-CCP antibodies for the diagnosis of RA is high (94.1-99.0%). Moreover, it has been reported that anti-CCP antibodies can be present many years before the first visit to the clinic (up to 18 years). Furthermore, the presence of anti-CCP antibodies at the first visit to the clinician predicts radiographic progression, as demonstrated by many studies that have shown a strong association of anti-CCP positivity with the development of bone erosions.Early diagnosis of RA coupled with rational use of disease-modifying anti-rheumatic drugs (DMARD) has been shown to have a favourable effect on the course of the disease. Early and accurate diagnosis has therefore become increasingly important. Implementing anti-CCP quick tests in general practices could facilitate an early detection of RA or the allocation to a high risk RA group. This, in turn, would guarantee an early referral of the patient to a rheumatologist and together with other clinical examinations can aid in the early diagnosis and treatment. As has been shown in many studies an early intervention is vital to preserve joint function and to improve patient care. In this study, we want to assess the relative risk for patients derived from GPs in Germany with new onset of non-specific MSK symptoms and anti-CCP test positivity to develop (subclinical) signs of inflammation in accordance with early RA. Those patients will be identified in general practices and will be tested for anti-CCP status. Anti-CCP positive patients will then be introduced to a rheumatologist to validate anti-CCP status and examine presence of clinical signs of early RA in addition to subclinical signs of MSK inflammation. Furthermore, to focus on the possibility of early detection of anti-CCP before the onset of clinically active arthritis, patients will be followed-up by a rheumatologist until detection of early RA or up to 36 months in total. Early RA will be examined using standard of care for signs of inflammation including clinical examination for swollen and tender joints. In addition, ultrasound will be performed to assess joint inflammation as well as fluorescence optical imaging technique (Xiralite®) to sensitively illustrate changes in microvascularisation as a marker of subclinical inflammation. In cases of RA diagnosis, the study ends with the date of diagnosis and patients will receive treatment according to local guidelines earlier and medical care will be continued in clinical routine care conditions outside of the study. Moreover, the cooperation status between GPs and rheumatologists will be evaluated using qualitative interviews. Feasibility of the diagnosis of early RA in at risk patients as well as the feasibility of the transferral of these patients from the general practice to the rheumatologist will be assessed. Training of GPs for detection of early RA will be improved. Overall, the hypothesis of the study is that patients with new onset of unspecific MSK-symptoms and who are positive for anti-CCP, which both are risk factors for developing RA, will be earlier introduced to and monitored by a rheumatologist for proper clinical examination and potential treatment when establishing RA, which in turn will not only improve patient care, disease outcomes and quality of life, but might also be cost effective.

Study Design

• Study Type: Observational
• Actual Enrollment: 986 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: PREVALENCE OF ANTI-CYCLIC CITRULLINATED PEPTIDE (Anti-CCP) POSITIVITY AND SUBCLINICAL SIGNS OF INFLAMMATION IN PATIENTS WITH NEW ONSET OF NON-SPECIFIC MUSCULOSKELETAL SYMPTOMS POSSIBLY RELATED TO EARLY RHEUMATOID ARTHRITIS IN GENERAL PRACTICES IN GERMANY
• Actual Study Start Date: April 27, 2017
• Actual Primary Completion Date: December 16, 2021
• Actual Study Completion Date: February 15, 2022

Groups and Cohorts

Group/Cohort	Intervention/treatment
antiCCP positive; Patients with a positive result in the anti-CCP quick test and positive in antiCCP ELISA will be examined by Rheumatologist for detection of RA symptoms and followed-up for 3 years or until RA diagnosis no intervention is given	Other: no intervention is given; no intervention is given
antiCCP negative; Patient with negative result in antiCCP quick test or negative antiCCP ELISA will be followed-up after one year (and 3 years for ELISA negative patients) with a short questionnaire if musculoskeletal symptoms are still present or if RA was diagnosed	Other: no intervention is given; no intervention is given

Outcome Measures

Primary Outcome Measures :

1. Determination of the relative risk in patients with new onset of non-specific MSK symptoms who are anti-CCP positive to develop (subclinical) signs of inflammation in accordance with early RA in general practices in Germany [ Time Frame: every 6 months up to 3 years ]
   Determination if RA symptoms are present

Secondary Outcome Measures :

1. diagnosis of RA in the group of anti-CCP positive patients with new onset of non-specific MSK symptoms [ Time Frame: every 6 months up to 3 years ]
2. subclinical signs of inflammation using routine examination methods in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
3. subclinical signs of inflammation using fluorescence optical imaging technique in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
4. subclinical signs of inflammation using ultrasound in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
5. anti-CCP level over time in anti-CCP positive patients [ Time Frame: over 3 years ]
6. EQ5D [ Time Frame: every 6 months up to 3 years ]
   Questionnaire to assess Quality of Life profile of anti-CCP positive patients
7. SF36 [ Time Frame: every 6 months up to 3 years ]
   Questionnaire to assess Quality of Life profile of anti-CCP positive patients
8. HAQ [ Time Frame: every 6 months up to 3 years ]
   Questionnaire to assess disability profile of anti-CCP positive patients
9. PHQ-9 [ Time Frame: every 6 months up to 3 years ]
   Questionnaire to assess depression profile of anti-CCP positive patients
10. WPAI [ Time Frame: every 6 months up to 3 years ]
    Questionnaire to assess work ability profile of anti-CCP positive patients
11. assessment of time to disease in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
12. assessment of correlation of anti-CCP level in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
13. assessment quality of life (QoL) in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
14. assessment work ability profile in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
15. assessment subclinical signs of inflammation in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
16. assessment risk of depression in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
17. assessment of grade of disability in anti-CCP positive patients [ Time Frame: every 6 months up to 3 years ]
18. diagnosis of RA in the group of ELISA test anti-CCP negative patients with new onset of non-specific MSK symptoms [ Time Frame: 1 year ]
19. diagnosis of RA in the group of ELISA test anti-CCP negative patients with new onset of non-specific MSK symptoms [ Time Frame: 3 years ]
20. diagnosis of RA in the group of quick test anti-CCP negative patients with new onset of non-specific MSK symptoms [ Time Frame: 1 year ]
21. Qualitative assessment of general practitioners' (GP) routine care [ Time Frame: 1 year ]
    qualitative interviews with the GP to evaluate current status of how patients with MSK symptoms are treated/forwarded in general practices

Biospecimen Retention:   Samples With DNA

blood samples

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

population without pre-classified RA but new onset of non-specific musculoskeletal (MSK) symptoms

Criteria

Inclusion Criteria:

• New onset of non-specific MSK symptoms, including, but not limited to, arthralgia of the hands and the large joints such as wrists, knees, and shoulders
• Written informed consent obtained prior to the initiation of any study protocol-required procedures
• General understanding of study procedure and informed consent
• Age ≥ 18 and ≤ 65 years

Exclusion Criteria:

• RA diagnosed according to modified EULAR/ACR (american college of rheumatology)-criteria
• Other known arthritis
• Other known reasons for MSK symptoms, e.g. mechanical, traumatic, etc.
• MSK symptoms previously reported at another (general) practice
• Alcohol, drug or chemical abuse
• Underage or incapable patients

Contacts and Locations

Locations

Germany

CIRI

Frankfurt am Main, Hessia, Germany, 60596

Sponsors and Collaborators

Fraunhofer Institute for Molecular Biology and Applied Ecology

Bristol-Myers Squibb

Goethe University

Investigators

• Principal Investigator: Frank Behrens, MD; Fraunhofer IME

More Information

• Responsible Party: Dr. Frank Behrens, Head of clinical research department, Fraunhofer Institute for Molecular Biology and Applied Ecology
• ClinicalTrials.gov Identifier: NCT03267147
• Other Study ID Numbers: TMP-1016_01
• First Posted: August 30, 2017
• Last Update Posted: March 2, 2022
• Last Verified: March 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dr. Frank Behrens, Fraunhofer Institute for Molecular Biology and Applied Ecology:

Anti-CCP; rheumatoid arthritis

Additional relevant MeSH terms:

Arthritis; Arthritis, Rheumatoid; Inflammation; Joint Diseases; Musculoskeletal Diseases; Pathologic Processes; Rheumatic Diseases; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases