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ORIGINAL ARTICLE
Year : 2021  |  Volume : 19  |  Issue : 4  |  Page : 236-241

Classification criteria for seronegative rheumatoid arthritis based on rheumatologist's practice and experience


1 Department of Medicine and Rheumatology, SPS Hospital, Ludhiana, Punjab, India
2 Department of Medicine, PIMSR, Parul University, Vadodara, Gujarat, India

Date of Submission07-Jun-2021
Date of Decision27-Aug-2021
Date of Acceptance30-Aug-2021
Date of Web Publication07-Dec-2021

Correspondence Address:
Dr. Arti Muley
Department of Medicine, Parul Medical Institute and Hospital, Parul University, Vadodara, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_60_21

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  Abstract 


Background: Diagnosis of seronegative rheumatoid arthritis (SNRA) remains difficult because chronic synovitis is nonspecific and is seen in a large number of diseases. Although the 2010 American college of Rheumatology (ACR)/European League Against Rheumatism criteria enable early detection of seropositive rheumatoid arthritis (RA), it is not much helpful in identifying seronegative patients. Objective: The objective of the study was to suggest classification criteria for SNRA. Methods: This was a questionnaire-based study. A validated questionnaire was sent to rheumatologists all over the country to collect data regarding the points which they consider for detecting SNRA. The data so collected were analyzed to identify priority given to each point. Weightage given to these points was used to suggest systematic criteria for classifying SNRA. Results: Total 50 rheumatologists participated in the survey. They reported using the presence of inflammatory polyarthritis (62%), elevated acute phase reactants (high erythrocyte sedimentation rate [ESR] - 86% and high C-reactive protein [CRP] - 78%), absence of spondyloarthropathy features (68%), absence of antibodies (rheumatoid factor [RF] – 82% and anticitrullinated protein antibodies [ACPA] – 74%), and chronic infections for detecting SNRA. Based on these results, chronic inflammatory polyarthritis or synovitis confirmed by ultrasonography or magnetic resonance imaging, raised ESR and/or raised CRP, and negative RF and negative RF and ACPA were identified as mandatory criteria, while the absence of SPA features including psoriasis, absence of clinical features of connective tissue diseases, negative Antinuclear antibodies (ANA) by Immunofluorescence assay (IFA), and absence of HCV, HBSAg, HIV, TB as well as leprosy (in endemic regions) were identified as supportive criteria. Conclusion: We propose classification criteria for SNRA. This needs further validation and could be used for studies and clinical practice in future.

Keywords: Arthritis, diagnosis, rheumatoid, seronegative


How to cite this article:
Gera C, Muley A. Classification criteria for seronegative rheumatoid arthritis based on rheumatologist's practice and experience. Curr Med Issues 2021;19:236-41

How to cite this URL:
Gera C, Muley A. Classification criteria for seronegative rheumatoid arthritis based on rheumatologist's practice and experience. Curr Med Issues [serial online] 2021 [cited 2022 Jun 30];19:236-41. Available from: https://www.cmijournal.org/text.asp?2021/19/4/236/331835




  Introduction Top


Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology with chronic joint inflammation.[1] It is presumed to be classified as seropositive or seronegative based on the presence or absence of rheumatoid factor (RF) and/or anticitrullinated protein antibodies (ACPAs), respectively. Seropositive RA (SPRA) shares certain genetic and environmental risk factors and has been shown to have a more severe disease course but less is known about seronegative RA (SNRA). Diagnosis of SNRA remains difficult because chronic synovitis is a nonspecific feature and can be seen in a large number of diseases, for example, connective tissue diseases, crystal arthropathies, infection-related inflammatory polyarthritis, and spondyloarthropathy (SPA). Knowledge about clinical presentation and outcomes of SNRA is sparse, and performing studies is challenging as SNRA is difficult to classify and may consist of a heterogeneous population.[2] Although 2010 ACR/European League Against Rheumatism (EULAR) criteria enable early detection of RA in the disease course, they rely mainly on serology and may fail to detect some seronegative patients.[3] So if serology is negative, involvement of higher number of joints is required to fulfill classification criteria of RA and that's why primary physicians delay referral of seronegative patients till the disease is progressed, while they refer seropositive patients regardless of disease severity.[3] Absence of serological markers not only makes it difficult to classify but also delays the decision for starting disease modifying antirheumatic drugs (DMARDs).

Early and aggressive treatment of RA patients is beneficial, and serological markers are decision makers regarding starting of DMARDs.[4] As no classification criteria are available, previous studies on SNRA utilized ACR 1983/EULAR 2010 criteria minus serology to classify patients as SNRA.[3],[5],[6] As ACPA is said to be >97% specific[7] and RF is 60% specific for diagnosis of RA, their absence creates confusion regarding diagnosis of RA.

Thus, we felt need of a diagnostic criteria for SNRA and undertook an online survey among experts of the field for eliciting their opinion regarding which criteria should be considered for the diagnosis of SNRA in adults. The categorization of features identified from the study may contribute to improve diagnosis of SNRA in patients and as a consequence, reduce the delay of appropriate treatment. Thus, the aim of the study was to suggest classification criteria for SNRA so that this entity can also be diagnosed in time for better results.


  Methods Top


Study design

This was a questionnaire-based survey.

Setting

It was carried out online for 2 months. The questionnaire was sent in 1st week of the 2-month period (first phase). The participants were asked to answer questions, based on their clinical experience and send it back to the research team within 1 month. The questionnaire was sent to the nonresponders again with reminder in the 2nd week of the 2nd month (second phase). The responses received after completion of the two phases were included. No more reminders were sent to the nonresponders after the second phase. This process ensured independence of the participants, allowed participants to give frank opinion regarding their understanding of SNRA.

Participants

Rheumatologists of different age and experience from all over the country were included in the study.

Variables

Questions regarding rheumatologists' characteristics (gender, age, and address), setting in which they were working (own clinic/hospital/tertiary care institute/teaching hospitals), clinical experience as practicing rheumatologist, and the various signs, symptoms, and investigations that they considered relevant for diagnosing SNRA [Appendix 1].



Data sources

A one-page self-administered questionnaire was prepared and validated. Reliability was checked by matching test–retest answers, while face validity was checked by conducting a pilot study including subject experts to assess the questions for their structure. As SNRA is a subtype of RA, questions were designed utilizing diagnostic criteria of RA and its possible differentials [Table 1]. The questions were either multiple choice questions (MCQs) or few words answer type subjective questions. The validated questionnaire was further converted to a Google Form. E-mail addresses of rheumatologists from all over the country were collected through the National Rheumatologists' Diary, and the questionnaire was sent to them through e-mail. They were briefed about the survey and its purpose through a common message in the mail. Instructions for completing the survey were also mentioned along with it.
Table 1: Rheumatologist's characteristics

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Statistical methods

We developed descriptive categories to code the free text responses. The answers for MCQs were assessed as such. The data thus collected were analyzed to identify mandatory and supportive criteria on the basis of subject experts' responses to aid in formulating guidelines for classification as SNRA in adults. The criteria whose presence would clearly strengthen the classification were considered to be mandatory criteria. Going by probability, if >50% responded in favor of using a feature for classifying as SNRA, it was considered mandatory. The criterion whose presence may suggest the classification of RA but the absence of which does not rule out the classification was considered supportive criteria. Going by probability if 30%–50% responded in favor of using a feature to classify as SNRA, it was categorized as supportive.


  Results Top


This questionnaire was sent to 200 rheumatologists from various states of the country. Fifty responded to the mail and returned the filled survey questionnaire.

Majority (74%) of participants belonged to 30–50-year age group, while 24% belonged to 50–60-year age group. Seventy-two percent of rheumatologists were males. Participants were from different states of the country. Approximately half of them (46%) were practising rheumatology for <10 years, 37% for 11–20 years and 14% for more than 20 years. Nearly 37% of the respondents were working in a tertiary care institute, one-fourth (25%) were practicing in their own clinic while 12% belonged to an academic institute [Table 1]. Sixty percent of the participants reported to be seeing <30 SNRA patients/month, while 22%, 6%, 4%, and 6% reported to be seeing 31–60, 61–90, 91–120, and more than 120 patients of SNRA/month, respectively.

More than 75% felt that there was a need for defining criteria for diagnosis of SNRA. One-third of them (33%) said that <10% of their all RA patients were diagnosed as SNRA, while 42% reported that 10%–20% of their RA patients were diagnosed as SNRA.

More than 50% said they used the presence of inflammatory polyarthritis (62%), presence of elevated acute phase reactants (high erythrocyte sedimentation rate [ESR] - 86% and high C-reactive protein [CRP] - 78%), absence of SPA features (68%), and absence of antibodies (RF – 82% and ACPA – 74%) for diagnosis of SNRA [Table 2].
Table 2: Rheumatologist's responses

Click here to view


Twenty-eight percent of them reported to be using ANA in all patients to rule out underlying Connective tissue disorder (CTD), while 60% said they would do if it is indicated clinically. Approximately 80% said that they do HLA B 27 and ACE levels only when indicated to rule out other pathologies. Half of the participating rheumatologists said that they see radiological changes in <40% of patients of SNRA patients.

A large number (70%) of respondents did not answer the question regarding any peculiar features observed in SNRA patients, 18% felt SNRA is milder than seropositive RA and requires less medicine, 4% said it is similar to seropositive RA, and 4% said extrarticular manifestations are rare in seronegative variety.

When it was asked that which disease mimics SNRA, 26% answered CTD and another 30% felt it was psoriatic arthritis.

On questioning how they differentiate between fibromyalgia and SNRA, 54% of them said they see high acute phase reactants in SNRA but not in fibromyalgia. A significant number of participants (70%) said they see joint swelling in SNRA but not in fibromyalgia. A few of them (18%) said SNRA patients respond to NSAIDs but fibromyalgia patients do not.

Forty two percent of responders would always screen their patients for chronic infections (HCV, HBV, and tuberculosis) for diagnosis of SNRA, while 34% of them screened patients for infections only sometimes.

Forty two percent chose not to respond to the question that asked which features make them confident for classifying as SNRA. Rest of the responses were inflammatory symmetric polyarthritis (36%), negative ACPA (14%), negative RF (12%), clinical exclusion of other diseases (10%), presence of erosions (8%), absence of clinical features of CTD (4%), and no new feature on follow-up (4%).

Approximately two-thirds of participants (70%) reported to have seen change in diagnosis of SNRA patients to some other disease on follow-up, while 28% denied having any such observation [Table 2].

Thus, no peculiar feature of SNRA was reported, while almost equal weightage was given to negative anti-CCP, negative RF, and clinical exclusion of other diseases.

Hence, the presence of chronic inflammatory polyarthritis, elevated acute phase reactants (ESR and CRP), and absence of antibodies (RF and ACPA) were categorized in the mandatory criteria category, while the absence of infection, absence of SPA (psoriasis/inflammatory bowel disease/reactive arthritis features) features, absence of ANA, radiological (periarticular osteopenia/joint space narrowing/periarticular erosions), and ultrasound findings were categorized as supportive.

Based on our analysis, we propose the following classification criteria for SNRA

Mandatory: (All should be present):

  1. Chronic inflammatory polyarthritis (Documented joint swelling of 5 or more joints on examination)
  2. Raised ESR and/or raised CRP
  3. Negative RF and negative ACPA.


Supportive: (1–3 depending upon clinical features):

  1. Absence of SPA features including psoriasis
  2. Synovitis confirmed by ultrasonography OR magnetic resonance imaging.
  3. Absence of clinical features of connective tissue diseases and negative ANA by IFA.
  4. Absence of HCV, HBSAg, HIV, TB, and leprosy (in endemic regions).



  Discussion Top


RA is an autoimmune joint disease with potential to cause structural damage to joints and disabled mobility.[8] Whereas 1987 ACR classification criteria gave high weightage to clinical features, ACR/EULAR 2010 criteria are more dependent on serological markers giving rise to a possibility that only one or two involved joints also could be diagnosed as RA. However, in the absence of RF and ACPA, higher number of joint involvement is required to make a diagnosis of RA. This is supported by the finding by Sang-Tae choi and Lillian Barra et al., where number of swollen and tender joints were remarkably greater in SNRA patients compared to seropositive RA patients using EULAR 2010 criteria.[3]

There are many mimickers of RA which makes it difficult to differentiate RA from other similar polyarthritis specially when serological markers are absent. In addition to this, in the absence of serological markers, RA is usually diagnosed when disease activity is high, which causes further delay in diagnosis as well as treatment decision.

It has been suggested by some that SNRA is a less severe entity with less radiographic damage[9],[10],[11] as compared to SPRA. In studies focusing on prognosis, clinical progression and treatment response of seronegative arthritis showed better response to treatment and favorable radiographic outcomes as compared to SPRA.[6] In another study, ACPA-negative patients treated within the 1st 6 months experienced a significant improvement in (health assessment questionnaire) score compared with those treated later.[4] Hence, it was a common belief that seronegative patients can be treated less aggressively than seropositive patients.[12],[13]

However, some recent studies have reported similar disease activity, remission rates, and radiographic progression in patients with seronegative and seropositive RA after 2 years of follow-up.[14] Few studies have even reported more severe inflammatory activity and worse radiographic outcome in SNRA compared to SPRA assessed clinically and by ultrasound[3] although they showed better response to treatment.[2]

Studies on SNRA which have been done so far have mainly relied on five factors to recruit their patients (inflammatory joints, high ESR, high CRP, negative RF, and negative ACPA),[15] but some proportion of recruited SNRA patients were later excluded from the group in view of alternative diagnosis[2] indicating that there was a lack of clarity regarding diagnosis of SNRA at the time of initiation of study.

This highlights the need of early detection and aggressive therapy in SNRA similar to SPRA[2] which in turn warrants defining criteria for identifying SNRA as early as possible. Since no infinitely effective and safe intervention is available without cost and discomfort, the search for appropriate classification rules is justified. Any disease for classification purpose and better understanding needs some basic criteria to make uniform communication about disease. We here present new classification as a standardized approach to identify individuals with SNRA for whom the risk of persistence of symptom or structural damage warrants intervention with DMARDs.

These new criteria are based on the responses to a validated questionnaire obtained from known rheumatologists and need further validation on a different validation cohort. However, till this can be done, these criteria redefine SNRA, reflecting our collective hope that this entity could be prevented from progressing to the stage of longstanding untreated disease due to delay in diagnosis.


  Conclusion Top


There has been a lack of clarity regarding SNRA and need of defining classification criteria for the same is being felt since long. We propose criteria for classifying SNRA which can be used to identify SNRA early.

Acknowledgments

We express our gratitude to Dr Varun Dhir and Dr Ajay Wanchu for validation of Questionnaire.

Research quality and ethics statement

All authors of this manuscript declare that this scientific study is in compliance with standard reporting guidelines set forth by the EQUATOR Network. The authors ratify that this study required Institutional Review Board/Ethics Committee review, and hence prior approval was obtained IRB Min. No. SPSH/L/308 dated 22/11/2018. We also declare that we did not plagiarize the contents of this manuscript and have performed a Plagiarism Check.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Choi SW, Lim MK, Shin DH, Park JJ, Shim SC. Diagnostic performances of anti-cyclic citrullinated peptides antibody and antifilaggrin antibody in Korean patients with rheumatoid arthritis. J Korean Med Sci 2005;20:473-8.  Back to cited text no. 1
    
2.
Barra L, Pope JE, Orav JE, Boire G, Haraoui B, Hitchon C, et al. Prognosis of seronegative patients in a large prospective cohort of patients with early inflammatory arthritis. J Rheumatol 2014;41:2361-9.  Back to cited text no. 2
    
3.
Choi S, Lee KH. Clinical management of seronegative and seropositive rheumatoid arthritis: A comparative study. PLoS One 2018;13:e0195550.  Back to cited text no. 3
    
4.
Farragher TM, Lunt M, Plant D, Bunn DK, Barton A, Symmons DP. Benefit of early treatment in inflammatory polyarthritis patients with anti-cyclic citrullinated peptide antibodies versus those without antibodies. Arthritis Care Res (Hoboken) 2010;62:664-75.  Back to cited text no. 4
    
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Nordberg LB, Lillegraven S, Aga AB, Sexton J, Olsen IC, Lie E, et al. Comparing the disease course of patients with seronegative and seropositive rheumatoid arthritis fulfilling the 2010 ACR/EULAR classification criteria in a treat-to-target setting: 2-year data from the ARCTIC trial. RMD Open 2018;4:e000752.  Back to cited text no. 5
    
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Paalanen K, Rannio K, Rannio T, Asikainen J, Hannonen P, Sokka T. Does early seronegative arthritis develop into rheumatoid arthritis? A 10-year observational study. Clin Exp Rheumatol 2019;37:37-43.  Back to cited text no. 6
    
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Quinn MA, Gough AK, Green MJ, Devlin J, Hensor EM, Greenstein A, et al. Anti-CCP antibodies measured at disease onset help identify seronegative rheumatoid arthritis and predict radiological and functional outcome. Rheumatology (Oxford) 2006;45:478-80.  Back to cited text no. 7
    
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Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016;388:2023-38.  Back to cited text no. 8
    
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Hecht C, Englbrecht M, Rech J, Schmidt S, Araujo E, Engelke K, et al. Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Ann Rheum Dis 2015;74:2151-6.  Back to cited text no. 9
    
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van den Broek M, Dirven L, Klarenbeek NB, Molenaar TH, Han KH, Kerstens PJ, et al. The association of treatment response and joint damage with ACPA-status in recent-onset RA: A subanalysis of the 8-year follow-up of the best study. Ann Rheum Dis 2012;71:245-8.  Back to cited text no. 10
    
11.
Asikainen J, Nikiphorou E, Kaarela K, Lindqvist E, Häkkinen A, Kautiainen H, et al. Is long-term radiographic joint damage different between men and women? Prospective longitudinal data analysis of four early RA cohorts with greater than 15 years follow-up. Clin Exp Rheumatol 2016;34:641-5.  Back to cited text no. 11
    
12.
de Punder YM, Hendrikx J, den Broeder AA, Valls Pascual E, van Riel PL, Fransen J. Should we redefine treatment targets in rheumatoid arthritis? Low disease activity is sufficiently strict for patients who are anticitrullinated protein antibody-negative. J Rheumatol 2013;40:1268-74.  Back to cited text no. 12
    
13.
Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960-77.  Back to cited text no. 13
    
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Boer AC, Boonen A, van der Helm van Mil AHM. Is anti-citrullinated protein antibody-positive rheumatoid arthritis still a more severe disease than anti-citrullinated protein antibody-negative rheumatoid arthritis? A longitudinal cohort study in rheumatoid arthritis patients diagnosed from 2000 onward. Arthritis Care Res (Hoboken) 2018;70:987-96.  Back to cited text no. 14
    
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Nell VP, Machold KP, Stamm TA, Eberl G, Heinzl H, Uffmann M, et al. Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann Rheum Dis 2005;64:1731-6.  Back to cited text no. 15
    



 
 
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