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Spondyloarthritis
Original research
Identification of the first signs or symptoms in different spondyloarthritis subtypes and their association with HLA-B27: data from REGISPONSER and RESPONDIA registries
  1. María Ángeles Puche-Larrubia1,2,3,
  2. Lourdes Ladehesa-Pineda1,2,3,
  3. Janitzia Vázquez-Mellado4,
  4. Alejandro Escudero-Contreras1,2,3,
  5. Jordi Gratacós5,
  6. Xavier Juanola6,
  7. Eduardo Collantes-Estévez2,3,
  8. Pilar Font-Ugalde2,3 and
  9. Clementina López-Medina1,2,3
  1. 1Department of Rheumatology, Reina Sofia University Hospital, Cordoba, Spain
  2. 2GC-05 Group, Maimonides Institute for Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain
  3. 3Medical and Surgical Sciences, University of Cordoba, Cordoba, Spain
  4. 4Department of Rheumatology, Hospital General de Mexico, Mexico City, Mexico
  5. 5Department of Rheumatology, Hospital Universitario Parc Taulí, Barcelona, Spain
  6. 6Department of Rheumatology, Hospital Universitari de Bellvitge, Barcelona, Spain
  1. Correspondence to Dr María Ángeles Puche-Larrubia; mangeles.puche{at}gmail.com

Abstract

Objective To describe and analyse the initial symptoms attributable to patients with spondyloarthritis (SpA) and their association with HLA-B27 status.

Methods This was an observational, cross-sectional and multicentre study with patients who fulfilled the European Spondyloarthropathy Study Group criteria for SpA from the Registry of Spondyloarthritis of Spanish Rheumatology (REGISPONSER) and Ibero-American Registry of Spondyloarthropathies (RESPONDIA) united registries. Differences in the first sign(s) or symptom(s) were compared across diagnoses and between HLA-B27 status. The diagnostic delay between patients who start the disease with musculoskeletal manifestations (MMs) and extra-MMs (EMMs) was compared.

Results A total of 4067 patients were included (2208 from REGISPONSER and 1859 from RESPONDIA) (ankylosing spondylitis (AS): 68.3%, psoriatic arthritis (PsA): 19.9%, undifferentiated SpA: 11.8%). Overall, 3624 (89.1%) patients initiated the disease with MMs and 443 (10.9%) with EMMs. Low back pain (61.7%) and lower-limb arthritis (38.5%) were the most frequent initial symptoms. In AS patients, the absence of HLA-B27 seems to be related to an increase in the probability of starting the disease with cervical pain and peripheral manifestations. In PsA, the onset of arthritis and psoriasis was more prevalent in HLA-B27-negative patients, while initiation with axial manifestations was more predominant in HLA-B27-positive patients. The diagnostic delay was longer in patients with initial MMs than in those with EMMs (7.2 (34.8) vs 4.5 (7.6) years, respectively).

Conclusion In this SpA population, MMs were the most prevalent initial symptoms, with differences across diagnoses and depending on the presence of the HLA-B27 antigen.

  • spondyloarthritis
  • arthritis, psoriatic
  • low back pain

Data availability statement

Data are available on reasonable request. Contact the corresponding author of the manuscript.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2023-003235

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Early diagnosis of spondyloarthritis (SpA) is crucial for minimising the impact of the disease. However, this early diagnosis can be difficult, as there is no agreement on what constitutes the initial symptom.

    WHAT THIS STUDY ADDS

    • This study suggests that SpA usually starts with musculoskeletal manifestations, which differ based on the diagnosis and HLA-B27 status.

    • The diagnostic delay was longer in patients with musculoskeletal manifestations as the first symptom.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This study demonstrates that SpA can start with a huge variety of symptoms.

    • Clinicians and general practitioners should be aware of the need to accurately recognise rheumatic symptoms due to the longer diagnostic delay in patients who initiate the disease with musculoskeletal manifestations.

    Introduction

    Spondyloarthritis (SpA) encompasses a heterogeneous group of inflammatory rheumatic disorders characterised by axial skeleton and sacroiliac joint involvement, peripheral symptoms, extra-articular manifestations (psoriasis, uveitis and inflammatory bowel disease (IBD), among others), and a strong association with the HLA-B27 antigen. Classically, SpA patients have been categorised into several subtypes depending on the presence of peripheral and/or extramusculoskeletal manifestations (EMMs), such as ankylosing spondylitis (AS), psoriatic arthritis (PsA), IBD-associated SpA (IBD-SpA), reactive arthritis (ReA), undifferentiated SpA (u-SpA) and juvenile SpA (Juv-SpA).1 2

    Despite the increase in knowledge about this disease, studies have established a mean delay of 2–6 years between symptom onset and the definitive diagnosis of SpA.3 Early diagnosis of SpA is important to minimise disease burden by establishing early treatment.4 Reasons for diagnostic delay are multifactorial, one of which is the difficulty of identifying SpA at an early stage.5 6 Recently, the Assessment of Spondyloarthritis International Society (ASAS) defined ‘early axial SpA’ as patients with a diagnosis of axial SpA with a duration of axial symptoms less than or equal to 2 years.7 However, this definition has only been developed for axial SpA because of the low rate of studies exploring other types of SpA.8 The definition for early SpA should imply the correct identification of the initial symptom of SpA. However, what should we consider as an initial symptom? There is currently no consensus on whether only musculoskeletal manifestations (MMs) or EMMs should be considered the onset in the whole spectrum of SpA. A matter of debate is whether to consider the appearance of uveitis or psoriasis as the initial symptom of SpA or only consider that SpA begins with the appearance of MMs. In addition, we do not know how the onset of symptoms differs depending on the diagnosis and presence of the HLAB-27 antigen.

    Our starting hypothesis was that MMs (inflammatory low back pain, arthritis, enthesitis or dactylitis) is the most frequent form of disease onset and that this may vary depending on the diagnosis and the presence of HLA-B27 antigen. However, we believe that the disease may also begin with EMMs and should take these factors into account and screen for MMs in those patients who present for early diagnosis.

    The purpose of this study was to: (A) describe the initial sign or symptom (either MMs or EMMs) in the different SpA subtypes based on the clinical diagnosis by the rheumatologist; (B) describe the initial symptom stratified by the clinical diagnosis and by the presence of HLA-B27 and determine if HLA-B27 may influence the form of onset of the disease; (C) quantify the mean time that separates the appearance of the EMMs from the MMs among patients who start the disease with EMMs; (D) compare the diagnostic delay between patients who start the disease with EMMs or MMs and (E) analyse the clinical factors associated with different forms of initiation.

    Patients and methods

    Design

    This was an observational, cross-sectional and multicentre study that included patients from the REGISPONSER (Registry of Spondyloarthritis of Spanish Rheumatology) and RESPONDIA (Ibero-American Registry of Spondyloarthropathies) registries. Despite being a cross-sectional registry, both REGISPONSER and RESPONDIA recorded the onset date of each symptom, so that temporal sequence could be determined, and they shared the same variables so that the two registries could be united.

    Patients

    REGISPONSER is a national and multicentre registry that incorporated consecutive SpA patients who fulfilled the European Spondyloarthropathy Study Group (ESSG)9 criteria for SpA between March 2004 and March 2007. Thus, patients could have a diagnosis according to their rheumatologist of AS, PsA, IBD-SpA, ReA, u-SpA or Juv-SpA. The study was conducted by Spanish Group for the Study of Spondyloarthritis of the Spanish Rheumatology Society with 31 participating centres. More information about the design, sampling and recruitment of patients is detailed in a previous publication.10

    RESPONDIA has a similar design and shares the case report form and all of the variables studied with REGISPONSER.11 It was conducted between 2006 and 2007. Thirty-three centres from eight Latin American countries participated in this registry. The inclusion criteria were the same as in REGISPONSER. Consecutive patients with SpA according to the criteria of the ESSG were included.

    The overall population included 4410 patients (2366 from REGISPONSER and 2044 from RESPONDIA). However, for this specific analysis, we focused on patients with a diagnosis of AS, PsA or u-SpA with the aim of having a more homogeneous population and because these were the more prevalent groups, resulting in 4067 patients (2208 from REGISPONSER and 1859 from RESPONDIA) (online supplemental figure 1). The AS and u-SpA nomenclature was maintained because it was the one used in both registries at the time that they were carried out.

    Collected variables

    From the REGISPONSER and RESPONDIA registries, we collected the following variables:

    1. Sociodemographic data: age, sex and race.

    2. Data on symptom onset: symptoms that have appeared in the patient throughout their disease (inflammatory low back pain, buttock pain, coxitis, cervical pain, enthesitis, dactylitis, psoriasis, lower and upper-limb arthritis, uveitis and IBD). Participants’answers to the question ‘indicate the first sign or symptom attributable to the disease’ were recorded, as well as the year of the first MMs and EMMs, allowing us to determine the first symptom(s) in each patient. It must be considered that patients could start the disease with more than one symptom. Patients who started the disease with MMs and EMMs at the same time were considered as starting with EMMs, with the aim of comparing them with those who started the disease only with MMs.

    3. Clinical data: diagnosis according to the rheumatologist (AS, PsA and u-SpA), presence of HLA B27 antigen, family history of SpA, C reactive protein and erythrocyte sedimentation rate were collected. Disease duration (years between the date of the SpA diagnosis and study visit) and symptom duration (years between the date of symptom onset and the study visit) were recorded. Finally, we defined diagnostic delay as the difference between symptom duration and disease duration.

    The Bath Ankylosing Disease Activity Index12 and Ankylosing Spondylitis Disease Activity Score13 were collected in all patients to evaluate disease activity. Function was evaluated through the Bath Ankylosing Spondylitis Functional Index,14 and structural damage was evaluated using the Bath Ankylosing Spondylitis Radiology Index for the spine and total axial skeleton (which includes the spine and sacroiliac joints).15

    1. Treatment: Data from concomitant and/or previous treatments were analysed, such as the use of oral corticosteroids, non-steroidal anti-inflammatory drugs, conventional disease-modifying anti-rheumatoid drugs (DMARDs) (sulfasalazine, methotrexate or leflunomide) and biological DMARDs (anti-TNF treatment).

    Statistical analysis

    First, a descriptive analysis of the clinical and sociodemographic characteristics of the two populations included in the study (REGISPONSER and RESPONDIA) and in the whole population was carried out. Descriptive data are expressed as the mean and SD for quantitative variables and absolute and relative frequencies for qualitative variables.

    Second, we evaluated the percentage of patients who started the disease with each one of the symptoms in the overall population and per diagnosis. Subsequently, within each diagnosis, the prevalence of each onset symptom was stratified based on the HLA-B27 status (among patients with available data for HLA-B27 antigen) to evaluate whether the presence of this antigen influences the onset of the disease. Differences in the first symptom across diagnosis and between HLA-B27 carriers were compared using the χ2/Fisher’s exact test.

    Among the patients who started the disease with EMMs, we quantified the average time that separates the appearance of the different EMMs from the MMs, and we compared this average between HLA-B27-positive and HLA-B27-negative patients using the Mann-Whitney U test.

    Next, we compared the diagnostic delay between patients who started the disease with EMMs versus those starting with MMs using the Mann-Whitney U test to evaluate whether the initiation of the disease with EMMs led to a shorter diagnostic delay. In addition, cumulative probability plots were used to display the cumulative distribution in diagnostic delay stratified by the first symptom (EMMs or MMs).

    Finally, factors associated with the most prevalent initial symptom were evaluated using χ2/Fisher’s exact tests for qualitative variables and Student’s t-test/Mann-Whitney U tests for continuous variables.

    All tests were two tailed, and a p<0.05 was considered to indicate significance. Data were collected, processed and analysed using IBM SPSS Statistics V.25 (SPSS) and RStudio V.4.0.4.

    Results

    Description of the population

    A total of 4067 patients were included in the analysis (2208 from REGISPONSER and 1859 from RESPONDIA), including 68.3% AS (n=2778), 19.9% PsA (n=808) and 11.8% u-SpA (n=481). Descriptions of the clinical and sociodemographic characteristics of the two populations included in this study (REGISPONSER and RESPONDIA) are presented in table 1. A total of 67.2% of the patients were men, their mean age was 46.9 (14.7) years, and their mean age of onset was 27.1 (36.4) years. The majority of the population was HLA-B27 positive (69.5%).

    View this table:
    Table 1

    Demographic and clinical characteristics of the of the two populations included in the study: REGISPONSER and RESPONDIA

    Initial sign or symptom

    Overall, 3624 (89.1%) patients initiated disease with MMs, 251 (6.1%) patients started disease with both MMs and EMMs at the same time, and 192 (4.7%) patients started disease with only EMMs. The prevalence of the initial symptom in the overall population was as follows (in descending order): low back pain (61.7%), lower-limb arthritis (38.5%), buttock pain (35.8%), upper-limb arthritis (21.1%), cervical pain (20.4%), psoriasis (15.3%), coxitis (11.2%), dactylitis (8.3%), uveitis (2.7%) and IBD (2.2%) (figure 1).

    Figure 1
    Figure 1

    Description of the first symptoms according to the SpA diagnoses. SpA, spondyloarthritis.

    The percentage of patients who started the disease with each symptom according to the diagnosis is represented in figure 1.

    Initial sign or symptom according to HLA-B27

    A total of 2703 patients had available data for HLA-B27 antigen status (online supplemental figure 1). The association between HLA-B27 antigen and disease onset according to diagnosis is represented in table 2. In AS patients, the absence of HLA-B27 seems to be associated with an increase in the probability of initiating the disease with cervical pain (24.2% vs 15.6%), peripheral manifestations (lower-limb arthritis, upper-limb arthritis, enthesitis and dactylitis), psoriasis (8.5% vs 1.8%) and IBD (4.2% vs 1.4%) in comparison with HLA-B27-positive patients. In PsA, the initiation of upper-limb arthritis (61% vs 38.4%) and psoriasis (62.1% vs 37%) was more prevalent in HLA-B27-negative patients, while the initiation of low back pain (22.1% vs 38.4%) and buttock pain (13.6% vs 28.8%) was more prevalent in HLA-B27positive patients.

    View this table:
    Table 2

    Influence of the HLA-B27 gene on disease onset according to diagnosis

    Time separating EMMs from MMs

    In patients who initiated the disease with EMMs (N=443) (either EMMs and MMs at the same time (n=251) or only EMMs as the first symptom(s) (n=192)), the average time that separated the appearance of EMMs from MMs was 11.5 (9.2) years. The shortest average time that separated the appearance of EMMs from MMs was in the case of uveitis (5.8 (6.2) years), followed by IBD (6.2 (6.7) years) and finally psoriasis (11.8 (9.2) years). Patients with negative HLA-B27 had more years of separation between the EMMs of the MMs ones 12.0 (9.9) vs 7.9 (7.1) years in comparison with HLA-B27 positives.

    Association between the first symptom and the diagnostic delay

    Overall, the diagnostic delay was longer in patients with initial MMs than in those with initial EMMs (7.2 (34.8) vs 4.5 (7.6) years, p=0.000). Similarly, in patients with AS, the diagnostic delay was longer in patients who initiated the disease with an MMs in comparison with those who initiated with an EMMs (8.3 (39.1) vs 6 (8.6) years, p=0.028). Conversely, in patients with PsA, the diagnostic delay was longer in patients who initiated the disease with an EMMs (2.67 (4.7) vs 3.91 (7) years, p=0.009). Finally, no differences were found in patients with u-SpA. Figure 2 shows the cumulative probability plots representing the diagnostic delay according to whether the first symptom was MMss or EMMs.

    Figure 2
    Figure 2

    Probability plot showing the cumulative distribution of the diagnostic delay according to the first symptom (musculoskeletal or extramusculoskeletal). The green line represents patients who initiated the disease with extramusculoskeletal manifestations (EMM), and the red line represents patients who initiated the disease with a musculoskeletal manifestation (MM). The horizontal axis represents the diagnostic delay, and the vertical axis represents the cumulated percentage of patients. SpA, spondyloarthritis.

    Factors associated with different onset symptom

    Back pain versus buttock pain as initial symptom

    In the population, factors associated with low back pain versus buttock pain (table 3) as the first symptom were male sex (71.6% vs 64.8%), lower-limb arthritis (42.9% vs 33.7%) and uveitis (20.9% vs 15.2%).

    View this table:
    Table 3

    Factors associated with low back pain versus buttock pain as the initial symptom

    Cervical pain versus low back pain as initial symptom

    Factors associated with cervical pain versus low back pain (table 4) as the first symptom in the overall population were cutaneous psoriasis (38.5% vs 14.4%), negative HLA-B27 (44.5% vs 24.1%) and peripheral involvement (arthritis (54.8% vs 39.2%) and dactylitis (25.9% vs 9.8%)).

    View this table:
    Table 4

    Factors associated with low back pain versus cervical pain as the initial symptom

    Upper-limb versus lower-limb arthritis as the initial symptom

    Finally, factors associated with upper-limb arthritis versus lower-limb arthritis (online supplemental table 1) as the first symptom were female sex (48.7 vs 39.2%), cutaneous psoriasis (66.4% vs 30.8%), HLA-B27 negativity (63.6% vs 33%) and absence of axial symptoms (low back pain (50.9% vs 75.4%) and buttock pain (28.8% vs 44.6%)).

    Discussion

    In this study, we aimed to identify and characterise the first symptoms of SpA for an early diagnosis of the disease. This study suggests that MMs (ie, low back pain, buttock pain and lower-limb arthritis) are the initial symptom of SpA in the majority of cases, with differences across diagnoses and depending on the presence of the HLA-B27 antigen. In addition, our results may imply that the initiation of the disease with MMs led to a longer diagnostic delay compared with EMMs as initial symptoms.

    Among all the onset symptoms, low back pain stands out as the most prevalent in our population. Its higher frequency can be explained by the fact that most patients have an AS diagnosis whose characteristic onset symptom is low back pain and that it is the central symptom of all subtypes of SpA. Low back pain was also the initial onset symptom in a previous study conducted in the REGISPONSER-early cohort,6 with patients whose inclusion criteria were a disease course of ≤2 years from the onset of symptoms or the appearance of the first sign of disease. One difficulty in the early diagnosis of SpA is the high frequency of low back pain in the general population. It is necessary to look for features of SpA in those patients with chronic low back pain that, if present, increase the suspicion of SpA.16

    When stratifying according to diagnosis, we observed in our population that in those pathologies in which axial symptoms predominate (AS and u-SpA), their initial symptom was low back pain. Conversely, in those with predominant peripheral symptoms (PsA), the initial symptom was lower-limb arthritis. Surprisingly, in this cohort, psoriasis was the second most frequent onset symptom in PsA, although in previous literature, the majority of PsA patients start with cutaneous psoriasis.17 18 In an Italian study,19 it was observed that 26.1% of seronegative rheumatoid arthritis patients had nail lesions and skin psoriasis previously unrecognised by their rheumatologist when evaluated by a dermatologist. These lesions can be minimal and are sometimes only recognised by dermoscopy or ultrasound. This could mean that an active search for psoriasis is recommended for seronegative arthritis, and if it is not visible, an evaluation by a dermatologist may be necessary.

    In this analysis, we also tested whether HLA-B27 may be related to the early-onset form of the disease. We found that the absence of this antigen in AS patients was associated with the initiation of cervical pain and peripheral involvement. Similarly, HLA-B27-negative PsA patients seem to initiate the disease predominantly with peripheral symptoms, while HLA-B27-positive PsA patients seem to initiate the disease with axial symptoms (ie, low back pain, buttock pain and coxitis). These results in PsA patients are in line with previous literature showing that patients with HLA-B27-positive PsA have a higher risk of developing axial symptoms than HLA-B27-negative patients.20 21 Although studies comparing axial PsA with axSpA show a higher prevalence of HLAB27 positivity in those with axSpA,22 HLA-B27-positive PsA individuals showed a worse prognosis and more radiographic damage, and it is the only associated common risk factor found between the two.23 24

    A total of 10.9% of patients initiated the disease with EMMs. Among these, the meantime separating EMMs from MMs was approximately 11 years. When stratifying according to the presence of the HLA-B27 antigen, the number of years increases in the HLA-B27-negative forms, meaning that HLA-B27-negative patients may need more time to fully develop the clinical picture of SpA; this finding agreed with previous studies in the DESIR cohort.20 Studies have shown that up to 50%, 30% and 3%–10% of patients with acute anterior uveitis, psoriasis and IBD, respectively, will develop SpA at some point in their lives.25–27 Although the number of patients who initiated the disease with EMMs is low, these patients require a multidisciplinary team (ophthalmologists, gastroenterologists, dermatologists) who, during the follow-up, remember to consider the possibility of a rheumatic disease and, in the event of a suspicious symptom of SpA, refer the patient to a rheumatologist and vice versa for early diagnosis.

    Our results also show that the form of initiation of the disease could be associated with the diagnostic delay. We found that patients who started the disease with MMs had a longer diagnostic delay than those who initiated with EMMs. Possibly, when a patient initiates an EMMs, such as psoriasis, uveitis or IBD, an active search for a disease suggestive of SpA is performed. However, because low back pain-type MMs are so common in the general population, it may take several years for a patient to be diagnosed. Interestingly, inverse results were found in PsA patients, in whom the diagnostic delay was longer in those who initiated the disease with EMMs (mainly psoriasis). This can be explained because the joint manifestations of PsA can often be confused with osteoarthritis. Another possible explanation is that patients with PsA have atypical forms of low back or neck pain that do not raise suspicion of axial involvement. These findings demonstrate the importance of the implementation of screening tools and questionnaires for detecting patients with suspicion of PsA in dermatology clinics.

    Buttock pain has been described as a very typical symptom of axial SpA. In fact, 42.3% of patients with a diagnosis of AS started the disease with such symptoms. For this reason, we considered it worthwhile to evaluate the characteristics of patients who started the disease with buttock pain in comparison with lumbar pain. We found that lumbar pain was associated with male sex, lower limb arthritis and uveitis, whereas patients initiating with buttock pain were more frequently female and younger than those who initiated with lumbar pain. On the other hand, factors associated with cervical pain versus low back pain as the first symptom were cutaneous psoriasis, negative HLA-B27 status and peripheral involvement (arthritis and dactylitis), confirming that cervical pain could represent the initiation of PsA with axial involvement. In fact, it is not uncommon to find radiological cervical involvement in patients with PsA (35%–75%). Radiographic manifestations can affect the upper or lower cervical spine, with the upper involvement resembling that caused in rheumatoid arthritis with erosions or atlantoaxial subluxation and the lower involvement resembling SpA with syndesmophytes, ossification of the anterior longitudinal ligament, and facet joint arthritis.28 29 Finally, factors associated with upper-limb arthritis versus lower-limb arthritis as the first symptom were female sex, cutaneous psoriasis, HLA-B27 negativity and absence of axial symptoms. This means that many patients initiate the disease in the upper limbs, as they may have a diagnosis of PsA. This is in line with what has been found in the recent ASAS-PerSpA study,30 in which patients with PsA had predominantly upper limb and small joint involvement.

    Our study has some limitations and strengths. One limitation is the possibility of recall bias that patients may have when remembering the first symptom with which the disease began, and this should be considered when interpreting the results. There is also a high number of patients with missing information for HLA-B27 antigen. The analysis on association with HLA-B27 has been done in patients with available data for HLA-B27 leading to possible underestimation of patients with PsA in this subanalysis (who fit the profile of patients in which HLA-B27 is not always evaluated). Another limitation of this study is the inability to make causal assumptions when interpreting numerous statistically significant results and having a very large sample that may favour them. In addition, the diagnostic groups were not homogeneous in the number of patients, with a greater number of patients with AS and having to eliminate patients with IBD-SpA and Juv-SpA diagnoses because of the low number of patients in these groups. However, this is in line with current clinical practice, in which IBD-SpA and Juv-SpA show a very low frequency in comparison with other diagnoses. Finally, the last limitation is the use of the ESSG as an inclusion criterion, which enables the inclusion of patients with a diagnosis of u-SpA and prevents the identification of those with non-radiographic axSpA. One strength of this study is the large number of patients and the representation of the whole spectrum of SpA thanks to joining both registries (RESPONDIA and REGISPONSER). Although this is a cross-sectional study, the availability of the dates of each symptom initiation allowed us to establish the sequence of events and to determine the initial symptom. Future prospective studies are necessary to avoid memory bias and to be able to use the current ASAS classification criteria.

    In summary, the findings of our study suggest that SpA commonly initiates with MMs, with low back pain likely being the most prevalent initial symptom within the AS and u-SpA populations, and lower-limb arthritis being prominent in PsA cases. However, these initial symptoms may vary according to the presence of HLA-B27. It should be noted that the diagnostic delay was greater in those patients who started the disease with MMs in our study, emphasising the correct recognition of rheumatic symptoms by general practitioners.

    Data availability statement

    Data are available on reasonable request. Contact the corresponding author of the manuscript.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Ethics Committee ('Comisión de Ética e Investigación Sanitarias') of Reina Sofia University Hospital from Cordoba (Spain). Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    Authors would like to thank all the investigators from the REGISPONSER and RESPONDIA study groups. REGISPONSER: P. Zarco-Montejo, Hospital Fundación Alcorcón, Madrid; C. González, Hospital Gregorio Marañón, Madrid; J. Mulero-Mendoza, Hospital Puerta de Hierro, Madrid; J.L. Fernández-Sueiro, Hospital Juan Canalejo, La Coruña; R.Almodóvar, Hospital Fundación Alcorcón, Madrid; J. Gratacós-Masmitjá, Hospital Parc Taulí, Barcelona; X. Juanola-Roura, Hospital Bellvitge, Barcelona; C. Montilla, Hospital Virgen de la Vega, Salamanca; E. Moreno, Hospital San Rafael, Barcelona; A. Juan-Mas, Hospital Fundación Son Llatzer, Mallorca; P. Fernández-Dapica, Hospital 12 de Octubre, Madrid; M.C. Fernández-Espartero, Hospital de Móstoles, Madrid; V. Villaverde, Hospital de Móstoles, Madrid; M.E. Brito-Brito, Hospital Universitario Ramón y Cajal, Madrid; J.C. Torre-Alonso, Hospital Monte Naranco, Oviedo; E. Batlle-Gualda, Hospital General Universitario, Alicante; E. Cuende-Quintana, Hospital Universitario Príncipe de Asturias, Madrid; T. Clavaguera-Poch, Hospital de Palmaos, Girona; M. Fernández-Prada, Hospital Universitario de Guadalajara, Guadalajara; and E. Judez-Navarro, Hospital Virgen del Perpetuo Socorro, Albacete. RESPONDIA: Alvarellos A, Hospital Privado de Córdoba, Córdoba, Argentina; Asnal C, Hospital Alemán, Buenos Aires, Argentina; Barreira JC, Hospital Británico, Buenos Aires, Argentina; Bernard Medina AG, Hospital F. Antonio Alcalde, Guadalajara, México; Bertolo MB, Universidade Campinas, Brazil; Bianchi WA, Santa Casa do Rio de Janeiro, Brazil; Bonfiglioli R, Pontifícia Universidade Católica de Campinas, Brazil; Carneiro S, Universidade Federal do Rio de Janeiro, Brazil; Carvalho HMS, Hospital de Base, Brasília, Brazil; Casado GC, Hospital Militar Central, Buenos Aires, Argentina; Casasola Vargas J, Hospital General de México, México City, México; Castro da Rocha FA, Universidade Federal do Ceará, Fortaleza, Brazil; Chacón RL, Policlínica Méndez Gimón, Caracas, Venezuela; Costa IP, Universidade Federal do Mato Grosso do Sul, Campo Grande, Brazil; Duarte AP, Universidade Federal de Pernambuco, Recife, Brazil; Espinoza-Villalpando J, Hospital Regional PEMEX, Reynosa, México; Esteva MH, Hospital Central San Cristóbal, San Cristóbal, Táchira, Venezuela; Fuentealba C, Hospital San Boraja Arriarán, Santiago, Chile; Granados Y, Hospital Núñez Tovar, Maturín Monagas, Venezuela; Huerta-Sil G, CLIDITER, México, México; Keiserman M, Pontifícia Universidade Católica de Porto Alegre, Brazil; Kohem CL, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Leite NH, Faculdade Souza Marques, Rio de Janeiro, Brazil; Lima SAL, Hospital do Servidor Público Estadual de São Paulo, São Paulo, Brazil; Maldonado-Cocco JA, IREP, Buenos Aires, Argentina; Meirelles ES, Universidade de São Paulo, Brazil; Menin R, Faculdade de Medicina de São José do Rio Preto, Brazil; Neira O, Hospital del Salvador, Santiago, Chile; Paira S, Hospital JM Cullen, Santa Fé, Argentina; Pimentel F, Complexo Hospitalar Egas Moniz, Lisbon, Portugal; Pinheiro M, Universidade Federal de São Paulo, Brazil; Polito E, Santa Casa de Belo Horizonte, Brazil; Resende G, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil; Ribeiro SLE, Universidade Federal do Amazonas, Manaus, Brazil; Rillo OL, Hospital Tornú, Buenos Aires, Argentina; Santiago MB, Escola de Saúde Pública da Bahia, Salvador, Brazil; Santos H, Instituto Portugués de Reumatología, Lisboa, Portugal; Scherbarth H, Mar del Plata, Argentina; Sauma MFLC, Universidade Federal do Pará, Belém, Brazil; Skare TL, Hospital Evangélico de Curitiba, Brazil; Sousa E, Complexo Hospitalar Lisboa Norte, Lisboa, Portugal; Spangenberg E, Instituto Nacional de Reumatología, Montevideo, Uruguay; Valin V, Universidade Federal do Espírito Santo, Vitória, Brazil; Vera C, Hospital Luis Vernaza, Guayaquil, Ecuador; Verdejo U, Hospital Carlos van Buren, Valparaíso, Chile; Vieira WP, Hospital Geral de Fortaleza, Brazil; Wong R, S. Plaza, Rosario, Argentina.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • Twitter @drapuche03, @clemenlpez

    • PF-U and CL-M contributed equally.

    • Contributors MÁP-L: formal analysis, investigation, methodology, writing original draft. LL-P: data curation, formal analysis, investigation, methodology, writing review editing. JVM, JG and XJ: data curation, investigation, writing review editing. AE-C: investigation, supervision, writing review editing. EC: conceptualisation, investigation, methodology, supervision, writing review editing. PF-U: investigation, methodology, project administration, writing review editing. CL-M: data curation, formal analysis, investigation, methodology, writing original draft. CL-M accepts full responsibility for the work, had access to the data and controlled the decision to publish (guarantor).

    • Funding This ancillary analysis has been funded with research grant 'Ayudas en Investigación en SpA SER-GRESSER' from the Spanish Foundation of Rheumatology (FER).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.