|Ahead of print publication
Clinical profile of adults and children with reactive arthritis in India – A cohort study
Koshy Nithin Thomas, Anamika Kumari Anuja, Latika Gupta
Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||14-May-2020|
|Date of Acceptance||16-Aug-2020|
Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Background: An evolving clinicodemographic spectrum is reported in reactive arthritis (reA) with the changing microbial profile in recent times. Moreover, understanding of chronic disease patterns is limited due to widespread beliefs of a self-limiting nature. We thus assessed the clinical profile of a cohort of acute reA and compare them with chronic reA.
Methods: A hospital-based study of prevalent triggers and demographic features, articular and extra-articular manifestations, and radiological findings was undertaken in children and adults with reA at a tertiary care center in northern India.
Results: Sixty-eight cases (8 juvenile, 41 acute, and 27 chronic) of age 26 years (18–34, M:F 5.8:1) and disease duration 36 (19–60) days were enrolled. Enteritis was the most common preceding trigger (37, 54%), followed by genitourinary infection (25, 36%), irrespective of gender. The clinical spectrum mirrored previous descriptions, with arthritis in most (95%), enthesitis in 33%, and conjunctivitis and circinate balanitis being the most common extra-articular features (8% each). Numerous cases (n = 7) did not fulfill the Braun's criteria at the current visit though a high representation of sacroiliitis was noted (20%, 12%) in acute as well as chronic reA. Enthesitis was more common in the acute reA (P = 0.018) and mucocutaneous features occurred only at inception. Otherwise, the clinical profile was similar in cases triggered by urethritis and enteritis, and in children as compared with adults.
Conclusion: These observations of varied spectrum of reA assume larger importance in light of the emerging concept of a unified clinic-pathologic spectrum of spondyloarthritis.
Keywords: Arthritis, acute and chronic, outcome reactive
| Introduction|| |
Reactive arthritis (reA) is one subset of spondyloarthritis (spA) that has received less attention in rheumatology research lately. Contrary to beliefs of declining incidence with earlier management of gut and urinary infections with antibiotics, it continues to be a problem in the developing world. Recent observations suggest regional differences in triggers and outcomes.
A diagnosis of definite reA depends on a formal demonstration of the underlying pathogen. However, since the infection precedes arthritis, presentation to the rheumatologist occurs much later most of the times. The underlying trigger has resolved by then, and it is too late to initiate an investigation. Thus, the diagnosis of reA remains a challenge not only due to the timeline of events, but also the high cost and poor availability of polymerase chain reaction (PCR) assays at most centers in the developing world. For postenteric reA, serological tests such as immunoglobulin A antibodies against gut pathogens can be positive in up to 80% of the general population due to the high background prevalence of gut infections in India, limiting use for diagnosis.
Furthermore, despite investigations, an etiological agent could be identified in 50%–63% cases in most studies, outside a point source epidemic situation., The scenario is worse in children, with no formal definition of reA in the ILAR criteria. Thus, the history of an antecedent symptomatic infection is thought to be most relevant for a diagnosis of ReA.
Courcoul et al. described that 15% of cases of reA progress to chronicity even in the current decade. In a population of 1.3 billion, with an incidence of 0.6–27/100,000 in population-based studies, a high burden of reA is expected in India. Unfortunately, global research on the disease is in decline, and data on chronic forms of the disease are virtually nonexistent. Thus, we studied the clinical profile in acute reA and compared them with chronic reA.
| Methods|| |
Patients with reA (Braun's criteria or as per the consensus of at least two rheumatologists) assessed at the department of clinical immunology and rheumatology between January 2019 and March 2020 with active symptoms, were enrolled in the Institutional Review Board certified study (IEC 2018-124-IMP-105). Clinical details and laboratory parameters were recorded on a prespecified case record form designed for another study (supplementary file 2). A 44 Tender joint/44 swollen joint count and 15 enthesitis count was done (SF-2). The Maastricht Ankylosing Spondylitis enthesitis index (MASES), Leeds enthesitis index (LEI), and spA Research Consortium of Canada (SPARCC) enthesitis indices were assessed. Dactylitis was defined as a sausage-shaped swelling of fingers or toes. Dactylitis was defined as acute if the digit was tender and erythematous or chronic if swollen but asymptomatic digit. Patients with age <16 were classified as juvenile reA. Inflammatory back pain (IBP) was defined as low back pain with morning stiffness for more than 7 days. Patients presenting within 6 months of the onset of symptoms were classified as inception and the rest as a prevalent cohort.
DNA extraction was done as previously described and HLA-B27 was assessed using amplification refractory mutation PCR., Sacroiliitis was defined as those meeting the New York radiological criteria (bilateral Grade 2 sacroiliitis OR unilateral Grade 3 sacroiliitis) for ankylosing spondylitis.,
In both adults and children, non-steroidal anti-inflammatory drugs (NSAIDs) with or without intra-articular steroids were thefirst line of therapy. Anti-tumor necrosis factors and conventional synthetic disease-modifying antirheumatic drugs were advised in the event of persistent disease at 3 months despite two or more NSAIDs, with the latter being preferred when thefirst failed or could not be given for any reason.
Data are presented as numbers (percentage) for qualitative variables and as median (interquartile range) for quantitative variables. Statistical analysis was done using IBM SPSS version 20 for Windows PC [BM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp]. Qualitative variables were compared by the Chi-Square test (Fisher's test where appropriate), and quantitative variables by the Mann–Whitney U test, with P ≤ 0.05 as the threshold of statistical significance.
| Results|| |
Clinical characteristics of the cohort
Sixty-eight patients (41 inception and 27 prevalent) of reA of age 26 years (18–34, M:F 5.8:1) and episode duration 36 days (19–60 days) were enrolled. There was a total of 6 (8.8%) pediatric cases in our cohort. The median duration of illness and time from infection to arthritis in the chronic cohort was 4 (2–12) years and 9 (5–29) days, respectively. All fulfilled Braun's criteria for reA in the current episode, apart from seven cases [Supplementary Table 1].
Enteritis was the most common preceding trigger (37, 54%), followed by genitourinary infection (25, 36%), irrespective of gender. Gut infections triggered all cases of juvenile-onset reA. A family history of related disorders of the spA spectrum was seen in 10.5% (psoriasis 4.5% and undifferentiated spA 6%). Of the total of 27 cases in the prevalent cohort, 19 had a relapsing course while eight had a chronic course. Cases in the prevalent cohort had a median of two episodes in the past (1–4.5), with 60% having two or more flares.
Arthritis occurred in most (95%) cases, oligoarthritis (55%) being the most common pattern. Knee (88%) arthritis was seen in most, followed by the ankle (38%), midtarsal, elbow, wrist (10%), and small joints of the hands (2%–4%).
Nearly one-third had enthesitis (33%), tibial tuberosity being the most common (34%). However, dactylitis (14%) and IBP (25%) were less frequent.
Pelvic radiographs suggested sacroiliitis in 19% of patients.
Conjunctivitis and circinate balanitis were the most common extra-articular spA manifestations (8% each). Other cutaneous manifestations included psoriasiform skin lesions (4.5%), oral ulcers (3%), and genital ulcers (1.5%). Uveitis was seen in four patients, of which, in one case, it preceded the development of arthritis. Urethritis was seen in two patients with enteritis-triggered reA and one patient with genitourinary-related reA.
Comparisons between the clinical, radiographic, and laboratory features of the inception and prevalent cohort.
Total enthesitis (20 vs. 3) as well as MASES and SPARCC indices were higher in the inception group (P = 0.018, 0.03, 0.001). Mucocutaneous and ocular involvement was seen only in the inception cohort. None of the patients of chronic reA had extra-musculoskeletal features accompanying the disease flares. Musculoskeletal and extra-articular features of the acute and chronic cohort were comparable except for increased enthesitis in the acute cohort [Figure 1] and [Figure 2] Equal numbers of inception and prevalent cohort had sacroiliitis.
|Figure 1: Consistent manifestations of reactive arthritis: Arthritis and sacroiliitis|
Click here to view
|Figure 2: Comparison of musculoskeletal features of acute and chronic cohort of reactive arthritis|
Click here to view
The clinical profile was similar in children as compared with adults [Supplementary Table 2], and in the cases with urethritis and enteritis triggers [Supplementary Table 3].
HLA B27 was detected in 75% (37/49) patients with positivity of 76% (32/42) in males and 71% (5/7) in females.
Clinical profile in adults
Sixty-two patients (35 inceptions and 27 prevalent) of reA of age 26 years (19–34, M: F 6.7:1) and episode duration 36 days (17–64 days) were enrolled. The median duration of illness and time from infection to arthritis in the chronic cohort was 4 (2–12) years and 9 (5–29) days, respectively. All fulfilled Braun's criteria for reA in the current episode, apart from seven cases [Supplementary Table 1].
Enteritis was the most common preceding trigger (31, 50%), followed by genitourinary infection (25, 40%), irrespective of gender. A family history of related disorders of the spA spectrum was seen in 9.7% (psoriasis 3.2% and undifferentiated spA 6.5%). Of the total of 27 cases in the prevalent cohort, 19 had a relapsing course while eight had a chronic course. Cases in the prevalent cohort had a median of two episodes in the past (1–4.5), with 60% having two or more flares.
Arthritis occurred in most (95%) cases, oligoarthritis (55%) being the most common pattern. Knee (87%) arthritis was seen in most, followed by the ankle (37%), elbow, wrist (10%–11%), and small joints of the hands (3%–5%).
Nearly one-third had enthesitis (32%), tibial tuberosity being the most common (35%). However, dactylitis (14%) and IBP (24%) were less frequent.
Pelvic radiographs suggested sacroiliitis in 16% of adults.
Conjunctivitis was the most common extra-articular spA manifestations (8%). Other cutaneous manifestations included circinate balanitis (6.5%), oral ulcers (6.5%), psoriasiform skin lesions (4.8%), and genital ulcers (1.6%). Uveitis was seen in three patients (4.8%), of which, in one case, it preceded the development of arthritis. Urethritis was seen in four patients (6.5%). Total enthesitis as well as MASES and SPARCC enthesitis index was higher in the acute cohort. The other clinical and laboratory parameters were comparable between the acute and chronic groups amongst adult patients [Table 1].
Clinical profile in children
Six patients (all inception) of juvenile reA of age 14 years (10.75–15, M:F 4:2) and episode duration 33 days (18–44 days) were enrolled. All fulfilled Braun's criteria for reA in the current episode. Gut infections triggered all cases of juvenile-onset reA. A family history of Psoriasis was seen in one patient.
Arthritis was present in all cases with oligoarthritis (50%) being the most common pattern. Knee, ankle, and wrist were the affected joints, involved in 100%, 50%, and 16% cases, respectively. Enthesitis was seen in 50% of patients while dactylitis was present in 16%. Two cases of juvenile reA complained of inflammatory back pain.
Pelvic radiographs in two cases suggested sacroiliitis in 40% (2/5). Both were male patients of 15 years of age.
Conjunctivitis and circinate balanitis were present in 33% and 16% of juvenile reA cases.
The clinical profile in children was comparable to that in adults [Supplementary [Table 2].
Follow-up of inception cohort
Eighty-five percent (35/41) of patients in the inception cohort were followed up for a median period of 8 months (6–12) up till June, 2020, either through outpatient visits or telephonically. At 6 months, 72% (21/29) patients were in remission and 27% (8/29) were off treatment. At the time of the last assessment, 72% (24/33) were in remission and 42% (14/33) were off treatment. At the time of last visit, 14 patients were on NSAID only, 4 patients were on sulfasalazine and one patient was on weekly methotrexate. A lower MASES index at baseline was associated with remission at 6 months (P = 0.02). A lower LEI index also showed a trend to remission at 6 months (P = 0.05). However, there were no predictors of remission at last visit.
| Discussion|| |
This study describes the clinical profile of 68 patients with reA. Gastrointestinal infections were the prime inciting event, and one in 10 cases did not have antecedent infections despite a strong clinical suspicion of reA. One in five had sacroiliitis and fulfilled the New York criteria at inception. Cases in the prevalent cohort had a lower incidence of enthesitis than those enrolled at inception.
The male predominance and pattern of arthritis were consistent with previously reported literature. reA occurred at a younger age (26 years) compared to the previous hospital-based, population based as well as point-source epidemic studies (34–54 years)., This could be attributed to the higher burden of gut infection in India, which individuals are exposed to from childhood itself. Besides the trigger (all pediatric cases being of enteric origin), there were no clinical differences between children and adults with the disease.
Infectious triggers in reA vary with the geographic location, of which urethritis is reportedly more common. However, more than half the cases had gastrointestinal illness in the current series., While chlamydial infections dominate in studies employing genitourinary or synovial PCR, gut infections are most often due to Salmonella More Details typhimurium. Interestingly, two patients, in whom urethritis preceded arthritis, were on treatment with intra-vesicular Bacillus Calmette-Guerin (BCG) for bladder carcinoma. An increased incidence of polyarthritis and involvement of the small joints of the hand has been seen in BCG-related reA., A similar presentation was seen in one of the two patients in this cohort as well.
Unfortunately, a lack of symptomatic triggering infections is common, especially in chlamydia urethritis and Yersinia More Details-related gastrointestinal infections. Despite detailed laboratory testing, the infectious trigger is identifiable in only 50% to 63% cases using available tools., Circinate balanitis and conjunctivitis could be diagnostic in some instances with a missed history of preceding infection, where uspA is otherwise suspected. These were also the most common extra-articular features in the current study.
Oligoarthritis involving the knee and ankles was the most common pattern as expected, though one in three cases manifested with monoarthritis alone. Arthritis of the hand joints is reported in nearly half of Chlamydia-induced reA. However, in our cohort, hand involvement was seen in <10% cases.,
Sacroiliitis was seen in 20% in the inception cohort and 12% in the prevalent cohort [Figure 1] compared to 10% (2/20) at inception and 34% (15/44) in the prevalent cohort in an earlier study. For Yersinia-triggered reA, 21% of acute cases reportedly have sacroiliitis on pelvic radiographs. The spA spectrum is known to have deep pathogenic links with gut inflammation, which can be silent for almost a decade before the diagnosis. Previously, we have seen in an adult cohort of AS, nearly 40% reported thefirst symptoms onset in childhood. Thus, it seems plausible that the disease goes undetected for a few years. An earlier exposure to gut infections may be the forerunner to earlier sacroiliitis in the Indian population. This may also explain a higher prevalence of ERA among the various subsets of jIA in the Indian population. Microscopic gut inflammation is seen in up to 60% of patients with spA. Whether an earlier exposure to gut infections leads to early sacroiliitis in Indian patients with reA is a hypothesis that merits further exploration. However, ours being thefirst study to demonstrate this, it may be validated in larger multicentric epidemiologic studies while the cause is investigated by in animal andin vitro experiments.
This is thefirst hospital-based series that describes the characteristics of chronic and relapsing reA. Previously short studies of acute cohorts and longer follow-ups from point-source epidemics of post Salmonella typhimurium reA have provided some insight into the natural history of the disease., Thompson et al. reported chronic and relapsing symptoms in nearly two-thirds after a Salmonella triggered reA. A higher enthesitis index (MASES and LEI) at baseline predicted the persistence of symptoms at 6 months highlighting that the burden of enthesitis at baseline is an important predictor of the development of chronic reA. We found a lower prevalence of enthesitis in those with the long-standing disease. Besides, the lower enthesitis scores (both SPARCC and MASES) raises the case for a more significant number of these patients being classified as axial spA. The boundaries between axial and peripheral spA are increasingly blurred, with the emerging evidence from clustering analysis of large data sets. Zeidler et al. have suggested that future classification sets should include information on infectious triggers, as reA can be the missing link in studies on spA. This is of greater relevance given that geographic regions outside of Europe display a higher prevalence of reA.
This study describes the common and oft-forgotten subset of spA that is often encountered in rheumatology clinics in the developing world. This assumes larger importance in light of the emerging concept of a unified clinic-pathologic spectrum of spA., It also had the advantage of being a hospital-based study assessing patients while they were symptomatic, unlike most previous studies, which relied on retrospective case records for data collection., A limitation of the study was that the radiographs were assessed by only one person. Another limitation was that majority of the patients were followed up telephonically thus assessment was based mainly subjective. While defining the widely varied clinical spectrum despite stringent diagnostic criteria, it offers a glimpse into the chronic nature in a subset of patients, while building the case for a large-scale assessment of this entity.
| Conclusion|| |
The occurrence of reA in adults, as well as children, continues to require care at a tertiary center in India. The chronic nature of the disease and a high prevalence of radiographic sacroiliitis warrants a review of the perception that it is a self-resolving disease. There is a pressing need to recognize early predictors of poor outcome and revise therapeutic strategies addressing the same.
Financial support and sponsorship
This study was funded by an intramural grant awarded to LG.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Misra R, Gupta L. Epidemiology: Time to revisit the concept of reactive arthritis. Nat Rev Rheumatol 2017;13:327-8.
Courcoul A, Brinster A, Decullier E, Larbre JP, Piperno M, Pradat E, et al
. A bicentre retrospective study of features and outcomes of patients with reactive arthritis. Joint Bone Spine 2018;85:201-5.
Brinster A, Guillot X, Prati C, Wendling D. Evolution over thirty years of the profile of inpatients with reactive arthritis in a tertiary rheumatology unit. Reumatol Clin 2018;14:36-9.
Braun J, Kingsley G, van der Heijde D, Sieper J. On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th
International Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999. J Rheumatol 2000;27:2185-92.
Hannu T. Reactive arthritis. Best Pract Res Clin Rheumatol 2011;25:347-57.
Kaeley GS, Eder L, Aydin SZ, Gutierrez M, Bakewell C. Dactylitis: A hallmark of psoriatic arthritis. Semin Arthritis Rheum 2018;48:263-73.
Gupta L, Bhattacharya S, Agarwal V, Aggarwal A. Elevated levels of serum MRP8/14 in ankylosing spondylitis: Associated with peripheral arthritis and active disease. Clin Rheumatol 2016;35:3075-9.
Tonks S, Marsh SG, Bunce M, Bodmer JG. Molecular typing for HLA Class I using ARMS-PCR: Further developments following the 12th
International Histocompatibility Workshop. Tissue Antigens 1999;53:175-83.
Linden SV, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. Arthritis Rheum 1984;27:361-8.
Leirisalo-Repo M, Suoranta H. Ten-year followup study of patients with yersinia arthritis. Arthritis Rheum 1988;31:533-7.
Mason E, Wray L, Foster R, Jamil MS, Guy R, McNulty A, et al
. Reactive arthritis at the Sydney Sexual Health Centre 1992-2012: Declining despite increasing chlamydia diagnoses. Int J STD AIDS 2016;27:882-9.
Townes JM, Deodhar AA, Laine ES, Smith K, Krug HE, Barkhuizen A, et al
. Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: A population-based study. Ann Rheum Dis 2008;67:1689-96.
Uotila TM, Antonen JA, Paakkala AS, Mustonen JT, Korpela MM, Pirkanmaa Waterborne Outbreak Study Group. Outcome of reactive arthritis after an extensive Finnish waterborne gastroenteritis outbreak: A 1-year prospective follow-up study. Clin Rheumatol 2013;32:1139-45.
Thomson GT, DeRubeis DA, Hodge MA, Rajanayagam C, Inman RD. Post-Salmonella
reactive arthritis: Late clinical sequelae in a point source cohort. Am J Med 1995;98:13-21.
Colmegna I, Cuchacovich R, Espinoza LR. HLA-B27-associated reactive arthritis: Pathogenetic and clinical considerations. Clin Microbiol Rev 2004;17:348-69.
Tinazzi E, Ficarra V, Simeoni S, Artibani W, Lunardi C. Reactive arthritis following BCG immunotherapy for urinary bladder carcinoma: A systematic review. Rheumatol Int 2006;26:481-8.
Bernini L, Manzini CU, Giuggioli D, Sebastiani M, Ferri C. Reactive arthritis induced by intravesical BCG therapy for bladder cancer: Our clinical experience and systematic review of the literature. Autoimmun Rev 2013;12:1150-9.
Zanwar A, Gupta L, Misra R. Balanitis circinata. Eur J Rheumatol 2018;5:285-6.
Khan MA. Update on spondyloarthropathies. Ann Intern Med 2002;136:896-907.
Leirisalo-Repo M, Helenius P, Hannu T, Lehtinen A, Kreula J, Taavitsainen M, et al
. Long-term prognosis of reactive Salmonella
arthritis. Ann Rheum Dis 1997;56:516-20.
Kunjir V, Venugopalan A, Chopra A. Profile of Indian patients with juvenile onset chronic inflammatory joint disease using the ILAR classification criteria for JIA: A community-based cohort study. J Rheumatol 2010;37:1756-62.
Mielants H, Veys EM, Cuvelier C, De Vos M, Goemaere S, De Clercq L, et al
. The evolution of spondyloarthropathies in relation to gut histology. II. Histological aspects. J Rheumatol 1995;22:2273-8.
Sepriano A, Ramiro S, van der Heijde D, van Gaalen F, Hoonhout P, Molto A, et al
. What is axial spondyloarthritis? A latent class and transition analysis in the SPACE and DESIR cohorts. Ann Rheum Dis 2020;79:324-31.
Zeidler H, Hudson AP. Reactive arthritis, a missing link: comment on the recent article from Sepriano et al
. Ann Rheum Dis 2020;annrheumdis-2020-217326.
[Figure 1], [Figure 2]