Concurrence of Rheumatoid Arthritis and Ankylosing Spondylitis: Analysis of Seven Cases and Literature Review

Introduction The association of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in a single patient is a rarely described phenomenon. AS and RA are conditions that can have a high impact on the morbidity and mortality of patients. Methods We described the clinical, epidemiological, analytical, and radiological characteristics of 81 patients with concomitant diagnosis of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Of these patients, seven were diagnosed at our hospital. A literature review was carried out using Medline, Embase, Scopus, and virtual hospital libraries, including the period from January 1950 to April 2020. Results Regarding the results, 71% of the patients were men, with a mean age of 53 years (±14.83). RA was the first disease diagnosed in 52% of the cases. Approximately 53% of the patients had rheumatoid nodules, and 83% reported inflammatory lumbar pain during their evaluation. Erosions were observed on radiographs of the hands and/or feet in 85% of the cases, and almost all the patients (80/81) had sacroiliitis on imaging studies. Approximately 92% of the cases were rheumatoid factor (RF) positive and 90% HLA B-27 positive. Conclusions The coexistence of RA and AS is highly uncommon. With the data obtained in this review, it seems that there exist erosive radiological patterns, positivity for RF, involvement of the axial skeleton, and rheumatoid nodules at a higher frequency than those patients with a single diagnosis of the two entities. More data are needed to corroborate this association.


Introduction
e association of rheumatoid arthritis (RA) and ankylosing spondylitis (AS) in a single patient is a rarely described phenomenon [1]. AS and RA are conditions that can have a high impact on both the quality of life and the morbidity and mortality of patients [2][3][4]. Initially, both diseases can manifest similar clinical symptoms such as morning stiffness, pain of an inflammatory nature, and arthritis [2][3][4]. For this reason, in a patient with RA and axial affectations or a patient with AS and symmetric peripheral joint affectations, it is advisable to extend the study to determine if there is a concurrence of these two diseases [4]. Until the 1970s, both processes were not fully distinguishable from one another; however, the discovery of HLA B-27 and its association with AS marked a turning point.
RA is a disease that predominantly affects women, with a prevalence of 0.5-1% and a typical clinical presentation consisting of symmetric polyarthritis and small joints, with the axial skeleton usually remaining unchanged [1]. In contrast, AS is a disease that predominantly affects male, with a prevalence of 0.1-0.2%, whose main clinical manifestation is inflammatory axial pain and which can manifest with peripheral arthritis in up to 30% of cases (mainly asymmetric and in the lower limbs) [3]. e exact incidence of the coexistence of both diseases in the same person is unknown. However, according to published data, it is estimated that it oscillates between 1 in 500,000 and 1 in 2,000,000 [3,4]. Up until 1995, approximately 44 cases [3,4] had been recorded, with a number of discrepancies existing in the literature review; however, the research here presented describes 81 cases (including 7 from our own center).

Methods
e RA database of our center (658 patients) was reviewed beginning with the first diagnosis of the association between RA and AS. A total of 18 HLA B-27+ patients were selected. Of these, 7 met AS classification criteria [5] and, as a result, were evaluated by the same physician in person on a single occasion, after having signed the informed consent form.
Subsequently, a literature review was carried out (including the period from January 1950 to April 2020) using the following terms: rheumatoid arthritis, ankylosing spondylitis, coexistence and/or concomitance, and/or association and/or concurrence. A total of 42 articles were obtained, of which 35 were selected (in 7 of them, this association was not adequately described or they were nonspecific population studies). e search platforms used were PubMed, Medline, Embase, Scopus, and virtual hospital libraries. All papers were considered regardless of language.

Statistical Analysis.
A descriptive analysis of the categorical variables was carried out using absolute and relative frequencies, and in the case of numerical variables, analysis was done through the mean and standard deviation or median and the 25th and 75th percentiles, according to compliance with the assumption of normality. Bivariate analysis was carried out using Student's t-test or the Mann-Whitney U test to contrast numerical variables, and the chi-squared test or Fisher's exact test was used to contrast the hypotheses of categorical variables, as appropriate. e significance level was set at 0.05, and all tests were two-tailed. e statistical package SPSS version 24 was used.

Results
81 patients were included in the study here presented. Of these, 74 were those detected in the literature review  and 7 from our center. Of the total number of cases, 58 were men (71%), with a mean age of 53 years (±14.83), and a mean age of the onset of the disease was 34 years (±14.87). RA was the first disease diagnosed in 52% of cases. e mean duration of the disease (RA or AS) up to the time of diagnosis was 18 years (±13. 16). e first symptom suffered was lower back pain in 48% (38/76), followed by arthritis in 46% (35/ 76) of the cases. 52% of the patients (38/73) had rheumatoid nodules, and 83% had suffered from inflammatory lower back pain at some point during their evaluation. Uveitis was detected in 13% of the patients (11/81). Extra-articular symptoms manifested in 18% (15/81), including 4 cases of Felty syndrome, most of which having manifested when conventional immunosuppressive therapy and/or biological therapy had not been available (Table 1).
Regarding imaging studies, spinal syndesmophytes were present in 73% of cases. 85% (65/76) presented erosions of the hands and/or feet in their radiographs. Radiological sacroiliitis was observed in almost all patients (80/81).
Regarding laboratory findings, RF was positive in 92% and, in 16 of 18 cases in which anti-CCP antibodies were quantified, these turned out to be positive. Finally, almost 90% of the patients were HLA B-27 positive ( Table 2). No difference was of statistical significance because the sample size was small. e treatment used was only carried out in 47 of the 81 cases. Of these, 83% had received a course of corticosteroids at one point in time. Nonsteroidal anti-inflammatory drugs were used in 59% of the cases. 25% of the patients were administered gold salts (with the last case being registered in 1995). Both hydroxychloroquine and sulfasalazine were used in 19% of the cases. With regard to methotrexate, there is evidence that the first patient was treated in 1993, with a total of 15 cases being treated. Anti-TNF-alpha therapy was used in 5 cases, in 2 of them infliximab and in another 2 adalimumab. Other less frequently used therapies were leflunomide, rituximab, D-penicillamine, azathioprine, and synoviorthesis (Table 3).

Discussion
In 1958, Wilkinson and Bywaters published a descriptive study of 222 patients with spondylitis that was carried out from 1940 to 1955 [36]. In one of the cases, a 55-yearold male patient was described as having symmetric arthritis, small joints, and subcutaneous nodules and was RF+. Later, in the evolution of his disease, he manifested typical AS symptoms, which at that time were diagnosed as "rheumatoid spondylitis." is appears to be the first well-documented case of the coexistence of RA and AS. Based on this description, approximately 81 cases have been published (including 7 cases from our center). It is a highly infrequent association in a single patient that is a diagnostic challenge due to the similarities that exist between both diseases, mainly from a clinical perspective [4]. It is likely that the coexistence of both processes in a single patient is underestimated, as shown in a study in 2017, where in 286,601 patients with RA, the association with other autoimmune processes was evaluated, observing that 1.16% of patients also manifested AS [1].
AS and RA are considered to be two independent diseases due to their clinical, genetic, pathogenic, and analytical differences [3]. at is why the probability of the coexistence of these two entities in the same patient is low. However, some authors suggest that the initial cause that acts as a trigger in both diseases may be the same [28].
ere are some different characteristics between each of these pathologies. For example, AS mainly affects the axial skeleton, and almost all patients report lower back pain with inflammatory characteristics, also associated with enthesitis. ese signs and symptoms are usually asymmetric, rarely involving the upper limbs [28]. Regarding patients with RA, joint involvement is fundamentally symmetrical,     [3,4]. Regarding HLA B-27, its role throughout the course of the disease is not clear in patients with RA and it can be positive in up to 9% of cases [31].
In addition, imaging studies provide findings that are more characteristic of one disease than the other. For example, in RA, the erosive pattern is frequent, mainly affecting the proximal interphalangeal and metacarpophalangeal joints, with a symmetrical distribution, while in AS, these findings are exceptional, classically presenting an asymmetric and nonerosive pattern. Finally, the discovery of radiographic sacroiliitis is uncommon in patients with RA [31].
In this review, the ratio of males to females was approximately 3 to 1. One explanation for this could be that in almost half of the patients, the initial disease was AS, an entity that, as is known, mainly affects men (1.34). In patients with arthritis, this was mainly symmetric and it displayed an erosive pattern (85%).
56% of patients manifested subcutaneous nodules, a figure higher than that of patients with RA and without AS, which is approximately 40% [2]. 13% of patients presented uveitis throughout their disease; this figure is usually 20-30% in patients with AS and without associated RA [4].
Another important finding to highlight was the presence of syndesmophytes, found in 74% of cases after radiological studies. ese last data are in accordance with the fact that the manifestation of AS plays a determining role in axial affectation when both entities coexist. 92% of the patients were RF+, and 90% were HLA B-27+. e previous statistic highlights the susceptibility of the patients' joints and puts into question the extent to which inflammatory rheumatic diseases have well-defined pathophysiological borders.
With regard to treatment, a lot of discrepancies still exist due to the emergence of new therapies such as diseasemodifying antirheumatic drugs (DMARDs) and biological agents. In this sense, it should be noted that 25% of the registered cases were treated with gold salts (a therapy currently in disuse in most countries). With the data presented, we do not know whether the association of both diseases conditions a resistance to the treatments currently available for both RA and AS.
With these data and as a summary, in young patients diagnosed with RA who present with extra-articular manifestations (such as uveitis) and clinical activity data in the axial skeleton, the coexistence of ankylosing spondylitis should be suspected and further studies should be carried out (mainly HLA B-27, X-rays of the dorsolumbar spine/ sacroiliac joints, and, where appropriate, MRI scans). Similarly, in patients with AS who manifest symmetric arthritis, mainly in the upper limbs, and with erosive lesions found in radiological studies, the possibility of a concomitant diagnosis of RA should be considered.
Regarding this work's weaknesses, the number of patients is limited, much of the published data is not very precise, and, in addition, the heterogeneity of the patients and the anachronism of the data make them difficult to analyze and, therefore, draw more precise conclusions.
Even so, to date, no other review exists that has been carried out in such an exhaustive manner. For this reason, we consider that its dissemination is important since it is likely that this association is being underestimated in clinical practice.  Case Reports in Rheumatology 5

Conclusions
e association of RA and AS is highly infrequent; approximately 81 cases have been documented to date. e data presented in this review suggest that this association confers different characteristics since, in most cases, the patients have an erosive radiological pattern, RF and anti-CCP antibody positivity, and involvement of the axial skeleton and more frequently exhibit cutaneous nodules relative to patients with an isolated diagnosis of one of the two entities. More research is needed to support this conclusion.

Conflicts of Interest
e authors declare that they have no conflicts of interest.