INTRODUCTION
Spondyloarthritis (SpA) is a heterogeneous group of chronic inflammatory rheumatic diseases. These diseases are characterized by various articular and extra-articular manifestations. According to the dominant involvement, we divide them into two groups: axial and peripheral SpA (1). Axial SpA (axSpA) primarily affects the spine and sacroiliac (SI) joints. According to the new classification of the European Alliance of Associations for Rheumatology (EULAR) axSpA is divided into non-radiographic form (nr-axSpA) and radiographic (r-axSpA) form with diagnostic delay, and the latter was previously called ankylosing spondylitis (AS) (2). A strong link between the tissue histocompatibility gene HLA B27 and the etiology of SpA is well-known (3). According to the classification criteria of the Assessment of SpondyloArthritis international Society (ASAS) HLA B27 is included as one of the significant characteristics of this group of diseases (4). There is a hypothesis that enthesitis is a precursor of pathophysiological events in SpA (5). The functional deficit of patients with SpA represents a burden not only for the patient but also for society as a whole (6).
The characteristic pathophysiological changes of axSpA are sacroiliitis and spondylitis, which cause inflammatory back pain, stiffness and fatigue, and are most often manifested in the third decade of life (7). In addition to the axial skeleton, root and peripheral joints, tendons (especially the Achilles tendon) and entheses can be affected. According to data obtained through research conducted in Great Britain in 2017, the incidence of axSpA is 8 per 100,000, and the prevalence is 15.8 per 10,000 (8). Making the diagnosis of axSpA is a challenging task, which leads to delays in diagnosis and timely treatment.
Nonsteroidal antirheumatic drugs (NSAIDs), glucocorticoids, conventional synthetic drugs that modify the course of the disease (disease-modifying antirheumatic drugs, DMARDs) and biologic and targeted synthetic DMARDs are used during treatment (1). Certain drugs that we use in the treatment of patients with SpA can cause changes in the semen analysis (spermiogram). It is a known fact that sulfasalazine (SSZ) can lead to reversible changes in semen parameters (9, 10). Long-term use of acetylsalicylic acid and, very rarely, NSAIDs, can have a reversible effect on semen quality (10).
Chronic inflammation due to axSpA can cause infertility in patients. It can have an effect on the libido and erectile function and lead to reduced testicular function (11, 12). A strong link was found between the underlying disease and semen quality (11).
CASE REPORT
A patient, who was born in 1984, came to the rheumatologist appointment presenting with symptoms of back pain, groin pain and chest pain. The symptoms are of an inflammatory nature, with a duration of over 3 years. The patient did not previously suffer from severe pain, he did not undergo surgery, and did not have children. There is no history of inflammatory rheumatic disease, psoriasis or infertility in the family. During the clinical examination, a slight trunk inclination was observed with an antalgic gait in the right leg. During palpation, there was pain in the left sacroiliac (SI) joint and after bending over the flexion arch of the lumbar spine was not formed. There was pain in the sternocostal entheses during palpation. Right hip movement was restricted and painful. The patient was referred for diagnostic treatment under suspicion of axSpA. HLA typing was done, according to the usual A, B and DR locus protocol. The patient had a positive HLA-B27 test. Serological findings for other rheumatic diseases (rheumatoid factor (RF), antinuclear antibodies (ANA)) were negative. Magnetic resonance imaging (MRI) was performed according to the protocol for SpA and, following that, chronic changes in the left sacroiliac joint and osteodegenerative changes in the right hip were confirmed along with areas of bone marrow edema of the femoral head and a reactively smaller amount of free fluid and synovial thickening. A diagnosis of HLA B27 positive nr-axSpA was made. NSAID therapy was initially introduced in an anti-inflammatory dose, but there was no significant therapeutic effect. Due to the symptomatology in the right hip area and the MR findings, the patient was referred to an orthopedist who recommended hip arthroscopy. Given that the clinical features also included involvement of peripheral joints, sulfasalazine (SSZ) was introduced into therapy with a gradual increase to a daily dose of 2 g. Biological therapy was planned, so additional pre-therapeutic diagnostic processing was performed. Five months after sulfasalazine (SSZ) was introduced into therapy, drug-induced infertility was suspected. Semen analysis (spermiogram) and endocrinological examination were not routinely performed before the basic therapy was introduced. According to the protocol, the diagnostic treatment of infertility included a semen analysis (spermiogram), hormone testing (sex hormones, thyroid stimulating hormone, TSH) and testicular ultrasound. The semen analysis findings showed signs of oligoasthenozoospermia with the following characteristics: reduced absolute sperm count (9.95 — ref. int. > 39 million/ml), reduced sperm concentration (2.94 — ref. int. > 15 million/ml), reduced sperm motility percentage (17 — ref.int. > 40%), reduced percentage of progressively motile sperm (17 — ref.int. > 32%) and immotile sperm result: 83/ml. No abnormalities were found in other findings. It is a known fact that sulfasalazine (SSZ) can cause reversible oligospermia, so the aforementioned drug was discontinued, and therapy was continued with NSAIDs. At the control semen analysis (spermiogram), which was performed three months after the discontinuation of sulfasalazine (SSZ), all of the semen parameter findings were completely normal. In the further course of treatment, certolizumab pegol was introduced into therapy, but it was discontinued at the first evaluation control due to primary ineffectiveness. The patient stopped coming for check-ups, so the further course of the disease is unknown.
DISCUSSION
The causes of infertility in men suffering from SpA are multifactorial. They are related to the underlying disease, drug therapy and other urological, endocrinological and genetic causes. Chronic systemic inflammation can have an effect on the libido and erectile function (11). Research shows that patients suffering from AS have reduced sperm motility, elevated values of luteinizing and follicle-stimulating hormone, and decreased serum testosterone levels compared to healthy individuals (11). Long-term AS leads to impairment of the patient’s sexual activity both due to reduced sexual desire and functional deficit due to the ongoing disease (11). According to a study conducted by Almeida BP et al., varicoceles are frequent in patients with AS and they occur in as many as 40% of patients (13). Their clinical significance should be assessed and then treated accordingly (14).
Most studies on the effects of sulfasalazine (SSZ) on fertility were conducted on patients suffering from inflammatory bowel diseases (15, 16). The mechanism of toxicity of sulfasalazine (SSZ) on infertility is unknown (10, 15). The assumption is that the active metabolite, sulfapyridine, leads to oxidative stress with consequent effects on semen quality (10, 15). The use of sulfasalazine (SSZ) in the period longer than 2 months leads to reversible changes in semen parameters (10, 16). Research shows that improvement in semen parameters and fertility is achievable if sulfasalazine (SSZ) is changed to another salicylate derivative, without sulfapyridine, such as mesalazine (17-19).
Long-term use of acetylsalicylic acid, and, very rarely NSAIDs, can reversibly affect the semen quality and lead to a decrease in the sperm count and change in sperm motility, vitality and morphology (10). The toxic effects of drugs depend on their dosage (10). Research shows that treatment with inhibitors of tumor nephrotic factor alpha (anti-TNFα) leads to a decrease in the activity of the underlying disease and consequently to an improvement in semen parameters (20). The safety of short-term and long-term use of anti-TNFα in testicular function has also been proven (11, 20).
CONCLUSION
In this paper we present the case of a patient suffering from nr-axSpA, who was treated with sulfasalazine (SSZ) and developed drug-induced reversible oligospermia. When treating patients with SpA in fertile age, it is important to routinely monitor sexual function and implement the process of family planning (21). The possible effect of sulfasalazine (SSZ) on semen parameters should also be kept in mind. If there is information or suspicion about infertility, it is necessary to do an evaluation of sex hormones, a semen analysis (spermiogram) and testicular ultrasound (11). Improvement of reproductive health is achieved by treating the underlying disease, in addition to comprehensive patient counseling and a multidisciplinary approach.
Acknowledgments: The authors report no acknowledgments.
Funding: For this work authors did not receive any funding.
Conflict of interest statement: The authors declare no conflict of interest.