Ankylosing Spondylitis: a Case Report

Introduction: Ankylosing spondylitis is a chronic inflammatory disorder which primarily affects the axial skeleton, the major characteristic of the disease being the early involvement of the sacroiliac joints. The condition manifests by chronic inflammatory back pain and, as the disease progresses, patients will develop extreme impairment of spinal mobility because of spinal fusion. Case presentation: A 66-year-old man, diagnosed with HLA-B27-positive ankylosing spondylitis, permanent atrial ﬁ brillation, ischemic cardiac disease, arterial hypertension, type 2 diabetes mellitus and stage 3A chronic kidney disease, was admitted for cervicalgia radiated to both shoulders and bilateral mechanical gonalgia. His son was also diagnosed with ankylosing spondylitis at the age of 29 years. Regarding the history of ankylosing spondylitis treatment, initially, the patient was prescribed nonsteroidal antiinflammatory drugs (NSAIDs); because of the inadequate response to NSAIDs, biological therapy with an anti-TNF agent was initiated (Infliximab). Fifteen months after the initiation of Infliximab, the patient presented with worsening symptoms; an-ti-Infliximab antibodies were detected, therefore he was switched to another anti-TNF agent, Adalimumab. Upon current admission, the clinical examination revealed thoracic kyphosis and marked limitation of cervical and lumbar spine mobility. Blood tests revealed mild anemia, inflammatory syndrome and azotate retention. The pelvic X-ray showed grade 3-4 bilateral sacroiliitis. The continuation of treatment with Adalimumab and Sulfasalazine was decided, with close monitoring of the patient. Conclusions: Ankylosing spondylitis is a multisystem inflammatory disorder, whose natural course includes periods of flares and remission. The peculiarity of this case consists in the early development of anti-Infliximab antibodies (secondary non-responder).

hritis was analysed 6 ; in the AS group, the HLA-B27 frequency was 72.1%, similar to that found in several regions in the Mediterranean area 6 (Table 1).
Multiple etiological factors have been shown to be involved in AS: genetic background, immune reaction, microbial infection, endocrine factors 4 .
Th e critical role genetic factors play in the genesis of AS is already known 7 . Hereditary factors were fi rst confi rmed within families in a scientifi c paper published in 1961 by De Blecourt et al 8 . Twin studies have showed that there is a signifi cantly higher similarity between monozygotic twins (63%) than dizygotic twins (23%). One of the most important genetic factors is major histocompatibility complex (MHC) class I allele HLA-B27; 90-95% of AS patients are HLA-B27 positive, while 1-2% of HLA-B27-positive populations develop AS 9 . However, studies have shown that the overall contribution of HLA-B27 to AS heritability is only 20%, thus suggesting that other genetic factors contribute to the genesis of AS, some of which are HLA-B7, HLA-B16, HLA-B35, HLA-B38, as well as several non-MHC nonsynonymous single nucleotide polymorphisms 10 .
AS is related to a number of autoimmune diseases, including infl ammatory bowel disease, psoriasis and anterior uveitis, indicating that these diseases may share a common genetic basis and immunological processes with AS.
Microbial infection acts as a triggering factor for the host innate immune system and AS development. Placed in a germ-free environment, HLA-B27 transgenic rats failed to develop features of SpA. Th is changed when commensal bacteria were introduced into the germ-free models, suggesting possible interactions between HLA-B27 and the microbiome 11,12 .

INTRODUCTION
Spondyloarthritis (SpA) is a potentially disabling form of chronic infl ammatory arthritis and has been classifi ed as axial spondyloarthritis (axSpA) and peripheral SpA 1 . Ankylosing spondylitis (also named radiographic axial spondyloarthritis) represents a subtype of axial spondyloarthritis, characterized by signifi cant abnormalities of aff ected sacroiliac joints at conventional radiography. Ankylosing spondylitis (AS) is an infl ammatory rheumatic disease with a heterogeneous clinical presentation. Th e term 'ankylosing' is derived from the Greek word "ankylos", which means stiff ening of a joint, and "spondylos", which means vertebra. Th e main symptom of the disease is chronic infl ammatory back pain, accompanied by morning stiff ness, which improves with exercise 2 . It is often associated with one or more articular lesions, including synovitis, enthesitis, and dactylitis, as well as extra-articular manifestations such as uveitis, psoriasis, infl ammatory bowel disease, cardiovascular involvement 3 . Th e disease is more frequently encountered in men, the mean age of onset being between 20 and 30 years 1 .
ankles and still elevated serum levels of infl ammatory markers (ESR 46 mm/h, CRP 26.7 mg/L); treatment with Sulfasalazine and Infl iximab (5 mg/kg iv at 0, 2 and 6 weeks, and then every 6-8 weeks) was prescribed. In February 2015, the patient presented for reevaluation; the clinical examination, as well as laboratory tests (ESR 18 mm/h, CRP 2.6 mg/L), showed an adequate response to Infl iximab therapy.
In December 2015, the patient was hospitalized for another ankylosing spondylitis fl are-up. High levels of infl ammatory markers (ESR 20 mm/h, CRP 17.16 mg/L) were noted and anti-Infl iximab antibodies were detected, therefore the patient was switched to treatment with Adalimumab (40 mg subcutaneously every two weeks) and Sulfasalazine (500 mg x5/day).
In October 2016, the patient presented for clinical and biological reevaluation. Infl ammatory markers were within normal range (ESR 15 mm/h, CRP 3.07 mg/L).
Upon current admission, the osteo-articular examination revealed thoracic kyphosis, marked limitation of cervical and lumbar spine mobility and also restriction of the thoracic cavity expansion. Th e occiput-to-wall distance was 29 cm, the tragus-acromion distance was 17 cm, the chin-to-chest distance was 10 cm, the fi nger-to-fl oor distance was 37 cm, Schober = 1cm, chest expansion=1 cm (Figures 1-6). Th e electrocardiogram revealed atrial fi brillation with a heart rate of 70 beats/ min. Th e pelvic X-ray showed grade 3-4 bilateral sacroiliitis ( Figure 7). 13,14 .

CASE PRESENTATION
In February 2017, a 66-year-old male patient presented for cervicalgia radiating to the thoracic spine and both shoulders, associated with morning stiff ness that lasted more than 2 hours, which improved with mobility or exercise, and bilateral mechanical gonalgia. Th e symptoms gradually intensifi ed over the last 7 days. His past medical history included HLA-B27-positive ankylosing spondylitis (diagnosed in 1996), permanent atrial fi brillation treated with beta-blockers and oral anticoagulant, ischemic heart disease, chronic heart failure NYHA class II, arterial hypertension, type 2 diabetes mellitus and stage 3A chronic kidney disease. Th e patient's son was diagnosed with ankylosing spondylitis at the age of 29 years.
In 1996, the patient presented low back infl ammatory pain, alternating buttock pain and lumbosciatica; based on clinical and paraclinical investigations, the diagnosis of HLA-B27-positive ankylosing spondylitis was established. Treatment with Indomethacin (150 mg/day) and Sulfasalazine was initiated, interrupted after 3 months. In June 2014, the patient presented with important tumefaction of the knees and ankles and infl ammatory syndrome (ESR 60 mm/h and CRP 145.3 mg/L). Sulfasalazine, along with Diclofenac, were prescribed. In September 2014, the patient returned to the hospital with persistent tumefaction of both knees and

DISCUSSION
Th e clinical picture of AS is initially dominated by persistent infl ammatory lumbosacral pain, associated with restricted range of motion of the lumbar spine and later on by the limitation of the thoracic cavity expansion, along with imaging fi ndings of sacroiliitis 15 . AS can be diagnosed based on clinical, laboratory and imaging fi ndings that are characteristic for axial spondylarthritis 3 . Th e fi rst classifi cation criteria for AS were debated in 1963, at the European Congress of Rheumatology in Rome 16 . In 1966, 2 elements (uveitis and thoracic pain) were removed from the criteria, because of low specifi city and sensitivity. New York criteria were modifi ed in 1984 (Table 2) by using infl ammatory back pain components reported by Calin et al 17 .
Th e positive diagnosis of AS can be established if at least one clinical criteria (infl ammatory back pain, limitation of lumbar spine or limitation of chest expansion) plus radiologic criteria (bilaterally grade 2 or unilateral grade 3-4 sacroiliitis) are fulfi lled. Th ese criteria have high specifi city but low sensitivity, as they cannot be used for the early diagnosis of AS 15 . Both the restricted motion of the lumbar spine and the limitation of the thoracic cavity expansion are elements that are not initially present. Also, in the early stages of the disease, sacroiliitis may not be visible on the X-ray and it may take up to 9 years to be identifi ed on pelvic X-ray. Th erefore, in patients with early/pre-radiographic phase of AS, when there is clinical suspicion of sacroiliitis, Paraclinical investigations showed a good response to Adalimumab. Th e patient was discharged and the continuation of treatment with Adalimumab and Sulfasalazine was recommended, along with antihypertensive, anticoagulant and anti-arrhythmic therapy.    tion of social participation 20 . Th e initial treatment for most patients with AS includes a series of nonpharmacologic (Table 3) measures and nonsteroidal antiinfl ammatory drug (NSAID) therapy.
In most patients diagnosed with axial SpA who are symptomatic, NSAIDs are recommended as initial therapy. Th e NSAIDs have been considered the cornerstone of pharmacologic intervention for AS since 1949, when phenylbutazone was available for use 21 . It takes about 1-2 weeks for an NSAID to reach an optimal eff ect, but sometimes a longer treatment period is required in order to determine the best drug option and the adequate dose. Once an NSAID has been determined to be eff ective within two to four weeks, then it is used on demand, according to symptoms; some patients require ongoing daily therapy to maintain the benefi t 20 . In patients who have an inadequate response to initial therapy with two diff erent NSAIDs used consecutively in an optimal dose for at least two to four weeks each, tumor necrosis factor (TNF)-alpha inhibitors represent the next line of treatment in patients with AS, any of them being an acceptable option 21 (Table 4).
Th e clinical response is usually rapid. Th e number needed to treat (NNT) in order to achieve a partial remission is estimated to be from 2.3 to 6 22 . However, some patients may experience an inadequate response (failure) to Infl iximab therapy, which can be either computed tomography or magnetic resonance imaging of the sacroiliac joints should be obtained 16 .
Regarding the diff erential diagnosis of AS, the major entities that should be considered are lumbar strain or muscle spasm, which has an acute onset often with a precipitating event, herniated disc, with a clinical picture that is dominated by pain radiating below the knee, often associated with neurological defi cits (numbness, tingling, weakness, absent or decreased deep tendon refl exes). Magnetic resonance imaging of the lumbar spine is helpful for the diagnosis. Osteoarthritis is another entity that should be taken into consideration. Compared to the pain from AS, which is infl ammatory in nature, the pain from osteoarthritis worsens with activity and often does not associate infl ammatory symptoms. Radiographic evaluation is suggestive for asymmetric joint-space narrowing, subchondral sclerosis and osteophytes. Other diseases that may mimic AS are rheumatoid arthritis, psoriatic arthritis, reactive arthritis, fi bromyalgia, myalgia and diff use idiopathic skeletal hyperostosis (DISH) 3,19 .
Th e main objectives of the management of patients with SpA are to improve short-and long-term healthrelated quality of life through relief of symptoms such as pain, stiff ness and fatigue, maintenance of function, prevention of complications of spinal disease such as dorsal kyphosis, minimization of extraspinal and extraarticular manifestations and preservation/normalisa-  were signifi cantly decreased compared to previous values. However, 10 months later (15 months after the beginning of Infl iximab therapy), the patient presented with worsening symptoms; high levels of infl ammatory markers (ESR 20 mm/h, CRP 17.16 mg/L) were noted and anti-Infl iximab antibodies were detected. Th e inadequate response in this case falls into the second category: loss of effi cacy or secondary failure to TNF inhibitor (secondary non-responder). A common mechanism responsible for the development of secondary failure is immunogenicity due to the formation of antibodies against the TNF antagonists. Th ese antibodies interfere with the binding of TNF to its receptor. Th e presence of antibodies against TNF antagonists will lead to lower serum drug levels and less duration of response. In a retrospective study, patients with loss of response to Infl iximab with detectable antibodies were examined; change to another TNF inhibitor was associated with a complete or partial response in 92% of patients, whereas increasing the dose led to only a 17% response (P<0.004) 23 . Patients with high titres of anti-drug antibodies (levels of antibodies against IFX >9 μg/mL) do not respond well to dose intensifi cation of the same drug, but switching to a diff erent agent pertaining to the same therapeutic class may restore the clinical response (P<0.03) 24 . In patients primary or secondary. Primary failure or lack of efficacy is characterized by the absence of any improvement after starting treatment with a TNF inhibitor and receiving therapy for at least 12 weeks. Secondary failure, or loss of effi cacy, is characterized by an initial improvement with drug therapy, followed by relapse (worsening or recurrence of disease activity). Patients who do not tolerate the particular TNF (adverse events like rashes, injection site reactions etc.) are defi ned as experiencing a form of secondary drug failure. In case of inadequate response or intolerance to initial biologic agent, switching to a diff erent biologic agent, such as another TNF inhibitor or an anti-IL-17 antibody is recommended. Th e frequency of good responses to TNF inhibitors is still substantial, but decreases with the use of subsequent agents, compared with the fi rst use.
In our patient, after inadequate response to initial therapy with two diff erent nonsteroidal anti-infl ammatory drugs (Indomethacin and Diclofenac) and an immunomodulatory (Sulfasalazine), biologic therapy was initiated (Infl iximab, 5 mg/kg iv at weeks 0, 2 and 6, and then every 6-8 weeks), while continuing therapy with Sulfasalazine. When the patient returned to the hospital for reevaluation, 5 months after the initiation of biologic therapy, the clinical examination showed improvement and the infl ammatory markers   Th e clinical case described presents a possible treatment complication that may arise in patients with AS. When a patient loses response to a TNF antagonist, pharmacokinetic and immunogenic assessment with drug levels and antibodies should be performed, based on which the optimal choice of pharmacological therapy should be made.
Compliance with ethics r equirements: "Th e authors declare no confl ict of interest regarding this article". "Th e authors declare that all the procedures and experiments of this study respect the ethical standards in the Helsinki Declaration of 1975, as revised in 2008 (5), as well as the national law. Informed consent was obtained from the patient included in the study" with low levels of antibodies, dose escalation is also an option; another approach to loss of response in patients with antibodies is to add an immunosuppressive agent. Concomitant use of immunomodulators, such as methotrexate, reduces the risk of antibody formation against TNF antagonist agents and improves clinical outcomes. In our case, the patient was switched to a diff erent anti-TNF agent (Adalimumab, 40 mg subcutaneously every two weeks), while continuing the administration of Sulfasalazine (500 mg x 5/day).