INTRODUCTION
Ankylosing spondylitis (AS) is a part of spondyloarthritis (SpA), a group of chronic inflammatory arthropathies. SpA affects mainly the spine and sacroiliac (SI) joints (axial form of SpA), but also peripheral joints and entheses (peripheral form of SpA) and some extra-articular sites. Ninety-five percent of the white AS population is HLA-B*27 positive. The estimated worldwide prevalence of AS is between 0.01 and 0.2% (1). AS is more common in men, with male to female ratio being 2–3:1 (2). In women, the disease has a later onset, the time period from the onset of symptoms to the diagnosis is longer, and the disease is more often associated with fibromyalgia (FM) (3). As the disease progresses, irreversible structural changes in the spine and joints occur, which lead to deterioration of the functional status and quality of life in these patients. Although these changes are more pronounced in male patients, it is also known that women who initially have high disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) have a more severe form of the disease and a worse treatment outcome (4). With the introduction of magnetic resonance imaging (MRI), it became possible to diagnose the disease at an early stage, before the occurrence of irreversible changes in the spine and joints. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat the axial form of the disease. In case of their ineffectiveness or intolerance, biological therapy is used for treatment, i.e. tumour necrosis factor alpha (TNF-α) inhibitors, interleukin 17 inhibitors and Janus kinase (JAK) inhibitors. TNF-α inhibitors, especially adalimumab, have been used for the longest time, therefore the experience with the use of this drugs is the greatest.
This case report presents the case of a 63-year-old female who was diagnosed with advanced HLA-B*27 positive AS and polymyalgia rheumatica (PMR). This is the first described case of the co-existence of these two diseases in a female person. So far, it was described in the case report in which the authors express the opinion that shoulder pain is probably part of the clinical features of spodyloarthritis (5). But, in the case series report, the authors express the opinion that shoulder pain is part of the clinical features of PMR (6). They believe that in these five patients there is a coexistence of two diseases. In both articles, only male patients were presented. Also, case reports have been published in which patients with late-onset spondyloarthritis were described and their symptoms resembled those of polymyalgia rheumatica (7, 8).
In the following part, we will present the course of the patient’s illness and the therapeutic dilemmas that arose during the treatment period. This case report will end with a discussion based on the effects of adalimumab in these two diseases.
CASE REPORT
The first examination of the patient was in 2018 at the Physical Medicine and Rehabilitation with Rheumatology Division, University Hospital of Split. No one in the patient’s family suffers from rheumatic diseases, psoriasis or inflammatory bowel disease (IBD). The patient previously suffered from a duodenal ulcer, and she is now being treated for arterial hypertension and her blood count shows an increased number of eosinophils. Over the last ten years, the patient has been experiencing chronic back pain. The back pain was predominantly mechanical in nature. At the beginning of 2015, the diagnosis of spondyloarthritis was ruled out by a rheumatologist but only on the basis of clinical examination. The patient is allergic to diclofenac. Since the end of 2015, the patient was treated for PMR with glucocorticoids (GK) and several NSAIDs as recommended by an infectious disease specialist and a rheumatologist. The reason why the patient was referred to an infectious disease specialist was due to elevated acute phase reactants. PMR was diagnosed in accordance with 2012 EULAR/ACR provisional classification criteria (9). The patient presented with pain and stiffness of the cervical spine and shoulder girdle muscles, with a slight weakness of the pelvic girdle muscles. Laboratory findings showed elevated acute phase reactants (ESR 46 mm/h, CRP 32 mg/L). The patient had a quick and satisfactory clinical response to a medium dose of GK therapy with a decrease in inflammatory markers. Due to long-lasting pain in the entire spine and limited mobility of the lumbar spine (Schober’s test 3,5 cm), additional diagnostic tests were performed in 2018. Laboratory findings showed elevated acute phase reactants again, HLA typing showed the presence of HLA-B*27 antigen, radiographs of SI joints showed loss of joint space and bilateral partial ankylosis (grade III bilateral sacroiliitis according to the New York criteria – Figure 1). An MRI revealed signs of bilateral chronic sacroiliitis with partial ankylosis of the middle parts with subchondral sclerosis of the cranial and caudal parts of the joints (Figure 2). Linear subchondral bone marrow oedema was detected in the caudal part of the right SI joint. Only small effusion was detected in both joints. Fibromyalgia (FM), which is diagnosed primarily based on the symptoms, medical history and physical exam, was excluded. AS was diagnosed in accordance with the modified New York criteria (1994) and NSAIDs in full anti-inflammatory doses along with GK and proton pump inhibitors were introduced into the treatment with a moderate effect.
Due to constantly elevated acute phase reactants and persistent back pain, in 2019, bone scintigraphy was also performed. Apart from already known diagnoses, no other cause of the mentioned complaints was found in the case of this patient. Despite medication and regular physical therapy, spinal pain, especially in the cervicothoracic and thoracolumbar areas, was constantly present. This pain prevented the patient from performing work and carrying out daily activities. Therefore, the patient requested a change of workplace first and, following that, she took an early retirement.
In August 2020, the patient developed sudden abdominal pain. MSCT of the abdomen was performed and due to the suspicion that the patient had developed obstructive ileus, she was treated operatively at the Department for Abdominal Surgery. No cause of ileus was found during the operation. An appendectomy was performed, and the tissue of the appendix was found to be normal according to the pathohistological findings. The patient was diagnosed with subileus of unknown cause. At that time, the patient was being treated for AS and PMR with the combination of meloxicam and methylprednisolone in a dose of 6 mg. When the MSCT of the abdomen was later analysed by a team of rheumatologists and radiologists, changes that confirmed the diagnosis of AS were observed on sacroiliac joints (Figure 3).
In September 2020, the patient developed abdominal pain once again due to subileus. The finding of MSCT of the abdomen was very similar to the previous one, the calprotectin level was 648 μg/g (normal values are <50 μg/g) and small bowel follow-through findings were normal. The patient continued to take meloxicam and methylprednisolone as this combination of drugs is the most effective for the symptoms of AS and PMR.
In October 2020, she was hospitalized once again and treated for the same reasons, but this time the calprotectin values were significantly lower (68 μg/g). Antibodies for celiac disease and MR enterography were also performed, and all findings were normal. The patient was then referred to another hospital where a capsule endoscopy was performed. During this procedure, the capsule endoscopy camera was retained in her small intestine. The patient underwent surgery and 7.5 cm of her small intestine was removed. Pathohistological findings were described as normal.
In April 2021, after the patient underwent gastroscopy, colonoscopy and small bowel follow-through, she was treated by a gastroenterologist due to sideropenic anemia. NSAIDs and GK were excluded from therapy by a gastroenterologist and the patient was advised to use only paracetamol. The patient was also recommended to undergo an MR enteroclysis and a colonoscopy with biopsy.
In August 2021, additional exacerbation of inflammatory back pain was observed. The pain level was 9/10 according to the Visual Analogue Scale (VAS), and the acute phase reactants were elevated (ESR 33 mm/h, CRP 28.5 mg/L). The patient was referred for an MRI of the thoraco-lumbar spine according to the spondyloarthritis protocol. The findings of the MRI of the thoracic spine showed the presence of anterior spondylitis at the Th5/Th6 level (Romanus lesion), and chronic lesion in the front ends of the vertebral bodies at the Th8/Th9 level (chronic Romanus lesion) as seen in Figure 4. The patient also underwent an MR enteroclysis and a colonoscopy with biopsy in September 2021. MR enteroclysis showed a 3 cm long narrowing of the preterminal ileum. Synovitis of the right hip joint and sacroiliitis of the right SI (subchondral oedema of the sacrum) joint were also observed as incidental findings. The pathohistological findings of the biopsy of the terminal ileum showed a normal histological architecture with mononuclear and secondary follicles of medium density in the lamina propria.
In the meantime, the patient started taking methylprednisolone again (on her own accord) in a dose of 4 mg due to the exacerbation of the PMR symptoms.
Due to high disease activity of AS measured by the BASDAI questionnaire (9.6), severe pain measured by VAS (9/10) and morning stiffness lasting longer than two hours, our rheumatology team decided to start the treatment of AS with adalimumab.
We decided to introduce adalimumab into the therapy because of its proven effectiveness in the treatment of AS, as well as in the treatment of inflammatory bowel disease. Laboratory findings showed increased inflammatory markers and the anaemia of chronic disease again.
Treatment with adalimumab began in October 2021. The patient received 40 mg of the drug subcutaneously every 2 weeks. After the third dose of the drug, the patient already felt better. The pain and stiffness were significantly less intense and shorter in duration, but the mobility of the lumbar part of the spine remained the same. The Schober’s mobility index was 3.5 cm, same as before the introduction of adalimumab into treatment. Since the patient felt better, she decided to stop taking methylprednisolone. Very quickly, her pain and stiffness in the shoulder girdle muscles got worse and there was an increase in the inflammatory markers. Methylprednisolone in a dose of 6 mg was reintroduced to therapy. Additionally, we introduced methotrexate (MTX) in a dose of 10 mg once a week as a GK-sparing agent but also with the aim of reducing the immunogenicity of adalimumab. GK and MTX significantly reduced the symptoms of PMR.
We evaluated the effectiveness of adalimumab treatment of AS in February 2022, four months after the introduction of the drug. Disease activity and pain level were lower (BASDAI 5.2; VAS 4/10) and morning stiffness was shorter than before, lasting up to one hour.
Abdominal pains no longer occured. Reactants of the acute phase were lower (ESR 16 mm/h, CRP 21.0 mg/L), and anaemia of chronic disease was no longer found.
DISCUSSION
In the discussion, we will try to answer these three questions:
1. Is it reasonable to treat a 60-year-old patient with an advanced form of AS and partial ankylosis of the SI joints with a biologic drug?
2. Was adalimumab the best choice for the treatment of this patient?
3. Why didn’t we observe a drastically positive effect of adalimumab in the treatment of AS like it was observed in some other diseases?
Answers to these questions are as follows.
Ad 1. We believe that it was reasonable to introduce adalimumab into the treatment despite the partial ankylosis of the SI joints, considering that acute lesions of the thoracic spine are still visible on MRI findings and that this patient still experiences pronounced inflammatory back pain. A good treatment effect and good safety profile of adalimumab is found even in patients with advanced AS and complete spinal ankylosis who still complain of stiffness and inflammatory back pain. Such results were described both on the national level and internationally (10, 11).
Ad 2. Adalimumab has a proven effectiveness in the treatment of both AS and inflammatory bowel disease. Although this patient, despite experiencing abdominal pain and occasionally increased levels of calprotectin in her stool (the patient was then treated with meloxicam), did not have a diagnosis of inflammatory bowel disease, gastrointestinal complaints decreased and the patient was not treated in the hospital again after the introduction of adalimumab into therapy. On the other hand, TNF-α inhibitors have no effect in the treatment of PMR (12). Some studies showed that the IL-6 inhibitor, tocilizumab, can be effective in the treatment of resistant PMR (13) but tocilizumab has no effect in the treatment of AS. Therefore, we believe that adalimumab, combined with GK and MTX in the treatment of PMR, is the best choice for the treatment of AS in the case of this patient.
Ad 3. Although significant improvement was achieved with the introduction of adalimumab into therapy, this patient still experiences morning stiffness of the spine that lasts for about an hour and disease activity with a BASDAI score above 5. The moderate effect of adalimumab can be explained by a high initial index of disease activity (BASDAI 9.6), as previously described in literature (4).
CONCLUSION
This is the first described case of advanced AS and PMR in a female patient. NSAIDs did not have a satisfactory effect on the treatment of AS in our patient. After only four months of treatment, adalimumab reduced pain measured through VAS pain scoring and disease activity measured through BASDAI by about half. Also, according to the patient’s own opinion, it significantly reduced abdominal pain and improved her overall quality of life. As expected, adalimumab had no effect on PMR, but MTX and GK were effective in the treatment of PMR.
Author Contributions: Conceptualization, J.A. and D.Š; writing – original draft preparation, J.A., D.Š.; writing – review and editing I.M. and D.M.K; data analyses S.L.K. All authors have read and agreed to the published version of the manuscript.
Acknowledgments: The authors report no acknowledgments.
Funding: For this work authors did not receive any funding.
Informed Consent Statement: Written informed consent was obtained from the patient.
Conflict of interest statement: JA, IM and DŠ report that they have received a fee from Fresenius Kabi. SLK, KD and DMK declare no conflict of interest. Some parts of this case report were reported in the Kabi-Care journal (and they were written in the Croatian language) which is intended only for medical professionals in Croatia with prior registration and password protection. A written permission was obtained from Fresenius Kabi to use parts of this professional paper in this scientific paper.
REFERENCES / LITERATURA
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<jrn>11. van der Heijde D, Pangan AL, Schiff MH, Braun J, Borofsky M, Torre J, et al. Adalimumab effectively reduces the signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis. Ann Rheum Dis. 2008;67(9):1218–21.PubMedhttps://doi.org/10.1136/ard.2007.082529</jrn>
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Figure 1. Anteroposterior radiograph oblique view of sacroiliac joints showing partial ankylosis of both SI joints defined as grade III sacroiliitis by the New York criteria
Figure 2. MRI of sacroiliac joints – coronal T1 weighted image illustrates narrowing of joint space with partial ankylosis and periarticular fat metaplasia
Figure 3. Abdominal CT – coronal MPR image showing bilateral grade III sacroilitiis with joint space narrowing, sclerosis and both sacral and iliac bone erosions
Figure 4. MRI of thoracic spine on T2 STIR sagittal sections. Anterior spondylitis of Th5/Th6 level (Romanus lesion), and chronic lesion at the Th8/Th9 level (chronic Romanus lesion)