INTRODUCTION
Giant cell arteritis (GCA) is a systemic vasculitis of the large vessels affecting patients over the age of 50 years, commonly the elderly (1 – 3). The disease is often associated with rheumatic polymyalgia (RPM) (1 – 3). The cranial form is known as temporal arteritis (TA), which usually presents with headache, although jaw claudication and vision loss are also possible, apart from constitutional symptoms such as fever or malaise (1 – 3). Vision loss can lead to permanent blindness if untreated (1 – 3). The pathophysiology of the disease is unclear, but interleukin 6 (IL-6) is known to play a role (1 – 3). Diagnosis is made using imaging techniques, Doppler ultrasonography, computed tomography (CT), or magnetic resonance (MR) angiography, but temporal artery biopsy is the gold standard (1 – 3). Screening for involvement of other vessels in TA is done in some, but not all centers (1, 2).
Glucocorticoids (GCs) remain the main treatment. Usually prednisone at a dose of 1 mg/1 kg body mass is recommended, or pulses of methylprednisone at a dose of 1 g for more serious ocular symptoms to prevent blindness (1 – 4). Doses are subsequently tapered upon improvement until remission is achieved (1 – 4). However, high-dose or long-term use of GCs can lead to a number of side effects, including cataracts, increased intraocular pressure, hypertension, hyperglycemia, osteoporosis, gastritis, ulcers, immunosuppression, and infection. The majority of patients require one to two years of GC treatment before discontinuation (1 – 3, 5). Due to bone loss which can lead to fracture, additional treatment should be started, especially in those with osteoporosis, including biphosphonates, teriparatide, or denosumab (1). Because of these side effects, alternative steroid-sparing treatment is needed. Methotrexate, azathioprine, leflunomide, mycophenolate, cyclosporin, cyclophosphamide, and biologics like abatacept and tumor necrosis factor (TNF) α inhibitors, have shown moderate to weak, or negative results (1 – 5). These drugs have shown efficacy in the treatment of other rheumatologic diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and some vasculitides, but evidently the pathophysiology of GCA is distinct (3, 5).
Recent studies, in particular the GiACTA trial by Stone et al. in 2017 and others, showed that tocilizumab (TCZ), an IL-6 inhibitor, yielded great results in inducing remission and reducing relapse and cumulative steroid dose (1 – 5). However, questions on the long-term efficacy and safety of TCZ in GCA remain, including preventing blindness and increased risk for lower gastrointestinal tract perforation (1). TCZ was approved for GCA treatment by the European Commission (2) in September 2017. Notable follow-up studies have yet to emerge, but recently various case reports have surfaced looking at these questions. One such case report points out hypofibrinogenemia as a possible side effect which can increase bleeding risk; also, it reports neutropenia and thrombocytopenia as, albeit rare, side effects (6). Another case describes fatal tuberculosis reactivation in a GCA patient treated with TCZ, despite an initial negative screening result (7). TCZ was also shown to induce cutaneous sarcoidosis in a GCA patient, although this was also previously found in RA patients on TCZ (8).
Apart from TCZ as a steroid-sparing agent, other possibilities are being investigated, including ustekinumab, a human IgG1 kappa monoclonal antibody, which has also shown initial good results, but further investigation is required (3, 5). Studies are also already underway or planned for anakinra and gevokizumab (IL-1β inhibitor), rituximab (B cell depletion), and baricitinib (Janus kinase [JAK] inhibitor) (3).
As of March 2018, the Croatian Society for Rheumatology has recommended TCZ for GCA in disease relapse, in refractory disease where GCs could not be successfully tapered, and as an initial treatment in patients with comorbidities or at high risk (9). These recommendations describe refractory disease in patients where the initial GC dose could not be tapered after 4 to 6 weeks of treatment, or in patients who remained on a dose of prednisone over 0.2 mg/kg/day after 6 months, or on a dose over 0.1 mg/kg/day (9) after 12 months. TCZ can be considered as an initial treatment in patients with unregulated hypertension or diabetes, cardiovascular comorbidity, severe osteoporosis, glaucoma, a history of ulcer disease, or at high risk of developing side effects of GC use (9).
In our center, GCA is diagnosed approximately 4–5 times a year, and currently about 20–25 patients with GCA are being managed. TCZ was indicated in the three patients with refractory disease and comorbidities presented below.
CASE SERIES
Clinical characteristics and treatment summary of the patients are shown in Table 1.
The first patient, a 66-year-old female, presented with fever 40° C, and left-sided headache over the previous month, in July 2018. The patient had prior diagnoses of asthma and arterial hypertension. She was referred to a neurologist by her family doctor, having been previously examined by a pulmonologist for a respiratory tract infection and treated with antibiotics. Laboratory workup showed elevated C-reactive protein (CRP) (169 mg/L), and brain computed tomography (CT) showed no notable pathology. Upon excluding neurological disease, the neurologist referred the patient to an infectologist, and subsequently to a rheumatologist who discovered the patient also complained of vision loss. Temporal arteritis was immediately suspected, and the patient was hospitalized for treatment and further workup. The patient received an initial dose of methylprednisone 80 mg. On the following day, the patient was seen by a neuroophthalmologist, and visual field testing showed signs of optic neuropathy. General workup, including routine chest X-ray and abdominal ultrasound, along with more specific tests including color Doppler ultrasound of the temporal arteries and magnetic resonance imaging (MRI) of the aortic arch and its branches, did not show significant pathology. Densitometry verified the presence of osteoporosis. Due to progression of vision loss, in collaboration with a neuroophthalmologist the patient received pulses of methylprednisone 1,000 mg over three days with tapering, which resulted in significant regression of symptoms and normalization of CRP (2.4 mg/L). The patient was discharged on oral methylprednisone 56 mg with a tapering scheme, and ibandronic acid along with calcium and vitamin D for osteoporosis.
During follow-up the patient was stable until September, when she presented with leg weakness and numbness in the left leg. Due to the earlier diagnosis of osteoporosis and GC treatment, the patient was hospitalized for further assessment of possible vertebral fractures. MRI of the lumbosacral spine showed multiple vertebral compression fractures from L2 to L4, confirming the earlier suspicion. The patient was started on teriparatide and pain medication for osteoporosis with vertebral fractures, and discharged on prednisone 30 mg. Initiation of TCZ was planned as an alternative treatment due to the higher dose of GC and progression of osteoporosis with vertebral fractures. In October the patient was started on TCZ 162 mg subcutaneously (SC) once weekly, with a GC tapering scheme. She was followed up by a rheumatologist and neuroophthalmologist. As of November 2019, she has remained on TCZ, stable, without relapse or any serious side effects except for recent minor neutropenia, due to which the TCZ dosage has been reduced to biweekly application.
The second patient, an 81-year-old female, presented with right-sided vision loss and temporomandibular joint pain in March 2018. The patient had previously been diagnosed with cervical discopathy, arterial hypertension, and glaucoma. She was referred to hospital by her general ophthalmologist. She was examined by a neuroophthalmologist, and visual field testing confirmed optic neuropathy. Laboratory test results showed elevated CRP (102.1 mg/L). Temporal arteritis was diagnosed, and pulses of methylprednisone 1,000 mg were started. The following day, temporary artery ultrasound was performed showing arterial wall thickening of the right temporal artery. Temporal artery biopsy was suggested, but rejected by the patient. On the third day, the patient was hospitalized due to poor general condition. She was treated and observed over six days, then discharged on oral methylprednisone 64 mg with a tapering scheme. During follow-up, the patient was referred to a rheumatologist who hospitalized her for further investigation. As a part of additional workup, a routine abdominal ultrasound was performed, which was insignificant apart from gallstones. MRI cranial angiography was normal. Rheuma factor (RF), anti-cyclic citrullinated peptide (CCP), anti-nuclear antibodies (ANA), extractable nuclear antigen (ENA), and anti-neutrophil cytoplasmic antibodies (ANCA) were negative. Densitometry confirmed osteoporosis. The patient was discharged on methlyprednisone 40 mg and ibandronic acid, calcium, and vitamin D for osteoporosis.
The patient was further followed by a rheumatologist and neuroophthalmologist, but the GC dose could not be tapered below 32 mg without symptoms worsening, specifically that of left-sided vision loss, and since the patient was basically blind in the right eye, this was unacceptable. In July, the patient was considered for TCZ treatment by her rheumatologist. In October, after essential workup for biologic treatment, she was started on TCZ 162 mg SC once weekly. In the following months, TCZ was administered without any remarkable side effects, with regular check-ups by a rheumatologist and neuroophthalmologist, and GC was successfully tapered. As of November 2019, the patient has been stable on TCZ and methylprednisone 2 mg.
The third patient was an 83-year-old female followed by a rheumatologist since 2013 for RPM on methylprednisone, varying between 2 and 8 mg. The patient had previous diagnoses of arterial hypertension and glaucoma, and later developed osteoporosis, along with vertebral compression fractures, and cervical and lumbar discopathy. In March 2017 the patient was seen by a neurologist for neck pain which radiated to the occipital and parietal regions of the head as well as the mandible. She also complained of difficulty swallowing and left-sided ear pain. She had elevated CRP (120.6 mg/L). The patient was then referred to a rheumatologist who increased the methylprednisone dosage to 12 mg daily with a tapering scheme. During follow-up 2 weeks later she was clinically better, but symptoms worsened when the GC dose was tapered to 4 mg. At this point the patient was hospitalized for treatment and further workup under suspicion of temporal arteritis. An initial dose of methylprednisone 80 mg was administered. Routine chest X-ray and abdominal ultrasound, color Doppler ultrasound of the temporal, carotid, and vertebral arteries, and CT aortography were performed, and did not show any significant pathology. The neuroophthalmogist exam did not reveal optic neuropathy. RF, anti-CCP, ANA, ENA, and ANCA were negative. The patient was discharged on oral methylprednisone 32 mg with a tapering scheme, along with calcium and vitamin D for osteoporosis, as she did not tolerate alendronic acid and tetraparatide, which she had been taking previously. The patient was followed by a rheumatologist and remained stable on methylprednisone 4 mg. She was hospitalized in May 2018 for physical rehabilitation.
In March 2019, taking into consideration the patient’s comorbidities and persistent GC use, TCZ was considered as an alternative GCA treatment option. Pre-biologic workup yielded a positive quantiferon test, and the patient was started on prophylactic isoniazid, followed by TCZ at the end of April 2019. The patient quickly developed neutropenia, and her liver enzymes became elevated, which could have been due to TCZ or isoniazid. As such, both drugs were discontinued as early as June 2019, after which the laboratory results normalized. The patient has remained stable on methylprednisone 4 mg, and is being routinely followed by a rheumatologist.
DISCUSSION
The three patients discussed in this case series from our center all presented with similar symptoms highly suggestive of GCA. The first two patients with vision loss along with other symptoms which fall within the domain of GCA (headache, jaw claudication, fever) were highly convincing, and therefore a temporal artery biopsy was not performed, as is common practice in our center, was not performed. Although temporal artery biopsy is still the gold standard for diagnosis, it seems that many centers, including ours, are moving more towards non-invasive imaging techniques, namely ultrasound, as opposed to biopsy. The third patient developed typical symptoms of GCA after an established diagnosis of RPM, and the association between these entities is well-known. It is worthy to emphasize that these patients, due to the nonspecific symptoms, are frequently referred to one or even two other specialists before reaching a rheumatologist. All patients were treated with GCs, the first two with pulses of large doses due to the expressed vision loss, and especially the second patient who had already lost vision in the right eye. As described in the case presentations, the patients were also evaluated for additional large vessel involvement, autoimmune disease, and paraneoplastic syndrome, but only temporal arteritis was found, along with osteoporosis that required treatment. All three cases, taking into consideration the high GC dose or long-term GC use as well as the risk factors including osteoporosis and glaucoma, warranted alternative steroid-sparing treatment. The first two patients have shown favourable clinical results on TCZ, effectively reducing or eliminating GC use, and remaining in remission for over a year, without relapse or serious side effects other than for the recent minor neutropenia in one patient. Unfortunately, the third patient developed neutropenia almost immediately, leading to discontinuation of the drug. Still, two high-risk GCA patients have been successfully treated with TCZ, and likely there will be more candidates in the future.
Other centers in Croatia have reported similar positive experiences in treating GCA with TCZ. A recent case series from the University Hospital Center Zagreb reports a total of 7 patients diagnosed with GCA, presenting with similar symptoms like our patients but with a greater emphasis on headache and RPM, having been successfully treated with TCZ with no relapses or side effects (10). A separate, interesting report from the same center describes two cases of rheumatoid arthritis patients on etanercept developing GCA, one of which was successfully treated with TCZ (11). The Clinical Hospital Dubrava reports treating 13% of GCA patients with TCZ, but the report only lists the characteristics of GCA patients over the previous 10 years and does not go into more detail on the topic of TCZ treatment, although one case was described in another report (12, 13). That case report describes a 69-year-old patient who presented with fever and high inflammatory markers, and was diagnosed with GCA after imaging showed inflammation of the carotid arteries and aorta (13). Since the patient was still showing signs of active disease after a year on GCs, TCZ was started and complete remission was achieved after three months (13). The further outcome has not been reported.
CONCLUSION
The positive experiences presented here, albeit on a small case series, of treating GCA patients at high risk for GC treatment with the alternative TCZ, contribute to the current recommendations. Additionally, these data support the evidence of TCZ as an effective steroid-sparing drug for patients with GCA, especially those with refractory disease or at risk, such as patients with glaucoma and osteoporosis with vertebral fractures. Our initial experience with TCZ is good, and likely there will be more cases in the future.
Acknowledgements: Mladen Defranceschi, Tatjana Zekić, Tamara Mišljenović Vučerić
Conflict of interest statement: Authors declare no conflict of interest.
REFERENCES / LITERATURA
<jrn>10. Bosnić D, Sentić M, Mayer M, et al. Tocilizumab u liječenju bolesnika s arteritisom divovskih stanica – Serija bolesnika iz KBC-a Zagreb. Reumatizam. 2019;66(1):19. [Internet]</jrn>
Table 1. GCA patient case series presentation and treatment summary
Legend/Legenda: GC/GK – glucocorticoid/glukokortikoid; TCZ – tocilizumab