Rheumatoid arthritis (RA) is an inflammatory autoimmune process, and the dysregulated overproduction of interleukin-6 (IL-6) plays an important role in its pathogenesis. Tocilizumab (TCZ) is a humanized monoclonal antibody targeting the IL-6 receptor, and is recommended for use in RA. (1) There is evidence demonstrating good outcomes with TCZ in patients who have disease refractory to B-cell depletion with rituximab (RTX), a chimeric monoclonal antibody targeting CD20 B-cells, with up to 18 months9 follow-up. (2) Long-term data, however, on the efficacy, safety and tolerability of TCZ in RA that is refractory to sDMARDs, anti-TNF and RTX are lacking.
Objectives
To evaluate the long-term efficacy and safety of TCZ in real patients with RA refractory to synthetic DMARDs, anti-TNF agents and B cell depletion therapy with RTX, beyond 2 years.
Methods
We retrospectively studied 45 patients from two centres who received TCZ for median 48-months (range, 9–72) duration. All patients received anti-TNF and RTX previously. Efficacy and safety was evaluated according to the EULAR response criteria and EMEA guidance, respectively. Wilcoxon matched ranks test was used to assess changes in outcomes.
Results
Of 45 patients, 36 (80%) had previously discontinued RTX due to inefficacy and 9 (20%) due to intolerance. At most recent follow-up, median 48 months, 30 of 45 (67%) patients were continuing TCZ and 15 (33%) had discontinued, 7 due to inefficacy and 8 others due to intolerance. Of 36 patients with RTX-refractory RA, 25 (69%) were continuing TCZ and 11 had discontinued due to, inefficacy in 6 (17%) and intolerance in 5 (14%): 2 patients due to diverticulitis, 2 due to upper respiratory tract infections and 1 due to discitis. Of the 9 patients with RTX-intolerance, 5 (56%) were continuing TCZ and 4 (44%) had discontinued: 1 patient due to inefficacy and 3 due to intolerance, who had a prior history of hypogammaglobulinemia and infections associated with RTX. There were no significant differences in lipid profile in 25 of 36 of patients continuing TCZ therapy whereas 11 required statin therapy.
Conclusions
A majority of patients with RA refractory to synthetic DMARDs, anti-TNF and RTX responded to TCZ. Lipid profile in a majority of patients was stable in the long-term. Key messages: 1. The efficacy of TCZ is sustained in the long-term in patients with RTX-refractory RA. 2. TCZ appears to be safe in patients previously treated with RTX. TCZ does not alter lipid profile in a majority of the patients with RTX-refractory RA.
References
NICE. National Institute of Health and Care Excellence: tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198). http://www.nice.org.uk/guidance/ta2472012 Addimando O, Possemato N, Macchioni P, Salvarani C. Efficacy and safety of tocilizumab in refractory rheumatoid arthritis: a real life cohort from a single centre. Clin. Exp. Rheumatol. 2014;32(4):460–464
Acknowledgement
The authors would like to thank Angela Smith, Pauline Buck, Nicola Whitbread, Nicola Daly and Lindsay Kidd for their help with maintaining a record of patients receiving tocilizumab at the two centres.
To evaluate the long-term efficacy and safety of tocilizumab (TCZ) in clinical patients with rheumatoid arthritis (RA) refractory to synthetic disease-modifying antirheumatic drugs, anti-tumor necrosis factor agents, and B-cell depletion therapy with rituximab (RTX).We conducted a single-center retrospective study of 22 patients with RA treated with TCZ. We collected data including demographics and medication histories. We recorded clinical parameters including tender joint counts and swollen joint counts, and laboratory parameters including inflammatory makers and lipid profiles over regular intervals of TCZ treatment.In all, 22 patients with RA were included, 20 of whom were female. The median age at the first dose of TCZ was 62 years (range: 35-75 years). The mean duration of the disease from diagnosis with RA to May 2015 was 15.7 years (range: 6-30 years). A total of 15 out of 22 patients remained on TCZ at the end of the study, and in all, there was an improvement in markers of disease activity following initiating TCZ. The effect was sustained for a mean of 35 months (SD±15.5 months, range: 9-72 months). Of the 17 patients who failed to respond to RTX previously, 12 patients remained on TCZ. In all, eight out of 22 patients developed adverse events, five of whom discontinued TCZ. In contrast to previously documented short-term data, TCZ did not result in a statistically significant (P<0.05) long-term deterioration in lipid profile for any of the lipid parameters measured in our cohort (mean ± SD at initiation of TCZ to most recent follow-up: total cholesterol 5.25±1.05 to 5.28±0.77 mmol/L, high-density lipoprotein 1.72±0.54 to 1.67±0.43 mmol/L, low-density lipoprotein 3.05±0.98 to 2.98±0.81 mmol/L, and cholesterol to high-density lipoprotein ratio 3.41±1.23 to 3.40±1.22).The efficacy of TCZ in patients with RA refractory to disease-modifying drugs, including anti-tumor necrosis factor blockade and RTX, is sustained over 3 years. TCZ confers a good safety profile in the long term even in patients who previously developed adverse events to other rheumatic drugs. In the long run, there is no statistically significant deterioration in lipid profile during treatment with TCZ.
Syrian hamsters have been used as an animal model in different branches of medical sciences and veterinary sciences since 1930.This is partly because many aspects of their physiology are more similar to those of humans than many other laboratory animals.A socially bonded pair of hamster is the best animal model to study the circadian rhythm and anxiolytic drugs.A trial was conducted at Biogen Animal Facility, Bangalore to assess the haematological and physiological effects of Syrian hamsters in social housing versus social separation.Forty hamsters (20 males and 20 females) were randomly housed in pairs in 10 replicates and one control group with 10 replicates in polycarbonate cage with wire grid lids, corn cob litter material and soft nesting material.The social separation was not done in the control group till the end of the study.Blood collection from the orbital sinus was done at the end of social housing and at the end of social separation from male hamsters.Serum cortisol, total leukocyte count (TLC) count, differential count, platelet and packed cell volume were analyzed.The results indicated that socially separated males had significantly (P < 0.05) higher serum cortisol levels than socially housed and control groups.There was higher significant difference (P<0.01) in haemoglobin, TLC and PCV of socially separated males over socially housed males and control group males, whereas; there was no significant difference found in platelets count in all the groups.There was a marked reduction in the activity of socially separated male hamsters than socially housed.
Abstract Background/Aims Syphilis has seen a resurgence in the United Kingdom in recent years. It is a sexually transmitted disease caused by Treponema pallidum spirochaete infection, and typically presents as painless genital ulceration in its primary stage; left untreated it can progress rapidly to secondary and tertiary stages with multi-system involvement and wide-ranging symptoms, hence it being labelled ‘the great imitator’. We report a case of a patient presenting with classical features of giant cell arteritis (GCA), ultimately being diagnosed with neuro-ocular syphilis. Methods A 65-year-old man with a background of hypertension and migraines presented to our hospital with a 3-week history of temporal headache, scalp tenderness and jaw ache. He described lethargy, weakness and weight loss. On examination he had a prominent left temporal artery, with concurrent scalp tenderness; neurological and general medical examination were otherwise normal. Blood tests showed an erythrocyte sedimentation rate (ESR) of 66 and a C-reactive protein (CRP) of 115, leading to a strong clinical suspicion of GCA. He was commenced on 60mg of oral prednisolone with immediate improvement of his symptoms at this dose. Subsequent temporal artery ultrasound and temporal artery biopsy were negative for GCA. On tapering his steroids to 40mg he experienced partial relapse of his symptoms. Following Neurology review his steroid taper was adjusted to decrease more slowly. On 20mg of prednisolone the patient began experiencing stabbing retro-orbital pain and visual blurring, and was assessed by Ophthalmology with no local cause for his symptoms identified - he was therefore pulsed with intravenous methylprednisolone for a flare of GCA. Despite an initial response, the patient continued to experience intermittent symptoms on steroids; imaging with PET-CT did not show evidence of inflammation or malignancy and an MRI of his brain and orbits was normal. Results The patient eventually re-presented to Ophthalmology with floaters, pain and decreased vision and a spot diagnosis of posterior placoid chorioretinitis was made after retinal examination. Characteristic yellowish ovoid lesions confluent in the macular area were noted, as well as ellipsoid zone loss with nodular retinal pigment epithelium on optical coherence tomography (OCT) imaging. This condition is pathognomonic of neuro-ocular syphilis and serological testing confirmed the diagnosis, with a high rapid plasma reagin (RPR) titre of 1:512. He was treated with a course of intramuscular Ceftriaxone with a rapid resolution of his symptoms, and was successfully weaned off all steroid therapy. Conclusion Diagnosing GCA remains a clinical challenge for rheumatologists, especially in cases with typical symptoms and signs but negative confirmatory testing on imaging and histology. There are a wide range of conditions that resemble GCA, and neuro-ocular syphilis is one such diagnosis that has been reported in the literature as a mimic, as demonstrated by this important case. Disclosure S. Ali: None. S. Lekh: None. C. Tench: None.
This study was conducted to investigate the possible protective role of (CoQ10) on reproductive dysfunction of male rats induced by sodium fluoride (NaF). thirty two rats were divided into four even groups and treated for 56 days as follows: the first group served as control (C) The second group (G1) received coenzyme Q10 at dose of 10 mg/Kg.B.W; while third group (G2) received 100ppmsodium fluoride in drinking water and fourth groups (G3) received NaF 100 ppm and CoQ10 10 mg/Kg.B.W for 56 days. The results showed that exposure of rats to NaF caused decrease in serum testosterone (T) and luteinizing hormones (LH) concentrations. Whereas Administration of CoQ10 caused an increase the concentrations of theses hormones in group G3 as compared with group G2. Testicular morphometric and histopathological alterations were observed in group G2 in the form of marked microvacuolation in the basal level of germinal cells, amyloid deposited within seminiferous tubules with disarrangement and depletion of germ cells. Whereas testicular histological alterations were improved in rats treated with CoQ10. In conclusion, the results of the present study showed that use of Co Q10 can alleviating the deleterious effects on male reproductive function following exposure to NaF, may be via improvement the testicular functions or other related endocrine glands.
Abstract Background/Aims BSR states: “GCA is a medical emergency. Patients should be evaluated by a specialist ideally on the same working day if possible and in all cases within 3 working days.” Currently in this DGH there is no pathway for diagnosis and management of GCA. Patients are referred from their GP and A&E directly to the Ambulatory emergency care unit (AECU), but it is not guaranteed they will be seen by a specialist within 3 days. We were also receiving inappropriate referrals for possible GCA such as patients under the age of 50 or chronic headache. We have 7-day access to acute ultrasonography in this DGH. We aimed to utilise this service in our fast-track GCA pathway. Aims: 1. All patients with suspected GCA to be seen within 3 working days by specialist. 2. Reduce the number of inappropriate referrals. 3. Reduce irreversible sequelae (visual loss, scalp tissue necrosis and stroke) Methods We developed a fast-track pathway containing referral criteria, directions for obtaining urgent ultrasonography and management advice. This was uploaded onto the intranet and was put up as posters in the AECU (see pathway). Baseline measurement: data were collected from ambulatory care referrals over a 5-month period. 29 patients were referred as possible GCA. After introduction of the pathway, data were re-collected over a 3-month period, with nine patients referred as possible GCA. Results Outcomes measured: The percentage of inappropriate referrals decreased by 16% . The percentage of patients reviewed by rheumatology within 3 days increased from 44% to 78%. The percentage of sequelae did not change. Visual loss occurred in both groups at presentation (transient in one patient). Prior to pathway implementation, 31% of patients referred had raised CRP/ESR. ESR/CRP was not tested in 34% of referrals. Following implementation, 100% of patients had CRP and ESR tested; of these 66% had raised CRP/ESR. Conclusion We have shown that having a fast-track pathway in place results in higher likelihood of a specialist evaluation within 3 days, as per BSR guidelines. To improve we suggest implementation of dedicated same-day AECU appointments for Rheumatology Specialists. Disclosure P.M. Lakhani: None. S. Ali: None. E. Sames: None. P. Agarwal: None. R. Lisk: None.
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