We worked toward developing a core outcome set for clinical research studies in polymyalgia rheumatica (PMR) by conducting (1) patient consultations using modified nominal group technique; (2) a systematic literature review of outcome measures in PMR; (3) a pilot observational study of patients presenting with untreated PMR, and further discussion with patient research partners; and (4) a qualitative focus group study of patients with PMR on the meaning of stiffness, using thematic analysis. (1) Consultations included 104 patients at 4 centers. Symptoms of PMR included pain, stiffness, fatigue, and sleep disturbance. Function, anxiety, and depression were also often mentioned. Participants expressed concerns about diagnostic delay, adverse effects of glucocorticoids, and fear of relapse. (2) In the systematic review, outcome measures previously used for PMR include pain visual analog scores (VAS), morning stiffness, blood markers, function, and quality of life; standardized effect sizes posttreatment were large. (3) Findings from the observational study indicated that asking about symptom severity at 7 AM, or “on waking,” appeared more relevant to disease activity than asking about symptom severity “now” (which depended on the time of assessment). (4) Preliminary results were presented from the focus group qualitative study, encompassing broad themes of stiffness, pain, and the effect of PMR on patients’ lives. It was concluded that further validation work is required before a core outcome set in PMR can be recommended. Nevertheless, the large standardized effect sizes suggest that pain VAS is likely to be satisfactory as a primary outcome measure for assessing response to initial therapy of PMR. Dissection of between-patient heterogeneity in the subsequent treatment course may require attention to comorbidity as a potential confounding factor.

No abstract

Background Musculoskeletal stiffness in polymyalgia rheumatica (PMR) follows a circadian rhythm. In rheumatoid arthritis (RA) patients, a timed release tablet of prednisone taken at 10pm led to a significant decrease in morning stiffness which was correlated with decreased night time plasma IL-6 [1]. However, the effects of timed release glucocorticoids on morning stiffness and the circadian profile of IL-6 in PMR have not been investigated. Previous studies of cytokines in PMR only collected blood samples at one time point mainly in the morning, without specifying the exact timing [2]. Objectives To determine whether IL-6 follows a circadian rhythm in patients with newly diagnosed untreated PMR, and to compare the effects of morning and night time glucocorticoids on overnight IL-6 and morning stiffness. Methods 10 patients with newly diagnosed PMR were randomised to two treatment groups with either night time modified-release prednisone 7mg (Lodotra) or morning immediate-release prednisolone 7mg. Hourly blood samples over 24-hours were taken before (Night A) and after 2 weeks treatment (Night B) to measure plasma IL-6. Patients were then treated with morning prednisolone 15mg and after 2 weeks a single measurement of IL-6 was performed at 9am (Day C). Duration of morning stiffness was recorded on each occasion. IL-6 assays were performed in Germany using the MILLIPLEX MAP kit. Results IL-6 showed a marked circadian variation in PMR, with a rise during the early hours of the morning which was partially suppressed by 7mg morning prednisolone and almost completely suppressed by 7mg night time prednisone (Figure 1a and 1b). Night time prednisone reduced morning stiffness by 90% compared to 42% with the morning prednisolone (p=0.044, t-test, figure 1c). Conclusions PMR, like RA, has a marked circadian variation in plasma IL-6. Both IL-6 and symptoms of morning stiffness are suppressed more by night time low dose glucocorticoids. This observation raises the possibility that PMR may be controlled by lower doses of glucocorticoids given at night compared to current conventional morning treatment. References Buttgereit, F., et al., Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in RA (CAPRA-1): a double-blind, randomised controlled trial. Lancet, 2008. 371(9608): p. 205-214. Spies, C.M., et al., More Night Than Day - Circadian Rhythms in Polymyalgia Rheumatica and Ankylosing Spondylitis. Journal of Rheumatology, 2010. 37(5): p. 894-899. Disclosure of Interest None Declared

Background Research into the pathogenesis of rheumatoid arthritis (RA) has been focusing on identifying disease biomarkers that can predict response to therapy. Early work identified differing levels of pro-inflammatory cytokines within a cohort of RA patients [1]. A recent study looking at the role of a modified release glucocorticoid preparation in the management of RA may have identified a distinct subgroup of patients who are resistant to therapy [2] with raised circulating levels of the cytokines TNF-α, IL-4, IL-1 receptor antagonist (IL-1ra) and IL-1β compared to treatment responders. The concept of glucocorticoid resistance in RA has been observed in other studies and across the spectrum of inflammatory disorders [3,4]. Objectives This study explores the the possibility of identifying a treatment resistant phenotype subset of patients with RA through peripheral serum cytokine measurements. Methods 41 patients with RA were recruited from general rheumatology clinics in the South-West of the United Kingdom (Bristol and Plymouth). Additional exclusion criteria included active malignancy, active infection and co-existing auto-immune disease. Patient blood samples were taken in the morning to minimise diurnal cytokine variations and cytokine assays were performed using a MILLIPLEX® MAP multiplex assay kit at a commercial laboratory in Germany. Results Results were analysed according to the number of patients who had raised serum TNF-α, IL-4, IL-1ra and IL-1β above the cohort median for each cytokine. The frequencies of the number of patients who had 0,1,2,3 or all 4 cytokines raised were recorded. This revealed a biphasic distribution of patients with 16/41 patients having 3 or 4 raised cytokines versus 22/41 patients having only 1 or 0 cytokines raised. Only 3 patients had 2 raised cytokines. This is a much smaller figure than predicted, as we would expect the population to be normally distributed. The P value for the Chi squared test comparing the observed population versus the expected normal distribution was <0.0001. Conclusions These results confirm previous observations that a distinct subset of patients with rheumatoid arthritis patients can be identified through the serum cytokine signature. Previous studies seem to imply that these patients may exhibit a glucocorticoid resistant phenotype. Further work is planned to explore the association of these two subsets of rheumatoid arthritis with various clinical characteristics. References Ulfgren AK, et al. Interindividual and intra-articular variation of proinflammatory cytokines in patients with rheumatoid arthritis: potential implications for treatment. Ann Rheum Dis 2000;59(6):439-47. Clarke LL et al. Alleviation of morning joint stiffness by low-dose prednisone in rheumatoid arthritis is associated with circadian changes in IL-6 and cortisol. International Journal of Clinical Rheumatology 2011;6(3):273-279 doi 10.2217/ijr.11.12. Sliwinska-Stanczyk P et al. The effect of methylprednisolone on the proliferation of PBMCs obtained from steroid-sensitiv...

Case report - Introduction Cogan syndrome is a very rare disorder of probable autoimmune vasculitic origin, first described in 1934. The age of onset seems to range from 3 to 50 years with an average age of disease onset at 29 years. It is characterised by audiovestibular dysfunction and ocular inflammation. The cause remains unknown and the epidemiology of the disease is purely based on case reporting. As of 2015, there were fewer than 250 case reports. Interestingly, it seems extremely rare in Arabic and Middle Eastern countries in which a new case has been recently diagnosed and is being reported in this abstract. Case report - Case description A 14-year-old girl of Arabic origin first presented to the ENT specialist with a 3-week history of balance problems, left tinnitus and sensorineural hearing loss in both ears worse on the left. She first received treatment for vestibular neuritis with no improvement. Two months later, she complained of bilateral red eyes and excessive lacrimation when diffuse interstitial keratitis was diagnosed by the ophthalmologist. An array of blood tests including a full autoimmune disease was arranged and a rheumatology opinion was sought. The patient had a normal inflammatory response and her screen for antinuclear antibodies, extractable nuclear antigen, rheumatoid factor and antineutrophil cytoplasmic antibodies were all negative. A full virology screen was also negative. Having failed to respond to all supportive treatment modalities, a trial of a tapering 2-week course of prednisolone starting at 25mg daily was instigated. The patient’s symptoms improved by more than 50% on glucocorticoids subsequent to which the diagnosis of Cogan syndrome was anticipated. As the patient’s symptoms relapsed when glucocorticoids were stopped, she was recommenced on prednisolone 25mg in line with azathioprine 100mg daily. The patient’s hearing, which was almost lost in the left ear, improved significantly by more than 70% initially, and then to normal hearing as stated by the patient supported by special ENT testing. Her balance problems and vertigo also improved remarkably. Her tinnitus, which was the last symptom to resolve, almost went away over the subsequent 2 months. The patient had already come off glucocorticoids 6 months down the line, and stayed on azathioprine 75-100mg daily for almost a year after which gradual weaning was trialled and then eventually succeeded. She has now been off azathioprine for 6 months without experiencing any disease relapse. Case report - Discussion Cogan syndrome can be difficult to diagnose particularly in children. The diagnosis is essentially clinical depending on the presence of audio-vestibular symptoms and interstitial keratitis along with a prompt response to immunosuppressive medication. In this patient, the consistent clinical picture supported by the positive response to glucocorticoids especially in the absence of an alternative diagnosis would have made the diagnosis of Cogan syndrome likely. Given the rarity of this disorder, there are no classification criteria as yet hence the ongoing need for case reporting. Moreover, there is no clear guidance on the duration of immunosuppressive treatment of this condition. Case report - Key learning points It is pivotal in managing conditions with a suspected autoimmune origin to have a multidisciplinary approach involving other relevant specialties in a holistic approach. The prompt response to glucocorticoid therapy still remains the key in securing the diagnosis of a number of conditions in clinical practice especially in the absence of diagnostic criteria and/ or supportive investigations such as serological and tissue-based testing. Case reporting has a crucial role in enhancing awareness of rare medical conditions.