Study procedures

4.3 Quality control 4.4 Descriptive analysis

4.5 Comparison of clinical variables between flare versus remission groups 4.6 Survival analysis

4.7 Composite clinical biomarker score 4.8 Long-term clinical outcomes 4.9 Discussion

4.10 Summary

4.2 Study procedures

4.2.1 Patient recruitment

A total of 78 patients attended a baseline study visit. Of these, 3 patients did not meet the eligibility criteria and were not recruited: one was enrolled in another long-term clinical trial, and 2 patients were taking leflunomide. A further patient did not receive the patient

information sheet prior to their baseline visit - as the ethical approval of the study mandated that all patients receive the information sheet at least a day in advance of their baseline visit, this patient was provided with an information sheet and their baseline visit rescheduled.

Unfortunately, the patient did not attend this rescheduled appointment, and despite multiple attempts could not be contacted before the closure of the study recruitment period and hence was not enrolled in the study. A further patient had received systemic glucocorticoids within 3 months of their baseline visit – in this case, their baseline visit was rescheduled to a later date and they were subsequently successfully enrolled.

Of the 74 patients who were enrolled in the study, 30 (41%) patients did not meet the criteria for DMARD cessation. 19/74 (26%) patients failed DMARD cessation criteria owing only to the presence of PD signal on baseline ultrasound scan, 4/74 (9%) failed solely due to DAS28-CRP≥2.4, and 3 (4%) failed owing to both DAS28-CRP≥2.4 and PD signal on ultrasound. A further 5 patients, who were recruited prior to the protocol amendment to change the

117

remission criteria to DAS28-CRP<2.4 (see Methods 3.2), satisfied DAS28-CRP remission but did not satisfy ACR/EULAR Boolean remission and hence did not stop DMARD therapy in accordance with the protocol version in force at the time. Following the protocol amendment, ethical approval was granted to offer these patients a further study appointment using the amended remission criteria – only one patient accepted this offer, and they were subsequently eligible for DMARD cessation.

4.2.2 Patient outcomes

Of the 44 patients who stopped DMARDs, 21 patients maintained DAS28-CRP remission for the 6 months of study follow-up. One of these patients had synovitis of both ankles and a 5th MTP joint at review 176 days after DMARD cessation, demonstrated both by clinical and ultrasonographic examination. Despite clearly exhibiting objective evidence of active disease, their DAS28-CRP score (which does not include assessment of the ankles or feet) was within the remission range (1.58). Nevertheless, the patient was deemed to have experienced an arthritis flare, received an intramuscular steroid injection and was referred back to their rheumatology team for recommencement of DMARD therapy. This did not constitute a breach of the study protocol, which permits recommencement of DMARDs in those patients with PD signal at the month 6 ultrasound scan. A further 3 patients had grade 1/3 PD signal at the wrist on their month 6 ultrasound scan, but no clinical synovitis, and maintained DAS28-CRP remission. As ultrasound findings do not form part of the clinical remission criteria, these patients were classified as maintaining clinical remission for the purposes of data analysis.

A DAS28-CRP score ≥ 2.4 was recorded for 22 patients during the follow-up period, who were classified as having experienced an arthritis flare. An additional patient was reviewed 69 days after DMARD withdrawal before the first substantial protocol amendment – although this patient had a DAS28-CRP score within the remission range (1.46), they did not satisfy ACR/EULAR Boolean remission. Thus, according to the study protocol in force at the time they were treated as having experienced an arthritis flare, and were referred back to their rheumatology team for recommencement of DMARD therapy. Therefore, had this visit occurred after implementation of the first substantial amendment, this patient would in effect have been lost to further follow-up. Nevertheless, the remainder of all patients successfully completed the follow-up period.

118

In summary, of the 44 patients who discontinued DMARD therapy, 23 (52%) were classified as experiencing an arthritis flare, 20 (45%) maintained DFR and 1 (2%) was effectively lost to follow-up (Figure 4.1). In order to maintain consistency in data analysis, two separate

approaches have been implemented to account for this latter patient dependent on the outcome measure of interest. For analyses where the outcome is binary (i.e. flare vs. remission), the patient has been excluded as it is unclear whether they would have maintained DAS28-CRP remission to the end of the 6 month study period. For analyses where the outcome is time-to-flare, the patient has been analysed as being censored in remission after 69 days follow-up.

4.2.3 Adverse events

Arthritis flare was recorded as an adverse event in 24 patients (i.e. including the patient who was classified as flare prior to the first substantial amendment). Routine influenza and pneumococcal vaccination during study follow-up were also recorded as adverse events (11 events, 10 patients) to allow for subsequent identification during longitudinal data analysis. A further 66 adverse events were recorded, none of which were judged to be a consequence of DMARD cessation (Table 4.1). There were no serious adverse events.

Figure 4.1 – Flow diagram showing patient recruitment and outcomes.

119 Table 4.1 – Adverse events occurring in the study.

Category Adverse Event Number of

Events

Urinary tract infection 1

Respiratory Breathlessness 2

Incidental finding of asbestos-related pleural plaque 1

Nasal polyposis 1

Metabolic Hypercholesterolaemia 3

Increase in diabetes mellitus medications 1

Circulatory Outpatient coronary imaging 2

Increase in ischaemic heart disease medications 1

Musculoskeletal

Arthritis flare 24

Elbow epicondylitis 2

Muscle cramp 1

Lower back pain 1

Myalgia & lethargy following intravenous bisphosphonate 1

Pain around knee replacement 1

Sialadenitis 1

Skin

Actinic keratosis 3

Basal cell carcinoma 2

Dry skin 1

Itch 1

Gastrointestinal

Diarrhoea 2

Abdominal pain 2

Irritable bowel syndrome 1

Inguinal hernia 1

Routine elective screening colonoscopy 1

Fatty liver change on ultrasound 1

Ophthalmological Red/dry eyes 2

Elective phacoemulsification 2

Elective ocular punctoplasty 1

Other

Of note, one patient was treated with a 7-day course of oral prednisolone for nasal polyposis at 5 months after DMARD cessation. This patient subsequently maintained DFR at their month six follow-up visit. This was annotated on the study database to allow for subsequent identification during longitudinal data analysis.

120 4.3 Quality control

4.3.1 Study visits

A total of 184 study visits were conducted, the timings of which are detailed in Table 4.2 All visits were performed according to the study protocol with no protocol deviations. Two patients were unable to attend their month 3 visit owing to personal/family commitments – both of these patients subsequently attended their month 6 visit as scheduled.

4.3.2 Missing data

4.3.2.a Prospectively recorded clinical data

ESR measurements were not available for 3 patients at baseline owing to insufficient blood sample (2 patients) and failure by clinical laboratory to perform test (1 patient). These values were left missing in the final dataset, with exclusion of these records as necessary in analyses based on ESR values. Aside from this, prospectively recorded clinical data were otherwise complete for all other variables.

4.3.2.b Retrospectively recorded clinical data

Medical notes were available for all patients and the quality of documentation was generally excellent. Symptom duration before first rheumatology review was not documented in three medical records. For two cases the patient-recollected value was recorded as a substitute – however, one patient could not recollect their symptom duration and this value was left

Table 4.2– Number of study visits.

Timing of visit Number

Baseline 74

Month 1 42

Month 3 26

Month 6 23

Unscheduled (patient-requested) 19

Total 184

121

missing in the final dataset. Similarly, time from first rheumatology review to

commencement of first DMARD was not recorded in two medical records. Both of these patients could not recall this duration, and hence these two values were left as missing in the final dataset.

Aside from the above, retrospectively recorded clinical data were otherwise complete for all other variables.