Sarah Fowler

Minocycline in Rheumatoid Arthritis: A 48-Week, Double-Blind, Placebo-Controlled Trial

Rheumatoid arthritis is a chronic, sometimes incapacitating systemic disease of unknown cause that affects at least two million Americans [1, 2]. Various pharmacologic agents are used to manage rheumatoid arthritis, but none is completely effective. On the basis of the theory that persistent Mycoplasma infection may cause rheumatoid arthritis, some physicians have prescribed and reported benefit from lengthy courses of tetracyclines [3, 4]. A small 1-year clinical trial comparing tetracycline, 250 mg/d, with placebo could not show significant benefit in patients with rheumatoid arthritis [5]. Because of these contradictory outcomes, the treatment of rheumatoid arthritis with antibiotics has remained controversial. Tetracyclines have several nonantibiotic effects that may be beneficial for patients with rheumatoid arthritis. Minocycline, a semi-synthetic tetracycline that is rapidly absorbed and has a prolonged half-life, inhibits collagenase activity of gingival fibroblasts from diabetic rats, even in a germ-free environment [6, 7]. Oral minocycline at a dose of 100 mg twice a day for 10 days reduced collagenase activity in the synovial tissue of patients with rheumatoid arthritis [8]. Moreover, the addition of minocycline to synovial tissue cultures from patients with rheumatoid arthritis also resulted in the inhibition of this enzyme. Other properties of tetracycline analogs include inhibition of protein synthesis by rapidly dividing cells [9], perturbation of leukocyte functions [10, 11], interference with lymphocyte proliferation [12-14], and anti-inflammatory effects [15] that are probably related to its antioxidant activity [16, 17]. Minocycline can also suppress the induction of experimental arthritis in rats [18]. Recently, favorable results from uncontrolled clinical studies of minocycline in rheumatoid arthritis were reported [19, 20]. In addition, Kloppenburg and colleagues [21, 22] observed improvement when minocycline was added to baseline nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs or corticosteroid therapy in a 26-week randomized, placebo-controlled trial. We conducted a 48-week, randomized, double-blind, multicenter trial to determine the efficacy and safety of minocycline in treating rheumatoid arthritis when it is added to background NSAIDs or low-dose prednisone therapy in patients not receiving concomitant disease-modifying antirheumatic drugs. Methods Protocol Development The protocol for the Minocycline in Rheumatoid Arthritis (MIRA) Trial was developed by the investigators from the clinical centers, the coordinating center, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases on the basis of protocols for clinical trials of therapies for rheumatoid arthritis that were previously done by the Cooperative Systematic Studies of Rheumatic Diseases (CSSRD) program [23, 24]. Inclusion criteria for those CSSRD trials were two of the following: nine or more tender joints capable of response, an erythrocyte sedimentation rate of 28 mm/h or greater, and morning stiffness lasting 45 minutes or longer. To simplify recruitment of patients, we modified these criteria to require the presence of nine or more tender joints capable of response with no minimum specified for either the erythrocyte sedimentation rate or for morning stiffness. The study protocol was reviewed and approved by institutional review boards at each participating clinical center. Patients To be eligible for the minocycline trial, patients had to meet the 1987 American Rheumatism Association (now the American College of Rheumatology) classification criteria for rheumatoid arthritis [25]. Patients were required to have active disease, defined as nine or more tender joints and six or more swollen joints capable of assessable improvement. Patients had to be 18 years of age or older and to have experienced onset of rheumatoid arthritis at 16 years of age or older. Patients receiving NSAIDs or low-dose corticosteroids (prednisone equivalent of a daily dose of 10 mg or less) were required to be receiving stable concurrent medication for 4 weeks before entering the study; these medications were to be kept stable throughout the study. One change from equivalent doses of one NSAID to another was permitted during the trial. Phenylbutazone, oxyphenbutazone, or parenteral steroids (including intra-articular corticosteroids) and disease-modifying antirheumatic drugs were not allowed for 4 weeks before the study; the use of these drugs during the trial was a protocol violation. Women were required to be postmenopausal, surgically sterile, or practicing a reliable method of contraception and to have a negative pregnancy test result. Before randomization, eligible patients for the minocycline trial could have received therapeutic trials of hydroxychloroquine and, at most, one other disease-modifying antirheumatic drug (oral or parenteral gold salts, d-penicillamine, azathioprine, methotrexate, or sulfasalazine) unless therapy was discontinued for toxicity. Patients could have tried any number of disease-modifying antirheumatic drugs if discontinued for toxicity, provided that no drug was administered for more than 3 months or, for parenteral gold salts, was not given in a cumulative dose of more than 500 mg. These exclusion criteria were designed to avoid recruiting patients with a history of repeated failures of therapeutic trials of disease-modifying antirheumatic drugs but did allow entry of those who had discontinued therapy with these drugs because of toxicity before prespecified dosages or durations were reached. Patients were not eligible at screening if they had known hypersensitivity to tetracycline; required long-term tetracycline therapy for another disorder; required ongoing therapy with antacids containing aluminum, calcium, or magnesium; or had received anticoagulant therapy. We excluded patients with chronic illnesses that would limit successful participation in the trial and patients classified as American Rheumatism Association-Steinbrocker functional class IV [26]. Three patients who met eligibility criteria at their screening visit were found to have too few affected joints at their baseline (randomization) visit and were inadvertently randomized. We included these patients in the analysis. All three patients were in the placebo group and were not considered responders to treatment. Removing these patients did not change the results of the trial. Study Design The MIRA trial was a six-center, double-blind, randomized, placebo-controlled trial comparing minocycline and placebo in treating rheumatoid arthritis. Patients were randomly assigned within the clinical center (that is, the clinical center was a stratifying factor), and randomization was blocked using randomly chosen block sizes between 4 and 6 to minimize the possibility that staff would guess the next treatment assignment. For 48 weeks, patients received two 50-mg capsules of minocycline hydrochloride or a visually similar placebo taken with water twice daily on an empty stomach. To minimize interference with the absorption of minocycline, patients were instructed not to ingest food or iron within 2 hours of receiving study medication. Investigators were allowed to adjust the dosage (without breaking the treatment code) if patients experienced side effects. Measurements The following measurements were obtained at the baseline and randomization visits and every 12 weeks thereafter. Evaluator Assessments Sixty diarthrodial joints were examined for the presence or absence of tenderness, and 58 were examined for swelling (hips excluded). Joint counts for tenderness and for swelling were the sum of the number of affected joints [27]. These joints were also evaluated for the severity of both tenderness and swelling on a 4-point scale. For tenderness, 0 = none, 1 = mild (positive response on questioning), 2 = moderate (spontaneous response elicited on examination), and 3 = severe (withdrawal by patient on examination); for swelling, 0 = none, 1 = mild (detectable synovial thickening without loss of bony contours), 2 = moderate (loss of distinctness of bony contours), and 3 = severe (bulging synovial proliferation with cystic characteristics). The sum of these determinations for all joints constituted a collective scores for either swelling or tenderness [23]. To foster agreement, evaluators attended a training session at the coordinating center before the trial. During the trial, all joint assessments for each patient were done by the same evaluator if possible. (During the trial, 94% of patients receiving minocycline and 92% of those receiving placebo had their joints evaluated by the same examiner at every visit.) Grip strength was measured bilaterally using a mercury strain sphygmomanometer [28]. An evaluator assessed disease activity on the day of the examination using a scale of 1 to 5: absent, mild, moderate, severe, or very severe activity [29]. For functional class, patients were assessed according to the American Rheumatism Association-Steinbrocker classification [26] (at baseline and 48 weeks only). Patient Assessments Patients were asked about the duration of morning stiffness they experienced on the day before each study visit [23]. Function was assessed on eight activities of daily living with the Modified Health Assessment Questionnaire (MHAQ) [30]. Patients used a scale of 0 to 3: activity without any difficulty, with some difficulty, with much difficulty, and unable to do; thus, the higher the score, the greater the incapacitation. Patients were also asked to give an overall assessment of their disease activity for the preceding day on a scale of 1 to 5: absent, mild, moderate, severe, and very severe [29]. Ancillary Assessments Laboratory determinations included urinalysis, complete blood count with differential, and a chemistry profile at the screening visit and every 4 weeks through week 12 an

Partial vs radical nephrectomy for T1 renal tumours: an analysis from the British Association of Urological Surgeons Nephrectomy Audit

To analyse and compare data from the British Association of Urological Surgeons Nephrectomy Audit for perioperative outcomes of partial (PN) and radical nephrectomy (RN) for T1 renal tumours.

Perioperative outcomes of 6042 nephrectomies in 2012: surgeon-reported results in the UK from the British Association of Urological Surgeons (BAUS) nephrectomy database.

To present the perioperative outcomes from the British Association of Urological Surgeons (BAUS) nephrectomy dataset for 2012, the first year of public reporting of individual surgeon outcomes in the UK.

Contemporary surgical management of renal oncocytoma: a nation's outcome

To report on the contemporary UK experience of surgical management of renal oncocytomas.

The British Association of Urological Surgeons (BAUS) radical prostatectomy audit 2014/2015 – an update on current practice and outcomes by centre and surgeon case‐volume

To describe contemporary radical prostatectomy (RP) practice using the British Association of Urological Surgeons (BAUS) data and audit project and to observe differences in practice in relation to surgeon or centre case‐volume.

PCNL Access by Urologist or Interventional Radiologist: Practice and Outcomes in the United Kingdom

To compare outcomes of urologist vs interventional radiologist (IR) access during percutaneous nephrolithotomy (PCNL) in the contemporary UK setting.

The British Association of Urological Surgeons radical cystectomy audit 2014/2015: An update on current practice, and an analysis of the effect of centre and surgeon case volume

Objective: The Consultant Outcomes Publication has made it mandatory to submit surgeon-level data on radical cystectomy (RC) practice in England. The current analysis describes contemporary surgical practice and compares this by surgeon and centre case volume. Materials and methods: Between 1 January 2014 and 31 December 2015, data on 3742 RCs performed by 161 surgeons over 84 centres were recorded on the British Association of Urological Surgeons audit and data platform. Centre case volumes were grouped as high (> 60), medium (30–60) and low (< 30), while surgeon case volumes were grouped as high (> 30), medium (8–30) and low (< 8). All data averages were for the combined 2-year period. Results: The median number of RCs performed was 16/surgeon and 31/centre; 45.4% of cases were performed for muscle-invasive transitional cell carcinoma (TCC). The commonest performed urinary diversion was ileal conduit (85.2%), followed by orthotopic bladder substitution (5.7%). Open radical cystectomy (ORC) was performed in 67.8%, robotically-assisted cystectomy (RARC) in 20.6% and laparoscopic cystectomy (LRC) in 9.1% of cases. RARC was more likely to be performed by high-volume surgeons and centres. The majority of patients underwent a lymph node dissection (LND), with rates varying from 79.5% to 90.3%. Reported rates of high-grade complication were generally low across all groups, suggesting under-reporting. There was a trend towards higher reported transfusion rates as centre volumes decreased. The median length of stay (LOS) was 7–9 days for minimally invasive approaches compared to open surgery, which was 11–12 days. Mortality rates were low across all groups. Conclusions: Compliance with the data registry is high. ORC remains the most common approach. High-case volume surgeons and centres more commonly offer RARC. The majority of patients undergo LND. There is a trend towards higher reported rates of transfusion as centre volume decreases. LOS is shorter in RARC and LRC in comparison to ORC, but is otherwise similar across centres and surgeons. Level of evidence: 2b

Open radical cystectomy in England: the current standard of care – an analysis of the British Association of Urological Surgeons (BAUS) cystectomy audit and Hospital Episodes Statistics (HES) data

To establish the current standard for open radical cystectomy (ORC) in England, as data entry by surgeons performing RC to the British Association of Urological Surgeons (BAUS) database was mandated in 2013 and combining this with Hospital Episodes Statistics (HES) data has allowed comprehensive outcome analysis for the first time.

Results of the British Association of Urological Surgeons female stress urinary incontinence procedures outcomes audit 2014-2017

To analyse the results of the stress urinary incontinence (SUI) audit conducted by the British Association of Urological Surgeons (BAUS), and to present UK urologists’ contemporary management of SUI.

PD16-10 IS PCNL A SAFE AND EFFECTIVE OPTION FOR OCTOGENARIAN PATIENT?. ANALYSIS OF OVER 4000 CASES FROM A NATIONAL DATABASE.

CONCLUSIONS: Patients experiencing more pain with their stent than the inciting stone are less willing to treat asymptomatic renal stones and are more willing to accept greater postoperative risk in order to forgo future ureteral stents. With increased emphasis on shared medical decision making, an enhanced understanding of factors affecting these decisions is important in order to appropriately counsel patients.