Duncan Porter

Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial

BACKGROUND Present treatment strategies for rheumatoid arthritis include use of disease-modifying antirheumatic drugs, but a minority of patients achieve a good response. We aimed to test the hypothesis that an improved outcome can be achieved by employing a strategy of intensive outpatient management of patients with rheumatoid arthritis--for sustained, tight control of disease activity--compared with routine outpatient care. METHODS We designed a single-blind, randomised controlled trial in two teaching hospitals. We screened 183 patients for inclusion. 111 were randomly allocated either intensive management or routine care. Primary outcome measures were mean fall in disease activity score and proportion of patients with a good response (defined as a disease activity score <2.4 and a fall in this score from baseline by >1.2). Analysis was by intention-to-treat. FINDINGS One patient withdrew after randomisation and seven dropped out during the study. Mean fall in disease activity score was greater in the intensive group than in the routine group (-3.5 vs -1.9, difference 1.6 [95% CI 1.1-2.1], p<0.0001). Compared with routine care, patients treated intensively were more likely to have a good response (definition, 45/55 [82%] vs 24/55 [44%], odds ratio 5.8 [95% CI 2.4-13.9], p<0.0001) or be in remission (disease activity score <1.6; 36/55 [65%] vs 9/55 [16%], 9.7 [3.9-23.9], p<0.0001). Three patients assigned routine care and one allocated intensive management died during the study; none was judged attributable to treatment. INTERPRETATION A strategy of intensive outpatient management of rheumatoid arthritis substantially improves disease activity, radiographic disease progression, physical function, and quality of life at no additional cost.

Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis

Objectives Mavrilimumab, a human monoclonal antibody targeting the alpha subunit of the granulocyte-macrophage colony-stimulating factor receptor, was evaluated in a phase 2 randomised, double-blind, placebo-controlled study to investigate efficacy and safety in subjects with rheumatoid arthritis (RA). Methods Subcutaneous mavrilimumab (10 mg, 30 mg, 50 mg, or 100 mg) or placebo was administered every other week for 12 weeks in subjects on stable background methotrexate therapy. The primary endpoint was the proportion of subjects achieving a ≥1.2 decrease from baseline in Disease Activity Score (DAS28-CRP) at week 12. Results 55.7% of mavrilimumab-treated subjects met the primary endpoint versus 34.7% placebo (p=0.003) at week 12; for the 10 mg, 30 mg, 50 mg, and 100 mg groups, responses were 41.0% (p=0.543), 61.0% (p=0.011), 53.8% (p=0.071), and 66.7% (p=0.001) respectively. Response rate differences from placebo were observed at week 2 and increased throughout the treatment period. The 100 mg dose demonstrated a significant effect versus placebo on DAS28-CRP<2.6 (23.1% vs 6.7%, p=0.016), all categories of the American College of Rheumatology (ACR) criteria (ACR20: 69.2% vs 40.0%, p=0.005; ACR50: 30.8% vs 12.0%, p=0.021; ACR70: 17.9% vs 4.0%, p=0.030), and the Health Assessment Questionnaire Disability Index (−0.48 vs −0.25, p=0.005). A biomarker-based disease activity score showed a dose-dependent decrease at week 12, indicating suppression of disease-related biological pathways. Adverse events were generally mild or moderate in intensity. No significant hypersensitivity reactions, serious or opportunistic infections, or changes in pulmonary parameters were observed. Conclusions Mavrilimumab induced rapid clinically significant responses in RA subjects, suggesting that inhibiting the mononuclear phagocyte pathway may provide a novel therapeutic approach for RA.

Triple therapy in early active rheumatoid arthritis: A randomized, single‐blind, controlled trial comparing step‐up and parallel treatment strategies

OBJECTIVE The Tight Control of Rheumatoid Arthritis study previously demonstrated that an intensive step-up disease-modifying antirheumatic drug (DMARD) treatment strategy targeting persistent disease activity was superior to routine care in the management of early rheumatoid arthritis (RA). We undertook this study to test the hypothesis that early parallel triple therapy achieves better outcomes than step-up therapy within an intensive disease management regimen. METHODS Ninety-six patients with early RA (mean disease duration 11.5 months) were randomized to receive step-up therapy (sulfasalazine [SSZ] monotherapy, then after 3 months, methotrexate [MTX] was added, and when the maximum tolerated dosage of MTX was reached, hydroxychloroquine [HCQ] was added) or parallel triple therapy (SSZ/MTX/HCQ). All patients were assessed monthly for 12 months. If their disease activity score in 28 joints (DAS28) was > or =3.2, the dosage of DMARDs was increased according to protocol, and swollen joints were injected with triamcinolone acetonide (maximum dosage 80 mg per month). A metrologist who was blinded to the treatment allocation performed assessments every 3 months. The primary outcome measure was the mean decrease in the DAS28 score at 12 months. RESULTS Both groups showed substantial improvements in disease activity and functional outcome. At 12 months, the mean decrease in the DAS28 score was -4.0 (step-up therapy group) versus -3.3 (parallel therapy group) (P = 0.163). No significant differences in the percentages of patients with DAS28 remission (step-up therapy group 45% versus parallel triple therapy group 33%), DAS28 good response (60% versus 41%, respectively), or American College of Rheumatology criteria for 20% improvement (ACR20) (77% versus 76%, respectively), ACR50 (60% versus 51%, respectively), or ACR70 (30% versus 20%, respectively) responses were seen. Radiologic progression was similar in both groups. CONCLUSION This study confirms that highly effective control of disease activity can be achieved using conventional DMARDs as part of an intensive disease management strategy. Within this setting, step-up therapy is at least as effective as parallel triple therapy.

Late Ebola virus relapse causing meningoencephalitis: a case report

Summary Background There are thousands of survivors of the 2014 Ebola outbreak in west Africa. Ebola virus can persist in survivors for months in immune-privileged sites; however, viral relapse causing life-threatening and potentially transmissible disease has not been described. We report a case of late relapse in a patient who had been treated for severe Ebola virus disease with high viral load (peak cycle threshold value 13·2). Methods A 39-year-old female nurse from Scotland, who had assisted the humanitarian effort in Sierra Leone, had received intensive supportive treatment and experimental antiviral therapies, and had been discharged with undetectable Ebola virus RNA in peripheral blood. The patient was readmitted to hospital 9 months after discharge with symptoms of acute meningitis, and was found to have Ebola virus in cerebrospinal fluid (CSF). She was treated with supportive therapy and experimental antiviral drug GS-5734 (Gilead Sciences, San Francisco, Foster City, CA, USA). We monitored Ebola virus RNA in CSF and plasma, and sequenced the viral genome using an unbiased metagenomic approach. Findings On admission, reverse transcriptase PCR identified Ebola virus RNA at a higher level in CSF (cycle threshold value 23·7) than plasma (31·3); infectious virus was only recovered from CSF. The patient developed progressive meningoencephalitis with cranial neuropathies and radiculopathy. Clinical recovery was associated with addition of high-dose corticosteroids during GS-5734 treatment. CSF Ebola virus RNA slowly declined and was undetectable following 14 days of treatment with GS-5734. Sequencing of plasma and CSF viral genome revealed only two non-coding changes compared with the original infecting virus. Interpretation Our report shows that previously unanticipated, late, severe relapses of Ebola virus can occur, in this case in the CNS. This finding fundamentally redefines what is known about the natural history of Ebola virus infection. Vigilance should be maintained in the thousands of Ebola survivors for cases of relapsed infection. The potential for these cases to initiate new transmission chains is a serious public health concern. Funding Royal Free London NHS Foundation Trust.

Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study

Background: Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. Aim: To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP. Methods: A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) ⩾2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS. Results: At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy. Conclusions: In this “true-to-life” study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies.

Effect of social deprivation on disease severity and outcome in patients with rheumatoid arthritis

OBJECTIVE Social deprivation is now recognised to have an important impact on morbidity and mortality. This study sought to ascertain the effect of deprivation, if any, on disease severity, functional disability, and outcome in rheumatoid patients in Glasgow. METHODS 814 patients with rheumatoid arthritis (RA) were assessed for clinical, functional, and laboratory indices of disease activity. Deprivation categories for individual patients were determined using the Carstairs index. Five year follow up is available for 440 patients. RESULTS The study population of RA patients live largely in the most deprived areas. Patients from deprived areas have significantly poorer function at outset and at five years as defined by the Health Assessment Questionnaire (HAQ) score. This is not attributable to differences in disease duration in patients from the most deprived regions or compliance with treatment. Furthermore, these patients do not achieve over five years the initial functional level of those living in the most advantaged localities. CONCLUSION RA patients from deprived areas have poorer function, which is associated with greater need—medical, social, and paramedical. Strategies and resources for healthcare need to be adjusted according to this variation.

Targeting ultrasound remission in early rheumatoid arthritis: the results of the TaSER study, a randomised clinical trial

Objective To investigate whether an intensive early rheumatoid arthritis (RA) treat-to-target (T2T) strategy could be improved through the use of musculoskeletal ultrasound (MSUS) assessment of disease activity. Methods 111 newly diagnosed patients with RA or undifferentiated arthritis (symptom duration <1 year) were randomised to strategies that aimed to attain either DAS28-erythrocyte sedimentation rate (ESR)<3.2 (control) or a total power Doppler joint count≤1 during a combined DAS28-ESR/MSUS assessment (intervention). MSUS examination was indicated if: DAS28-ESR<3.2 or DAS28-ESR≥3.2 with two swollen joints. Step-up disease-modifying antirheumatic drug (DMARD) escalation was standardised: methotrexate monotherapy, triple therapy and then etanercept/triple therapy. American College of Rheumatology (ACR) core-set variables were assessed 3 monthly by a metrologist blinded to group allocation. MRI of dominant hand and wrist, and plain radiographs of hands and feet were undertaken at baseline and 18 months for grading by two readers using the Outcome Measures in Rheumatology (OMERACT) Rheumatoid Arthritis MRI Scoring System (RAMRIS) and van der Heijde/Sharp Score, respectively. The coprimary outcomes were mean change from baseline of DAS44 and RAMRIS erosion score. Results Groups were matched for baseline clinical, demographic and radiographic features. The intervention group received more intensive DMARD therapy. Both groups demonstrated significant improvements in DAS44 (mean change: control −2.58, intervention −2.69; 95% CI difference between groups −0.70 to 0.48; p=0.72). There were no significant between-group differences for any ACR core-set variables, except DAS44 remission after 18 months (control 43%, intervention 66%; p=0.03). There was minimal progression of MRI and radiographic erosions and no difference in imaging outcomes or serious adverse event rates. Conclusions In early RA, a MSUS-driven T2T strategy led to more intensive treatment, but was not associated with significantly better clinical or imaging outcomes than a DAS28-driven strategy. Trial registration number NCT00920478.

UK cost-utility analysis of rituximab in patients with rheumatoid arthritis that failed to respond adequately to a biologic disease-modifying antirheumatic drug

ABSTRACT Objective: To evaluate the incremental cost effectiveness of rituximab in patients with rheumatoid arthritis that failed to respond adequately to tumour necrosis factor-α inhibitors (biologic disease-modifying antirheumatic drugs; bDMARDs). A cost-utility model has been developed to simulate the long-term incremental cost and benefits of rituximab using data from clinical trials and registries. Methods: The model estimates the lifetime disease progression of up to 10 000 hypothetical rheumatoid arthritis (RA) patients that failed one bDMARD. It compares cost and outcomes of two treatment sequences, representing the current UK standard both with and without rituximab. The population characteristics match those of the Randomised Evaluation of Long-term Efficacy of rituximab in RA (REFLEX) phase III randomised control trial. Clinical outcomes were based on an indirect comparison of published American College of Rheumatology response rates, adjusted for differences in placebo. To estimate medical resource use, health assessment questionnaire (HAQ) scores were grouped into five categories with UK registry data informing the average cost for each category. Quality-adjusted life years (QALYs) gained were mapped from disease severity (HAQ scores). Results: Compared to a standard UK treatment sequence (assuming the sequential use of bDMARDs) the introduction of rituximab led to a QALY gain of 0.526 years. The incremental cost-effectiveness ratios (ICERs) based on total direct medical cost were £11 601. Adding rituximab to a treatment sequence with no sequential use of biologic generates an ICER of £14 690. Conclusion: Rituximab has lower average annual treatment costs compared to other bDMARDs and is a highly cost-effective treatment option for patients who have failed to respond adequately to one bDMARD. The cost per QALY gained of rituximab falls well below commonly accepted thresholds within the UK. Potential weaknesses of the model include the paucity of data on the efficacy of bDMARDs or non-biologic DMARDs when used as second-line options; the lack of consensus about the most appropriate therapy in patients who fail all available bDMARDs; probable underestimation of the non-drug related medical costs; indirect measurement of QALY gains with rituximab therapy; and the necessity of synthesising data from a number of clinical trials with different populations and study drugs.

Treatment of rheumatoid arthritis with etanercept with reference to disease-modifying anti-rheumatic drugs: long-term safety and survival using prospective, observational data

OBJECTIVE The objective of this study was to examine the long-term safety of etanercept (ETN) in comparison with conventional DMARDs in a large observational cohort of RA patients in the UK. METHODS Data were made available from the British Society of Rheumatology Biologics Register for a cohort of patients with RA treated with ETN and a reference cohort of RA patients treated with conventional DMARDs (maximum follow-up 10 years). The adjusted risk of events was compared using Cox proportional hazards models. RESULTS There were 3529 eligible ETN-treated patients (16,919 person-years) and 2864 conventional DMARD-treated patients (11,095 person-years), with notable differences between groups at baseline. Crude mortality rates were 12.0 vs 20.1 events per 1000 person-years for ETN and conventional DMARD patients, respectively, with an adjusted hazard ratio (aHR) of 0.72 (95% CI 0.54, 0.96). There was no difference in the long-term risk of serious infections (aHR = 1.02, 95% CI 0.83, 1.25). However, the risk was increased for ETN in the first 2 years (aHR = 1.56, 95% CI 1.16, 2.09; aHR = 1.32, 95% CI 1.06, 1.65). The aHRs (95% CIs) of various outcomes were cancer, 0.84 (0.68, 1.03); lymphoproliferative malignancy specifically, 0.51 (0.28, 0.95); all other serious adverse events, 0.70 (0.56, 0.87) and cardiac events specifically, 0.52 (0.37, 0.72). CONCLUSION There was no evidence of adverse outcome from long-term exposure to ETN. There was evidence of improved survival, reduced cardiovascular events and reduced lymphoproliferative malignancies.

Tightening Up? Impact of Musculoskeletal Ultrasound Disease Activity Assessment on Early Rheumatoid Arthritis Patients Treated Using a Treat to Target Strategy

To determine the level of agreement and potential impact on disease‐modifying antirheumatic drug (DMARD) escalation decisions and of adding musculoskeletal ultrasound (MSUS) assessment of disease activity to the Disease Activity Score in 28 joints (DAS28) in early rheumatoid arthritis (RA).