Approaches to optimising access to NICE-approved biologic anti-TNFs for patients with rheumatoid arthritis with moderately active disease.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is associated with joint pain and stiffness. Biologics represent some of the most effective treatments for RA, but previous guidance from the National Institute for Health and Care Excellence (NICE) has limited their use to patients with severely active disease. This has meant patients with moderately active RA have been treated as if they have an acceptable disease state, despite many cases where the inflammation has a major impact on joint damage, mobility, pain and quality of life. However, recent guideline changes (NICE TA715) have approved the use of three biologics - adalimumab, etanercept and infliximab - for the treatment of moderately active RA. MAIN BODY: In response to these changes, we have held discussions with medical teams from across the UK to consider the main implications for implementation of these new recommendations, as well as any differences in approach that may exist at a local level. Several key challenges were identified. These included establishing methods of educating both physicians and patients concerning the new availability of the biologic treatments, with suggestions of various organisations that could be approached to circulate informative material. Identifying which patients with moderately active RA stand to benefit was another discussion topic. Relying solely on scoring systems like Disease Activity Score in 28 Joints (DAS28) was acknowledged to have limitations, and alternative complementary approaches such as ultrasound, as well as assessing a patient's co-morbidities, could also be useful tools in determining those who could benefit from biologics. An additional challenge for the process of patient identification has been the increase in the use of telemedicine consultations in response to the coronavirus disease 2019 (COVID-19) pandemic. More use of patient-reported outcomes was raised as one possible solution, and the importance of maintaining up-to-date databases on patient disease scores and treatment history was also stressed. CONCLUSION: While challenges exist in education and identifying patients who may benefit from the use of biologics, the NICE TA715 recommendations hold great potential in addressing an unmet need for the treatment of moderate RA.

Crystallising the role of adrenocorticotrophic hormone in the management of acute gout: a review.

OBJECTIVES: Acute gout is traditionally treated with NSAIDs, corticosteroids, and colchicine. However, the presence of comorbid conditions and advancing age, often seen in hospitalised patients, may prevent their use. We reviewed the published data on the use of ACTH in the treatment of acute gouty arthritis. METHODS: A search was performed up to June 2017. We included clinical trials or case studies/series where ACTH had been administered in human subjects as a treatment for acute gout or pseudogout. RESULTS: Data consistently demonstrated ACTH to be fast-acting, typically relieving the painful symptoms of acute gout within 24 h of treatment. Furthermore, the average number of days needed to achieve 100% resolution of gout symptoms in patients treated with ACTH was similar to those of the corticosteroid triamcinolone. Retrospective data confirm the efficacy of ACTH or the synthetic analogue Synacthen in the treatment of acute gout in patients with comorbidities such as cardiovascular disease, chronic kidney disease, and hypertension, including those who were hospitalised, with all patients responding after 1-3 doses. ACTH appears to be well-tolerated with side effects being minor and transient in nature. Importantly, ACTH/Synacthen has no clinically significant effect on glucose and potassium levels or blood pressure. Clinical evidence from available case studies supports these findings. CONCLUSIONS: ACTH is a fast acting, efficacious and well-tolerated option for patients with acute gout when traditional therapies have failed or are contraindicated. However, large, carefully designed, randomised controlled trials are required to confirm these findings.

Adherence to biologic therapy - Does it vary with ethnicity?

BackgroundPoor adherence to therapy remains a significant barrier to improving clinical outcomes in rheumatic diseases and carries a major financial burden. It has been linked to medication related patient beliefs, which were reported to differ between ethnic groups. Little is known about these variations in biologic therapies cohorts. The purpose of this study was to identify potential determinants of adherence to biologic drugs including an assessment of the influence of beliefs about medicines and compare determinants of adherence between patients of Caucasian versus other ethnicities (OE). Relationship of adherence to disease outcome was further explored. MethodsA prospective survey was undertaken of patients with inflammatory arthritis prescribed self-administered subcutaneous biologic therapies at our centre. Data were collected using a) self reported adherence b) five item compliance questionnaire for Rheumatology (CQR5) and c) Beliefs about Medications questionnaire (BMQ) specific-five items each for necessity and concern scales. The replies were assessed against the disease activity score measured on the day of recruitment to the survey. Results80 patients contributed to the survey. 90% were prescribed TNF inhibitors. 40 patients were of Caucasian origin and 40 belonged to OE-predominantly of South Asian descent (85%). Disease activity score (DAS) was significantly higher in OE patients with 3.7 (standard deviation (SD) 1.3) compared to Caucasian patients with a DAS of 2.9 (1.6) (p = 0.031). Negative beliefs (i.e. higher concern scale scores) about therapy were significantly more prevalent (24/40) (60%) in the OE group compared to the Caucasian cohort (14/40 (35%) (p = 0.043). 17/40 (42.5%) of OE patients were poorly adherent to biologic therapy compared to 12/40 (30%) of Caucasian participants (p = 0.308). Most respondents (68/80, 85%) agreed that their biologic therapies were necessary for their health. Amongst 12/80 (15%) who disagreed, only two were in the non-adherent group. ConclusionTo our knowledge, this is the first study to demonstrate ethnic differences in disease activity score and related negative beliefs regarding subcutaneous biologic therapies in people with rheumatic diseases.

Should All Patients Trial Subcutaneous Methotrexate Prior to Commencing Biologic Therapy? A Real World Study.

Introduction: Methotrexate (MTX) is the bed rock of inflammatory arthritis management. However, intolerance is a limiting factor for drug optimisation and retention. There is data to suggest subcutaneous (SC) MTX is better tolerated. It is less clear whether this strategy is effective in those where the oral preparation is inefficacious and its potential to avoid escalation to biologic therapy. Objectives: To analyse the reasons for switching to SC MTX in a real-world setting, clinical outcomes achieved and proportion requiring biologic prescription. Materials and Methods: A retrospective survey of patients prescribed SC MTX in a university teaching hospital identified 352 patients. 298 switched from oral to SC MTX- 164 stopped oral MTX due to side effects, 134 stopped due to inefficacy, and 54 started SC MTX as first line therapy. 103 patients progressed to biologic therapy. Rheumatoid arthritis (RA): DAS-28 improved from a mean of 4.06 (0.63-8.06) to 2.83 (0.14-7.32) following the switch (p<0.0001). Psoriatic arthritis (PsA): total joint count improved from a mean of 7 (0-42) to 2 (0-25) (p<0.0001). Swollen joint count improved from a mean of 2 (0-26) to 1 (0-6) (p=0.09). Discussion: SC MTX is an effective solution for RA and PsA, irrespective of whether oral MTX is inefficacious or intolerable. Where oral MTX was ineffective, a switch to SC achieved low disease activity despite multi-morbidity, long disease course and protracted oral MTX exposure. This intervention prevented over two-thirds of patients requiring biologics. SC MTX is a durable strategy with excellent disease outcomes and substantial economic benefits.

The diagnosis and management of systemic autoimmune rheumatic disease-related interstitial lung disease: British Society for Rheumatology guideline scope.

Interstitial lung disease (ILD) is a significant complication of many systemic autoimmune rheumatic diseases (SARDs), although the clinical presentation, severity and outlook may vary widely between individuals. Despite the prevalence, there are no specific guidelines addressing the issue of screening, diagnosis and management of ILD across this diverse group. Guidelines from the ACR and EULAR are expected, but there is a need for UK-specific guidelines that consider the framework of the UK National Health Service, local licensing and funding strategies. This article outlines the intended scope for the British Society for Rheumatology guideline on the diagnosis and management of SARD-ILD developed by the guideline working group. It specifically identifies the SARDs for consideration, alongside the overarching principles for which systematic review will be conducted. Expert consensus will be produced based on the most up-to-date available evidence for inclusion within the final guideline. Key issues to be addressed include recommendations for screening of ILD, identifying the methodology and frequency of monitoring and pharmacological and non-pharmacological management. The guideline will be developed according to methods and processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.1.

Pulmonary complications of biological therapies in children and adults with rheumatic diseases.

The management of rheumatic conditions, including those occurring in children, has improved dramatically over the last decade following the introduction of biologic disease-modifying anti-rheumatic drugs (bDMARDS) into the therapeutic arsenal. The benefits have been realised in multiple aspects of disease including signs and symptoms, bone and cartilage destruction, disability and quality of life. Overall, bDMARDS have an acceptable safety profile in the short to medium term in adults and children, however, that following longer term use remains unclear. As these drugs target key signalling molecules and cells of the immune system, adverse events are not unanticipated. In this review we will discuss pulmonary complications of biologic therapies used in the management of rheumatic diseases in both children and adults.

Non-infectious pulmonary toxicity of rituximab: a systematic review.

OBJECTIVE: Rituximab (RTX), a B-cell depleting mAb, has been reported to cause pulmonary toxicity in many patients. As the use of this biologic is increasing, we have undertaken a systematic review of the literature to gauge the nature and extent of non-infection-related RTX-induced lung disease. METHODS: A systematic literature review was undertaken to document all reported cases of RTX-associated interstitial lung disease (RTX-ILD), evaluating the epidemiological, clinical, radiological, histopathological, laboratory and management data from the available primary sources. The search was conducted using PubMed, the Cochrane Library and EMBASE up to June 2010 using the terms RTX in the advanced search option without limitations and all relevant publications reviewed manually. In addition, unpublished data from the Food and Drug Administration, the European Medicines Agency and the manufacturer (Roche) were evaluated to complement this search. Identified articles were included if they displayed a potential relationship between the administration of RTX and ILD following exclusion of other likely causes. RESULTS: A total of 121 cases of potential RTX-ILD were identified from 21 clinical studies/trials, 30 case reports and 10 case series. The most common indication for RTX was diffuse large B-cell lymphoma. RTX-ILD occurred more frequently in male patients and was most common during the fifth and sixth decades of life. In most cases, RTX was part of combination chemotherapy, but in 30 (24.7%) cases it was given as monotherapy. The mean and median number of cycles of RTX before disease onset was four, but cases following the first cycle or as late as the 12th cycle were also identified. The mean time of onset, from the last RTX infusion until symptom development or relevant abnormal radiological change was 30 days (range 0-158 days). Abnormal radiological findings were similar in all patients, with diffuse bilateral lung infiltrates apparent on chest radiographs and/or thoracic CT. Hypoxaemia was seen in all cases and pulmonary function tests were uniformly abnormal with a characteristic diffusion capacity deficit and restrictive ventilatory pattern. RTX-ILD was fatal in 18 cases. CONCLUSION: ILD is a rare but potentially fatal complication of RTX therapy. This diagnosis should be considered in any patient who develops respiratory symptoms or new radiographic changes while receiving this biologic agent.

Does methotrexate increase the risk of varicella or herpes zoster infection in patients with rheumatoid arthritis? A systematic literature review.

OBJECTIVES: Methotrexate (MTX) has become the foundation disease-modifying anti-rheumatic drug (DMARD) for RA. However, concern exists regarding its possible association with infectious complications including varicella zoster virus (VZV) and herpes zoster (HZ). Furthermore, no consensus exists regarding pre-MTX VZV screening or the use of VZV vaccine. METHODS: We undertook systematic literature review (SLR) investigating the relationship between the use of MTX in patients with RA and VZV and HZ infection. Additionally, the European Centre for Disease Prevention and Control, HPA, the CDC, Rheumatology societies and WHO web sites and publications were consulted. RESULTS: Thirty-five studies fulfilled the inclusion criteria comprising 29 observational studies and 6 case reports. The case reports and 13 observation studies considered the association between MTX and HZ. Three of the observational studies reported a positive association although in 5 cases, patients were concurrently treated with prednisolone. Five studies concluded that there was no association between HZ and MTX. Three studies comparing the infection rates of MTX with other RA therapies found that MTX did not result in higher HZ infection rates. Three studies examining the association between HZ and MTX treatment duration failed to show a link. CONCLUSIONS: No evidence exists to support an association between MTX and VZV infection in RA patients and the data regarding the role of MTX in HZ development is conflicting. The role of pre-MTX VZV screening is controversial and, as it may delay initiation of RA treatment, we suggest against VZV screening in this context.

Interleukin-6 and cytochrome-P450, reason for concern?

Interleukin 6 (IL-6) plays a central role in the immunopathogenesis of rheumatoid arthritis (RA) and tocilizumab [TCZ] (an anti-IL-6 receptor antibody) has been shown to be effective in the treatment of the condition. As up-regulation of IL-6 reduces the activity of cytochrome P450 (CYP) enzymes, blockade of this cytokine may enhance CYP function. This may lead to reduced bioavailability of CYP-metabolized drugs. Due to the increasing use of TCZ, we undertook a systematic literature review to explore such interactions. Our search was conducted in MEDLINE, EMBASE, Web of Science, FDA and EMEA websites for in vitro and in vivo studies, clinical trials and reviews mentioning TCZ and CYP on the basis of the title and abstract. Appropriate articles were further screened based on full-text review to select only those reporting IL-6, TCZ and their potential interaction with CYP-metabolized drugs. Two in vitro studies showed that TCZ-reversed IL-6 induced reduction of CYP isozymes. CYP3A4 mRNA expression was most reduced by IL-6 followed by CYP2C9 and CYP2C19. This change was prevented with TCZ. Three clinical studies investigated the interaction showing simvastatin (CYP3A4 substrate) bioavailability reduced by TCZ and omeprazole bioavailability was decreased by TCZ-induced CYP2C19 activity. The bioavailability of dextromethorphan (CYP2D6 and CYP3A4 substrates) was shown to be unaffected by TCZ treatment. The observed increase in CYP isozyme activity by TCZ is of clinical relevance as the bioavailability of the CYP isozyme substrates were decreased in vivo. As CYP3A4 is the isozyme responsible for the largest proportion of drug metabolism, it is probable that the bioavailability of other drugs may be reduced by TCZ. Thus, clinicians should exercise caution when co-prescribing TCZ and CYP-metabolized drugs. More studies are required to investigate this interaction further.