The prevalence and impact of polypharmacy in rheumatology.

Polypharmacy is increasingly common in rheumatology due to the complex nature of managing chronic autoimmune diseases. To date there has been limited research into the impact of polypharmacy on rheumatology patients. In this article we reviewed the literature to characterize the prevalence of polypharmacy and its effect on patients. In addition, we have highlighted some key drug-drug interactions to consider involving DMARDs as well as complementary and alternative medicines. There is emerging evidence demonstrating that polypharmacy contributes to adverse outcomes and alters treatment response. This association is best described in RA and is less clear in other patient cohorts. It is also unclear whether polypharmacy is directly harmful or just a surrogate marker for other factors affecting outcomes. Rheumatologists should be aware of the risk of polypharmacy as well as specific drug-drug interactions that can occur in managing chronic autoimmune disease.

Tapering versus steady-state methotrexate in combination with tocilizumab for rheumatoid arthritis: a randomized, double-blind trial.

Objective: To explore whether tocilizumab + tapering MTX has comparable efficacy and safety vs tocilizumab + stable MTX in adult RA patients with inadequate response to MTX. Methods: This randomized, placebo-controlled non-inferiority study involved patients with severe active RA [28-joint DAS (DAS28) >5.1] who had initiated tocilizumab + MTX at the study start. Patients received open-label tocilizumab (8 mg/kg i.v. every 4 weeks) and open-label MTX. At week 24, patients achieving good/moderate EULAR response were randomized to group A (double-blind MTX taper) or group B (double-blind MTX maintenance); both arms continued open-label tocilizumab. Primary analysis was the proportion of patients maintaining good/moderate EULAR response from week 24 to 60. Results: The study stopped early due to low recruitment, although the predetermined non-inferiority criteria were still met; 427 patients were enrolled to the open-label phase at week 0. At week 24, EULAR good/moderate response was achieved in 272 individuals (64.4%) who were randomized, 136 in each arm (36% withdrew/were not eligible). Additionally, 45.0% achieved DAS28 ⩽3.2, 33.5% achieved remission (DAS28 <2.6) and 64.2% had a DAS28 change ⩾1.2. After week 24 randomization, the proportion of patients maintaining good/moderate EULAR response to week 60 was significantly greater for MTX taper vs stable MTX (76.5 vs 65.4%; P = 0.036), and since the lower limit of the 95% CI was >0.9, the pre-determined criteria for non-inferiority was fulfilled despite reduced recruitment. Safety analysis revealed no unexpected tocilizumab safety signals. Conclusions: Tapering MTX in patients with RA receiving tocilizumab was non-inferior to continuing stable MTX in maintaining a good/moderate EULAR response. There were no unexpected safety signals; tocilizumab and MTX therapy was generally well tolerated in both groups. Trial registration number: EudraCT 2011-005260-20.

Update on biosimilars in rheumatology.

Biologic agents have become indispensable in the management of autoimmune disease particularly rheumatological conditions. The lives of countless individuals have been improved following treatment with these drugs. Unfortunately, their cost prohibits more widespread use around the globe. This critical issue has been addressed by the introduction of biosimilars into the market. These therapies have been developed to resemble the originator molecule as closely as possible and to increase competition in the therapy area thus allowing costs to be reduced. Our review is intended to offer an update on biosimilars including logistic considerations on their introduction into routine practice.

Evaluating the patient with low back pain.

In the UK, low back pain is the most common cause of disability in young adults and every year 6-9% of adults consult their GP about back pain. A thorough history and examination is required to exclude an alternative diagnosis, such as pain arising from the hip or trochanteric bursa and to categorise patients as having: serious spinal pathology, nerve root/radicular pain or non-specific back pain. Inflammatory back pain is often missed, particularly in the early stages when examination may be normal. The primary features are pain arising in patients under 40, thoracolumbar or sacroiliac pain and alternating buttock pain. Stiffness in the early morning and after rest is a hallmark of inflammatory back pain. There may also be peripheral joint involvement with evidence of inflammatory arthritis as well as extra-articular manifestations such as iritis, psoriasis and colitis. Sphincter disturbance leading to loss of bladder or bowel control should also be explored as it is a sign of spinal cord compression or cauda equina syndrome. Both of these are neurosurgical emergencies and need urgent referral for further investigation and possible intervention. The majority of patients with low back pain can be managed in primary care as the pain will usually be self-limiting. Patients with suspected inflammatory back pain should be referred to rheumatology as soon as possible in order to institute early management and prevent long-term deformity and disability. Patients with suspected serious spinal pathology should be referred urgently for further investigation. Red flag symptoms should raise concerns regarding a possible sinister cause such as malignancy and more than one red flag mandates urgent further investigation.

Early recognition improves prognosis in elderly onset RA. .

Although commonly diagnosed in the third to fifth decades of life, the incidence and prevalence of RA continue to increase up to the ninth decade. Age at onset is particularly relevant as the presentation may differ in elderly onset RA (EORA) compared with young onset RA (YORA). Patients with EORA frequently report a more acute presentation, especially if positive for rheumatoid factor (RF). Fever, fatigue and weight loss appear to be more common in EORA. Although small joints are most frequently involved in the RA population overall, there is common involvement of large joints in EORA and these proximal symptoms may mimic polymyalgia rheumatica (PMR). In YORA, approximately 80% of patients are seropositive for RF however a lower frequency has been reported in EORA. Anti-CCP antibodies have been detected in over 70% of patients with RA and are highly specific for RA. The value of anti-CCP antibodies is even higher in patients with an atypical presentation (e.g. PMR-like symptoms), or those who are RF negative. X-rays of the hands and feet should always be performed in patients with a suspected inflammatory arthritis. Baseline joint erosions are present in a similar proportion in patients with YORA and EORA. In the elderly, the differential diagnosis of RA is extensive as many conditions present in a similar way e.g. PMR, osteoarthritis, polyarticular gout, pseudogout and malignancy. Anti-CCP antibodies are very useful for identifying EORA patients with a polymyalgic onset. Ultrasonography or MRI can also be helpful in differentiating PMR from EORA.

Self-management pivotal in osteoarthritis.

Osteoarthritis is not caused by ageing per se, although prevalence does increase with age, and does not necessarily deteriorate over time. However, with the ageing population the incidence and prevalence of osteoarthritis will continue to rise. Osteoarthritis remains a clinical diagnosis and importantly radiographic changes and joint symptoms may be poorly correlated. The most commonly affected peripheral joints are the knees, hips and small joints of the hand especially the distal interphalangeal joints. A diagnosis of osteoarthritis should be reached clinically, without the need for investigations, in those older than 45 years, with mechanical joint pain, and/or with morning joint-related stiffness lasting less than 30 minutes. However, in unclear situations, blood tests and imaging can be very helpful to exclude other conditions such as gout, pseudogout, post-traumatic pain, inflammatory or septic arthritis. All patients with clinical osteoarthritis should be advised about activity and exercise irrespective of age, comorbidity, pain severity or disability. An effective exercise routine may include local muscle strengthening and general aerobic fitness and referral to physiotherapy should be considered. A rheumatological opinion should be sought if there is doubt regarding the diagnosis or symptoms persist despite treatment. NICE recommends yearly follow-up forall osteoarthritis patients who suffer from troublesome joint pain, have more than one symptomatic joint, more than one comorbidity and/or those patients taking regular medication for the condition.

Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-α therapy and correlates with aortic stiffness reduction. METHODS AND RESULTS: Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-α therapy by using (18)F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02±0.22 versus 1.74±0.22, P=0.0001). Following therapy, aortic TBR fell to 1.90±0.29, P=0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50±33% to 33±27%, P=0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51±0.33 to 2.05±0.29, P<0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09±1.77 to 8.63±1.42 m/s, P=0.04), which correlated with the reduction of aortic TBR (R=0.60, P=0.01). CONCLUSIONS: This study demonstrates that RA patients have increased aortic (18)F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-α therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA.

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.

Tocilizumab in patients with active rheumatoid arthritis and inadequate responses to DMARDs and/or TNF inhibitors: a large, open-label study close to clinical practice.

OBJECTIVE: To evaluate the safety and efficacy of tocilizumab in clinical practice in patients with rheumatoid arthritis (RA) with inadequate responses (IR) to disease-modifying antirheumatic drugs (DMARDs) or both DMARDs and tumour necrosis factor α inhibitors (TNFis). METHODS: Patients-categorised as TNFi-naive, TNFi-previous (washout) or TNFi-recent (no washout) -received open-label tocilizumab (8 mg/kg) every 4 weeks ± DMARDs for 24 weeks. Adverse events (AEs) and treatment discontinuations were monitored. Efficacy end points included American College of Rheumatology (ACR) responses, 28-joint disease activity score (DAS28) and European League Against Rheumatism responses. RESULTS: Overall, 1681 (976 TNF-naive, 298 TNFi-previous and 407 TNFi-recent) patients were treated; 5.1% discontinued treatment because of AEs. The AE rate was numerically higher in TNFi-recent (652.6/100 patient-years (PY)) and TNFi-previous (653.6/100PY) than in TNFi-naive (551.1/100PY) patients. Serious AE rates were 18.0/100PY, 28.0/100PY and 18.6/100PY; serious infection rates were 6.0/100PY, 6.8/100PY and 4.2/100PY, respectively. At week 4, 36.5% of patients achieved ACR20 response and 14.9% DAS28 remission (<2.6); at week 24, 66.9%, 46.6%, 26.4% and 56.8% achieved ACR20/ACR50/ACR70 responses and DAS28 remission, respectively. Overall, 61.6% (TNFi-naive), 48.5% (TNFi-previous) and 50.4% (TNFi-recent) patients achieved DAS28 remission. CONCLUSIONS: In patients with RA who were DMARD-IR/TNFi-IR, tocilizumab ± DMARDs provided rapid and sustained efficacy without unexpected safety concerns.

Biologic agents for rheumatoid arthritis--negotiating the NICE technology appraisals.

In England and Wales, the National Institute for Health and Clinical Excellence (NICE) has provided guidance [technology appraisals (TAs) 130, 186, 195, 198 and 225] on the use of biologic drugs for the treatment of RA. This is based on an analysis of efficacy, safety and cost-effectiveness, and has resulted in a complex management pathway that restricts freedom to prescribe biologics according to their licensed indications. Specifically, TNF antagonists are the only class of biologics that can be used first line in DMARD-inadequate responders, and only in patients with a persistent 28-joint DAS score of ≥5.1. Alternative biologic agents are denied to those with contraindications to anti-TNF drugs and are also not supported following intolerance to TNF antagonists. Rituximab is the only class of biologic permitted after TNF antagonist inefficacy, in the absence of a contraindication to its use, whereas abatacept and tocilizumab are licensed and may be a more efficacious choice at this stage in some patient groups. Furthermore, for patients who demonstrate sequential inadequate responses, treatment is restricted to one TNF antagonist, rituximab and tocilizumab, whereas abatacept is only a permitted choice when rituximab is contraindicated or has been withdrawn because of an adverse event. In this review, we discuss the treatment algorithm published by NICE, and suggest alternatives where perceived deficiencies exist.

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.

Reduction of direct and indirect costs in patients with AS receiving etanercept: results from an open-label 36-week extension of the ASCEND study in four European countries.

OBJECTIVE: To characterize the impact of etanercept (ETN) in AS on cost, work productivity and quality of life (QoL). METHODS: A Phase 4, open-label, multi-centre (UK, Scandinavia) extension study in AS. Eligible subjects (n = 84) were treated for 36-52 weeks with ETN 50 mg s.c. once weekly. Analysis included direct costs (transformed out-patient and in-patient care elements), indirect costs (sick leave and lost working days), efficacy and QoL. RESULTS: Annualized direct and indirect costs decreased (55.5%, P ≤ 0.008) during ETN treatment, as did out-patient and in-patient episodes (physiotherapist/physician visits, P = 0.012). Work productivity and QoL increased. CONCLUSION: ETN therapy significantly reduces direct and indirect health-care costs and increases work ability and QoL in AS. Trial Registration. EUDRACT, https://eudract.ema.europa.eu/, 2006-001061-42.

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.

Rheumatoid arthritis and the era of biologic therapy.

Biologic disease modifying anti-rheumatic drugs have transformed the management of rheumatoid arthritis (RA) since their introduction into clinical practice over a decade ago. Following large-scale clinical trials, a number of biologics, with different mechanisms of action, have been licensed for the condition. In this review, we will summarise the current evidence for biologic use in RA with an emphasis on their efficacy and tolerability. In addition, we will provide a commentary on the current limitations and unmet needs in this area and discuss the future of biologic intervention.

Improved patient-reported outcomes in patients with psoriatic arthritis treated with risankizumab: analysis of the Phase 3 trial KEEPsAKE 2.

OBJECTIVES: Determine the impact of 24-week risankizumab (RZB) versus placebo (PBO) on patient-reported outcomes (PROs) in patients with psoriatic arthritis (PsA) and inadequate response to one or two biologics (Bio-IR) and/or ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD-IR). METHODS: Patients in the Phase 3 trial, KEEPsAKE 2, were randomised (1:1) to RZB 150 mg or PBO by subcutaneous injection. PROs assessed: 36-Item Short-Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Patient's Assessment of Pain by visual analogue scale (VAS), Patient's global assessment of disease activity (PtGA), EuroQoL-5 Dimension-5 Level (EQ-5D-5L) and Work Productivity and Activity Impairment-PsA (WPAI-PsA). Least squares mean change from baseline at week 24 was compared between RZB versus PBO by mixed-effects repeated regression modelling. RESULTS: At week 24, RZB versus PBO treatment resulted in significant differences (95% CIs) in mean change from baseline in ranked secondary endpoints SF-36 physical component summary score (3.9 (2.4 to 5.3); p<0.001) and FACIT-Fatigue (2.2 (0.6 to 3.9); p=0.009) and improvements in pain (-8.1 (-12.8 to -3.5)), PtGA (-8.8 (-13.5 to -4.2)) and EQ-5D-5L index (0.08 (0.04 to 0.11)) and VAS (5.9 (1.9 to 9.8)) (all nominal p<0.01). More RZB-treated versus PBO-treated patients reported improvements from baseline at week 24 in 7 of 8 SF-36 subdomains (nominal p<0.05). At week 24, more RZB-treated versus PBO-treated patients reported improvements in 3 of 4 WPAI-PsA domains (nominal p≤0.01). CONCLUSION: Overall, RBZ treatment resulted in improvements in pain, fatigue, health-related quality of life and ability to perform work in Bio-IR and/or csDMARD-IR patients with PsA. TRIAL REGISTRATION NUMBER: NCT03671148.

Effect of upadacitinib on reducing pain in patients with active psoriatic arthritis or ankylosing spondylitis: post hoc analysis of three randomised clinical trials.

OBJECTIVE: Evaluate the effect of upadacitinib on pain outcomes in patients with active psoriatic arthritis (PsA) or ankylosing spondylitis (AS) across 3 randomised trials (SELECT-PsA 1 and 2 for PsA; SELECT-AXIS 1 for AS). METHODS: Patients were randomised to upadacitinib 15 mg once daily or placebo (all 3 studies), or adalimumab 40 mg every other week (SELECT-PsA 1 only). Pain outcomes included proportion of patients achieving ≥30%, ≥50% and ≥70% reduction from baseline in patient global assessment of pain and other end points. RESULTS: A higher proportion of patients receiving upadacitinib versus placebo achieved ≥30%, ≥50% and ≥70% reduction in pain end points as early as week 2; these improvements with upadacitinib were generally sustained or increased through year 1 (PsA 1/2 studies: 64%/48%, 58%/42% and 38%/22%, respectively; SELECT-AXIS 1 study: 76%, 72% and 54%). Results were similar with adalimumab in PsA 1 (59%, 49% and 32%). Patients who switched from placebo to upadacitinib 15 mg were able to reach a similar level of improvement as the continuous upadacitinib groups by year 1 (PsA 1/2 studies: 46%-60%, 35%-49% and 15%-34%; AS study: 83%, 72% and 46%). Results were similar with other pain end points. CONCLUSION: Rapid and sustained improvements in pain outcomes across several end points were consistently shown with upadacitinib over 1 year in patients with active PsA or AS who had either inadequate response to prior non-biologic or biologic disease-modifying antirheumatic drugs (PsA studies) or were biologic-naïve with inadequate response to non-steroidal anti-inflammatory drugs (AS study).