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Management of rheumatoid arthritis
RHEUMATOID ARTHRITIS
Management of rheumatoid arthritis
Key points C
The wide range of consequences of rheumatoid arthritis (RA), including adverse musculoskeletal function, cardiovascular, bone, septic and malignant effects, requires life-long holistic management by a multidisciplinary team
C
The inflammatory response is managed robustly using a treatto-target strategy, in which patients are assessed frequently, and treatment escalated if remission or low disease activity is not achieved
C
Treatment starts with conventional synthetic diseasemodifying antirheumatic drugs (csDMARD) and short-term glucocorticoids. Methotrexate is the anchor DMARD
C
Treatment escalation options when csDMARDs fail include biologic DMARDs targeting tumour necrosis factor, B cells, T cell co-stimulation and interleukin-6, and targeted synthetic DMARDs which inhibit intracellular signalling by Janus kinases
C
The combination of treat-to-target and the expanded range of therapeutic agents has profoundly changed the natural history of RA. Rates of orthopaedic surgery have dropped, mortality principally from cardiovascular disease has reduced, severe erosive deforming joint changes and complications such as vasculitis and amyloidosis are now a rarity
Patrick DW Kiely Elena Nikiphorou
Abstract Successful management of rheumatoid arthritis (RA) requires suppression of the autoimmune response, which results in synovial inflammation, cartilage and bone damage and is associated with a range of extra-articular manifestations including accelerated atherogenesis, cancer and sepsis. The strategy to achieve this is called ‘treat-totarget’ and requires frequent patient review to escalate therapy until remission or at least low disease activity is achieved. Numerous therapeutic agents are licensed to achieve this, starting with glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, followed by four different mode of action biologic DMARDs (targeting tumour necrosis factor, interleukin-6, B cells and T cell co-stimulation) and targeted synthetic DMARDs (inhibitors of JAK). For newly diagnosed patients, especially if treated within 3 months of onset, the outlook is immeasurably better than two decades ago before the treat-to-target strategy and biologic therapies were introduced. As a consequence the outcomes for many newly diagnosed patients include preserved function, maintained quality of life and no impact on mortality. For patients with longstanding disease, further joint damage can be prevented and severe complications of RA such as vasculitis and amyloidosis are now a rarity. Nonetheless RA is an aggressive destructive disease and its tendency to relapse requires disease-long patient review and treatment optimization to maintain control.
promptly, patients can be constrained from functioning or working, with long-lasting effects on mental and physical well-being. Accelerated atherosclerosis and cardiovascular morbidity, infection, some cancers including lymphoma, and chronic mental ill-health are just some of the key co-morbid conditions adding to the lifetime burden of RA and increasing mortality.
Keywords Biologic therapies; co-morbidities; DMARD; MRCP; rheumatoid arthritis; treat-to-target
Introduction Rheumatoid arthritis (RA) is a destructive inflammatory joint disease, principally affecting synovial joints. If not treated
The treat-to-target (T2T) principle and therapeutic window of opportunity Suppression of inflammation represents a key management principle, with the recommended strategy focusing on T2T. This requires the selection of an objective measurement (the target) of remission or low disease activity, frequent reviews and treatment optimization to achieve and maintain this.1The controversies and variability in current practice relate to: the chosen targete whether this should be an inflammation, a patient-reported outcome or a combination of these (Table 1) the necessary frequency of review, enabling treatment escalation if the chosen target has not been achieved; 4e6 weeks is recommended1,2 the choice and sequence of therapeutic agents. It is not clear how ‘deep’ the goal of remission should be in T2T terms (Table 1), for example based on clinical (swollen joint counts, acute-phase markers) and patient-reported (tender joint
Patrick DW Kiely MB BS BSc PhD (Cantab) FRCP is Consultant Rheumatologist at St George’s University Hospitals NHS Foundation Trust, London, UK. He is a founder member of the Early Rheumatoid Arthritis Network and co-author of the 2009 NICE Clinical Guideline for the management of rheumatoid arthritis. Competing interests: Dr Kiely has received support to attend educational meetings from Pfizer, UCB and Abbvie, and honoraria for lectures or advisory board attendance from Abbvie, BMS, Celltrion, Lilly, Napp, Pfizer, Roche, Sanofi. Elena Nikiphorou MB BS/BSc(Intercal) MRCP MD(Res) PGCME FHEA is a Consultant Rheumatologist at the Whittington Hospital, London, and Clinical Researcher at the Academic Rheumatology Department, King’s College London, UK. Her research interests include inflammatory arthritis, co-morbidity and long-term disease outcomes. She is the Chair of the EMerging EULAR NETwork, the largest organization of young rheumatologists across Europe. Competing interests: Dr Nikiphorou has received honoraria for lectures or advisory board attendance from Pfizer.
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RHEUMATOID ARTHRITIS
T2T composite disease activity measures in RA and contributing components Disease activity measure
Components
Interpretation
DAS DAS28
SJC, TJC, ESR/CRP, patient global SJC, TJC, ESR/CRP, patient global
CDAI
SJC, TJC, patient global, physician global
SDAI
SJC, TJC, ESR/CRP, patient global, physician global SJC28, TJC28, ESR/CRP, patient global patient global, pain, HAQa
Remission 1.6 Remission 2.6; disease activity: low 2.6e3.2, moderate 3.3e5.0, high 5.1 Remission 2.8; disease activity: low>2.8 and 10, moderate >10 and 22, high >22 Remission <3.3; disease activity: low 3.4e11, moderate 11.1e26, high 26.1e86 Remission: all scores 1 on a 1e10 scale Remission 3; low severity 3.1e6.0, moderate severity 6.1e12, high severity >12 Patient acceptable status <2, change of 3 or 50% considered relevant
ACR-EULAR Boolean RAPID 3 RAID
Pain, fatigue, functional disability, physical well-being, emotional well-being, coping
CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS, Disease Activity Score based on 53 tender and 44 swollen joint counts; DAS28, Disease Activity Score based on 28 joint counts and either ESR or CRP; ESR, erythrocyte sedimentation rate; HAQ, Health Assessment Questionnaire; RAPID 3, Routine Assessment of Patient Index Data 3; RAID, Rheumatoid Arthritis Impact of Disease; SDAI, Simplified Disease Activity Index; SJC, swollen joint count; TJC, tender joint count. a A subset of core values from the HAQ used in RAPID 3.
Table 1
counts, pain scores, global scores) criteria, or also requiring imaging criteria to be satisfied; these can include the absence of ultrasound power Doppler signal or inflammatory features on magnetic resonance imaging, or even serological remission in those positive for anti-citrullinated peptide antibodies (ACPAs). In contrast, for those presenting late or with established disease, a less stringent target such as low disease activity, rather than remission, is acceptable because the composite measures used to assess RA (Table 1) are influenced by accrued irreversible damage. Much emphasis is rightly placed on early detection, rapid referral and prompt institution of treatment with an aspirational ‘window of opportunity’ of 3 months from symptom onset to commencing disease-modifying treatment. In general terms, patients with newly diagnosed disease presenting with a short history are the most likely to achieve remission (even applying the most stringent remission criteria), if started on treatment within 3 months when a T2T strategy is applied. Securing the diagnosis of RA is crucial to commencing treatment within the window of opportunity. This relies on the person’s health-seeking behaviour and recognition of the features of inflammatory arthritis in primary care. This can be difficult as symptoms of inflammatory joint disease, such as early morning stiffness, precede clinically detectable signs of synovial swelling, as do ACPAs, which can predate symptoms by 10 years or more. To assist early diagnosis, classification criteria for RA, while developed for harmonized enrolment into clinical trials, provide a useful tool in clinical practice.3 In secondary care, ultrasonography has enhanced clinical diagnosis and decision-making by enabling the identification of synovial hypertrophy (Gray scale) and hyperaemia (power Doppler) in cases where symptomatic joints are not clinically swollen.
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Treatment choice The treatment of RA must be based on two-way communication and shared decision-making between the patient and the rheumatologist, with the support of a multidisciplinary team (MDT) including a specialist nurse, physician associate, physiotherapist, occupational therapist and podiatrist.2 Conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDs) For newly diagnosed patients, the cornerstone of pharmacological treatment starts with a combination of fast-acting glucocorticoid (intramuscularly, intra-articularly, orally) and slow-acting csDMARDs to maintain corticosteroid-free disease suppression in the long term. A key principle is administering enough glucocorticoid to reverse the symptoms and signs rapidly, but not an unnecessarily high dose, without treating for too long, to avoid adverse effects on bone density, infection risk, hypertension, glycaemic balance and mental health. csDMARD choices include methotrexate (MTX), hydroxychloroquine, sulfasalazine and leflunomide. Historically, gold and D-penicillamine have been used, but they now have no prominence in routine care. Other immunosuppressing drugs, such as ciclosporin A, tacrolimus, azathioprine, cyclophosphamide and mycophenolate mofetil, although useful in some immune-driven diseases, are generally not favoured in RA, other than in resistant cases. MTX is considered the anchor and firstline csDMARD in RA, either in monotherapy or in combination with other csDMARDs. High disease activity at diagnosis, a large number of involved joints, baseline erosions on plain X-ray, high-titre rheumatoid factor (RF) or ACPA and poor functional scores generally indicate a higher likelihood of erosive and progressive disease, especially if suboptimally treated. The presence of any of these stratifiers
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RHEUMATOID ARTHRITIS
might prompt the decision to use combination csDMARD as a first-line strategy. However, the benefit of a T2T approach is that, by providing regular and frequent review, those patients who fail to reach the chosen target will be identified quickly, providing the opportunity to intensify treatment and increasing the likelihood of remission. Optimization involves using effective doses of DMARDs, often in combination, and maximizing tolerability. Although MTX is the anchor drug, it is associated with sufficiently intrusive adverse effects (e.g. nausea, hair fall, malaise) to limit adherence in some patients, and hence effectiveness. Switching to subcutaneous administration and the use of folic acid up to 5 mg on 6 days a week enables many patients to stay on treatment. Combinations with non-overlapping adverse events, such as MTX and hydroxychloroquine, make causality assessment of these events easier, and the number of tablets to be taken daily (e.g. for sulfasalazine up to eight 500 mg tablets) is an important factor to consider.
natural history of RA, with striking inhibition of erosive damage, maintained function and consequently less need for orthopaedic surgery. However, there is variability in access to and use of these agents, most notably concerning eligibility criteria, with restrictions on their use imposed as a result of high costs. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines indicate that bDMARDs should be prescribed in a T2T model in all patients failing to achieve low disease activity or remission with csDMARDs;2 however, in some countries, including England and Wales, an additional threshold of a high Disease Activity Score (DAS28) of at least 5.1 is required for reimbursed use. This is contrary to the principles of T2T, as it means that patients with a moderate DAS28 score, higher than the least stringent T2T goal (DAS28 3.2, low disease activity) yet not as high as 5.1, are not permitted bDMARDs. Such patients are unlikely to achieve low disease activity with csDMARDs alone, and in the absence of bDMARDs have poor outcomes, including functional disability and end-stage joint destruction necessitating orthopaedic surgery.
Biologic DMARDs (bDMARDs) Approximately 40% of newly diagnosed patients fail to achieve a low disease activity or remission target with csDMARDs, because of either lack of efficacy or poor tolerability at the doses required for efficacy. Furthermore, patients who initially achieve remission when first diagnosed may experience loss of treatment efficacy during the course of their disease, despite combination csDMARDs and corticosteroids. In this situation, a biologic therapy (bDMARD) is used, and in most cases the desired target is then met. If efficacy is not achieved, or is subsequently lost, switching to a different bDMARD is indicated. Five tumour necrosis factor-a inhibitors (TNFis) are currently licensed in the UK for RA, with biosimilars of two of them also available. In addition, bDMARDs with three different modes of action are also licensed for RA (Table 2). All bDMARDs have proven efficacy in RA patients who have failed to respond to MTX, with clinical, functional and structural benefits demonstrated in randomized controlled trials. The standard clinical trial design has been to compare bDMARDs in combination with MTX versus placebo plus MTX. Key findings from studies are summarized in Table 3.
Stratified bDMARD use: although by group analysis there is little to distinguish the efficacy of one class of bDMARD over another, on an individual patient basis there are a number of stratifiers that permit optimal use of some bDMARDs over others in particular situations.4 Thus, to avoid toxicity, TNFis are not favoured in patients with interstitial lung disease, severe cardiac failure or multiple sclerosis; rituximab and abatacept appear safer in these situations. Similarly, tocilizumab is not favoured in patients with diverticular disease. Screening and pre-treatment is mandatory for latent tuberculosis for TNFi use, and hepatitis B before rituximab. Rituximab is also favoured over TNFis in patients with a recent history of lymphoma or malignancy; however, observational studies, albeit limited in terms of duration of follow-up and methodological difficulties, have failed to establish an increased risk of cancer (except non-melanoma skin cancer) in TNFitreated patients. Sero-positivity for RF and ACPA stratifies an optimal response to rituximab (especially in individuals with high total immunoglobulin G) and abatacept (especially in patients with high-titre ACPAs); however, it does not influence response to tocilizumab, and has a less clear impact on response to TNFis. Smoking
Variation in bDMARD use: since the introduction of bDMARDs nearly 20 years ago, there has been a radical change in the
bDMARDs and tsDMARDs and their targets for RA Target
Structure
Licensed agents
TNF
Anti-cytokine mAb
TNF CD20 IL-6 CD28 JAK 1 and 2 JAK 1 and 3
Soluble receptor Fc construct Anti-B cell surface receptor mAb Anti-cytokine receptor mAb CTLA4-Fc construct Chemical inhibitor Chemical inhibitor
Adalimumab, bo; certolizumab, bo; golimumab, bo; infliximab, bo, bs Etanercept, bo, bs Rituximab, bo, bs Tocilizumab, bo; sarilumab, bo Abatacept, bo Baricitinib Tofacitinib
bDMARDs, biologic disease-modifying antirheumatic drugs; bo, bio-originator; bs, biosimilar; IL, interleukin; JAK, Janus kinase; mAb, monoclonal antibody; TNF, tumour necrosis factor; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs.
Table 2
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Key study findings relating to efficacy of bDMARDs First-line biologic use C The outcome with bDMARDs of all classes has been found to be approximately 60% achieving ACR20, 40% achieving ACR50 and 20% achieving ACR70 responses in MTX-IR biologic-naive RA patients compared with continued MTX use with placebo. Thus, on a population basis, in trials of this format, there appears no advantage in terms of efficacy between the differing mode of action bDMARDs used as first-line treatment C In general, all bDMARDs exhibit better efficacy when co-prescribed with MTX. However, poor tolerability of MTX means that bDMARDs are used either with other csDMARDs or in monotherapy in up to a third of patients C The ADACTA and MONARCH trials have demonstrated superiority of anti-interleukin-6 receptor antibody (tocilizumab and sarilumab, respectively) monotherapy over adalimumab monotherapy in MTX-IR patients Second-line biologic use C The proportion of patients who respond to a second bDMARD after failure of response or tolerance to a TNFi is lower than the response seen to a first-line bDMARD, but also remarkably similar across all classes of bDMARDs. Thus, on a population basis, in trials of second-line biologics compared with placebo, there appears no advantage in terms of efficacy between the differing mode of action bDMARDs C In patients who switch from a TNFi to a second bDMARD, the response to a different mode of action biologic is somewhat better than that to a different TNFi on a population basis. Drug levels of some TNFis help to determine whether to use a second TNFi or a different mode of action bDMARD Head-to-head trials of bDMARDs and tsDMARDs C Within class: EXXELERATE demonstrated non-superiority of one TNFi over the other (certolizumab and adalimumab) in RA patients with prognostic factors for severe disease progression C Between class bDMARD trials include ORBIT, which demonstrated non-inferiority of rituximab in comparison to TNFi (adalimumab or etanercept) in seropositive biologic-naive patients, and AMPLE, which demonstrated non-inferiority of adalimumab to to abatacept in MTX-IR patients with early RA C Between class tsDMARDs versus bDMARDs: RA-BEAM has demonstrated superiority of baricitinib over adalimumab in bDMARD-naive MTX-IR patients, and ORAL has demonstrated numerical similarity of efficacy of tofacitinib and adalimumab versus placebo in MTX-IR patients ACR20, American College of Rheumatology (ACR) response of 20%; ACR50, ACR response of 50%; ACR70, ACR response of 70%; bDMARD, biologic disease-modifying antirheumatic drug; csDMARD, conventional synthetic DMARD; tsDMARD, targeted synthetic DMARD; IR, inadequate responder; MTX, methotrexate; RA, rheumatoid arthritis; TNFi, tumour necrosis factor inhibitor.
Table 3
adversely affects outcome with TNFis and abatacept, but seems to have less impact on the efficacy of rituximab and tocilizumab. Obesity also adversely affects outcomes. This can disadvantage patients given fixed-dose TNFi subcutaneous formulations as opposed to intravenous formulations dosed according to weight. For this reason, golimumab is recommended in high doses for patients weighing >100 kg. However, fixed-dose subcutaneous tocilizumab and abatacept are equally effective in head-to-head trials when compared with intravenous formulations dosed according to weight across all body mass index categories, although the magnitude of response is lower in patients weighing >100 kg. In contrast the response to rituximab is not influenced by body mass index.
drug concentration is subtherapeutic, non-adherence or the presence of neutralizing anti-drug antibodies is the likely explanation (rather than TNF inhibition being an inappropriate mode of action); therefore switching within class to another TNFi is as logical as changing to a different class of bDMARD in this situation.4 It is now commonplace to attempt dose reduction of csDMARDs and bDMARDs in patients who have achieved sustained remission (e.g. over a period of 1 year). A high proportion of patients have supratherapeutic concentrations of TNFis, and as many as 80% maintain good responses after dose reduction of bDMARDs. This is achieved by prolonging the interval between doses of subcutaneously or intravenously delivered therapies, or using lower doses, such as etanercept 25 mg, if commercially available. The next major advance in RA management will probably come from personalized medicine, enabling immediate selection of the correct drug at the correct dose first time.
Switching between bDMARDs: in patients who fail to respond, or lose efficacy to a bDMARD over time, it is usual practice to switch to a different bDMARD. Across all studies, the efficacy, in terms of ACR composite responses, is lower in patients given a second (or third) bDMARD compared with the response following first bDMARD use. This reflects our inability to select the correct mode of action bDMARD on an individual patient basis, as we lack patient-specific (as opposed to population) predictive biomarkers of efficacy and tolerability. In patients who lose response to a TNFi, the decision to switch to another TNFi or a different mode of action bDMARD can be assisted by measuring drug levels for adalimumab and certolizumab. If the drug concentration is in the therapeutic range, the lack of efficacy is likely to be related to an incorrect mode of action, so a non-TNFi is the logical next choice. However, if the
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Targeted synthetic DMARDS (tsDMARDs) A new therapeutic class of DMARDs that inhibit the intracellular enzymes Janus kinases (JAKs) have recently been licensed (Table 2). When cytokines, hormones or growth factors bind to cell surface receptors, this triggers an intracellular activation of JAKs that ultimately enables mediation of the effects of this cell surface binding to take place at the nucleus e known as intracellular signalling. JAK inhibitors are synthetic chemical compounds that inhibit JAK activation and thereby perturb the intracellular signalling
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RHEUMATOID ARTHRITIS
counteract the increased cardiovascular mortality in RA patents. Optimizing bone health with vitamin D3 supplements and, where necessary, bone-sparing therapies such as bisphosphonates is also important, as both RA and glucocorticoid therapy are associated with reduced bone mineral density and osteoporosis. There is evidence that all these extra-articular sequelae are ameliorated if remission is achieved and maintained. For example in the Dutch Behandel Strategieen (BeSt) trial, participants with sustained remission (DAS <2.4) over 10 years demonstrated a survival rate comparable to that of the general population, irrespective of treatment arm. To ensure good outcomes, an essential feature of long-term care is a holistic review by the MDT, at least annually, to assess and treat co-morbidities and the other varied consequences of RA. A
that follows cytokine binding to cellular receptors. They have been called ‘targeted synthetic DMARDs’ (tsDMARDS) as their structure and mechanism of action are distinct from those of csDMARDs and bDMARDs. Clinical trials have demonstrated efficacy of tsDMARDs across composite disease activity and structural outcomes in csDMARD-naive, csDMARD inadequate responder and bDMARD inadequate responder patients. tsDMARDs are orally available, rapid in onset of action and have a similar order of magnitude of efficacy to bDMARDs (Table 3). The unique mode of action, oral bioavailability, efficacy as monotherapy and rapid onset of action make them an attractive treatment option. However, as with bDMARDs, observational post-marketing surveillance is necessary to confirm trial data and long-term tolerability.
Other considerations
KEY REFERENCES 1 Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010; 69: 631e7. R, Bijlsma J, et al. EULAR recommendations 2 Smolen JS, Landewe for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017; 76: 960e77. 3 Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62: 2569e81. 4 Kiely PDW. Biologic efficacy optimisation. A step towards personalised medicine. Rheumatol 2016; 55: 780e8. 5 Ledingham J, Gullick N, Irving K, et al. BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying antirheumatic drugs. Rheumatol 2017; 56: 865e8.
Notwithstanding the challenge of monitoring and achieving sustained low disease activity or remission in RA, an important part of disease management includes awareness and monitoring of toxicity across the spectrum of DMARDs. All licensed agents ecsDMARDs, tsDMARDs and bDMARDs e have clearly defined toxicities and monitoring requirements to detect and minimize these. Increased risk of sepsis is of paramount concern, and prompt recognition and treatment is important. Some agents and classes of agents have specific toxicities and monitoring requirements, fully explained in the product characteristics, with guidelines how to manage these recently updated for csDMARDs.5 Beyond the joints, the consequences of unsuppressed inflammation for RA patients include an increased risk of significant adverse cardiovascular outcomes, including accelerated atherogenesis, serious infections, lymphoma and some cancers, with reduced life expectancy as a consequence. The MDT has an important role in ensuring that cardiovascular risk factors such as blood pressure, lipids and HbA1c are monitored and treated to
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. Which of the features in this presentation increases her chance of achieving long-term remission? A She has symmetrical involvement of the wrists, metacarpophalangeal joints and knees B She has a low CRP concentration C She is RF- and ACPA-positive D She has been started on treatment within 3 months of symptom onset E She has been given combination csDMARDs and bridging prednisolone
Question 1 A 45-year-old woman presented with a 2-month history of early morning stiffness in the wrists, fingers and knees. On clinical examination, there was soft tissue swelling of the right wrist and the right and left second and third metacarpophalangeal joints, and an effusion in the left knee. Investigations C-reactive protein (CRP) 11 mg/litre (<10) Rheumatoid factor (RF) 45 kIU/litre (<30) Anti-citrullinated peptide antibodies (ACPA) 200 U/ml (<73)
Question 2 A 29-year-old woman presented with a 6-month history of early morning stiffness and joint pain affecting the shoulders, wrists, fingers, knees and toes. On clinical examination, there was painful restriction of shoulder, wrist and knee movement. There
She is found to have rheumatoid arthritis, and treatment with combination conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and bridging prednisolone is started.
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was also soft tissue swelling and tenderness of the wrists, metacarpophalangeal joints, proximal interphalangeal joints and knees, and tenderness of all the metatarsophalangeal joints.
Question 3 A 56-year-old man with RF and ACPA positive early rheumatoid arthritis had failed to achieve remission with combination csDMARDs including methotrexate. He smoked 10 cigarettes per day and his body mass index was 35. His Disease Activity Score (DAS28) score was 5.3 and he was eligible for biologic DMARD treatment.
Investigations CRP 57 mg/litre (<10) RF 20 kIU/litre (<30) Anti-citrullinated peptide antibodies (ACPA) negative X-rays of the feet showed small metatarsophalangeal joint erosions
Which of the following is most likely to have a negative impact on treatment optimization to TNFi? A Choice of i.v. monoclonal antibody (mAb) rather than subcutaneous mAb B Gender C He smokes D He is RF and ACPA positive E His DAS is >5.1
Which of the following is least likely to be associated with a poor prognostic outcome? A Her age of presentation is less than 30 years B She has a high number of affected joints C The RF and ACPA are negative D She has had symptoms for 6 months E She has erosive disease
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Management of rheumatoid arthritis
Key points C
The wide range of consequences of rheumatoid arthritis (RA), including adverse musculoskeletal function, cardiovascular, bone, septic and malignant effects, requires life-long holistic management by a multidisciplinary team
C
The inflammatory response is managed robustly using a treatto-target strategy, in which patients are assessed frequently, and treatment escalated if remission or low disease activity is not achieved
C
Treatment starts with conventional synthetic diseasemodifying antirheumatic drugs (csDMARD) and short-term glucocorticoids. Methotrexate is the anchor DMARD
C
Treatment escalation options when csDMARDs fail include biologic DMARDs targeting tumour necrosis factor, B cells, T cell co-stimulation and interleukin-6, and targeted synthetic DMARDs which inhibit intracellular signalling by Janus kinases
C
The combination of treat-to-target and the expanded range of therapeutic agents has profoundly changed the natural history of RA. Rates of orthopaedic surgery have dropped, mortality principally from cardiovascular disease has reduced, severe erosive deforming joint changes and complications such as vasculitis and amyloidosis are now a rarity
Patrick DW Kiely Elena Nikiphorou
Abstract Successful management of rheumatoid arthritis (RA) requires suppression of the autoimmune response, which results in synovial inflammation, cartilage and bone damage and is associated with a range of extra-articular manifestations including accelerated atherogenesis, cancer and sepsis. The strategy to achieve this is called ‘treat-totarget’ and requires frequent patient review to escalate therapy until remission or at least low disease activity is achieved. Numerous therapeutic agents are licensed to achieve this, starting with glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, followed by four different mode of action biologic DMARDs (targeting tumour necrosis factor, interleukin-6, B cells and T cell co-stimulation) and targeted synthetic DMARDs (inhibitors of JAK). For newly diagnosed patients, especially if treated within 3 months of onset, the outlook is immeasurably better than two decades ago before the treat-to-target strategy and biologic therapies were introduced. As a consequence the outcomes for many newly diagnosed patients include preserved function, maintained quality of life and no impact on mortality. For patients with longstanding disease, further joint damage can be prevented and severe complications of RA such as vasculitis and amyloidosis are now a rarity. Nonetheless RA is an aggressive destructive disease and its tendency to relapse requires disease-long patient review and treatment optimization to maintain control.
promptly, patients can be constrained from functioning or working, with long-lasting effects on mental and physical well-being. Accelerated atherosclerosis and cardiovascular morbidity, infection, some cancers including lymphoma, and chronic mental ill-health are just some of the key co-morbid conditions adding to the lifetime burden of RA and increasing mortality.
Keywords Biologic therapies; co-morbidities; DMARD; MRCP; rheumatoid arthritis; treat-to-target
Introduction Rheumatoid arthritis (RA) is a destructive inflammatory joint disease, principally affecting synovial joints. If not treated
The treat-to-target (T2T) principle and therapeutic window of opportunity Suppression of inflammation represents a key management principle, with the recommended strategy focusing on T2T. This requires the selection of an objective measurement (the target) of remission or low disease activity, frequent reviews and treatment optimization to achieve and maintain this.1The controversies and variability in current practice relate to: the chosen targete whether this should be an inflammation, a patient-reported outcome or a combination of these (Table 1) the necessary frequency of review, enabling treatment escalation if the chosen target has not been achieved; 4e6 weeks is recommended1,2 the choice and sequence of therapeutic agents. It is not clear how ‘deep’ the goal of remission should be in T2T terms (Table 1), for example based on clinical (swollen joint counts, acute-phase markers) and patient-reported (tender joint
Patrick DW Kiely MB BS BSc PhD (Cantab) FRCP is Consultant Rheumatologist at St George’s University Hospitals NHS Foundation Trust, London, UK. He is a founder member of the Early Rheumatoid Arthritis Network and co-author of the 2009 NICE Clinical Guideline for the management of rheumatoid arthritis. Competing interests: Dr Kiely has received support to attend educational meetings from Pfizer, UCB and Abbvie, and honoraria for lectures or advisory board attendance from Abbvie, BMS, Celltrion, Lilly, Napp, Pfizer, Roche, Sanofi. Elena Nikiphorou MB BS/BSc(Intercal) MRCP MD(Res) PGCME FHEA is a Consultant Rheumatologist at the Whittington Hospital, London, and Clinical Researcher at the Academic Rheumatology Department, King’s College London, UK. Her research interests include inflammatory arthritis, co-morbidity and long-term disease outcomes. She is the Chair of the EMerging EULAR NETwork, the largest organization of young rheumatologists across Europe. Competing interests: Dr Nikiphorou has received honoraria for lectures or advisory board attendance from Pfizer.
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T2T composite disease activity measures in RA and contributing components Disease activity measure
Components
Interpretation
DAS DAS28
SJC, TJC, ESR/CRP, patient global SJC, TJC, ESR/CRP, patient global
CDAI
SJC, TJC, patient global, physician global
SDAI
SJC, TJC, ESR/CRP, patient global, physician global SJC28, TJC28, ESR/CRP, patient global patient global, pain, HAQa
Remission 1.6 Remission 2.6; disease activity: low 2.6e3.2, moderate 3.3e5.0, high 5.1 Remission 2.8; disease activity: low>2.8 and 10, moderate >10 and 22, high >22 Remission <3.3; disease activity: low 3.4e11, moderate 11.1e26, high 26.1e86 Remission: all scores 1 on a 1e10 scale Remission 3; low severity 3.1e6.0, moderate severity 6.1e12, high severity >12 Patient acceptable status <2, change of 3 or 50% considered relevant
ACR-EULAR Boolean RAPID 3 RAID
Pain, fatigue, functional disability, physical well-being, emotional well-being, coping
CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS, Disease Activity Score based on 53 tender and 44 swollen joint counts; DAS28, Disease Activity Score based on 28 joint counts and either ESR or CRP; ESR, erythrocyte sedimentation rate; HAQ, Health Assessment Questionnaire; RAPID 3, Routine Assessment of Patient Index Data 3; RAID, Rheumatoid Arthritis Impact of Disease; SDAI, Simplified Disease Activity Index; SJC, swollen joint count; TJC, tender joint count. a A subset of core values from the HAQ used in RAPID 3.
Table 1
counts, pain scores, global scores) criteria, or also requiring imaging criteria to be satisfied; these can include the absence of ultrasound power Doppler signal or inflammatory features on magnetic resonance imaging, or even serological remission in those positive for anti-citrullinated peptide antibodies (ACPAs). In contrast, for those presenting late or with established disease, a less stringent target such as low disease activity, rather than remission, is acceptable because the composite measures used to assess RA (Table 1) are influenced by accrued irreversible damage. Much emphasis is rightly placed on early detection, rapid referral and prompt institution of treatment with an aspirational ‘window of opportunity’ of 3 months from symptom onset to commencing disease-modifying treatment. In general terms, patients with newly diagnosed disease presenting with a short history are the most likely to achieve remission (even applying the most stringent remission criteria), if started on treatment within 3 months when a T2T strategy is applied. Securing the diagnosis of RA is crucial to commencing treatment within the window of opportunity. This relies on the person’s health-seeking behaviour and recognition of the features of inflammatory arthritis in primary care. This can be difficult as symptoms of inflammatory joint disease, such as early morning stiffness, precede clinically detectable signs of synovial swelling, as do ACPAs, which can predate symptoms by 10 years or more. To assist early diagnosis, classification criteria for RA, while developed for harmonized enrolment into clinical trials, provide a useful tool in clinical practice.3 In secondary care, ultrasonography has enhanced clinical diagnosis and decision-making by enabling the identification of synovial hypertrophy (Gray scale) and hyperaemia (power Doppler) in cases where symptomatic joints are not clinically swollen.
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Treatment choice The treatment of RA must be based on two-way communication and shared decision-making between the patient and the rheumatologist, with the support of a multidisciplinary team (MDT) including a specialist nurse, physician associate, physiotherapist, occupational therapist and podiatrist.2 Conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDs) For newly diagnosed patients, the cornerstone of pharmacological treatment starts with a combination of fast-acting glucocorticoid (intramuscularly, intra-articularly, orally) and slow-acting csDMARDs to maintain corticosteroid-free disease suppression in the long term. A key principle is administering enough glucocorticoid to reverse the symptoms and signs rapidly, but not an unnecessarily high dose, without treating for too long, to avoid adverse effects on bone density, infection risk, hypertension, glycaemic balance and mental health. csDMARD choices include methotrexate (MTX), hydroxychloroquine, sulfasalazine and leflunomide. Historically, gold and D-penicillamine have been used, but they now have no prominence in routine care. Other immunosuppressing drugs, such as ciclosporin A, tacrolimus, azathioprine, cyclophosphamide and mycophenolate mofetil, although useful in some immune-driven diseases, are generally not favoured in RA, other than in resistant cases. MTX is considered the anchor and firstline csDMARD in RA, either in monotherapy or in combination with other csDMARDs. High disease activity at diagnosis, a large number of involved joints, baseline erosions on plain X-ray, high-titre rheumatoid factor (RF) or ACPA and poor functional scores generally indicate a higher likelihood of erosive and progressive disease, especially if suboptimally treated. The presence of any of these stratifiers
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might prompt the decision to use combination csDMARD as a first-line strategy. However, the benefit of a T2T approach is that, by providing regular and frequent review, those patients who fail to reach the chosen target will be identified quickly, providing the opportunity to intensify treatment and increasing the likelihood of remission. Optimization involves using effective doses of DMARDs, often in combination, and maximizing tolerability. Although MTX is the anchor drug, it is associated with sufficiently intrusive adverse effects (e.g. nausea, hair fall, malaise) to limit adherence in some patients, and hence effectiveness. Switching to subcutaneous administration and the use of folic acid up to 5 mg on 6 days a week enables many patients to stay on treatment. Combinations with non-overlapping adverse events, such as MTX and hydroxychloroquine, make causality assessment of these events easier, and the number of tablets to be taken daily (e.g. for sulfasalazine up to eight 500 mg tablets) is an important factor to consider.
natural history of RA, with striking inhibition of erosive damage, maintained function and consequently less need for orthopaedic surgery. However, there is variability in access to and use of these agents, most notably concerning eligibility criteria, with restrictions on their use imposed as a result of high costs. European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) guidelines indicate that bDMARDs should be prescribed in a T2T model in all patients failing to achieve low disease activity or remission with csDMARDs;2 however, in some countries, including England and Wales, an additional threshold of a high Disease Activity Score (DAS28) of at least 5.1 is required for reimbursed use. This is contrary to the principles of T2T, as it means that patients with a moderate DAS28 score, higher than the least stringent T2T goal (DAS28 3.2, low disease activity) yet not as high as 5.1, are not permitted bDMARDs. Such patients are unlikely to achieve low disease activity with csDMARDs alone, and in the absence of bDMARDs have poor outcomes, including functional disability and end-stage joint destruction necessitating orthopaedic surgery.
Biologic DMARDs (bDMARDs) Approximately 40% of newly diagnosed patients fail to achieve a low disease activity or remission target with csDMARDs, because of either lack of efficacy or poor tolerability at the doses required for efficacy. Furthermore, patients who initially achieve remission when first diagnosed may experience loss of treatment efficacy during the course of their disease, despite combination csDMARDs and corticosteroids. In this situation, a biologic therapy (bDMARD) is used, and in most cases the desired target is then met. If efficacy is not achieved, or is subsequently lost, switching to a different bDMARD is indicated. Five tumour necrosis factor-a inhibitors (TNFis) are currently licensed in the UK for RA, with biosimilars of two of them also available. In addition, bDMARDs with three different modes of action are also licensed for RA (Table 2). All bDMARDs have proven efficacy in RA patients who have failed to respond to MTX, with clinical, functional and structural benefits demonstrated in randomized controlled trials. The standard clinical trial design has been to compare bDMARDs in combination with MTX versus placebo plus MTX. Key findings from studies are summarized in Table 3.
Stratified bDMARD use: although by group analysis there is little to distinguish the efficacy of one class of bDMARD over another, on an individual patient basis there are a number of stratifiers that permit optimal use of some bDMARDs over others in particular situations.4 Thus, to avoid toxicity, TNFis are not favoured in patients with interstitial lung disease, severe cardiac failure or multiple sclerosis; rituximab and abatacept appear safer in these situations. Similarly, tocilizumab is not favoured in patients with diverticular disease. Screening and pre-treatment is mandatory for latent tuberculosis for TNFi use, and hepatitis B before rituximab. Rituximab is also favoured over TNFis in patients with a recent history of lymphoma or malignancy; however, observational studies, albeit limited in terms of duration of follow-up and methodological difficulties, have failed to establish an increased risk of cancer (except non-melanoma skin cancer) in TNFitreated patients. Sero-positivity for RF and ACPA stratifies an optimal response to rituximab (especially in individuals with high total immunoglobulin G) and abatacept (especially in patients with high-titre ACPAs); however, it does not influence response to tocilizumab, and has a less clear impact on response to TNFis. Smoking
Variation in bDMARD use: since the introduction of bDMARDs nearly 20 years ago, there has been a radical change in the
bDMARDs and tsDMARDs and their targets for RA Target
Structure
Licensed agents
TNF
Anti-cytokine mAb
TNF CD20 IL-6 CD28 JAK 1 and 2 JAK 1 and 3
Soluble receptor Fc construct Anti-B cell surface receptor mAb Anti-cytokine receptor mAb CTLA4-Fc construct Chemical inhibitor Chemical inhibitor
Adalimumab, bo; certolizumab, bo; golimumab, bo; infliximab, bo, bs Etanercept, bo, bs Rituximab, bo, bs Tocilizumab, bo; sarilumab, bo Abatacept, bo Baricitinib Tofacitinib
bDMARDs, biologic disease-modifying antirheumatic drugs; bo, bio-originator; bs, biosimilar; IL, interleukin; JAK, Janus kinase; mAb, monoclonal antibody; TNF, tumour necrosis factor; tsDMARDs, targeted synthetic disease-modifying antirheumatic drugs.
Table 2
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Key study findings relating to efficacy of bDMARDs First-line biologic use C The outcome with bDMARDs of all classes has been found to be approximately 60% achieving ACR20, 40% achieving ACR50 and 20% achieving ACR70 responses in MTX-IR biologic-naive RA patients compared with continued MTX use with placebo. Thus, on a population basis, in trials of this format, there appears no advantage in terms of efficacy between the differing mode of action bDMARDs used as first-line treatment C In general, all bDMARDs exhibit better efficacy when co-prescribed with MTX. However, poor tolerability of MTX means that bDMARDs are used either with other csDMARDs or in monotherapy in up to a third of patients C The ADACTA and MONARCH trials have demonstrated superiority of anti-interleukin-6 receptor antibody (tocilizumab and sarilumab, respectively) monotherapy over adalimumab monotherapy in MTX-IR patients Second-line biologic use C The proportion of patients who respond to a second bDMARD after failure of response or tolerance to a TNFi is lower than the response seen to a first-line bDMARD, but also remarkably similar across all classes of bDMARDs. Thus, on a population basis, in trials of second-line biologics compared with placebo, there appears no advantage in terms of efficacy between the differing mode of action bDMARDs C In patients who switch from a TNFi to a second bDMARD, the response to a different mode of action biologic is somewhat better than that to a different TNFi on a population basis. Drug levels of some TNFis help to determine whether to use a second TNFi or a different mode of action bDMARD Head-to-head trials of bDMARDs and tsDMARDs C Within class: EXXELERATE demonstrated non-superiority of one TNFi over the other (certolizumab and adalimumab) in RA patients with prognostic factors for severe disease progression C Between class bDMARD trials include ORBIT, which demonstrated non-inferiority of rituximab in comparison to TNFi (adalimumab or etanercept) in seropositive biologic-naive patients, and AMPLE, which demonstrated non-inferiority of adalimumab to to abatacept in MTX-IR patients with early RA C Between class tsDMARDs versus bDMARDs: RA-BEAM has demonstrated superiority of baricitinib over adalimumab in bDMARD-naive MTX-IR patients, and ORAL has demonstrated numerical similarity of efficacy of tofacitinib and adalimumab versus placebo in MTX-IR patients ACR20, American College of Rheumatology (ACR) response of 20%; ACR50, ACR response of 50%; ACR70, ACR response of 70%; bDMARD, biologic disease-modifying antirheumatic drug; csDMARD, conventional synthetic DMARD; tsDMARD, targeted synthetic DMARD; IR, inadequate responder; MTX, methotrexate; RA, rheumatoid arthritis; TNFi, tumour necrosis factor inhibitor.
Table 3
adversely affects outcome with TNFis and abatacept, but seems to have less impact on the efficacy of rituximab and tocilizumab. Obesity also adversely affects outcomes. This can disadvantage patients given fixed-dose TNFi subcutaneous formulations as opposed to intravenous formulations dosed according to weight. For this reason, golimumab is recommended in high doses for patients weighing >100 kg. However, fixed-dose subcutaneous tocilizumab and abatacept are equally effective in head-to-head trials when compared with intravenous formulations dosed according to weight across all body mass index categories, although the magnitude of response is lower in patients weighing >100 kg. In contrast the response to rituximab is not influenced by body mass index.
drug concentration is subtherapeutic, non-adherence or the presence of neutralizing anti-drug antibodies is the likely explanation (rather than TNF inhibition being an inappropriate mode of action); therefore switching within class to another TNFi is as logical as changing to a different class of bDMARD in this situation.4 It is now commonplace to attempt dose reduction of csDMARDs and bDMARDs in patients who have achieved sustained remission (e.g. over a period of 1 year). A high proportion of patients have supratherapeutic concentrations of TNFis, and as many as 80% maintain good responses after dose reduction of bDMARDs. This is achieved by prolonging the interval between doses of subcutaneously or intravenously delivered therapies, or using lower doses, such as etanercept 25 mg, if commercially available. The next major advance in RA management will probably come from personalized medicine, enabling immediate selection of the correct drug at the correct dose first time.
Switching between bDMARDs: in patients who fail to respond, or lose efficacy to a bDMARD over time, it is usual practice to switch to a different bDMARD. Across all studies, the efficacy, in terms of ACR composite responses, is lower in patients given a second (or third) bDMARD compared with the response following first bDMARD use. This reflects our inability to select the correct mode of action bDMARD on an individual patient basis, as we lack patient-specific (as opposed to population) predictive biomarkers of efficacy and tolerability. In patients who lose response to a TNFi, the decision to switch to another TNFi or a different mode of action bDMARD can be assisted by measuring drug levels for adalimumab and certolizumab. If the drug concentration is in the therapeutic range, the lack of efficacy is likely to be related to an incorrect mode of action, so a non-TNFi is the logical next choice. However, if the
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Targeted synthetic DMARDS (tsDMARDs) A new therapeutic class of DMARDs that inhibit the intracellular enzymes Janus kinases (JAKs) have recently been licensed (Table 2). When cytokines, hormones or growth factors bind to cell surface receptors, this triggers an intracellular activation of JAKs that ultimately enables mediation of the effects of this cell surface binding to take place at the nucleus e known as intracellular signalling. JAK inhibitors are synthetic chemical compounds that inhibit JAK activation and thereby perturb the intracellular signalling
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counteract the increased cardiovascular mortality in RA patents. Optimizing bone health with vitamin D3 supplements and, where necessary, bone-sparing therapies such as bisphosphonates is also important, as both RA and glucocorticoid therapy are associated with reduced bone mineral density and osteoporosis. There is evidence that all these extra-articular sequelae are ameliorated if remission is achieved and maintained. For example in the Dutch Behandel Strategieen (BeSt) trial, participants with sustained remission (DAS <2.4) over 10 years demonstrated a survival rate comparable to that of the general population, irrespective of treatment arm. To ensure good outcomes, an essential feature of long-term care is a holistic review by the MDT, at least annually, to assess and treat co-morbidities and the other varied consequences of RA. A
that follows cytokine binding to cellular receptors. They have been called ‘targeted synthetic DMARDs’ (tsDMARDS) as their structure and mechanism of action are distinct from those of csDMARDs and bDMARDs. Clinical trials have demonstrated efficacy of tsDMARDs across composite disease activity and structural outcomes in csDMARD-naive, csDMARD inadequate responder and bDMARD inadequate responder patients. tsDMARDs are orally available, rapid in onset of action and have a similar order of magnitude of efficacy to bDMARDs (Table 3). The unique mode of action, oral bioavailability, efficacy as monotherapy and rapid onset of action make them an attractive treatment option. However, as with bDMARDs, observational post-marketing surveillance is necessary to confirm trial data and long-term tolerability.
Other considerations
KEY REFERENCES 1 Smolen JS, Aletaha D, Bijlsma JW, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010; 69: 631e7. R, Bijlsma J, et al. EULAR recommendations 2 Smolen JS, Landewe for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017; 76: 960e77. 3 Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62: 2569e81. 4 Kiely PDW. Biologic efficacy optimisation. A step towards personalised medicine. Rheumatol 2016; 55: 780e8. 5 Ledingham J, Gullick N, Irving K, et al. BSR and BHPR guideline for the prescription and monitoring of non-biologic disease-modifying antirheumatic drugs. Rheumatol 2017; 56: 865e8.
Notwithstanding the challenge of monitoring and achieving sustained low disease activity or remission in RA, an important part of disease management includes awareness and monitoring of toxicity across the spectrum of DMARDs. All licensed agents ecsDMARDs, tsDMARDs and bDMARDs e have clearly defined toxicities and monitoring requirements to detect and minimize these. Increased risk of sepsis is of paramount concern, and prompt recognition and treatment is important. Some agents and classes of agents have specific toxicities and monitoring requirements, fully explained in the product characteristics, with guidelines how to manage these recently updated for csDMARDs.5 Beyond the joints, the consequences of unsuppressed inflammation for RA patients include an increased risk of significant adverse cardiovascular outcomes, including accelerated atherogenesis, serious infections, lymphoma and some cancers, with reduced life expectancy as a consequence. The MDT has an important role in ensuring that cardiovascular risk factors such as blood pressure, lipids and HbA1c are monitored and treated to
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here. Which of the features in this presentation increases her chance of achieving long-term remission? A She has symmetrical involvement of the wrists, metacarpophalangeal joints and knees B She has a low CRP concentration C She is RF- and ACPA-positive D She has been started on treatment within 3 months of symptom onset E She has been given combination csDMARDs and bridging prednisolone
Question 1 A 45-year-old woman presented with a 2-month history of early morning stiffness in the wrists, fingers and knees. On clinical examination, there was soft tissue swelling of the right wrist and the right and left second and third metacarpophalangeal joints, and an effusion in the left knee. Investigations C-reactive protein (CRP) 11 mg/litre (<10) Rheumatoid factor (RF) 45 kIU/litre (<30) Anti-citrullinated peptide antibodies (ACPA) 200 U/ml (<73)
Question 2 A 29-year-old woman presented with a 6-month history of early morning stiffness and joint pain affecting the shoulders, wrists, fingers, knees and toes. On clinical examination, there was painful restriction of shoulder, wrist and knee movement. There
She is found to have rheumatoid arthritis, and treatment with combination conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and bridging prednisolone is started.
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was also soft tissue swelling and tenderness of the wrists, metacarpophalangeal joints, proximal interphalangeal joints and knees, and tenderness of all the metatarsophalangeal joints.
Question 3 A 56-year-old man with RF and ACPA positive early rheumatoid arthritis had failed to achieve remission with combination csDMARDs including methotrexate. He smoked 10 cigarettes per day and his body mass index was 35. His Disease Activity Score (DAS28) score was 5.3 and he was eligible for biologic DMARD treatment.
Investigations CRP 57 mg/litre (<10) RF 20 kIU/litre (<30) Anti-citrullinated peptide antibodies (ACPA) negative X-rays of the feet showed small metatarsophalangeal joint erosions
Which of the following is most likely to have a negative impact on treatment optimization to TNFi? A Choice of i.v. monoclonal antibody (mAb) rather than subcutaneous mAb B Gender C He smokes D He is RF and ACPA positive E His DAS is >5.1
Which of the following is least likely to be associated with a poor prognostic outcome? A Her age of presentation is less than 30 years B She has a high number of affected joints C The RF and ACPA are negative D She has had symptoms for 6 months E She has erosive disease
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