Updated guidelines to managing rheumatoid arthritis (RA) include a treat-to-target strategy using a composite disease activity score, with frequent follow-up and escalation or switching of disease-modifying anti-rheumatic drug (DMARD) therapy.
In the SA Medical Journal, G Tarr, N Govind, M Seboka, E Gardiner and B Hodkinson review the guidelines for RA, te chronic disease which interferes with physical function, work productivity and health-related quality of life.
They say despite improvements in therapies over the past three decades, a third of these patients report work disability within five years of diagnosis, while their mental and physical quality of scores are worse than those of patients with other chronic illnesses like cardiovascular disease and diabetes.
Active disease can lead to irreversible joint damage, which is frequently associated with permanent functional disability, emphasising the importance of early aggressive therapy to control disease activity.
Monitoring and modification of therapy, including multiple successive therapies, may be required; up to 60% of patients will not meet treatment goals after their first disease-modifying anti-rheumatic drug (DMARD), and >60% of these will require at least a third DMARD course. With optimal treatment strategies, remission or low disease activity (LDA) can be achieved in up to 80% of patients.[3] In poorly resourced areas, outcomes tend to be worse.
Early diagnosis
Joint damage begins within the first three months of disease onset. There is a “window of opportunity” where early aggressive therapy can suppress inflammation before irreversible joint destruction has occurred. Early diagnosis and initiation of DMARD therapy are therefore critical.
Assessment
A composite disease activity score should be performed at every visit, which includes the number of tender and swollen joints (using 28 joint counts); global assessment of disease activity from the patient (‘How has your arthritis been over the last week?’), scoring between zero (very well) and 10 (very poor); and global assessment of disease activity by the physician, scoring between zero (very well) and 10 (very poor), with or without a serum acute-phase reactant. Disease activity can be classified into states of remission or low, moderate or high disease activity.
Disability
Physical disability can be measured with the Health Assessment Questionnaire-Disability Index – the self-administered questionnaire should ideally be completed six-12-monthly.
Radiography
Baseline hand and feet radiographs should be performed for diagnostic (marginal erosions, joint space narrowing and juxta articular osteopenia) and prognostic purposes. These images are not sensitive enough to detect changes early in the disease, but are readily available, reliable and low in cost. A chest radiograph can exclude rheumatoid lung disease or TB before therapy starts.
Musculoskeletal ultrasound
High-resolution musculoskeletal ultrasound (MSUS) is safe and relatively inexpensive, and allows accurate assessment of soft-tissue inflammation and joint erosions, and placement of intra-articular injections that is superior to clinical examination. And MRI, particularly contrast-enhanced MRI, is highly sensitive, demonstrating synovitis and tenosynovitis, and can detect erosions up to three years before they are evident on conventional radiographs.
Imaging in the diagnosis and management of RA
While MSUS-detected tenosynovial hypertrophy with Doppler signal and MRI-detected tenosynovitis at the metatarsophalangeal joints are very specific for RA, recent studies have found that MRI and MSUS did not add value to the diagnosis of RA compared with the 2010 ACR/EULAR classification criteria. MSUS is useful when there is diagnostic doubt.
At present, MSUS and MRI scans are not part of routine diagnosis and should be used to visualise soft-tissue and bone lesions of a problem joint, or to confirm or exclude synovitis where there is clinical uncertainty. Regular routine imaging of RA joints is not necessary.
Patient information and decision-making
The aim of treatment is to maintain a good quality of life and physical function, so a management plan should be developed based on shared decision-making between patients and clinicians, predicated on patients’ values, goals, preferences and comorbidities.
Goal of therapy
The goal of therapy is to achieve at least LDA, i.e, CDAI ≤10. Remission, or a state of no disease activity, may be defined by a composite disease activity score or by ACR/EULAR remission criteria. While remission is a reasonable goal for patients with early disease, aiming for remission may not be realistic for all RA patients.
Patients who achieve LDA/remission have a low risk of damage progression compared with those with moderate or high disease activity states, with better physical function, improved HRQoL, and fewer comorbidities including normalisation of cardiovascular risk factors, particularly when therapy is started in early disease.
DMARDs
These agents are divided into three broad groups: conventional synthetic (csDMARDs), biologic (bDMARDs) and targeted synthetic DMARDs (tsDMARDs). csDMARDs to treat RA include methotrexate (MTX), leflunomide (LEF), sulfasalazine (SSZ) and antimalarials (AMAs).
bDMARDs may be either biologic original (boDMARDs) or biosimilar (bsDMARDs). Among the bDMARDs registered for use in RA in SA, four are tumour necrosis factor inhibitors (TNFis): receptor blockers (etanercept (original and biosimilar)) or monoclonal antibodies (infliximab (original and biosimilar)), adalimumab (original and biosimilar) and golimumab; and three non-TNFis: ritixumab (original and biosimilar), tocilizumab and abatacept. tsDMARDs include the Janus kinase (JAK) inhibitors tofacitinib, baricitinib and upadacitinib.
Glucocorticoids
Side-effects limit the use of glucocorticoids (GCs) to short term and low dose (≤7.5 mg/day) in combination with DMARDs. Long-acting intramuscular methylprednisolone is an alternative to oral prednisone. GCs are not recommended as monotherapy for RA.
Sequential DMARD therapy for RA
Initiation of DMARD therapy with escalation of therapy according to sequential steps is recommended if the LDA target is not reached. If patients are taking a GC to remain at target, escalation of DMARD therapy is recommended over continuation of the GC.
First-line therapy:
MTX is the most widely prescribed csDMARD, has been used to treat RA for more than 50 years, and is the ‘anchor’ drug in RA. MTX is initiated at 7.5-15 mg weekly, orally or subcutaneously, with rapid dose escalation according to response and tolerability to a maximum of 25 mg weekly. Co-prescription with folate (5 mg-10 mg weekly) is recommended.
Second-line therapy:
Patients who fail MTX monotherapy should be treated with combination csDMARDs. The most commonly prescribed combination treatment is ‘triple therapy’ MTX + SSZ + CQ. Alternatively, MTX + LEF may be effective. Another approach is to switch to an alternative csDMARD monotherapy. Third-line therapy would involve MTX plus b/tsDMARD therapies, following eligibility criteria of the SA Rheumatism and Arthritis Association (SARAA).
De-escalation of therapy
GCs should be reduced and discontinued as soon as possible, ideally within three months, or once LDA is achieved. For patients who have maintained persistent LDA/remission without a GC for at least six to 12 months, DMARD tapering may be cautiously considered. Discontinuation of all DMARDs may be associated with disease flares, so at least one tolerated csDMARD at the lowest dose should be continued.
Tapering (dose reduction and/or interval increase), or even discontinuation of the b/tsDMARD, can be attempted but is frequently associated with disease flares. Reassuringly, most patients (>80%) will achieve target again once the bDMARD is restarted.
Analgesics and anti-inflammatory drugs
Analgesics should be prescribed and taken on an ‘as needed’ basis for pain control. Paracetamol is a very effective analgesic, and doses of up to 4g daily can be prescribed. Opioid analgesics should be limited to short-term use because of toxicity.
NSAIDs are effective in controlling pain and stiffness, but are purely symptomatic therapies in RA and offer no disease-modifying action. NSAIDs should be used at the lowest effective dose and for the shortest possible duration of time, and withdrawn once disease activity is controlled with DMARDs. The toxicity of these drugs should not be underestimated, and all NSAIDs should be used with caution.
Monitoring patients on therapy
There is no indication for ‘routine’ liver biopsy in patients on MTX therapy. Biopsy may be indicated in a patient with persistently elevated liver enzymes (greater than three times the upper level of normal) after DMARD discontinuation.
Measurement of serum creatinine is recommended at baseline and annually, unless more frequent monitoring is indicated. Annual metabolic blood tests (fasting glucose, glycated haemoglobin, lipogram) are appropriate. Baseline bone mineral density measurements are recommended in postmenopausal females with high fracture risk assessment tool (FRAX) scores and should be repeated at five-yearly intervals.
Because of the high risk of infection, including TB, RA patients and their physicians must remain vigilant for symptoms, and patients should be advised to seek medical attention for any symptoms of possible infection, to allow for prompt assessment and treatment. Loss of weight, fever or lymphadenopathy in a patient on a b/tsDMARD requires prompt investigation for TB.
G Tarr, MB BCh, MMed (Int Med) – Rheumatology Department, Institute of Orthopaedics and Rheumatology, Mediclinic Winelands Orthopaedic Hospital, Stellenbosch;
N Govind, MB BCh, MMed (Int Med) – Department of Medicine, Chris Hani Baragwanath Academic Hospital and Faculty of Health Sciences, University of the Witwatersrand;
S Seboka, MB BCh, MMed (Int Med) – Netcare-Olivedale Hospital, Johannesburg;
E Gardiner, MB ChB; – Department of Medicine, Livingstone Hospital, Gqeberha;
B Hodkinson, MB BCh, PhD – Rheumatology Division, Department of Medicine, Groote Schuur Hospital and Faculty of Health Sciences, University of Cape Town.
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