Rheumatoid Arthritis Treatment: The Treat-to-Target Ladder

Rheumatoid arthritis is treated by starting a disease-modifying antirheumatic drug (DMARD), usually methotrexate, as soon as the diagnosis is made, and adjusting therapy until the patient reaches remission or low disease activity. If there is no improvement by three months, or the target is not reached by six months, treatment is escalated. Dr. Sajal Ajmani, HOD – Rheumatology, Manipal Hospital, Dwarka, New Delhi, India, set out this treat-to-target ladder in three phases.

This article covers rheumatoid arthritis treatment as presented in the second half of Dr. Ajmani's masterclass: the drug classes, the EULAR recommendations he presented, the phase-by-phase algorithm, drug choice in pregnancy and liver disease, and how therapy is tapered once remission is secure. How the diagnosis is made and how disease activity is scored are covered in the complete guide to rheumatoid arthritis.

Rheumatoid arthritis medications: the three classes of DMARD

A DMARD is a drug that changes the course of rheumatoid arthritis by suppressing the immune process that damages the joints, rather than only relieving pain. Dr. Ajmani grouped the drugs used in rheumatoid arthritis into three classes.

Conventional synthetic DMARDs (csDMARDs). Hydroxychloroquine, leflunomide, sulfasalazine and methotrexate, which he described as the most important of them. These are oral, inexpensive and the foundation of treatment.

Targeted synthetic DMARDs (tsDMARDs). Tofacitinib, a Janus kinase (JAK) inhibitor. JAK inhibitors are oral small molecules that block signalling inside immune cells.

Biological DMARDs (bDMARDs). Injected or infused proteins aimed at a single component of the immune response. Dr. Ajmani divided them into two groups:

• Anti-TNF biologics, which block tumour necrosis factor, such as adalimumab and etanercept.
• Non-TNF biologics, including rituximab, which depletes B cells, and tocilizumab, which blocks the interleukin-6 (IL-6) pathway.

EULAR recommendations for rheumatoid arthritis treatment

Dr. Ajmani walked through the 2016 recommendations of EULAR (the European Alliance of Associations for Rheumatology) for the management of rheumatoid arthritis and pointed his audience to the 2022 update. The core principles he presented are these.

Start early and treat to a target

Therapy with DMARDs should start as soon as the diagnosis of rheumatoid arthritis is made. Treatment should aim at a target of remission or low disease activity in every patient. These targets are defined by the scores described in the guide to measuring disease activity.

Monitor frequently and adjust on a timetable

Monitoring should be frequent: every one to three months while the disease is active. If there is no improvement by three months after starting a drug, or the target has not been reached by six months, therapy should be adjusted. The timetable is the discipline of treat-to-target care: it prevents a patient from drifting for a year on a drug that is not working.

Methotrexate as the first-line drug

Methotrexate should be part of the first treatment strategy. Methotrexate for rheumatoid arthritis is taken once a week, never daily, and is prescribed with folic acid to reduce side effects. Patients on it need regular blood counts and liver and kidney function tests, and they are advised to limit alcohol.

When methotrexate cannot be used: pregnancy and liver disease

If the patient has a contraindication to methotrexate or cannot tolerate it, for example because of vomiting, another conventional DMARD is used. Dr. Ajmani named two contraindications in particular: a patient who is planning pregnancy, and a patient with liver disease. In these situations, sulfasalazine can be considered, and in his summary algorithm leflunomide or sulfasalazine replaces methotrexate.

His guidance on the two special situations was precise:

• Pregnancy: sulfasalazine is safe, but methotrexate and leflunomide are not.
• Liver disease: sulfasalazine is safer, but methotrexate and leflunomide are not safe.

Both methotrexate and leflunomide require reliable contraception, and they must be stopped well before a planned conception; leflunomide persists in the body for a long time and needs an accelerated washout with cholestyramine before pregnancy. Hydroxychloroquine is also considered compatible with pregnancy.

Steroids as bridge therapy

Short-term glucocorticoids can be used as bridge therapy, a temporary treatment to control inflammation, when starting or changing conventional DMARDs, in different doses and routes of administration, but they should be tapered as rapidly as possible. Dr. Ajmani's algorithm combines the first DMARD with a short course of steroids from the outset. The 2022 EULAR update tightened this point: glucocorticoids should be tapered and, where clinically feasible, stopped within three months.

The treat-to-target ladder, phase by phase

Dr. Ajmani summarised the recommendations as a three-phase algorithm. The checkpoints are the same at every phase: improvement by three months and target reached by six months.

Phase 1: the first conventional DMARD

Once a clinical diagnosis of rheumatoid arthritis is made, check whether the patient has any contraindication to methotrexate.

• No contraindication: start methotrexate.
• Contraindication: start leflunomide or sulfasalazine.

In either case, combine the first drug with a short course of steroids. If the patient improves by three months and achieves the target of low disease activity by six months, continue the same treatment. If there is no improvement by three months, or the target is not reached by six months, move to phase 2.

Phase 2: decide by prognosis

The next step depends on whether the patient has poor prognostic factors. Dr. Ajmani cited high rheumatoid factor and anti-CCP levels and established joint damage, including deformities or erosions on X-ray. The EULAR recommendations list the poor prognostic factors as persistently moderate or high disease activity despite conventional DMARDs, high acute phase reactants, a high swollen joint count, the presence of rheumatoid factor or anti-CCP (especially at high levels), early erosions, and failure of two or more conventional DMARDs.

• Poor prognostic factors present: add a biological DMARD or a JAK inhibitor.
• Poor prognostic factors absent: either change the conventional DMARD or add a second one. If methotrexate fails, for example, either switch to leflunomide or add leflunomide. Dr. Ajmani also gave sulfasalazine as an option when switching after three to six months.

Again, if there is improvement at three months and the target is achieved by six months, continue. If not, move to phase 3.

Phase 3: change the advanced therapy

Phase 3 means changing the biological DMARD or giving a JAK inhibitor. The same checkpoints apply: if there is improvement at three months and the target is reached by six months, continue; if not, change again.

Biologics and JAK inhibitors: combining, switching and screening

Combine with a conventional DMARD

Biological and targeted synthetic DMARDs should be combined with a conventional DMARD, usually methotrexate, because the combination works better and, for some biologics, reduces the formation of antibodies against the drug. In patients who cannot or do not want to take a conventional DMARD alongside, Dr. Ajmani noted that IL-6 pathway inhibitors such as tocilizumab, and targeted synthetic DMARDs such as tofacitinib, may have some advantages. Both classes have shown efficacy as monotherapy in clinical trials.

Switching when an advanced therapy fails

If one biological or targeted synthetic DMARD fails, the patient should be treated with another biological or targeted synthetic DMARD. If one anti-TNF therapy fails within three to six months, the patient can be changed either to another anti-TNF agent or to an agent with a different mode of action, such as a B-cell or IL-6 inhibitor.

Screening and safety before advanced therapy

Before any biological DMARD or JAK inhibitor is started, patients are screened for latent tuberculosis and for hepatitis B and C, because these drugs can reactivate dormant infection. Where tuberculosis is common, this screening is an essential safety step in the ladder.

The 2022 EULAR update also added a specific caution on JAK inhibitors. Following a large safety trial of tofacitinib, JAK inhibitors are used only after careful consideration, and only if no suitable alternative exists, in patients aged 65 or over, current or past long-term smokers, and patients with other risk factors for cardiovascular disease, cancer or blood clots.

Tapering treatment after sustained remission

Treatment does not stop when the target is reached. Dr. Ajmani was clear that sustained remission is the goal, and that remission should last at least 12 months before any therapy is decreased.

The order of tapering follows a set logic:

1. Steroids and painkillers first. Decreasing steroids and painkillers is the highest priority, because their long-term harms outweigh their benefit once the disease is controlled. Bridging steroids are not held until remission has lasted a year; they are tapered as rapidly as possible from the start, as described above.
2. Then the biological DMARD. If the patient has achieved remission or low disease activity after the steroid has been stopped, the dose of the biological DMARD can be slowly decreased.
3. Then the conventional DMARD. If the patient is in persistent remission, even the conventional DMARD dose can be decreased.

Tapering means reducing the dose or spacing out doses gradually, not stopping abruptly. Abrupt withdrawal of all DMARDs carries a high risk of flare, and patients whose disease flares after tapering usually regain control when the previous dose is restored.

Why speed matters

The ladder is built on time limits for a reason. Patients treated within 12 weeks of symptom onset have the lowest rate of joint destruction and the best chance of DMARD-free remission, a point developed in the complete guide. Every phase of the algorithm forces a decision at three and six months, so that a patient who is not responding moves up the ladder before irreversible damage accumulates.

For the diagnostic steps that precede treatment, including the 2010 criteria and the pitfalls of rheumatoid factor and anti-CCP, see how rheumatoid arthritis is diagnosed. The treatment of palindromic rheumatism and of cardiac involvement, both raised by attendees, is recorded on the masterclass Live Discussion page.