Table 5 RA recommendations

1. Start the first line of treatment strategy with conventional disease-modifying antirheumatic drug (cDMARD) monotherapy using methotrexate (15–25 mg/week) as soon as possible and ideally within 3 months of onset of persistent symptoms. For patient who cannot tolerate oral methotrexate, subcutaneous or intramuscular methotrexate can be prescribed. To choose the preferred method of methotrexate administration, it is advisable to use shared decision-making (oral vs subcutaneous vs intramuscular). To evaluate the patient’s reaction to treatment, methotrexate should be given for 8 to 12 weeks (LOE:1a GOR: A)

- In patient who could not tolerate MTX, try some steps to alleviate the side effects before switching to another DMARDs (such as increasing folic acid dose, splitting oral MTX dose over 24 h, or switching between oral and parenteral routes of MTX administration

2. When MTX is contraindicated, or patient could not tolerate it, consider treatment with leflunomide (20 mg/day) or sulfasalazine (2 g/day) as first line of treatment strategy. Consider hydroxychloroquine (200–400 mg) for first-line treatment as an alternative to oral methotrexate and leflunomide or sulfasalazine for mild or palindromic disease (LOE:1a GOR:A)

3. Offer additional (combined) cDMARDs (oral methotrexate, leflunomide, sulfasalazine, or hydroxychloroquine), in combination, in a step-up strategy when the treatment target (remission or low disease activity) has not been achieved after 3 months despite dose escalation

4. Significant improvement (DAS-28 ≥ 1.2) using cDMARDAs should be achieved by 3 months. If no significant improvement has been achieved, by 3 months, adding another DMARD to MTX or using a different combination DMARD therapy is advised (DMARDs doses should be optimized to the maximum tolerable licensed levels) (LOE: 1aGOR: A)

5. DMARD combination therapy means double or triple traditional/conventional DMARD therapy

6. Double DMARD therapy means: MTX + SSZ, MTX + HCQ, SSZ + HCQ, or MTX + LEF

7. Triple DMARD therapy means: MTX or LEF + SSZ + HCQ

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8. Glucocorticoids: short-term glucocorticoids should be considered when initiating or changing csDMARDs; the dose and route of administration may vary: orally at doses up to 7.5 mg/day, orally at 30 mg starting dose, as a single intramuscular injection of 120 mg methylprednisolone, or as a single 250 mg intravenous pulse therapy of methylprednisolone. Oral steroid therapy should be tapered as rapidly as clinically feasible, within 3 months from treatment start. Long-term use of GC, especially at doses above 5 mg/day, should be avoided because of the many potential risks

In adults with established RA, only continue long-term treatment with glucocorticoids when as follows:

○ The long-term complications of glucocorticoid therapy have been fully discussed, and all other treatment options (including biological and targeted synthetic DMARDs) have been offered

9. Symptom control

○ Consider oral nonsteroidal anti-inflammatory drugs (either traditional NSAIDs and COX-2 selective inhibitors), when control of pain or stiffness is inadequate. Consider the patient’s risk factors, such as age and pregnancy, as well as the possibility of gastrointestinal, liver, and cardio-renal toxicity

○ When treating symptoms of RA with oral NSAIDs:

▪ Offer the lowest effective dose for the shortest possible time

▪ Offer a proton-pump inhibitor (PPI)

▪ Review risk factors for adverse events regularly

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10. If the treatment target is not achieved after 6 months of DMARD combination therapy, addition of a bDMARD should be considered with or without MTX (LOE: 2a. GOR:B)

11. Only a specialist rheumatology team with experience in the administration of these drugs should initiate biological therapy and monitor treatment response and side effects

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12. The cutoff point of starting biologic therapy is high disease activity: DAS-28 > 5.1 or if DAS-28 > 4.2 and associated with 3 or more poor prognostic factors (significantly elevated acute phase reactant levels, high swollen joint count (> 4), the presence of significantly positive (high titres) rheumatoid factor or anti-CCP, the presence of early erosions (radiographic or sonographic, functional disability (HAQ or equivalent) score > 2, US Doppler activity ≥ 2 in ≥ 3 joints) (LOE: 3bGOR: B)

13. First-line biologic therapy: Use TNF-inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol, or golimumb) or IL-6 inhibitor (tocilizomab) as first-line bDMARD. cDMARD should be added to the biologic therapy. Alternatively, synthetic DMARD (tofacitinib, baricitinib, upadacitinib) can be considered (LOE: 2a. GOR: B)

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14. TNF inhibitors had been given a slight preference over other biologics due to availability of long-term registry data worldwide

15. Significant improvement using bDMARDAs should be achieved by 3 months, and the target should be achieved by 6 months. Treatment with TNF inhibitors should be continued only if there is an adequate response at 6 months following initiation of therapy. An adequate response is defined as an improvement in DAS-28 of 1.2 points or more

16. After initial response, treatment should be monitored no less frequently than 6 monthly intervals with assessment of DAS-28 (LOE:4 GOR: C)

17. If the patient has an inadequate initial response (primary failure), prescription of an alternative TNF-α inhibitor is not advised. Switch out of therapeutic class considering a drug with other working mechanism is advised

18. An alternative TNF-α inhibitor may be considered for patients in whom treatment is withdrawn due to an adverse event before the initial 6-month assessment of efficacy, provided the risks and benefits have been fully discussed with the patient and documented (LOE:3b GOR: C)

19. In case of secondary failure to anti-TNF agent (patients who respond to the therapy after an induction regimen but subsequently lose response during maintenance treatment), initially verify if the symptoms are due to active disease and confirm compliance. If verified, therapeutic drug monitoring is advised. In case of low drug levels with high antibodies, adding a csDMARD is advised; alternative is switching to another anti-TNF. However, if there is adequate drug level, no antibodies, it is advisable to switch out of the therapeutic class. If subtherapeutic drug levels, without antibodies, it is advisable to do dose escalation or add a csDMARD (LOE:3b GOR: C)

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20. If a first-line bDMARD has failed, a short course of low-dose corticosteroids can be considered, in addition to optimizing the csDMARD dose

21. Escalation of dose of the TNF-α inhibitors above their licensed starting dose is not recommended

22. If a second TNF inhibitor fails, patients should receive an agent with another mode of action

23. Treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose, and product price per dose). This may need to be varied in individual cases due to differences in the mode of administration and treatment schedules

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24. A bsDMARD of any of the reference boDMARDs should not be used if the respective boDMARD (or another bsDMARD of the same molecule) has failed to induce sufficient efficacy or vice versa

25. Use of the TNF-α inhibitors for the treatment of severe, active, and progressive RA in adults not previously treated with methotrexate or other csDMARDs is not recommended (LOE:2b GOR: C)

26. When switching from an anti-TNF drug (originator) to a biosimilar of that originator, one has to take into consideration that antidrug antibodies against the originator will cross-react with the biosimilar, causing treatment failure (LOE:4 GOR: C)

27. If target not achieved after 6 months, treatment changes to the following:

▪ A non-TNFi bDMARD [(tocilizumab or sarilumab, a human anti-IL-6 receptor antibody), rituximab (mainly for RA patients who has positive rheumatoid factor/Anti-CCP), Abatacept)] with/without csDMARD OR

▪ Targeted synthetic DMARDs tsDMARDs )as tofacitinib, baricitinib or upadacitinib) with/without csDMARD as third-line bDMARDs until reach remission

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28. bDMARDs (and tsDMARDs) should primarily be prescribed in combination with csDMARDs, such as methotrexate or leflunomide, leaving the option of monotherapy, with a preference for certain drugs (IL-6 pathway inhibitors and tsDMARDs), as an exception in case of intolerance or contraindication to all csDMARDs. (LOE:3b GOR: B)

29. It is not advisable to routinely test for antidrug antibodies and drug levels in clinical practice. Measuring serum drug level and levels of anti-drug antibodies are only advisable in cases of secondary failure, since a good clinical response would not lead to cessation of therapy even in the presence of antidrug antibodies, or low drug levels, and vice versa. Furthermore, the use of MTX, even at low doses (7.5–10 mg/week or more) reduces the incidence of antidrug antibodies (LOE:4 GOR: C)

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30. Drug tapering: (LOE:3b GOR: C)

• For individuals who have maintained their treatment target (remission or low disease activity) for at least a year without the use of glucocorticoids, think carefully about lowering dosages or quitting medications altogether as part of a step-down strategy. If the treatment aim is no longer fulfilled, return right away to the prior DMARD regimen

• If the patient has been taking biologic therapy and sustained remission, tapering bDMARD can be done, while the patient continue the conventional DMARDs therapy and with close monitoring of the disease activity. Return promptly to the previous bDMARD regimen if the treatment target is no longer met

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31. Personalized care: (LOE:4 GOR: C)

• Patients who develop elevated liver enzymes: double fold elevation; reduce MTX & LEF to half dose. If reach threefold, stop MTX and LEF

• Patients with HBV infection should receive antiviral treatment before starting bDMARDs with close monitoring after starting biological therapy

• In hypertensive patients, be careful regarding salt and water retention property of leflunomide. Baseline measurement of blood pressure is recommended with adjustment of blood pressure therapy if required

• In patients with NYHA class 3 or 4 heart failure, non-TNF inhibitor bDMARD or tsDMARD are recommended over TNF inhibitors

• Patients complicated with interstitial lung disease: MTX associated with corticosteroid is recommended as first-line therapy. IL-6 inhibitors should be considered as 1st line in bDMARDs then rituximab; while abatacept is the first choice in patients with nontuberculous mycobacterial lung disease

• In patients with history of lymphoproliferative disorder, rituximab is preferable over other bDMARDs

• tsDMARDs are better to be avoided in patients with high risk for cardiovascular problems or venous thromboembolism

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1. Non-pharmacological management (LOE:4 GOR: C)

• Physiotherapy

Adults with RA should have access to specialist physiatrist, with periodic review as follows:

○ Improve general fitness and encourage regular exercise

○ Learn exercises for enhancing joint flexibility, muscle strength, and managing other functional impairments

○ Learn about the short-term pain relief provided by methods such as transcutaneous electrical nerve stimulators (TENS), and wax baths

• Occupational therapy

Adults with RA should have access to specialist occupational therapy, with periodic review, if they have the following:

○ Difficulties with any of their everyday activities

○ Problems with hand function

• Hand exercise programmes

Due to the shortage of occupational therapists in Egypt, we recommend rheumatologists /physiatrist to take care with this aspect of therapy

Consider a tailored strengthening and stretching hand exercise programme for adults with RA with pain and dysfunction of the hands or wrists if as follows:

○ They are not on a drug regimen for RA.

○ They have been on a stable drug regimen for RA for at least 3 months.

The tailored hand exercise programme for adults with RA should be delivered by a practitioner with training and skills in this area

• Podiatry

○ All adults with RA and foot problems should have access to a podiatrist for assessment and periodic review of their foot health needs

○ Functional insoles and therapeutic footwear should be available for all adults with RA if indicated.

Due to the shortage of podiatrists in EGYPT, we recommend physiatrist to take care with this aspect of therapy

• Psychological interventions

○ Offer psychological interventions to help adults with RA cope with their condition, such as relaxation, stress management, and cognitive coping techniques

• Diet and complementary therapies

○ Explain to adults with RA who want to experiment with their food that there is not a lot of proof that will help their arthritis.

○ However, they might be inspired to adhere to the tenets of the Mediterranean diet (more bread, fruit, vegetables, and fish, less meat, and replace butter and cheese with products based on vegetable and plant oils)

○ Explain to individuals with RA who want to explore complementary therapies that while some may help with symptoms in the short term, there is little to no evidence to support their effectiveness over the long term.

○ If an adult with RA decides to try complementary therapies, advise them

1. These approaches should not replace conventional treatment

2. This should not prejudice the attitudes of members of the multidisciplinary team or affect the care offered

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2. Timing and referral for surgery (LOE: 3b. GOR:C)

A. Offer to refer adults with RA for an early specialist surgical opinion if any of the following do not respond to optimal nonsurgical management

○ Persistent pain due to joint damage or other identifiable soft tissue cause

○ Worsening joint function

Progressive deformity

○ Persistent localized synovitis not responding to conservative systemic and/or local management

B. Offer to refer adults with any of the following complications for a specialist surgical opinion before damage or deformity becomes irreversible

○ Imminent or actual tendon rupture

○ Nerve compression (for example carpal tunnel syndrome & cervical cord myelopathy)

○ Stress fracture

C. When surgery is offered to adults with RA, explain that the main expected benefits are as follows:

○ Pain relief

○ Improvement, or prevention of further deterioration, of joint function

○ Prevention of deformity

D. Adults with RA who have suspected or confirmed septic arthritis should get immediate combination medical and surgical therapy (especially in a prosthetic joint)

E. If an adult with RA develops any symptoms or signs that suggest cervical myelopathy

• Request an urgent MRI scan

• Refer for a specialist surgical opinion

F. Do not let concerns about the long-term durability of prosthetic joints influence decisions to offer joint replacements to younger adults with RA

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