Management of Rheumatoid Arthritis

Clinical Evaluation:

1.    It is advised to suspect that the patient is a case of Rheumatoid Arthritis if he has morning Stiffness lasting >1 hour, improving with activity, and small-joint arthritis affecting the hands and feet (Good Practice Statement). [3]

2.    You should diagnose a case of RA if the examination of the extremities reveals the presence of synovitis (soft tissue joint swelling), which will typically present as a symmetric polyarthritis affecting the metacarpophalangeal (MCP), metatarsophalangeal (MTP), and proximal interphalangeal (PIP) joints (Good Practice Statement). [4]

Laboratory Tests:

3.    It is advised to do:

·       Rheumatoid factor (RF): Present in 70–80% of RA cases (but not specific; seen in other autoimmune diseases and even in healthy elderly persons).

·       Anti-Cyclic Citrullinated Peptide (Anti-CCP) Antibodies: highly specific for RA (90–95%), aiding early diagnosis.

·       Inflammatory markers: elevated ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein) during activity (Good Practice Statement). [4-6]

 Imaging Studies:

4.    Do plain radiographs hands & feet that demonstrate periarticular osteopenia, joint space narrowing and bone erosions, and their absence does not rule out RA diagnosis (Good Practice Statement).

5.    Ultrasonography: may be of help if done by expert person in selected cases & should not be the only tool to rely on for diagnosis and treatment strategies (Good Practice Statement).

6.    You can use the ACR/EULAR 2010 classification criteria, to aid the diagnosis (Good Practice Statement). [4, 7, 8]

 Treatment of rheumatoid arthritis:

7.    We recommend starting treatment as soon as the diagnosis of RA is made. (SOR: Strong; LOE: High). [9]

8.    We recommend applying “Treat-to-target strategy”: treatment should be aimed at reaching a target of sustained remission or low disease activity in every patient, according to ACR/ EULAR provided Boolean- based and index- based remission criteria. (SOR: Strong; LOE: High). [10]

9.    We recommend frequent monitoring of the disease activity every 1–3 months during active disease and then every 3–6 months once remission/ low disease activity achieved, using a validated measure. We advise the use of CDAI (Clinical Disease Activity Index) as a tool to measure the activity state (Refer to annexes). Remission ≤ 2.8, low disease activity >2.8-10, moderate disease activity >10-22, high disease activity >22-76. (SOR: Strong; LOE: Moderate). [11]

10.     Therapy should be adjusted if there is no improvement by 50% from the baseline measures by 3 months after the start of treatment or the target has not been reached by 6 months (SOR: Strong; LOE: Moderate). [12].

11.     MTX should be part of the first treatment strategy. (SOR: Strong; LOE: High). [13]

12.     We strongly recommend starting the first line of treatment strategy with conventional disease-modifying antirheumatic drug (cDMARD) monotherapy using methotrexate (15–25 mg/week) s.c. or i.m. injections or oral tablets. Folic acid supplementation 5-10 mg /week should be given 24hrs after MTX administration (in a single or divided doses), not to be taken the day of MTX. (SOR: Strong; LOE: High). [14].

13.     We suggest implementing strategies to improve MTX tolerability in patients experiencing side effects, before switching to another DMARD. These include increasing folic acid dose, splitting oral MTX dose over 24 h, or switching between oral and parenteral routes of MTX administration. (SOR: Conditional; LOE: very low). [15]

14.     We advise treatment with Leflunomide (20 mg/day) or sulfasalazine (3 g/day), when MTX is not tolerated or contraindicated. Consider hydroxychloroquine (200–400 mg) for mild or palindromic disease without poor prognostic factors. (SOR: Conditional; LOE: Moderate). [16, 17]

15.     We suggest adding other csDMARD to MTX or using a different combination csDMARD therapy, if no significant improvement at least 50% from the baseline measures has been achieved by 3 months (DMARD combination therapy means double or triple csDMARDs therapy). (SOR: Conditional; LOE: very Low). [18]

16.     You should consider short-term glucocorticoids when initiating or changing csDMARDs (as a bridge therapy); the dose and route of administration may vary, orally at doses up to 5-10 mg/day, or a single intramuscular injection of 120 mg methylprednisolone. Oral steroid therapy should be tapered as rapidly as clinically feasible, within 3-6 months from treatment start provided that the patient doesn't flare. After 6 months, if the patient is still active & doesn't have access to bDMARDs or tsDMARDs, longer term steroids can be used up to 5 mg per day. (SOR: Strong; LOE: High). [19, 20]

17.     We advise starting bDMARDs or tsDMARDs after failure of 2 or more csDMARDs (when there is no significant improvement by at least 50% from the baseline measures by 3 months or treatment target is not achieved within 6 months). (SOR: Conditional; LOE: very low). [8]

18.     The choice of a bDMARD (bio-originator or biosimilar) depends on the availability of the drug, drug cost, associated co-morbidities and patient preference. (SOR: Strong; LOE: very Low). [21]

19.     When tsDMARDs (JAKi) are considered, risk factors must be taken into account:

·       Age > 65 years.

·       History of current or past smoking.

·       Cardiovascular risk factors: such as diabetes, obesity, and hypertension.

·       Risk factors for malignancy.

·       Current or previous history of malignancy.

·       Risk factors for thromboembolic events: e.g. history of myocardial infarction or heart failure, cancer, inherited blood clotting disorders or a history of blood clots, hormonal contraceptives or hormone replacement therapy, undergoing major surgery or prolonged immobility. (SOR: Strong; LOE: Moderate). [22]

20. If a bDMARD or tsDMARD has failed, treatment with another bDMARD or tsDMARD should be considered. Before switching, reassess adherence, comorbidities, diagnosis, and objective inflammation. Distinguish between:

·       Primary treatment failure:
–No clinically relevant  improvement (at least 50% from the baseline measures) or treatment target is not achieved within 6 months of adequate therapy.
– →In this case, switch to a drug with a different mechanism of action (e.g., from a TNFi to a non-TNFi  such as an IL-6 receptor inhibitor, rituximab, or a JAK inhibitor).

·       Secondary treatment failure:
– Loss of efficacy after an initial adequate response.
– Suggests immunogenic or pharmacokinetic failure → switching within the same class can be considered (e.g. from one TNFi to another), especially if immunogenicity or anti-drug antibodies are suspected.
– If the response is not regained, switch to a drug with a different mechanism of action.

 Patients who fail multiple b/tsDMARDs despite adequate therapy should be classified as having difficult-to-treat RA, in line with EULAR criteria

(SOR: Strong; LOE: Moderate). [23,35,36]

21.     bDMARDs and tsDMARDs could be combined with a csDMARD usually MTX; in patients who cannot use csDMARDs as comedication, IL- 6i and tsDMARDs may have some advantages compared with other bDMARDs. (SOR: Strong; LOE: High). [24-26]

22.You should give a trial of tapering the bDMARDs or tsDMARDs after GCs have been discontinued, if the patient has sustained disease remission (i.e. remission for ≥ 6 consecutive months) either by decreasing the dose or increasing the time intervals whenever applicable according to the drug used with continuation of other csDMARDs. (SOR: Strong; LOE: High). [27]

Recommendations in RA patients with comorbidities: 

23.     In patients who develop double-fold elevation of liver enzymes, reduce MTX & LEF to half dose. If reaches threefold or more, stop MTX and LEF, if persistent over 6 months re-evaluate the virology. (SOR: Strong; LOE: Moderate). [28].

24.     In patients with non-alcoholic fatty liver disease (NAFLD), Methotrexate is conditionally recommended over alternative DMARDs for DMARD-naive patients with NAFLD, normal liver enzymes and liver function tests, and no evidence of advanced liver fibrosis who have moderate-to-high disease activity.  (SOR: Conditional; LOE: very Low). [29]

25.     Patients with hepatitis B viral infection should receive antiviral treatment before starting bDMARDs with close monitoring as well as follow up with the hepatologists after starting biological therapy. (SOR: Strong; LOE: Low). [30]

26.     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.  (SOR: Conditional; LOE: very Low). [31]

27.     In patients with New York Heart Association class 3 or 4 heart failure, non-TNFi bDMARD are recommended. (SOR: Strong; LOE: Low). [32]

28.     Patients complicated with interstitial lung disease: Interleukin-6 inhibitor (IL-6i) or Rituximab could be considered. (SOR: Conditional; LOE: Low). [33]

29.     In patients with history of lymphoproliferative disorder, rituximab is preferable over other bDMARDs  (SOR: Conditional; LOE: very Low). [15]

30.     MTX, Leflunomide, Rituximab, Tocilizumab and JAKi are contraindicated in pregnancy & lactation. (SOR: Strong; LOE: High). [34]

31.     All TNFi, hydroxychloroquine, corticosteroids, and sulfasalazine can be used during pregnancy and lactation. (SOR: Conditional; LOE: Moderate). [34]