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KariPuolakka
TuulikkiSokka-Isler

Rheumatoid Arthritis

Essentials

  • If there are symptoms and joint findings suggesting rheumatoid arthritis (RA) and citrullinated peptide antibodies in blood, the patient should be referred to a rheumatology outpatient clinic.
    • If there is inflammation in several, particularly small, joints and citrullinated peptide antibodies in blood, the patient probably has RA but a slightly positive rheumatoid factor is often insignificant.
  • RA as an immunological disorder may begin several years before the appearance of symptoms, which may, at first, be unspecific, making it impossible to distinguish incipient RA from other types of arthritis.
    • A considerable share of cases of fresh arthritis remain unclassified at the early stage, and the specific diagnosis, such as psoriatic arthritis, may only become clear during follow-up.
  • Systemic glucocorticoids interfere with the diagnosis and should therefore not be started in primary health care, but a glucocorticoid can be injected into inflamed joints.
  • RA is a progressive, debilitating disease but effective medication started early can make most newly diagnosed patients asymptomatic within 3 months. Treatment should be started at a rheumatology unit.
  • Physical exercise will improve the patient's functional ability and reduce the risk of cardiovascular disease.

Epidemiology

  • About 30 adults per 100 000 per year develop seropositive RA.
  • The age at onset is most commonly 60-70 years but two in three of those developing the disease are younger than 65 years old.
  • Two in three patients are women.
  • Some people are genetically susceptible to RA.
  • Smoking doubles the risk of the disease.

General remarks

  • The onset of RA is usually insidious with unspecific symptoms, and it is not always possible to distinguish it from other forms of arthritis.
  • The 2010 EULAR/ACR criteria for the classification of RA facilitate diagnosis (see especially table 3 in http://onlinelibrary.wiley.com/doi/epdf/10.1002/art.27584).
  • RA can be diagnosed when arthritis has developed even in just one small joint, if the rheumatoid factor / citrullinated peptide antibodies are more than 3 times the upper limit of the reference range.
  • ESR and CRP may be normal.
  • Seronegative RA is rare.
    • In patients with seronegative arthritis, signs of skin psoriasis should be sought Psoriasis.
    • Dactylitis, enthesitis and intestinal symptoms suggest arthritis of the spondylarthritis group.
  • New patients with symptoms of arthritis need to see a rheumatologist unless the diagnosis is evident and treatment can be provided on the primary care level, as is often the case with gout Gout and Pseudogout.
  • Inflamed joints should be treated with glucocorticoid injections.
  • The basic medication consists of a combination of methotrexate, sulfasalazine and hydroxychloroquine. A low glucocorticoid dose (5-7.5 mg prednisolone) can be added to the regimen, particularly if the disease begins with polymyalgia.
  • If RA affects just a few joints, remission can often be rapidly achieved after starting methotrexate injections - possibly combined with hydroxychloroquine - and treating the joints with glucocorticoid injections.
  • RA not responding to initial treatment is treated with biologicals or with a janus kinase (JAK) inhibitor.

Symptoms

  • The onset of RA is usually insidious.
  • Morning stiffness, tender and swollen joints are typical.
  • In rare cases, the first joint symptoms occur in bouts of a few days recurring irregularly in various joints, with asymptomatic periods between such bouts (palindromic rheumatism).
  • Proximal interphalangeal and metacarpophalangeal joints, wrists, and balls of the feet are most commonly affected but any joint may be the first to become inflamed.
  • Fatigue, malaise and mild fever may occur as systemic symptoms.

Investigations in primary care

  • See the article Clinical examination of patients with joint inflammation in primary health care Clinical Examination of Patients with Joint Inflammation in Primary Health Care.
  • Palpation can be used to find out whether a patient with joint symptoms has arthritis.
  • An inflamed joint is characterised by soft swelling, tenderness, pain on movement and a limited range of motion. Restricted range of joint movement or tenderness in extreme positions may be a sign of oedema even in the absence of visible swelling. Joint pain in the absence of such findings suggests an aetiological factor other than RA.
    • It may be difficult to distinguish RA from osteoarthritis because osteoarthritis may also involve joint swelling. In fingers, osteoarthritis occurs in the distal or proximal interphalangeal joints, RA in proximal interphalangeal and metacarpophalangeal joints. Patients with osteoarthritis may develop rheumatoid arthritis.
    • Fist closure is often limited in patients with inflammation of small finger joints or with flexor tenosynovitis.
    • Tenderness on lateral squeezing of the knuckles or balls of the feet suggests arthritis.
  • The most essential laboratory tests: anti-CCP (cyclic citrullinated peptide) antibodies, RF, ESR, CRP, basic blood count with platelet count
    • In addition, tests for plasma ALT, ALP, creatinine, urate, serum Borrelia antibodies, chemical screening of urine, serum antinuclear antibodies, as well as antibodies to diagnose reactive arthritis; see Reactive Arthritis can be done, as considered necessary.
  • A patient with inflammation in even one small joint and clearly elevated citrullinated peptide antibodies probably has RA.
  • If synovial fluid can be aspirated, it should be tested for leukocytes (including differential count) and, apart from in women of fertile age, crystals; see article Investigation of synovial fluid Investigation of Synovial Fluid.
    • In patients with arthritis, synovial fluid is cloudy yellow, with a leucocyte count exceeding 2 000 × 106 /l.
    • Highly cloudy green or brownish orange synovial fluid suggests purulent arthritis, usually monoarthritis.
    • If purulent arthritis (particularly monoarthritis with fever) is suspected, the patient should be referred to an emergency department for diagnosis and treatment. Bacterial culture and gram staining (must be done within 2 h of collecting the sample) of synovial fluid should be done there. In addition, synovial nucleic acid detection test can be done.
  • Differential diagnosis (see also Painful Conditions of the Ankle and Foot in Adults Clinical Diagnosis of Joint Inflammation in the Adult Disease-Specific Signs and Symptoms in Patients with Inflammatory Joint Diseases)
  • Imaging of patients with arthritis should mainly be performed at a rheumatology outpatient clinic.

Principles of drug treatment

  • RA should be diagnosed and medication begun at a rheumatology outpatient clinic.

Beginning of treatment Combination Therapy in Rheumatoid Arthritis, Methotrexate for Rheumatoid Arthritis, Folic Acid and Folinic Acid for Reducing Side Effects in Patients Receiving Methotrexate for Rheumatoid Arthritis, Intra-Articular Steroids in the Knee for Rheumatoid Arthritis, Effects of Glucocorticoids on Radiological Progression in Rheumatoid Arthritis

  • The basic medication for RA consists of a combination of methotrexate, sulfasalazine and hydroxychloroquine, unless contraindicated (e.g. renal failure, sulfa allergy). Methotrexate is the most effective component of the combination, and in early disease subcutaneous methotrexate may be sufficient as monotherapy or combined with hydroxychloroquine.
  • Methotrexate should be given in doses of 20-25 mg once weekly. It is most effective and best tolerated when given by subcutaneous injection.
    • The bioavailability of oral methotrexate does not usually increase at doses exceeding 15 mg/week.
    • Due to tolerability issues, the dose may need to be reduced individually.
    • To reduce the risk of adverse effects, the treatment is routinely combined with 5 mg folic acid taken 5-10 h after methotrexate.
    • A proton pump inhibitor can safely be combined with the above doses of methotrexate.
  • A low glucocorticoid dose (5-7.5 mg prednisolone or equivalent) can be added to the regimen for a few months, particularly if the disease begins with polymyalgia.
    • Doses exceeding 7.5 mg increase the risk of adverse effects (osteoporosis, cataracts, diabetes, adrenocortical suppression).
  • Other "traditional" antirheumatic medication is very rarely needed.
  • If combination therapy and methotrexate are contraindicated or the patient cannot tolerate methotrexate, a biological antirheumatic drug or JAK inhibitor should be started.
    • Women must not use methotrexate within 1-3 months before planned pregnancy or during pregnancy or breast-feeding.
  • Inflamed joints should be treated with glucocorticoid injections.
  • The decision on drug treatment should be made together with the patient.
    • Encouraging guidance provided by a rheumatology nurse is important for committing the patient to treatment.

Before starting antirheumatic medication

  • Laboratory tests: basic blood count with platelets + differential count, ESR, CRP, ALT, ALP, plasma creatinine, GFRe Gfr Calculator, chemical screening of urine.
  • Before starting methotrexate, a chest x-ray should be taken.
    • These investigations should be done before the first visit to the rheumatology outpatient clinic, so that medication can be started immediately after making the diagnosis.
  • Any hypersensitivity to drugs, family planning, other diseases and medication should be considered and the patient's teeth checked.
  • Before starting to give a biological agent or a JAK inhibitor, another screening should be performed, to the extent considered appropriate.
    • Chest x-ray
    • Dental checkup/ortopantomography
    • Antinuclear antibodies
    • History of tuberculosis, with testing for secretion of interferon gamma by M. Tuberculosis sensitized cells, as necessary.
    • HBsAg, HBcAb and HCVAb, HIV antigen and antibodies, as considered necessary
    • The patient's vaccination status should be established and a pneumococcal vaccine given, as necessary.
    • Before giving TNF inhibitors, it should be ensured that the patient does not have a demyelinizing disease.
    • Before giving rituximab, plasma or serum IgG, IgM and IgA should be checked.

Monitoring of treatment

  • As the individual efficacy and tolerability of drug therapy cannot be predicted, patients should be closely monitored by laboratory tests (see tables T1 and T2) and clinically.
  • Recommendations concerning safety monitoring of antirheumatic medication vary to some extent in different areas. See also local recommendations.

One month after starting treatment

  • Visit to a rheumatology nurse or, if necessary, a physician

Three-month visit

  • If remission has not been achieved, medication should be intensified.
  • If methotrexate has been given orally, use of an injectable dosage form should now be started, and if the dose has been below 25 mg, it should be raised to this level now, unless there are contraindications to this.
  • If the response to treatment is poor, i.e., there are several swollen joints and a high CRP level, or if the patient cannot tolerate methotrexate, a biological agent or a JAK inhibitor should be added to the regimen.
  • If glucocorticoid medication had been started and remission has now been achieved, the glucocorticoid should be gradually discontinued.

Six-month visit

After six months

  • The frequency of monitoring depends on disease activity.
  • If remission has been achieved, follow-up visits should be scheduled for one and two years after the beginning of treatment.

Biological agents Adalimumab for Treating Rheumatoid Arthritis, Certolizumab Pegol for Rheumatoid Arthritis in Adults, Etanercept for the Treatment of Rheumatoid Arthritis, Golimumab for Rheumatoid Arthritis, Rituximab for Rheumatoid Arthritis, Tocilizumab for Rheumatoid Arthritis, Abatacept for Rheumatoid Arthritis, Anakinra for Rheumatoid Arthritis, Infliximab for Rheumatoid Arthritis, Biologics for Rheumatoid Arthritis, Biologics for People with Rheumatoid Arthritis Naive to Methotrexate, Biologics or Tofacitinib for People with Rheumatoid Arthritis Unsuccessfully Treated with Biologics

  • There are no differences in the efficacy of various biological agents, except for anakinra, which is less effective.
  • Any of the following can, in principle, be given as the first biological agent: TNF-alpha inhibitors (infliximab, etanercept, adalimumab, certolizumab pegol or golimumab), the T-cell inhibitor abatacept or the interleukin 6 inhibitors tosilizumab or sarilumab, or infusions of the B-cell inhibitor rituximab.
    • The most inexpensive biosimilars should preferably be used.
    • The safety profiles of various drugs differ slightly, affecting the choice of medication for each individual patient.
    • Rituximab infusions often only need to be given once a year, which makes the treatment easy for elderly patients with RA, in particular, and inexpensive.
  • Biological agents are usually more effective combined with methotrexate than in monotherapy.
  • Antibodies may develop against TNF-alpha inhibitors, except etanercept, which may decrease their efficacy.
    • Methotrexate reduces antibody formation.
    • Unnecessary breaks in medication should be avoided because low drug levels increase the risk of antibody formation.
  • If a patient cannot tolerate methotrexate
    • All biological agents and JAK inhibitors can also be used without methotrexate.

JAK inhibitors

  • The oral drugs tofacitinib, baricitinib, upadacitinib and filgotinib inhibit janus kinases in the intracellular signalling system and are as effective as biological agents, or even more effective. These are recommended for use with methotrexate but can also be used as monotherapy.

If treatment with a biological agent or a JAK inhibitor fails

Monitoring tests for antirheumatic drug therapy. Tests should also be performed 2-3 weeks after any increase in drug dose. ESR and CRP should be checked on visits to the doctor and otherwise as needed.

LääkeSafety monitoring tests
Methotrexate
At 3 weeks, 6 weeks, 12 weeks after beginning of treatment, then every 3-12 months,Basic blood count with platelets (+ differential count), ALT, creatinine
Hydroxychloroquine
No laboratory monitoring needed
Checkup by an ophthalmologist after 15 years of use
Sulfasalazine
At 3 weeks, 6 weeks, 12 weeks after beginning of treatment, then every 3-12 monthsBasic blood count with platelets (+ differential count), ALT
Biological antirheumatic drugs
  • Often used concomitantly with methotrexate, in which case monitoring protocol as for methotrexate.
  • In addition, after 3 months of tosilizumab or sarilumab, blood lipids should be tested.
  • See local guidelines for recommendations on safety monitoring tests when using biological drugs as monotherapy.
JAK inhibitors
Tofacitinib, baricitinib, upadacitinib and filgotinib
At 3 weeks, 6 weeks, 12 weeks after beginning of treatment, then every 3-6 monthsBasic blood count with platelets + differential count, ALT
At 3 monthsBlood lipids

Interpretation of the results of safety monitoring tests

Safety monitoring testsThreshold values and procedure
Blood testsLeukocytes (×109 /l)Neutrophils (×109 /l)Lymphocytes (×109 /l)Platelets (×109 /l)ALT
>3>1.0>0.5>100<2-3 × reference value
  • If the number of blood cells is below the reference range or ALT is elevated, medication should be reduced as considered necessary.
  • However, mild lymphopenia and macrocytosis commonly occur in association with the use of methotrexate, as do slightly elevated ALT levels, and these require no change to the treatment.
  • If the results of laboratory tests fall outside the threshold values specified in the table, medication should be interrupted and tests repeated in 1-2 weeks. Use of the drug can often be continued at lower doses, repeating the safety monitoring tests. A rheumatologist should be consulted, as necessary.
  • If agranulocytosis develops, the patient needs emergency referral to a hospital.
Creatinine/GFR
  • If the GFR is 30-60, the methotrexate dose should be halved, and if below 30, methotrexate cannot be used.

Considerations relating to antirheumatic medication

Risk of infections

Pregnancy and breast-feeding

  • Of antirheumatic drugs, sulfasalazine, hydroxychloroquine and glucocorticoids can be used during pregnancy and breast-feeding. TNF inhibitors can also be used, except for the last trimester of pregnancy. Methotrexate must be withdrawn 1-3 months before stopping contraception.
  • Men planning to father a child can use any antirheumatic medication.
  • For more details, see local guidelines, teratology information service and drug database(s).

Analgesics Celecoxib for Rheumatoid Arthritis

Comorbidities Bisphosphonates for Steroid Induced Osteoporosis

  • Rheumatic inflammation is an independent risk factor for atherosclerosis.
    • Effective inhibition of inflammation is the most important means of preventing atherosclerosis.
    • Lipid tests to assess the risk of cardiovascular disease should be done when acute inflammation has subsided, i.e. after 3 months of antirheumatic medication, for example.
    • The target lipid levels are the same as for other high-risk patients; see Treatment of dyslipidaemiasTreatment of Dyslipidaemias.
    • Smoking cessation may also have positive effects on the results of treatment of RA.
  • Higher doses of glucocorticoids impair glucose tolerance.
  • Rheumatic inflammation, reduced functional capacity and higher glucocorticoid doses make patients susceptible to osteoporosis.
    • In addition, glucocorticoids directly increase the risk of fractures.
    • All patients should be prescribed 1 g calcium + 800 IU vitamin D daily for osteoporosis prophylaxis.
    • Vitamin D testing (25(OH)D target exceeding 80 nmol/l) can be used to ensure a sufficient dose of vitamin D.
    • At doses of prednisolone exceeding 7.5 mg, bone densitometry and osteoporosis medication should be considered.
    • See the article Osteoporosis Osteoporosis.
  • Glucocorticoids precipitate the development of cataract.

Withdrawal of medication during infections

  • Unnecessary pausing of antirheumatic medication should be avoided.
  • Common cold or antimicrobial treatment prescribed in outpatient care for conditions such as urinary tract infection or sinusitis do not require pausing of antirheumatic medication. Caution should be exercised in giving trimethoprim to patients on methotrexate.
  • Methotrexate, biological agents and JAK inhibitors should be paused for the duration of more severe bacterial infections, such as pneumonia or sepsis requiring hospital treatment.
  • Important: The interleukin 6 inhibitors tosilizumab and sarilumab may mask symptoms and findings associated with serious infection and prevent the elevation of CRP levels.

Withdrawal of medication for procedures

  • "Conventional" antirheumatic drugs need not be withdrawn for elective surgery.
  • Biological agents should be paused so that elective surgery is done at the time the next drug dose would be given. JAK inhibitors should be paused for 3 days before the operation. See local guidance for further details.
  • In the case of endoscopic gastroenterological and gynaecological procedures and other small procedures, such as naevus resection, withdrawal of medication is unnecessary.
  • After uncomplicated surgical procedures, biological medication and JAK inhibitors can usually be restarted when the wound has healed.
  • For uncomplicated dental procedures, pausing of medication is unnecessary.

Rehabilitation Non-Pharmacological Interventions for Fatigue in Rheumatoid Arthritis, Balneotherapy for Rheumatoid Arthritis, Psychological Therapies for the Management of Chronic Pain in Adults, Dynamic Exercise Therapy for Rheumatoid Arthritis

  • Physical activity guidance is an important part of the treatment of RA. Physical exercise improves functional ability.
    • When visiting their doctor, patients should be encouraged to exercise.
    • Exercises may be guided by a physiotherapist, as necessary.
  • Conventional recommendations for health-enhancing physical activity can be given in most cases.
    • At least 2.5 hours of aerobic exercise per week
    • Strength training at least twice weekly
    • Such exercising has no negative effects on disease activity, pain or radiologically observed joint damage.

Aids Assistive Technology for Rheumatoid Arthritis, Occupational Therapy for Rheumatoid Arthritis

  • If joint damage has developed, the patient's functional capacity can be improved by using aids supplied by the place of treatment.
    • Wrist splints
    • Support insoles
    • Mobility aids
  • The expertise of occupational and physiotherapists should be utilized in matters associated with aids and appliances.

Surgery

  • See article Rheumatoid arthritis surgery Rheumatoid Arthritis Surgery.
  • With improved pharmacological treatment, the need for surgical treatment has considerably decreased.
  • Patients with a long history of the disease may need joint replacement or other types of surgery.
  • If rheumatoid arthritis has damaged peripheral joints, it may be associated with changes in the cervical spine. Atlanto-axial subluxation, which must be borne in mind when administering general anaesthesia, can be seen in flexion radiography of the cervical spine.
  • Disturbing rheumatic nodules and bursae can be removed.

Vaccinations in RA

Continuity of care Downtitration and Discontinuation Strategies of Tnf-Blocking Agents in Rheumatoid Arthritis

  • If remission is stable, after 2 years follow-up can be transferred to primary health care.
  • Patients on biological agents or JAK inhibitors should continue being monitored by a rheumatology unit. This can be partly done remotely using an electronic monitoring system.
  • Antirheumatic medication is normally used for several years or several decades because the symptoms of RA usually recur if medication is withdrawn.
    • If the patient's remission is stable for a long time, reduction of medication should be considered.
    • Total withdrawal of medication is rarely possible. 10-15% of patients with RA achieve long-term remission without medication.
    • If the disease is reactivated when medication is reduced, the medication that maintained remission should be resumed.
  • Long-term glucocorticoid treatment may cause adrenocortical suppression Pharmacological Glucocorticoid Treatment. This can be investigated by determining the serum cortisol concentration in the morning, when the patient has not taken a glucocorticoid for 24-48 h. Cortisol concentration exceeding 250 nmol/l will exclude glucocorticoid-induced adrenocortical suppression; see article Pharmacological glucocorticoid therapy Pharmacological Glucocorticoid Treatment.

Follow-up in primary care

  • Cooperation is necessary between the rheumatology outpatient clinic and primary health care.
  • Patients with RA should be followed up preferably by a physician who is very familiar with the treatment of the disease.
  • Assessment methods used for follow-up
    • Patient self-assessment scales
    • Laboratory tests
      • ESR, CRP
    • Palpation of symptomatic joints
      • Swollen and tender joints, ranges of joint motion
    • Pain appearing in a patient with RA is not necessarily due to activation of the disease but may be due to conditions such as osteoarthritis, rotator cuff problem, fibromyalgia or polyneuropathy.
    • The patient should be examined thoroughly to find out the cause.
    • What to do if RA is found to be activated
      • Check in the prescription centre whether the patient collected their antirheumatic medication (if such a service is available).
      • Increase doses of conventional antirheumatic drugs, replace oral methotrexate by the subcutaneous dosage form.
      • Give glucocorticoid injections into inflamed joints.
      • Consult a rheumatologist if the above measures do not correct the patient's status.

    References

    • Weman L, Vehmas J, Immonen J, et al. Real-world data on seropositive rheumatoid arthritis, then and now: ten-year outcomes of 1151 patients diagnosed between 1997 and 2011. Clin Exp Rheumatol 2023;41(1):151-158. [PubMed]
    • Rantalaiho V, Kautiainen H, Korpela M, et al. Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial. Ann Rheum Dis 2014;73(11):1954-61. [PubMed]
    • 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(9):2569-81. [PubMed]

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