Rheumatoid arthritis

Rheumatoid arthritis

The commonest inflammatory arthritis, a symmetrical autoimmune synovitis of the hands and feet that erodes bone within months and inflames the whole body; how it begins, how it is recognised and measured, and how methotrexate, steroids and then biologics or JAK inhibitors, aimed at remission, have changed its course.

Rheumatoid arthritis, from synovitis to erosions

6 scenes, 0:57

A film in six scenes on a white page. A knuckle joint lies across the screen, the metacarpal coming in from the left and the finger's first phalanx going out to the right, cut open lengthwise towards the viewer as the camera drifts round it: the ivory bone with cream marrow crossed by spongy bone, the rounded head of the metacarpal and the shallow cup of the phalanx each capped by pale blue cartilage, a thin film of pale yellow fluid between them, a thin coral synovium lining a pearl-coloured capsule. Then the synovium up close, a block of it cut open: a layer of pink lining cells on top, loose tissue below with cream fat cells, and a small vein cut along its length and another across, red cells flowing in them. Pale blue white cells roll along the vein's wall, squeeze through it into the tissue and crawl on; the larger ones grow into macrophages, pink specks of cytokine spread from them through the tissue, and the lining thickens, layer upon layer. Back to the whole joint: the synovium swells, deep coral, into fronds, and the fluid swells the capsule outwards. The inflamed synovium creeps from the joint's edges over the cartilage, which thins. At the edges of the bones, where the synovium touches bone not covered by cartilage, pits are eaten into the bone and fill with synovium. Last, with treatment, the synovium shrinks back to a thin lining and the swelling goes down, but the thinned cartilage and the pits in the bone stay.

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A healthy knuckle joint

Scenes

About this film

Rheumatoid arthritis is a disease of the synovium. White cells drawn from the blood fill it and drive an excess of cytokines such as TNF-α and IL-6; the synovium thickens, fluid swells the joint, the inflamed synovium grows over the cartilage as pannus and eats into the bone at the joint's edges. Treatment can quiet the inflammation, but cartilage and bone that are lost rarely come back, which is why it starts early.

Simplified: Not to scale: cells and cytokines are drawn at sizes that read, and months of disease pass in seconds. The joint is drawn as a smooth head and cup in a simple capsule; the ligaments, tendons and volar plate are left out. The lining is drawn as one kind of cell; its fibroblast-like and macrophage-like synoviocytes are not told apart. T and B cells are drawn alike, plasma cells and neutrophils are left out of the close-up, and the cells move far faster than they do. Each pink speck stands for many cytokine molecules, and all the cytokines are drawn alike. Pannus and erosions are drawn in every margin of one joint at once; in a patient they are patchy and differ from joint to joint. Treatment is shown in one scene; in life the response takes weeks to months, and some patients need several drugs before the disease is controlled.

2 sources
  1. Kumar and Clark's Clinical Medicine, 10th edition. Elsevier, 2021. Chapter 18, Rheumatology: synovial joints (p. 415) and rheumatoid arthritis (pp. 438–445).
  2. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656-64.
Contents6 sections

At a glance

  1. Rheumatoid arthritis is a chronic autoimmune synovitis, typically a symmetrical polyarthritis of the small joints of the hands and feet, with fatigue and a raised CRP. It affects about 0.5 to 1 per cent of adults in Europe, two to three times more women than men.
  2. It begins years before the joints swell: genes (the HLA-DRB1 shared epitope) and smoking lead to citrullinated proteins and antibodies against them (ACPA). The inflamed synovium, the pannus, then erodes cartilage and bone, fastest in the first two years.
  3. The diagnosis is clinical, helped by rheumatoid factor and anti-CCP antibodies, the CRP and ESR, and ultrasound or X-rays. A score of 6 or more of 10 on the 2010 ACR/EULAR criteria classifies it.
  4. Suspected inflammatory arthritis is referred urgently: treatment started within about 3 months of the first symptoms limits damage that later treatment cannot undo.
  5. Treatment aims at remission or low disease activity: methotrexate first with a short course of steroids, improvement by 3 months and the target by 6, otherwise a biologic is added, or a JAK inhibitor after weighing its risks.
  6. Methotrexate is taken once a week, never daily. JAK inhibitors are used in people aged 65 or more, smokers and those at raised cardiovascular or cancer risk only when nothing else suits.
  7. It is a systemic disease: cardiovascular disease is its main cause of death, and the lungs, eyes, skin, blood and upper cervical spine can all be affected.

Definition and overview

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease whose main target is the synovium, the lining of joints, tendon sheaths and bursae. Untreated, the inflamed synovium destroys cartilage and bone, deforms the joints and disables, and the same inflammation raises the risk of heart and lung disease and early death.

It is split by its antibodies, because they predict its course:

  • Seropositive RA, with rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA, measured as anti-CCP) or both, in about 70 to 80 per cent: more erosive, with more disease outside the joints.
  • Seronegative RA: often starts in the wrists and less symmetrically, is less erosive on average, and has a wider differential, especially psoriatic arthritis.

Most patients have a chronic course of flares and remissions. Some start with palindromic attacks, a red swollen joint for a day or two that leaves no trace, and about half of them go on to RA. The first months of symptoms, often put at 3 to 6, are the window in which treatment changes the course most; early RA is defined differently in different studies, up to 2 years. Difficult-to-treat RA is still active after a conventional DMARD and at least two biologics or JAK inhibitors with different mechanisms.

Etiology and pathophysiology

Who gets it

  • Genes: identical twins are concordant in about 12 to 15 per cent. The strongest gene is HLA-DRB1: several of its alleles (in HLA-DR4 and DR1) share a sequence at positions 70 to 74 of the DRβ chain, the shared epitope, which binds citrullinated peptides well. More than 100 other loci each add a little, among them PTPN22 (T cell signalling) and PADI4 (an enzyme that citrullinates).
  • Smoking, the main environmental cause: it roughly doubles the risk of ACPA-positive RA, and much more in carriers of the shared epitope. Silica dust acts alike.
  • Periodontitis: Porphyromonas gingivalis has its own citrullinating enzyme.
  • Female sex: RA often starts in the year after childbirth and tends to quieten in pregnancy. Obesity adds risk.

How it develops

  1. 1

    Citrullination

    Smoke and other irritants at mucosal surfaces, mostly the lung, switch on peptidylarginine deiminases, which turn arginine in proteins such as vimentin, fibrinogen and enolase into citrulline.
  2. 2

    Loss of tolerance

    In carriers of the shared epitope, the altered peptides are presented to T cells, which help B cells make ACPA and RF. The antibodies can be found up to 10 years before arthritis.
  3. 3

    Synovitis

    A second hit, not yet understood, carries the response into the joint. T cells, B cells, plasma cells and macrophages fill the synovium, new vessels grow, and fibroblast-like synoviocytes multiply and turn aggressive.
  4. 4

    Pannus and erosion

    The thickened synovium, the pannus, spreads over the cartilage. TNF, IL-6, IL-1 and enzymes break down cartilage, and RANKL drives osteoclasts to erode bone at the joint margins.
A knuckle joint, healthy and in rheumatoid arthritis
Two knuckle joints, metacarpophalangeal joints, cut lengthwise and drawn side by side on a white plate, the metacarpal above and the finger's first phalanx below. Each bone is ivory, with cream marrow crossed by struts of spongy bone. On the left, the healthy joint: the rounded head of the metacarpal and the shallow cup of the phalanx are each capped by a smooth pale blue layer of cartilage, kept apart by a thin film of pale straw synovial fluid, and enclosed on both sides by a pearl-coloured capsule lined by a thin, pale coral synovium. On the right, the same joint in rheumatoid arthritis: the synovium is deep coral, thick and folded into fronds, with pale blue white cells in it; the capsule bulges outwards round a larger pool of fluid holding neutrophils; deep coral tissue, the pannus, has crept from the joint's edges over the cartilage, which is thinner, so the bones lie closer; and at the edges of each bone, where the synovium meets bone not covered by cartilage, the bone is eaten away in pits filled with synovium, large cells with several nuclei, osteoclasts, lying in them.

Point at a name or a part to light it.

Rheumatoid arthritis is a disease of the synovium. The inflamed synovium thickens and fills with immune cells, fluid gathers in the joint, and the synovium grows over the cartilage as pannus and into the bone at the joint's edges. MRI shows the bone damage in the first 3–6 months, which is why disease-modifying drugs should be started within 3 months of onset.

Simplified: not to scale: the cartilage, the synovium, the gap between the bones and the fluid round them drawn thicker than life, and the cells far larger; the bone ends drawn as a smooth rounded head and a shallow cup, simpler than the real metacarpal head and base of the phalanx; the collateral ligaments, the tendons that cross the joint, the volar plate, the periosteum and the new blood vessels of the synovitis left out; a handful of cells for the many in a real synovium, and the lymphocytes, macrophages, plasma cells and neutrophils drawn as simple cells; the fibroblast-like synoviocytes of the lining not drawn one by one; changes that take months to years, and differ from joint to joint, all drawn in one joint at once; the spongy bone drawn as a few struts.

2 sources
  1. Kumar and Clark's Clinical Medicine, 10th edition. Elsevier, 2021. Chapter 18, Rheumatology: synovial joints (p. 415) and rheumatoid arthritis (pp. 438–445); Chapter 19, Bone disease: osteoclasts (p. 474).
  2. Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol. 2012;8(11):656-64.

Each step is now a target, which is why treatment has changed so much:

TargetIts role in RABlocked by
TNFtop of the cytokine cascade; switches on endothelium, synoviocytes and osteoclastsadalimumab, etanercept, infliximab, certolizumab, golimumab
IL-6acute phase response, anaemia, fatigue, osteoclaststocilizumab, sarilumab
T cell co-stimulation (CD80/86 to CD28)lets antigen-presenting cells activate T cellsabatacept
B cells (CD20)make RF and ACPA, present antigenrituximab
JAK enzymescarry the signals of IL-6, interferons and other cytokines inside the celltofacitinib, baricitinib, upadacitinib, filgotinib

How each class works and its risks are in biologic and biosimilar drugs. Blocking IL-17 or IL-23, which works in psoriatic arthritis, has worked poorly or not at all in RA trials: the two diseases are driven differently.

Clinical features

The joints

  • A symmetrical polyarthritis of the small joints, evolving over weeks to months: the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints, the wrists and the metatarsophalangeal (MTP) joints. The distal interphalangeal joints are usually spared; larger joints follow.
  • Pain and morning stiffness lasting more than an hour, better with use; fatigue, poor sleep, sometimes low fever and weight loss.
  • Warm, tender, boggy swelling; pain on squeezing across the MCP or MTP joints; weak grip.
  • Less often it starts suddenly, in a single large joint, as palindromic attacks, or in older people like polymyalgia rheumatica, the synovitis appearing as the steroid dose falls.
Which hand joints rheumatoid arthritis and osteoarthritis take
A right hand seen from the back, drawn twice side by side on a white plate: a soft, sand-coloured hand with pale nails, its bones showing through in ivory, from the ends of the radius and ulna, which fade out at the bottom, through the carpal bones of the wrist and the five metacarpals to the bones of the thumb and fingers. On the left, the hand in rheumatoid arthritis: see-through coral swellings, the colour of inflamed synovium, lie over the wrist's joints, over the knuckles (MCP joints) of all five digits and over the middle joints of the four fingers and the thumb's interphalangeal joint, and the skin bulges over them; the joints nearest the fingertips have none. On the right, the hand in nodal osteoarthritis: no soft swelling, but lips of new bone grown out from the edges of the joints nearest the fingertips of all four fingers and of the middle joints of the index and middle fingers, those joints' spaces narrowed and the skin knobbly over them; at the base of the thumb, the metacarpal has slipped partly off the trapezium and carries a lip of new bone, and the thumb is drawn in towards the index finger, narrowing the web between them.

Point at a name or a part to light it.

The joints a disease takes help tell it apart. Rheumatoid arthritis swells the wrists, the knuckles (MCP joints) and the fingers' middle joints (PIP joints) of both hands alike, and usually spares the joints nearest the fingertips (DIP joints). Nodal osteoarthritis takes the DIP joints most, the PIP joints less often and the base of the thumb, and leaves hard bony nodes rather than soft swelling.

Simplified: the bones drawn in simplified outlines after an anatomy atlas, without their ridges and grooves; one hand drawn for each disease; rheumatoid arthritis takes both hands alike; each disease's typical pattern drawn whole: a patient may have only some of these joints taken; the swelling of rheumatoid arthritis drawn as a see-through coral sac over each joint, standing for the swollen synovium and capsule, and over the wrist as one swelling across its joints and tendon sheaths; the nodes of osteoarthritis drawn as smooth lips of new bone either side of each finger joint and on the metacarpal at the thumb's base; in life they are lumpier; the erosions rheumatoid arthritis makes in the bones, the deformities either disease brings in time other than the squared thumb, osteoarthritis of the knuckles (its least common site in the hand), the tendons, muscles and other soft tissues under the skin, the sesamoid bones and the joints of the feet left out.

6 sources
  1. Kumar and Clark's Clinical Medicine, 10th edition. Elsevier, 2021. Chapter 18, Rheumatology: the hand (p. 421), nodal osteoarthritis (p. 435) and rheumatoid arthritis (pp. 439–442).
  2. Zhang W, Doherty M, Leeb BF et al. EULAR evidence-based recommendations for the diagnosis of hand osteoarthritis: report of a task force of ESCISIT. Ann Rheum Dis. 2009;68(1):8-17.
  3. Aletaha D 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.
  4. Jordaan P, Kruger N, McGuire D. Thumb base/carpo-metacarpal joint osteoarthritis. In: Held M, ed. Orthopaedics for Primary Health Care. University of Cape Town Libraries, 2021. CC BY 4.0.
  5. Adams JE, O'Brien V, Magnusson E, Rosenstein B, Nuckley DJ. Radiographic analysis of simulated first dorsal interosseous and opponens pollicis loading upon thumb CMC joint subluxation: a cadaver study. Hand (N Y). 2018;13(1):40-44.
  6. Gray H. Anatomy of the Human Body, 20th edition, ed. Lewis WH. Lea & Febiger, 1918. Figure 219, the bones of the left hand, volar surface.

Poorly controlled disease leaves deformities:

SiteDamage
Handsulnar deviation and palmar subluxation at the MCPs; swan-neck and boutonnière fingers; Z-shaped thumb
Wristthe subluxed ulnar head wears through the extensor tendons of the ring and little fingers, which suddenly drop; carpal tunnel syndrome from tenosynovitis
FeetMTP synovitis, an early sign; dropped metatarsal heads with painful calluses, hammer toes, a flat valgus hindfoot
Kneeseffusions and a Baker cyst, whose rupture mimics a deep vein thrombosis
Cervical spinesynovitis around the odontoid peg loosens the transverse ligament: atlantoaxial subluxation

Beyond the joints

Extra-articular disease comes mostly with strongly seropositive, long-standing, active disease, and is rarer with better treatment:

OrganFeatures
Skinrheumatoid nodules over pressure points (elbows, fingers, Achilles), in up to a quarter of patients, almost all seropositive
Lungsinterstitial lung disease; pleural effusions, exudates with a very low glucose; nodules (with dust exposure, Caplan syndrome); bronchiectasis; obliterative bronchiolitis
Heart and vesselsaccelerated atherosclerosis; silent pericarditis; rheumatoid vasculitis with nail-fold infarcts, leg ulcers and mononeuritis multiplex, now rare
Eyesdry eyes from secondary Sjögren syndrome; episcleritis; scleritis, painful and sight-threatening
Nervescarpal and tarsal tunnel syndromes; peripheral neuropathy
Bloodanaemia of chronic disease; high platelets with activity; Felty syndrome, splenomegaly with neutropenia and infections; a raised risk of lymphoma
OtherAA amyloidosis after years of uncontrolled inflammation, now rare; osteoporosis; muscle wasting

Judging activity

Activity is scored at each visit so that treatment changes by numbers, not impression:

  • DAS28: 28 joints (shoulders, elbows, wrists, MCPs, PIPs, knees) counted for tenderness and swelling, with the ESR or CRP and the patient's global assessment. The feet are not counted, so they are examined separately.
  • CDAI and SDAI: simple sums of the 28 tender and swollen joint counts and the patient's and physician's global assessments (SDAI adds the CRP).
  • ACR/EULAR Boolean remission, the strictest: at most one tender and one swollen joint, a CRP of 1 mg/dL or less, and a patient global assessment of 2 or less out of 10 (raised from 1 in 2022).
below this is remission
2.6DAS28
up to this is low disease activity
3.2DAS28
above this is high disease activity
5.1DAS28

Diagnosis and management

Tests

Joint swelling not explained by injury, especially of small joints or of more than one joint, is referred urgently. A normal CRP or a negative RF does not rule out RA, and steroids are best not started before the rheumatologist sees the patient, because they hide the synovitis.

TestWhat it shows
Anti-CCP antibodiessensitivity about 60 to 70 per cent, specificity about 95 per cent; high levels predict erosions
IgM rheumatoid factorin about 70 to 80 per cent of RA, but also in Sjögren syndrome, SLE, hepatitis C, endocarditis and up to a quarter of healthy older people
CRP and ESRraised with activity and used to follow it
Blood count, kidney and liver testsanaemia, high platelets; the baseline for DMARDs
Hepatitis B and C, ANA, urate, parvovirus B19 where it fitsother causes of polyarthritis; hepatitis matters before treatment
X-rays of hands and feetperiarticular osteopenia early, then joint space narrowing and marginal erosions; the baseline for damage
Ultrasound with power Doppler, MRIsynovitis and erosions before X-ray shows them; bone marrow oedema on MRI predicts erosions
Synovial fluidinflammatory fluid; crystals and culture exclude gout and sepsis

How each antibody is tested and read is in humoral immunity in rheumatic diseases.

Classification

The 2010 ACR/EULAR criteria apply to a patient with at least one swollen joint not better explained by another disease. A score of 6 or more of 10 classifies RA:

DomainPoints
Joints1 large: 0; 2 to 10 large: 1; 1 to 3 small: 2; 4 to 10 small: 3; more than 10, at least one small: 5
Serology (RF or ACPA)both negative: 0; low positive, up to 3 times the upper limit: 2; high positive: 3
CRP or ESR abnormal1
Symptoms for 6 weeks or more1

Small joints are the MCPs, PIPs, second to fifth MTPs, thumb interphalangeal joints and wrists; the distal interphalangeal, first carpometacarpal and first MTP joints are not counted. Typical erosions alone also classify. The criteria select patients for studies; a patient scoring 5 can still have RA.

The differential of an early polyarthritis includes viral arthritis (parvovirus B19, hepatitis B and C, rubella, chikungunya), which usually settles within weeks; psoriatic arthritis; lupus; polyarticular gout and calcium pyrophosphate disease; nodal osteoarthritis, which takes the distal joints; polymyalgia rheumatica; and haemochromatosis.

Treat to target

The strategy matters as much as the drug. The 2025 European recommendations:

  1. 1

    Start at diagnosis

    A disease-modifying drug as soon as RA is diagnosed, aiming for sustained remission, or low disease activity where remission is not realistic, agreed with the patient.
  2. 2

    Methotrexate first

    Methotrexate in the first strategy; leflunomide or sulfasalazine if it cannot be used. A short course of glucocorticoids is considered alongside, tapered and stopped as fast as is clinically possible, usually within about 3 months.
  3. 3

    Review every 1 to 3 months

    No improvement by 3 months, or the target not reached by 6, means a change: dose, adherence, then the next step.
  4. 4

    Add a biologic

    If the first conventional strategy fails, a biologic is added; a JAK inhibitor may be considered instead after weighing cardiovascular, cancer and clotting risks. Both work best with methotrexate; where no conventional DMARD can be given alongside, an IL-6 receptor blocker or a JAK inhibitor may have an advantage. Since 2025 this step no longer depends on poor prognostic factors, as it did in older guidance: failure of the first strategy is itself one.
  5. 5

    Switch if it fails

    Another biologic or JAK inhibitor, of the same class or a different one.
  6. 6

    Remission

    Once steroids are stopped and remission is sustained, continuing the DMARDs is preferred; the dose may be reduced, but stopping usually brings a flare.

Conventional synthetic DMARDs

DrugDoseWhat to watch
Methotrexate15 mg once weekly by mouth, raised over a few weeks to 20 to 25 mg; subcutaneous if absorption or nausea limits it; folic acid 5 mg weekly on another daynausea, mouth ulcers, raised transaminases, cytopenias, rare acute pneumonitis; teratogenic; reduced in kidney disease
Leflunomide10 to 20 mg dailydiarrhoea, hypertension, hepatotoxicity; a very long half-life, washed out with colestyramine before a pregnancy
Sulfasalazine500 mg daily, raised to 2 to 3 gnausea, rash, neutropenia, hepatitis, orange urine, reversible low sperm count; usable in pregnancy
Hydroxychloroquine200 to 400 mg daily, at most 5 mg/kgretinopathy after years, so the retina is screened (in the UK yearly after 5 years); used in combinations or mild disease

Blood counts, kidney and liver tests are checked every 2 weeks or so while the dose rises and about every 3 months once stable. Methotrexate works in 4 to 8 weeks.

Glucocorticoids and symptom relief

Glucocorticoids act within days and slow erosion, a bridge while DMARDs take effect: oral prednisolone tapered over weeks, an intramuscular depot of methylprednisolone 80 to 120 mg, or an injection into an inflamed joint. Long-term use brings osteoporosis, diabetes, cataract, infection and heart disease, so courses are kept low and short, with bone protection beyond 3 months. NSAIDs ease pain and stiffness but do not change the disease; they are used briefly, with gastric protection when needed and care for the heart.

Biologics and JAK inhibitors

After a conventional strategy fails, the options are the TNF inhibitors, the IL-6 receptor blockers tocilizumab and sarilumab, abatacept, rituximab (best in seropositive disease) and the JAK inhibitors. On average they work about equally well, so the choice rests on the patient: other diseases, plans for pregnancy, route, cost (biosimilars are now usual) and whether methotrexate can be taken. Tuberculosis and hepatitis B and C are screened for first. The details are in biologic and biosimilar drugs.

Beyond drugs

  • A team: nurse specialists, physiotherapy and exercise, occupational therapy, podiatry and psychological support.
  • Stopping smoking, which worsens the disease, blunts the drugs and drives lung and heart disease.
  • Surgery for established damage: tendon repair (urgent after a rupture), synovectomy, fusion, and joint replacement. Methotrexate is continued through surgery; a biologic is paused for one dosing interval.

Comorbidity

  • Cardiovascular disease: RA raises the risk by about half. Risk is assessed at least every 5 years; European recommendations multiply the score by 1.5 if it does not already include RA (the UK's QRISK3 does), and blood pressure, lipids and smoking are treated as usual. Controlling the arthritis lowers the risk too.
  • Interstitial lung disease: clinically important in about 1 in 10, more often in older male smokers with high RF or ACPA, often with a usual interstitial pneumonia pattern. It is looked for with lung function and high-resolution CT. American guidance favours mycophenolate, rituximab or azathioprine, and nintedanib for progressive fibrosis. Methotrexate pneumonitis is a different, acute illness; methotrexate is no longer thought to cause chronic RA lung disease.
  • Infection: vaccination against influenza, pneumococcus and COVID-19, and the non-live shingles vaccine before a JAK inhibitor; live vaccines are given before immunosuppression where possible and not during biologic or JAK inhibitor treatment.
  • Osteoporosis, lymphoma (about twice as common, linked to activity), depression.

Pregnancy

About half of women improve during pregnancy, and many flare in the months after delivery. A pregnancy is planned in remission. Methotrexate is stopped 1 to 3 months before conception, depending on the guidance followed, and leflunomide washed out; hydroxychloroquine, sulfasalazine and low-dose prednisolone can continue. Every TNF inhibitor can be continued through pregnancy after weighing the risks; certolizumab barely crosses the placenta. JAK inhibitors are stopped. An infant exposed in the second half of pregnancy to a biologic that crosses the placenta has no live vaccine, such as BCG, for 6 months. All biologics are compatible with breastfeeding; methotrexate, leflunomide and JAK inhibitors are not.

Epidemiology

RA affects about 0.5 to 1 per cent of adults in Europe and North America. Worldwide an estimated 17.6 million people had it in 2020, projected to reach about 32 million by 2050 as populations grow and age. It is two to three times commoner in women and can start at any age, most often between 30 and 60. It is particularly common in some Native American peoples and less common in rural Africa and East Asia. About 7 per cent of its burden worldwide, measured in disability-adjusted life years, is attributed to smoking.

Prognosis

Before modern treatment, most patients had erosions within two years, many stopped work within a few years of diagnosis, and life was shortened by several years, mostly through cardiovascular disease, infection and lung disease. With early treatment to target most patients now reach low disease activity and many reach remission, deformities and joint replacements are less common, and the excess mortality is narrowing.

A worse course is predicted by high-titre RF and especially ACPA, erosions at presentation, many swollen joints with a high CRP and poor function at onset, smoking and social deprivation, extra-articular disease, and failure of the first DMARD strategy. Perhaps 5 to 20 per cent, depending on the definition, develop difficult-to-treat RA. Drug-free remission is uncommon, so most patients need lifelong treatment and follow-up of activity, drug toxicity, damage, function, cardiovascular risk, lungs, bone and mood.

Check yourselfAnswer, then say how sure you were: a lucky guess still counts as a weak point.

1A 45-year-old woman has had painful swelling of both wrists and of six metacarpophalangeal joints for 10 weeks. Rheumatoid factor is weakly positive, anti-CCP antibodies are more than three times the upper limit of normal and the CRP is raised. How does she score on the 2010 ACR/EULAR classification criteria?

2A 72-year-old man on methotrexate 20 mg weekly for rheumatoid arthritis is given trimethoprim for a urinary infection. A week later he has mouth ulcers, bruising and a white cell count of 1.1 × 10⁹/L. What has most likely happened?

3A 70-year-old woman who smoked for 40 years has active rheumatoid arthritis despite methotrexate and then adalimumab. Which next step follows European guidance best?

4A 66-year-old woman with rheumatoid arthritis for 25 years is listed for a hip replacement under general anaesthesia. Recently she has had neck pain and tingling in both hands. What must be done before surgery?

5A 38-year-old smoker has joint pains without swelling, and her anti-CCP antibodies are strongly positive. Which statement is correct?

Linked topicsThe concepts this topic shares, and the topics they tie it to.

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Immune suppression

Methotrexate is the first disease-modifying drug; biologics follow if it isn’t enough.

  • Glucocorticoids and mineralocorticoids (corticosteroids)PharmacologyNot written yetGlucocorticoids are the fastest, broadest way to damp inflammation.
  • ImmunomodulatorsPharmacologyNot written yetDrugs that damp the immune response, such as azathioprine and ciclosporin, or boost it.
  • Treatment of rheumatic diseases with biologic and biosimilar drugsRheumatic diseasesBiologics such as TNF inhibitors block single signals of inflammation.
  • Systemic lupus erythematosusRheumatic diseasesHydroxychloroquine for everyone; glucocorticoids and immunosuppressants for flares and organ disease.
  • Polymyalgia rheumatica and fibromyalgiaRheumatic diseasesPolymyalgia rheumatica eases within two weeks on prednisolone 12.5–25 mg a day; fibromyalgia does not.
  • Large vessel vasculitis – Horton disease, Takayasu’s arteriitis, Buerger diseaseRheumatic diseasesGiant cell arteritis needs high-dose glucocorticoids at once, to save sight.
  • Idiopathic nephrotic syndromeRenal diseasesNot written yetMinimal change disease usually remits on glucocorticoids.
  • Autoimmune hepatitisGastrointestinal diseasesNot written yetPrednisolone, then azathioprine to keep it in remission.
  • Ulcerative colitis and Crohn’s diseaseGastrointestinal diseasesNot written yetGlucocorticoids for flares; immunosuppressants and biologics to keep remission.

Autoantibodies and immune complexes

Rheumatoid factor and anti-CCP antibodies.

  • Humoral immunity changes in Rheumatic diseasesRheumatic diseasesAutoantibodies and complement in rheumatic diseases.
  • Systemic lupus erythematosusRheumatic diseasesAnti-dsDNA antibodies and immune complexes; complement falls in flares.
  • Lupus nephritisRenal diseasesNot written yetImmune complexes in the glomeruli, a major cause of illness in lupus.
  • Antiphospholipid syndromeRheumatic diseasesAntiphospholipid antibodies raise the risk of blood clots and of pregnancy loss.
  • Membranous glomerulonephritisRenal diseasesNot written yetMost often antibodies against PLA2R on the podocytes.
  • Haemolytic anemias. HemolysisHematologic diseasesAutoimmune haemolysis: antibodies coat red cells (a positive Coombs test).
  • Drug allergy: type I, II, IIIToxicology and allergic disordersNot written yetType III reactions are immune complex disease, such as serum sickness.

Folate and vitamin B12

Folic acid is given with methotrexate to cut its side effects.

  • DNA replicationBiologyThymidine, one of DNA’s building blocks, is made with folate’s help.
  • Vitamins: clinical applicationsPharmacologyNot written yetVitamin B12 and folic acid as treatments.
  • Haematopoietic drugsPharmacologyNot written yetHydroxocobalamin and folic acid restore normal blood formation.
  • SulfonamidesPharmacologySulfonamides stop bacteria making folate, which we take from food; trimethoprim blocks a later step.
  • Antitumor chemotherapeuticalsPharmacologyNot written yetMethotrexate blocks dihydrofolate reductase.
  • Macrocytic and megaloblastic anemiasHematologic diseasesA lack of B12 or folate gives large red cells, from megaloblasts in the marrow; lack of B12 can also damage nerves.