Rheumatoid arthritis

• 1. Introduction

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  Rheumatoid arthritis is a long-term autoimmune disease, and as of 2020 it affected about 17.6 million people. In the developed world, it touches between half of one percent and one percent of adults. Each year, between 5 and 50 people in every 100,000 newly develop it. At its core is a case of mistaken identity. The immune system, built to find and destroy invaders, turns on the lining of a person's own joints. Nobody can yet say exactly what sets that mistake in motion. Several questions follow from that. Why do the same joints on both sides of the body tend to fall ill together? Why does a disease of the hands sometimes reach the lungs, the eyes and the heart? How can a blood test hint at trouble before a single symptom appears? And why do doctors now treat the disease early and hard, rather than waiting to see how it develops?

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• 2. Morning Stiffness

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  Stiffness that lingers for more than an hour after waking is one of the most telling signs of rheumatoid arthritis. Gentle movement often eases it in the early stages. Doctors lean on this pattern to separate the disease from osteoarthritis, where inflammation and early morning stiffness are much less prominent. The affected joints are swollen, warm, tender and painful. The small joints of the hands and feet are the usual targets, along with the neck. Shoulders and knees can be drawn in as well. The pattern is often fairly symmetrical, although the first presentation may be lopsided. The pain itself comes from the site of inflammation, which makes it nociceptive rather than neuropathic.

  The lining of a joint is called the synovial membrane, and its inflammation is known as synovitis. Left to run, it tethers tendons and erodes the joint surface. Fingers can twist into almost any shape. In the boutonniere deformity, also called the buttonhole deformity, the middle finger joint bends while the joint nearest the tip extends. The swan neck deformity runs the other way, with the middle joint hyperextended and the tip flexed. In the Z-thumb, one thumb joint is fixed in flexion and partly dislocated, and the thumb takes on the outline of a letter Z. Toes can develop the hammer toe deformity. In the worst cases, doctors use the name arthritis mutilans, chosen because the deformities can be so severe.

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• 3. Beyond The Joints

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  In 30 percent of people with the disease, a firm lump called a rheumatoid nodule appears. It is the most common feature outside the joints. Nodules usually form over bony spots that take repeated stress, such as the elbow, the heel or the knuckles, and they range from a few millimetres to a few centimetres across. They tend to travel with a positive rheumatoid factor and with severe, erosive joint damage. Overall, other organs are affected in more than 15 to 25 percent of cases.

  The lungs can scar, a condition called lung fibrosis. Caplan's syndrome describes lung nodules in people with the disease who have also been exposed to coal dust. The eyes can dry out when immune cells infiltrate the tear and salivary glands. Severe dryness can damage the cornea and cost a person some vision. Anemia is by far the most common blood abnormality. Chronic inflammation raises a hormone called hepcidin, so iron is poorly absorbed and gets locked away inside macrophages.

  The neck holds a quieter danger. Erosion near the top of the cervical spine, beyond 3 millimetres, can let vertebrae slip over one another and press on the spinal cord. Clumsiness comes first. Without care, the outcome can be quadriplegia or even death.

  The heart is perhaps the most worrying target. A 2005 study from the Mayo Clinic found that people with the disease have double the risk of heart disease, independent of diabetes, heavy drinking, cholesterol, blood pressure and body mass index. The reason remains unknown, though chronic inflammation is a suspect. Many patients also do not feel the usual chest pain of angina or a heart attack. Overall, the disease shortens life by an average of 3-12 years. In 2020 it caused 38,300 deaths, up from 28,000 in 1990.

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• 4. Genes And Triggers

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  When one identical twin has rheumatoid arthritis, twins raised in separate households share the disease only 12-15 percent of the time. That figure undercuts any simple story of inheritance. Even so, heredity matters. As of 2016, genetics was estimated to account for 40-65 percent of cases that test positive for rheumatoid factor, but only about 20 percent of those that test negative. A family history raises the risk around three to five times. The strongest signal sits in the HLA genes, which help the body tell self from non-self, and HLA-DR4 is the major genetic factor. Genome-wide studies have turned up around one hundred alleles tied to the disease.

  The environment adds its own weight. Smoking triples the risk compared with non-smokers, particularly in men, heavy smokers and people who are rheumatoid factor positive. Silica exposure has been linked to the disease, while modest alcohol consumption may be protective. Early research is also asking whether inflammatory arthritis becomes more common after COVID-19.

  Women are affected about two and a half times as often as men. In women the disease most often starts between 40 and 50, and in men somewhat later. Onset after childbirth and hormonal medications may help explain the imbalance. Children are not spared, since the disease occurs in one in 1,000 of them.

  No infectious agent has been consistently linked to the disease, and there is no sign of clustering that would point to contagion. The one steady association is periodontal disease. Two bacterial species found in inflamed gums are suspected of modifying proteins in a process called citrullination.

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• 5. Inside The Joint

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  Several years can pass between the first misfire of the immune system and the first symptom. Researchers describe three phases. The first is a non-specific inflammation. The second is an amplification driven by T cell activation. The third is a chronic phase, in which the cytokines IL-1, TNF-alpha and IL-6 injure tissue.

  The antibodies at the center of the story are rheumatoid factors, which target part of the antibody IgG, and ACPAs. ACPA stands for anti-citrullinated protein antibody, and one of its targets is citrullinated fibrinogen. Plasma cells make both kinds in large quantities. They activate macrophages and help drive intense inflammation in the synovium, where swelling, widened blood vessels and invading T cells collect. The antibodies in people with the disease also carry abnormal sugar chains, which are believed to promote joint inflammation. For 30 years, scientists have debated whether B cells or T cells matter more at the site. Neither is strictly needed there, only the autoantibodies.

  In the chronic phase, a mass of granulation tissue called pannus forms at the edges of the synovial lining. New blood vessels sprout and enzymes chew through tissue. Signals through RANKL and RANK trigger osteoclasts, the cells that break down bone. Raised calprotectin levels act as a biomarker of this destruction.

  A key culprit is the fibroblast-like synoviocyte. In the disease these cells turn aggressive. Among their traits are resistance to normal cell death, a talent for migrating and invading, and rewired metabolism. They also recruit immune cells and promote bone erosion. Therapies aimed at these cells are emerging, and researchers describe them as promising.

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• 6. Reading The Blood

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  Rheumatoid factor tests positive in roughly two thirds of people with the disease. The remaining third are called seronegative. The test is a blunt tool, because the same antibody appears in about 10 percent of healthy people. It also shows up in hepatitis C, Sjögren's disease and lupus. A newer test looks for ACPAs, usually through the anti-CCP test. It is positive in 61-75 percent of cases, with a specificity of around 95 percent. Like rheumatoid factor, ACPAs are often present before symptoms start. In 2008, a point-of-care test combined rheumatoid factor and anti-MCV, reaching a sensitivity of 72 percent and a specificity of 99.7 percent. Another marker, 14-3-3η, is now used to complement the older tests.

  Imaging has limits early on. X-rays may show nothing in the first stages. Later they reveal bony erosions and dislocations. Ultrasound with high-frequency transducers of 10 MHz or higher shows 20 percent more erosions than conventional radiography. Doppler ultrasound can pick up blood flow in an actively inflamed synovium, which matters because synovitis seems to be the best predictor of future joint damage.

  In 2010, the American College of Rheumatology and the European League Against Rheumatism jointly published new classification criteria. They scored four areas from 0 to 10 points. The areas were the number of joints involved, antibody results, an elevated sedimentation rate or C-reactive protein, and symptoms lasting six weeks or longer. A score of 6 or greater classifies a person as having the disease. The 1987 criteria had relied on joint damage visible on X-rays. The new version drops that, since such damage is exactly what treatment aims to prevent.

  Many conditions masquerade as the disease, among them gout, lupus, Lyme disease, hepatitis C and several forms of psoriatic arthritis. Once the diagnosis is made, progress is tracked with a score called DAS28. It counts tender and swollen joints among 28 sites, adds the sedimentation rate, and includes the patient's own rating of the past week from 0 to 100. Some measures, such as HAQ-DI, need no clinician at all, so patients can track themselves.

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• 7. The Drug Ladder

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  Methotrexate is the most important drug in rheumatoid arthritis, and it is usually the first one prescribed. There is no cure. Even so, disease-modifying antirheumatic drugs, or DMARDs, bring remission to approximately half of the people who take them, provided treatment starts early. Sulfasalazine and leflunomide are other common choices. A triple therapy of methotrexate, sulfasalazine and hydroxychloroquine can also control activity. Folic acid can ease the nausea and abdominal pain that methotrexate may cause.

  Hydroxychloroquine has an odd history. Its half-life was once thought to run 40-50 days, but more recent studies suggest about 5 days. The drug builds up in tissue, and steady levels take 3-4 months to arrive. That delay may explain why its effect feels so slow.

  Biologic drugs come next, generally only if methotrexate and other conventional agents fail after three months. They include TNF inhibitors such as infliximab, the interleukin 1 blocker anakinra, the interleukin 6 blocker tocilizumab and abatacept. Rituximab, which lowers levels of B cells, adds benefit when combined with methotrexate. After 6 months, 21 percent more people improved with that pairing. Biologics carry a higher rate of serious infections and a high cost. People must be screened for latent tuberculosis before starting a TNF inhibitor.

  Symptom relief runs on a separate track. Glucocorticoids are used briefly and at the lowest dose possible while slower drugs take hold. NSAIDs ease pain and stiffness but do not change the underlying disease, so they are no longer first line. The painkiller rofecoxib was withdrawn from the global market after its long-term use was tied to heart attacks and strokes. Benzodiazepines such as diazepam are not recommended for pain.

  More than 75 percent of women with the disease find symptoms improve during pregnancy. Methotrexate and leflunomide can harm the fetus and are not used in pregnancy. After delivery, symptoms worsen.

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• 8. Movement And Its Limits

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  Physical activity increases the production of synovial fluid, the lubricant that reduces friction in a joint. Regular exercise is recommended as safe and effective for keeping muscle strength and function, and carefully dosed exercise has produced significant gains. One approach pairs low-intensity resistance training with blood flow restriction. It builds strength while placing less mechanical stress on painful or unstable joints. Another pairs aerobic work with cryotherapy. Even when drugs control the disease, muscle function is not regained on its own. Physiotherapy, which may include cold and heat, electrical stimulation and hydrotherapy, helps fill that gap.

  Daily life gets practical support too. Extra-depth shoes and molded insoles may reduce pain during walking. Weak evidence supports wax baths for arthritis in the hands. Several studies suggest that high-vegetable diets improve symptoms while high-meat diets make them worse. Fish oil has been studied closely, but the evidence is not strong enough to call it an effective treatment.

  When drugs fail, surgery steps in. For the fingers, hands and wrists, a synovectomy may be needed to prevent pain or a ruptured tendon. Severely damaged joints may be replaced, as with knee replacement surgery, and physiotherapy is always necessary afterward. Evidence is insufficient to support surgery on arthritic shoulders.

  Alternative medicine fares poorly under scrutiny. The American College of Rheumatology says no herbal medicine has health claims backed by high-quality evidence. A herbal label of natural does not make a product safer, and some such products may be toxic or fatal. Tai chi may modestly improve joint range of motion. Acupuncture appears to be no better than sham acupuncture.

  In 1800, a French physician named Augustin Jacob Landré-Beauvais, who worked at the Salpêtrière Hospital in Paris, made the first recognized description of the disease. He lived from 1772 to 1840. The name rheumatoid arthritis came later, coined in 1859 by the British rheumatologist Alfred Baring Garrod. It comes from the Greek word rheuma, meaning flow or current. The suffix -oid means resembling, so the name describes joint inflammation that resembles rheumatic fever. The related word rhuma means watery discharge. It may refer to swollen joints, or to the disease worsening in wet weather.

  Some physicians have looked to art for older traces. The later paintings of Peter Paul Rubens show hands with increasing deformity, which some doctors consider consistent with the disease. Art historians urge caution. Painters of the 16th and 17th centuries followed stylized conventions for hands, most clearly in the Mannerist movement. Christ's upheld right hand, for instance, was conventionally painted in a pose that now looks deformed.

  The remedies tried over the years read like a pantry and a medicine cabinet shuffled together. They include an apple diet, nutmeg, nettles, bee venom, copper bracelets, a rhubarb diet, tooth extractions, fasting, honey, vitamins, insulin, magnets and even electroconvulsive therapy. None are known to have worked reliably.

  Open questions remain today. Vitamin D deficiency is more common in people with the disease, yet no one knows whether it is a cause or a consequence. Researchers are also investigating possible links with intestinal barrier dysfunction.

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