Arthritis, Then and Now (A Historical Perspective)

Post on March 22, 2013 by André Broussard, D.C.

Bret S. Stetka, MD
Mar 22, 2013

Full Article:  http://www.medscape.com/viewarticle/780895

Joint discomfort has been around for some time.

Described in ancient Egyptian medical texts,[1,2] arthritis — particularly gout — was one of the earliest diseases to be clinically recognized. Hippocrates (~460-357 BC) differentiated gout from other forms of arthritis, while an ayurvedic medicine text from 123 AD references a disease characterized by swollen, painful joints and occasional fever — in all likelihood, rheumatoid arthritis (RA).[1,2]

Evidence from archeological remains extends back much further, well into prehistory; dinosaurs, Neanderthals, and early humans all appear to have suffered arthritic aches and pains. Early Greek scholars, Hippocrates included, and later medieval Europeans, ascribed joint maladies to “rheumatism,” from “rheum,” or the “flux” of congested humors; and often more specifically to “gutta” — Latin for a “drop” of fluid and derivation of “gout.” Bad humors were thought to literally drip into affected joints.

Eventually, the humor hypothesis gave way to more modern medicine. Arthritis subtypes were identified and characterized, and management moved beyond herbal folk remedies, culminating in our current understanding and approach to one of the oldest known human diseases.

Encouraged by recent progress in the pathophysiologic understanding and treatment of the major arthritides, we’ve compared the oldest known disease accounts and therapies with the clinical picture of arthritis circa 2013.

Gout, Then

Humans have a long history of painful toes. Two of the oldest known medical texts, the Ebers and Edwin Smith papyri, both of which date from around 1550 BC, recognize gout as a distinct disorder. They also reference writings by Egyptian polymath Imhotep from a millennium earlier, suggesting that joint maladies were a medical consideration in the early centuries of Egyptian civilization.[1,2]

Hippocrates deemed gout — or “podagra,” from the Greek for “foot trap,” — the “unwalkable disease.,” He also drew a cultural distinction between this condition of the foot — what he called “arthritis of the rich” — and other forms of rheumatism, more common in lower social classes. Both Hippocrates and, later, Galen (129-200 AD) recognized the association between gout and more indulgent lifestyles namely rich foods and excessive alcohol intake.[1,3,4] Many centuries later, the “disease of kings” still appeared to proffer social credibility: According to a London Times article from 1900, “The common cold is well named — but the gout seems instantly to raise the patient’s social status.”[1,5]

Microscopy pioneer Antonie van Leeuwenhoek first reported the presence of crystals in a gouty tophus in 1679[1,6]: “I observed the solid matter which to our eyes resembles chalk, and saw to my great astonishment that I was mistaken in my opinion, for it consisted of nothing but long, transparent little particles…[like] a horse-tail cut to a length of one sixth of an inch.”

Nearly 2 centuries later at a public lecture, English physician Sir Alfred Baring Garrod was the first to report increased uric acid in the blood of patients with gout, later writing inThe Nature and Treatment of Gout and Rheumatic Gout, “[T]he deposited urate of soda may be looked upon as the cause, and not the effect, of the gouty inflammation.” Garrod also developed medicine’s first clinical chemical test: his “thread test” measured uric acid in serum or urine.[1,7-10]

The earliest known reference to gout management comes from the Ebers Papyrus,[1] suggesting that Egyptian healers opted for sandalwood incense treatments. Another ancient remedy, colchicine, is still used today. Originally derived from the autumn crocus, this mitotic inhibitor and anti-inflammatory agent was reportedly prescribed for gout by Byzantine physician Alexander of Tralles in the sixth century, and possibly far earlier by the ancient Greeks.[1,5]

As an aside for the history buffs, gout — again, possibly due to its predilection for the well-off — reportedly played a key role in the American Revolution. While British statesman William Pitt the Elder was absent because of a gout attack, Parliament was coaxed into levying a substantial tax on tea imports.[5] The Boston Tea Party ensued.

Gout, Now

Modern gout therapies are rooted in the late 1800s. Following his discovery, Garrod first suggested controlling hyperuricemia through a low-purine diet, still a major component of care today and leaving organ meats and certain fish off the table for gout sufferers. Around that time, uricosuric therapy with salicylates was also first used, later replaced by probenecid, sulfinpyrazone, benzbromarone, and the first xanthine oxidase inhibitor, allopurinol.

Joint aspiration is the modern gold standard for identifying gout; however, diagnosis has also undergone a major revolution with the use of diagnostic ultrasonography. Characteristic findings in a patient with other suspicious markers may abrogate the need for far more invasive arthrocentesis. Another advance highlighted at the American College of Rheumatology’s recent Annual Meeting is the coexistence of RA and gout; once thought rare, this is much more common than previously believed.[11]

In 2013, gout is now a very treatable disease. And last year, the American College of Rheumatology released their first-ever gout management guidelines.[12,13] Current recommendations include the use of a xanthine oxidase inhibitor, such as allopurinol or febuxostat, in cases of suspected gout, and targeting a serum uric acid level of 6.0 mg/dL or less. Patients should receive prophylactic colchicine during the first few months of treatment to prevent flares. Certain patients who might be given allopurinol should be screened for a propensity for developing allopurinol toxicity. Combinations of xanthine oxidase inhibitors and uricosuric drugs can be used if the desired serum uric acid is not achieved. Patients with renal insufficiency are a high-risk group, and their dosage of xanthine oxidase inhibitor needs to be adjusted accordingly. Pegloticase can be used in patients with refractory gout, particularly if tophi are present.

Osteoarthritis, Then

Evident in 70 million year-old dinosaur skeletons, early hominid remains, and Egyptian mummies, osteoarthritis (OA) is often cited as the oldest known disease — one that, in the words of rheumatologist Dr. Frédéric Massicotte, is “impervious to evolution.”

It’s surprising, then, that our most common joint disorder wasn’t clinically characterized until the late 1700s, when English physician William Heberden described “digitorum nodi” — now called “Heberden nodes” and considered a classic finding in OA. Heberden noted that these bony outgrowths at the distal interphalangeal joints were part of a disease process distinct from gout.

OA was further delineated in 1852 when Garrod, in addition to his gout contributions, recognized that the clinical profile of OA was unique from what at the time was called “asthenic gout” — which, in the long and confusing tradition of rheumatic nosology, he renamed “rheumatoid arthritis.” Before this, OA and what would come to be called RA were considered variants of a singular disorder called “arthritis deformans.”[10] In 1886, John Kent Spender, another English doctor, was the first to use the term “osteoarthritis.”

The earliest OA treatments, dating as far back as the Sumerians, were most likely various willow preparations. Willow bark and leaves contain salicylic acid, which the German company Bayer modified to acetylsalicylic acid, or aspirin, in 1897.[14]

Osteoarthritis, Now

Until relatively recently, OA was thought of primarily as a degenerative disorder due to general wear and tear on the joints.[15]Today, the clinical and pathologic picture is far more complex, with subchondral bone remodeling thought to play an important role in its pathogenesis.[16] Genetics are also thought to contribute significantly to OA development — with monozygotic twins having a concordance rate up to 70% higher than dizygotic twins[17] — as is nutrition.[10] Vitamin D deficiency is associated with increased OA risk, although new data suggest that supplementation does not reverse symptomatic disease.[18] The role of synovial inflammation and cytokine-driven mechanisms is also a rich area of current study. Considering the circuitous interaction of chondrocytes, subchondral bone, synovium, degradative enzymes, and cytokines, OA rivals RA in pathologic complexity.

Treatment of OA traditionally involves nonsteroidal anti-inflammatory drugs (NSAIDs) and over-the-counter analgesics; lifestyle modification, including exercise; and, in severe cases, surgery. But recent findings are opening exciting new therapeutic avenues. A2013 study published in Annals of Rheumatic Disease suggests that strontium ranelate might act as a disease-modifying osteoarthritis drug by stimulating formation of cartilage matrix,[19]whereas other recent work reported a reduction in OA symptoms with platelet-rich plasma injections.[20]

Ongoing research is also helping characterize the complex relationship between OA and exercise,[21] as well as the role of potential metabolic influences.[22] Weight plays more of a factor than once thought in OA. Adipose fat cells produce leptins — cytokines that ramp up the inflammatory response and probably aggravate the process of OA.[23,24]

Despite these encouraging advances, for now OA treatment remains mired in the past. Beyond symptomatic relief with NSAIDs, physical therapy, weight loss, bracing, and intra-articular injections of glucocorticoids and viscosupplements, treatment has not changed in more than 50 years. Promising work involving mesenchymal stem cells, with and without exogenousgrowth factors and novel scaffolds, may help revolutionize our approach to the management of OA.[25]

Rheumatoid Arthritis, Then

The earliest evidence of RA comes from pre-Columbian North America, with symmetrical, polyarticular erosive arthritis reported in Native American remains from as far back as 4500 BC in what is now Tennessee. In the Old World, despite there being early indications of other arthritides, evidence of RA does not appear until 1591, when French physician Guillaume de Baillou applied the age-old catch-all term “rheumatism” to a condition characterized by soreness, inflammation, stiffness, and pain. The lapse suggests that RA either migrated to Europe after New World colonization or arose in response to a new environmental exposure.[26]

Sporadic medical and literary depictions of RA-like illnesses followed, but the first convincing modern account of the disease was penned in 1800 by Augustin Jacob Landré-Beauvais, a French medical student at the Salpêtrière Hospital. In 9 female patients, he described a painful, inflammatory arthritis that left the hand joints swollen and deformed. He called the condition “asthenic gout,” distinguishing it from classic gout based on inflammation pattern, female predominance, polyarticular involvement, and its more chronic course.

Landré-Beauvais reported that “emollient pastes were applied, blood was let at the arm and foot, and subsequently baths were given for nearly six months, although they made the condition worse.” A “fortifying diet and “a few mild sedatives” were also prescribed. As in OA, the earliest RA treatments were most likely willow bark preparations high in salicylic acid.

Rheumatoid Arthritis, Now

In 2013, RA is understood as an inflammatory arthritis characterized by polyarticular, often symmetric, pain and swelling in the joints of the hands and feet. Numerous therapies are approved and effective in RA, among them NSAIDs; steroids; and disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine. Newer biologic agents, including tumor necrosis factor (TNF) inhibitors, are often used in patients who do not fully respond to DMARDs.

Recent advances are ushering in a new era in RA therapeutics. In November 2012, the US Food and Drug Administration approved the Janus kinase (JAK) inhibitor tofacitinib for use in RA — the first small-molecule RA therapy approved in years. Other JAK inhibitors, namely baricitinib, VX-509, and GLPG0634, are currently undergoing clinical trials, as are other promising agents, such as the spleen tyrosine kinase antagonist fostamatinib. [27-32]

The good news is that in the majority of patients with RA, disease can be put into remission. The bad news is we still cannot predict which drug or group of drugs is the best combination to give a specific patient. Peripheral blood marker research has been disappointing, but recent work with synovial biomarkers shows promise, hinting at personalized treatment in the near future.[33]

Ankylosing Spondylitis, Then

The prehistory of ankylosing spondylitis (AS) extends back 900,000 years to crocodile remains with 2 fused vertebrae, noted by paleopathologist Sir Marc Armand Ruffer to be “similar to those of spondylitis deformans seen in modern human beings.”[34]Ancient Egyptian and pre-Roman European remains also exhibit AS pathology, and Galen is thought to have provided the first known historical allusion to the malady.[35]

Examining a skeleton unearthed at a local cemetery, Irish physician Bernard Connor provided the first confirmed pathologic description of the deforming condition in 1693,noting that the vertebrae “were so straightly and intimately joined…that they really made but one uniform continuous bone.”[36,37] But it wasn’t until the 1800s that AS came to be appreciated as a distinct arthritic entity, on the basis of 2 patient cases published in The Lancet in 1824[37,38] and 1832.[37,39] Both were patients at London hospitals with spinal immobility and back and joint pain.

Through the late 1800s, the modern characterization of the disease took shape, thanks to contributions from Russian neurologist Vladimir von Bechterew (1857-1927), German pathologist Eugen Fraenkel (1853-1925), and French neurology professor Pierre Marie (1853-1940). It was Fraenkel who coined the term “ankylosing spondylitis” in 1904.[37]

Despite its new reputation as a distinct pathology, AS was still widely assumed by the medical community to be a variant of RA through the mid-20th century. Management approaches prior to this would have been similar.

Ankylosing Spondylitis, Now

NSAIDs and physical therapy accompanied by aggressive therapy with DMARDs and biologics is now the standard of care in treating AS. Regarding new advances in AS, a recent study published in the Journal of Rheumatology reported that bone mineral density of the femoral neck and total hip can help predict vertebral fracture risk in patients with AS and potentially facilitate preventative strategies.[40] Data increasingly support early imaging and diagnosis in AS, because early intervention has been shown to enhance treatment response; whether early therapy, namely biologics, can prevent bone formation remains to be seen.[41]

Two studies from 2012 published in Annals of Rheumatic Disease suggest that NSAIDs might have disease-modifying effects in AS in that they slow the rate of spinal bone formation, particularly in patients with elevated levels of acute-phase reactants.[42,43] And finally, 2 recent negative treatment trials,[44,45] as well as additional work looking for TNF-blocker alternatives,[46] offer insights into therapies that do not appear effective in AS.

Although AS can respond to many treatments often reserved for other conditions, such as RA, it is a different disease. As with its pathologic cousin psoriatic arthritis (PsA), selective biologic therapies will probably be needed to achieve more consistent remission in AS.[47]

Psoriatic Arthritis, Then

We owe our earliest knowledge of PsA to some charitable monks. During the Byzantine period, the practice of banishing persons with disfiguring diseases — “biblical leprosy” — gave way to a more benevolent approach to illness. Sufferers were often housed and cared for in monasteries, including the Monastery of Martyrius in Israel’s Judean Desert, where the remains of 3 adults were found to have skeletal findings consistent with PsA.[48]

PsA was not clinically characterized until much later. In 1818, French physician Jean-Louis-Marc Alibert first noted an association between psoriasis and arthritis. Like AS, “psoriasis arthritique” — as French physician Pierre Bazin termed PsA in 1860 — was for decades considered a variant of RA. This changed in 1948 with the discovery of a test for rheumatoid factor, an autoantibody present in up to 85% of patients with RA but only about 15% of those with PsA. In 1964, PsA was recognized as a distinct arthritic disease by the American College of Rheumatology.[49,50]

Psoriatic Arthritis, Now

Up to 15% of people with psoriasis are now known to have co-occurring arthritis; both conditions a result of autoimmune activity.[51] Treatment typically involves DMARDs, including methotrexate and sulfasalazine, as well as newer biologic therapies, such as TNF inhibitors.

Recent advances now hint at significant progress in PsA management. According to a study reported at the 2012 European League Against Rheumatism (EULAR) Congress, weight loss can greatly improve response to anti-TNF agents and should be a component of PsA care.[52,53] This is not a surprise, since obesity and PsA appear to be correlated.

Also in 2012, a surge of data from phase 3 clinical trials suggests a promising future for PsA pharmacotherapy. The interleukin-12 and -23 inhibitor ustekinumab, [54,55] the phosphodiesterase-4 inhibitorapremilast, [56] and the TNF inhibitor certolizumab pegol [57] were all shown to improve PsA symptoms. Furthermore, a studypublished in Annals of the Rheumatic Diseases reported that infliximab plus methotrexate therapy in methotrexate-naive patients with active PsA was more effective than methotrexate alone.[58]

In contrast, other work questioned whether methotrexate is “disease modifying” at all: A 6-month double-blind, randomized controlled trial found no evidence that methotrexate improves inflammatory synovitis in active PsA.[59] These data contradict the current clinical dogma of using methotrexate in PsA. Whether this information is true or just a blip on the radar screen remains to be seen. It is difficult to change old practice patterns, and nonetheless we should take care to not do away with dogma too quickly.

The methotrexate data mentioned above may also explain the growing notion that PsA is pathologically and clinically different from RA. Enthesopathy is driven by cytokines that are very different than those found with RA. In the future, spondyloarthropathies will in all likelihood be treated with a set of biologics distinct from those used in RA.[60]

Through 4500 years of study and countless namings, renamings, and descriptions, modern medicine has an impressive — yet far from complete — grasp on the complexities of joint disease. Promising research in psoriatic arthritis and the other major arthritides suggests that arthritis sufferers will see a number of welcome therapeutic advances in the near future, ideally safe, effective, often personalized approaches providing not just symptomatic but also disease-modifying relief — willow bark for the 21st century.

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