Treatment of rheumatic musculoskeletal disorders.

Non-medicinal therapies with water, salts, exercise, massage, supportive devices, and electricity have been used for centuries and continue to be of benefit for some people with musculoskeletal disorders. Historical texts refer to the two electuaries mithridatium and theriaca as early therapeutic attempts of man to provide relief of musculoskeletal symptoms and attempt disease cures. For over 200 years, morphine-derived products have been used for musculoskeletal pain. The development of acetyl salicylic acid was a major breakthrough in joint pain management. This was followed by the introduction of nonsteroidal anti-inflammatory agents, paracetamol, and the use of corticosteroids. The gold-based compounds were the initial disease-modifying drugs and have been followed by the highly successful biologics agents. The basic objectives of musculoskeletal pain management include: reduction or elimination of joint pain; improvement or restoration of joint function and mobility; improvement of muscle strength to protect cartilage, ligaments, and joint capsule; prevention and reduction of damage to joint cartilage and supporting structures.

Narcotic analgesics.

There is documentation of the use of opium derived products in the ancient history of the Assyrians: the Egyptians; in the sixth century AD by the Roman Dioscorides; and by Avicenna (980-1037). Reference to opium like products is made by Paracelsus and by Shakespeare. Charles Louis Derosne and Fredrich Wilhelm Adam Serturner isolated morphine from raw opium in 1802 and 1806 respectively, and it was Sertürner who named the substance morphine, after Morpheus, the Greek God of dreams. By the middle 1800s, Opium and related opioid derived products were the source of a major addiction in USA, and to some extent in the United Kingdom. Opioid products are of major therapeutic value in the treatment of pain from injury, post surgery, intractable pain conditions, and some forms of terminal cancer.

Clinical therapeutic trials.

The term clinical trial implies an investigation of a therapeutic intervention in the pursuit of evidence of benefit, short or sustained, and observations on the possibility of toxicity related to the therapeutic intervention. It is possible that the first clinical trial took place in the court of the Babylonian King Nebuchadnezzar circa 600 BC, as recorded in Chapter 1 of the Book of Daniel, verse 3-20. However, it is in the last 500 years that there has been good written documentation at attempts to interpret therapeutic benefit from the use of treatments. Lind's demonstration on the usefulness of oranges and lemons in the treatment of scurvy in 1747, and the unethical experiment by Edward Jenner (1749-1823) on the inoculation in 1796, of an 8-year-old boy, with cow pox obtained from a milk maid, followed by an attempt to give the young boy smallpox by direct inoculation 18 days later, are striking examples of clinical trials. Human ethics, strict clinical observations, statistics, the governed scientific purity of therapeutic agents, and safety testing of therapeutics, devices, and physical interventions, have created the basis for the modern clinical trial.

Medical aspects of the tour by Martin Martin (c 1660-1719) of the Western and Northern Islands of Scotland, Circa 1695.

This review is based investigations on the Western Isles, Scotland, by Martin Martin, a notable Scottish Highlander, academic and medical doctor, of the 17th-18th century. His extensive observations of the geography and peoples of these Isles were recorded in his books, "On the Description of the Western Islands of Scotland Circa 1695" and "A Late Voyage to St Kilda". In these books and subsequent papers there were some noteworthy observations on the occurrence (and as he says non-occurrence) of "epidemical" diseases and conditions afflicting the peoples of The Isle of Skye and the Western Isles of Scotland in this period, and these are discussed in this review. Martin also gives details of a wide variety of remedies that were observed or reported by inhabitants around that time. Some of these remedies are interesting for their relevance to the period but others are of doubtful merit. These are reviewed here more for their significance in the understanding of the diseases and conditions of humans and even in some cases animals at that time. Introductions by Charles Withers and R.W. Munro, 11 and re-assessments of the contributions of Martin and colleagues of that time have given insight into the health and condition of peoples of the Western Isles of Scotland(the Occidental) (Martin 1695; Martin 1716).

The illness of William Soutar (1898-1943).

William Soutar (1898-1943) was a Scottish poet, but many are unaware of his scholarly work which includes his famous "brain-rhymes". He was born in Perth Scotland in 1898. He was educated at Perth Primary School and Perth Academy and proved to be adept at sport and academics. In 1916, he joined the Royal Navy. In 1918, he had "food poisoning" after which he was hospitalized and developed severe joint pain which became a chronic illness. He had a brief attempt at medical studies at Edinburgh University, but soon switched to the Arts Faculty to study English. Despite various treatments, the joint pain was chronic and disabling. He developed tuberculous lung disease in 1929, and again despite treatments, the problem persisted, and he died in 1943.

Spondyloarthropathies and arthritis post-infection: a historical perspective.

The spondyloarthropathies are a group of conditions characterised by spinal joint pain and have related clinical, epidemiological and genetic-related features. Ankylosing spondylitis, reactive arthritis, the spinal form of psoriatic arthritis and Crohn's and colitis enteropathic arthritis are the major clinical entities of the spondyloarthropathies, and principally occur in HLA-B27 positive individuals. Ankylosing spondylitis is much more common in males than females. Patients are usually seronegative for rheumatoid factor, and extra-articular features including iridocyclitis, mucous membrane and skin lesions: aortitis, may occur in some patients. The reactive arthritis form classically occurs following an infection of the gastrointestinal or genitourinary tract. The Crohn's and colitis enteropathic arthritis forms often have an associated large joint asymmetrical arthritis. Also discussed are acute rheumatic fever and Lyme disease which are conditions where the individual develops arthritis after an infection.

Rheumatoid arthritis.

It is difficult to determine from ancient writings, old human specimens, and from Art over the centuries, as to when Rheumatoid Arthritis first appeared. It may be a relatively modern condition, as it was reasonably well described in the seventeenth century. Augustin Jacob Landre-Beauvais (1772-1840), University of Paris is credited, with the first clear description of the disease in his thesis. In 1859 Sir Alfred Baring Garrod (1819-1907), the "father of rheumatology", gave the disease its current name which was finally adapted in Britain by the Ministry of Health in 1922. Some forms of Juvenile Arthritis are related to adult Rheumatoid Arthritis (aka Still's disease). If untreated Rheumatoid arthritis can result in severe destructive joint damage and often there are associated severe systemic complications. Disease modifying agents have benefited the disease management, but it was the discovery of the anti TNF-alpha agents in the 1990s, and subsequently many additional Biologic agents, which have greatly changed the clinical outcome in Rheumatoid Arthritis.

Surgery of joints.

Crude forms of musculoskeletal surgery have been performed through history for the treatment of deformity, pain and the horrors of battle. In more modern times Muller is credited with the first synovectomy in rheumatoid arthritis in 1884, and a Synovectomy was first performed by Richard von Volkmann (1830-1889) for joint tuberculosis. Chemical synovectomy consisting of the intra-articular injection of various agents was popular for a while but is now largely discarded. Joint resection for sepsis and tuberculosis has been documented since the early 1800s, and also joint arthrodesis, and osteotomy. Modern arthroscopic techniques have added the utility of faster intra-joint inspection and treatment while reduced surgical time exposure and often applied with the use of limb regional anaesthetic nerve blocks, to avoid general anaesthetic. Joint arthroplasty has been developed since1800s, with the use of many artificial joint components. There have been many notable pioneers of this work who are documented in this text, among them Austin T. Moore (1899-1963), George McKee (1906-1991) and Sir John Charnley (1911-1982). The success of joint arthroplasty to the hip, knee, shoulder and other joints has resulted in life-changing benefit for hundreds of arthritis and injury sufferers.

Sjögren's syndrome.

Sjögren's syndrome (SS) is characterised as keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth) commonly associated with salivary gland enlargement, and is referred to as Primary Sjögren's syndrome. It is known as Secondary Sjögren's syndrome when it occurs in patients, with connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, polyarthritis nodosa, polymyositis, and systemic sclerosis. SS has also been associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation, human immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), chronic biliary cirrhosis, neoplastic and myeloplastic syndromes, fibromyalgia, and chronic fatigue syndrome.

Osteoarthritis.

The clinical appearance and radiological pattern of osteoarthritis have been identified in the skeletons of dinosaurs some 50-70 million years old, and in Egyptian mummies, and in ancient skeletons in England. Osteoarthritis patterns of joint involvement, often referred to as primary osteoarthritis, can be seen in the hands, spinal facet joints, hips, knees and feet, but can also be termed secondary osteoarthritis when seen in any joint that has had trauma, sepsis, surgery or metabolic insult. The prevalence of osteoarthritis increases with age. The histology and pathophysiology both demonstrate an inflammatory process. While there have been studies of genetic predisposition, the basic cause of primary osteoarthritis has not been determined.

John Alexander Mullin (1835-1899): The Canadian Physician who first described Osler's Nodes.

Sir William Osler (1849-1919), who became Regius Professor of Medicine at Oxford in 1905, first drew attention in 1909 to the painful nodes in subacute bacterial endocarditis, which now carry his eponym, and he published an account in the Quarterly Journal of Medicine, which he helped establish. Attention is drawn to the often overlooked fact that it was a Dr John Alexander Mullin (1835-1899) of Hamilton, Ontario, Canada, who first drew the attention of Sir William Oster to their occurrence. Confusion arose over the relationship between Osler's nodes and the skin lesions described by Theodore Caldwell Janeway (1872-1917), which are generally non-tender and found in acute bacterial endocarditis. The evidence is that there is essentially no difference since their pathogenesis and histological findings are identical.

Reactive arthritis: the convoluted history of Reiter's disease.

Reactive arthritis, previously known as Reiter's Syndrome or Disease was a post-dysenteric, asymmetrical acute large joint polyarthritis, with fever, conjunctivitis, iritis, purulent urethral discharge, rash and penile soft tissue swelling. Although the eponym was given to Hans Reiter, various forms of the condition have been recorded in history a few hundred years before Reiter. Two French doctors, Noel Fiessinger (1881-1946) and Edgar Leroy (d. 1965), presented a paper at la Societe des Hopitaux-in Paris on the 8th December 1916 on dysentery in 80 soldiers on the Somme, and four of whom developed a "syndrome conjunctivo-uretro-synovial". Their paper was given 4 days before Reiter's presentation on 12th December 1916 at the Society of Medicine in Berlin, on a German army officer with an illness similar to those described by Fiessinger and Edgar Leroy. It is documented that Hans Reiter was one of a number of University professors who signed an oath of allegiance to Adolf Hitler in 1932. For socio-ethical reasons and for clinical utility, Reiter's syndrome is now known as reactive arthritis.

Pharmacology of intra-articular triamcinolone.

INTRODUCTION: The inflammatory joint diseases of juvenile inflammatory arthritis (JIA), rheumatoid arthritis (RA) and osteoarthritis (OA): and also mild to moderate joint injury, all require a multidisciplinary approach to management. Intra-articular injections of corticosteroids have been shown to be a very beneficial adjunctive treatment in the management of the above disorders. It is, therefore, important that clinicians have a good understanding of the clinical actions of intra-articular injections. OBJECTIVE: This article explores the pharmacokinetics, pharmacodynamics, and clinical pharmacology of triamcinolone acetonide (TA) and triamcinolone hexacetonide (TH) in JIA, RA, and OA. METHODS: Literature search of TA and TH articles was conducted using key word searches in the PubMed and Google Scholar databases and through references within found articles. RESULTS: TA and TH intra-articular injections have been shown to provide good clinical benefit for up to 6 months and even longer. TH has been shown to decrease in the expression of citrullinated proteins, the monoclonal antibody F95, and peptidylarginine deiminase 4 in RA synovium. TA and TH intra-articular injections have a low side effect profile which is similar to other corticosteroid. They have minimal to no mineralocorticoid adverse effects and facial flushing 2-3 days post injections is the most common side effect recorded, and in almost all cases is no worse than nuisance. CONCLUSION: TA and TH are useful adjunct therapies in the management of JIA, RA, OA, and mild to moderate joint injury.

Osteoarthritis of the hand I: aetiology and pathogenesis, risk factors, investigation and diagnosis.

OBJECTIVE: Osteoarthritis (OA) of the hand can be a debilitating condition that hinders an individual's quality of life. With multiple joints within the hand that are commonly affected OA, an individual's ability to use their hand in everyday movements become more limited. The article aims to review literature on the aetiology and pathogenesis of OA, risk factors, characteristics of hand OA and the steps of diagnosis. KEY FINDINGS: The aetiology and pathogenesis of OA, in particular hand OA, is not fully understood. However, it is known that several factors play a role. Environmental factors, such as stress from mechanical loading, especially to vulnerable joints predispose individuals to developing OA. Extracellular matrix changes in protein levels have also been noted in individuals with OA. Linked to hand OA development are boney enlargements (Herbeden's and Bouchard's nodes). Several risk factors for OA include: age, obesity, gender, smoking, genetics, diet and occupation. Various diagnostic methods include a combination of using radiographic methods, clinical presentation, a number of developed measurements and scales. SUMMARY: With OA having several risk factors and various causes and contributing elements, it is important to elucidate the pathogenesis of OA and determine exactly how risk factors play a role in its development. Because of the contributions from several elements, diagnosis is best when it uses multiple methods. In turn, understanding OA and making better diagnoses could lead to improved management of the condition through both pharmacological and non-pharmacological interventions.

Osteoarthritis of the hand II: chemistry, pharmacokinetics and pharmacodynamics of naproxen, and clinical outcome studies.

OBJECTIVE: This article aims to review osteoarthritis of the hand and the role of the non-steroidal anti-inflammatory drug (NSAID) naproxen on its management. We discuss the chemical and pharmacological properties of naproxen and the NSAID class, with an emphasis on its mechanism and adverse reactions. In the context of part I of this paper in characterizing hand osteoarthritis (OA), we review clinical trials that have been conducted involving hand OA and naproxen. KEY FINDINGS: The therapeutic effect of NSAIDs stems from its role on inhibiting cyclo-oxygenase (COX)-1 or COX-2 enzyme activity in the body. These enzymes play a major role in maintaining several functions in the body and due NSAIDs' inhibitory effects; many principle adverse reactions occur with the use of NSAIDs such as: gastrointestinal tract issues, cardiovascular risks, renal, hepatic, central nervous system and cutaneous. Review of clinical trials involving naproxen and hand OA show that it is significantly more efficacious when compared with placebo. SUMMARY: These studies, along with the finding that naproxen is of least cardiovascular risk in the NSAID class, may show that it can be part of one of the approaches in managing the condition. It is important to note that the optimal NSAID to use varies for each individual. The finding that the use of naproxen leads to the smallest increase in cardiovascular risk appeals to those at-risk individuals who suffer from OA and require pharmacological treatment for relief.

The musculoskeletal abnormalities of the Similaun Iceman ("ÖTZI"): clues to chronic pain and possible treatments.

BACKGROUND AND INTRODUCTION: In 1991, a deceased human male was found frozen in a glacier pool in the Italian Alps in north west Italy, and is now carefully preserved in the South Tyrol Museum of Archaeology, in Bolzano, Italy. The bodily tissues of the 5,300 year old male (colloquially referred to as the Iceman or Ötzi) were well preserved despite damage related to freezing, and glacial movement. Associated articles of well-preserved clothing, tools, weapons and other devices were also present and have been studied in detail. Clinical examination and imaging investigations have also shown that the Icemen had experienced possible illnesses in his lifetime and had identifiable areas of arthritis and musculoskeletal injury. This report includes some key observations on the musculoskeletal state of Ötzi and reference to the involvement of tattoo markings. Some aspects about the aetiology of his abnormalities and inflammatory arthritis are considered along with possible treatments that he might have employed. METHODS AND RESULTS: We (WFK and MK) undertook a clinical musculoskeletal examination of the Iceman, details of which with available photographs and radiographic imaging pertaining to the musculoskeletal findings of the Iceman are reported here. The skin of the Iceman has numerous linear carbon tattoos, which are not of a decorative type. These have been presumed to possibly be "medicinal" tattoos administered for therapeutic reasons and may have been used in acupuncture-like treatment of pain. Spinal imaging identified areas of spinal damage and our observations have provided clues as to possible sites of spinal initiated pain and hence sites for administration of the "medicinal" tattoos. We observed body areas of the Iceman, in which imaging demonstrated arthritis and other forms of long-term musculoskeletal damage, but which do not have adjacent or corresponding "medicinal" tattoos. We contend that the back and leg "medicinal" tattoos correspond directly to sites of chronic right knee and right ankle pain, and left thoracolumbar pain. They also correspond to lower lumbar and sciatic referred radicular pain which may have a contributory cause related to the presence of a transitional lumbar 5 vertebra. Using recent published data (Keller et al. in Nature Commun 3:698, 2012. doi: 10.1038/ncomms1701 ) of the genome structure of the Iceman, we suggest some potential causes of the osteoarthritis or inflammatory joint injury may relate to presence of coronary heart disease (CHD) and Lyme disease (Borrelia burgdorferi) infection. We speculate on possible medical applications of natural products for self-medication. CONCLUSIONS: These observations highlight several diagnostic features of musculoskeletal conditions in the Iceman with the possibility that tattoos may have been used for diagnosis or location of his painful states. The origins of his musculoskeletal conditions are unclear but there are indications that Lyme disease and CHD may have been factors. The associations or use of natural products may give insights into their applications at the time of the life of the Iceman.

Osteoarthritis of the knee and hip. Part I: aetiology and pathogenesis as a basis for pharmacotherapy.

OBJECTIVES: Osteoarthritis (OA) of the knee and hip is among the most frequent and debilitating arthritic conditions. Aside from surgical intervention in severe cases, conventional treatment involves relieving painful symptoms with non-steroidal anti-inflammatory drugs (NSAIDs), narcotic and non-narcotic (weak) analgesics and physical therapy. To obtain insight into the extent of pathological changes in hip and knee OA we reviewed current literature on the pathogenesis of this state as a basis for current pharmacotherapy options. KEY FINDINGS: Key features of the pathological joint changes in OA include: cartilage destruction by pro-inflammatory cytokines, matrix metalloproteinases and prostaglandins, which promote a catabolic environment; subchondral bone remodelling and resorption; hypertrophic differentiation of chondrocytes; neovascularisation of synovial tissue; and focal calcification of joint cartilage. Despite the central involvement of hyaline cartilage in OA pathogenesis, the source of pain likely stems from the richly innervated synovium, subchondral bone and periosteum components of the joint. Tissue damage during joint degeneration generates nociceptive stimuli. The presence of inflammatory mediators, including bradykinin, prostaglandins and leukotrienes, lowers the threshold of the Aδ and C pain fibres, resulting in a heightened response to painful stimuli. SUMMARY: It is our opinion that it is important to base and centre the management of OA patients on the severity of patient-important outcomes, rather than purely an assessment of damage to the joint. The joint damage, as interpreted from radiographs, is not necessarily representative of the symptoms experienced. The management of OA primarily comprises pharmacological therapy, surgical interventions and various non-pharmacological interventions.

Osteoarthritis of the knee and hip. Part II: therapy with ibuprofen and a review of clinical trials.

OBJECTIVES: We review the pharmacological properties and clinical evidence pertaining to the efficacy of ibuprofen as a first-line treatment in hip and knee osteoarthritis (OA). In the context of our previous paper's exploration of the aetiology and pathogenesis of OA as a basis for pharmacotherapy, we discuss the pharmacokinetics (PK) and clinical pharmacodynamics (PD) of ibuprofen relevant to OA. KEY FINDINGS: Although widely used, the benefits and risks of ibuprofen, especially compared with other non-steroidal anti-inflammatory drugs (NSAIDs) and placebo, have only recently been evaluated in OA of the hip and knee in randomized-controlled clinical trials (RCT). The efficacy and occurrence of adverse reactions from ibuprofen was compared with placebo in a structural review of the literature and systematic review of RCTs in large-scale clinical trials. Ibuprofen has been found to result in approximately 50-60% improvement over placebo in WOMAC scores, including those reflecting inflammatory joint pain in knee and hip OA or other indices of pain, disability and impaired function. Mega-trials performed in comparison with the newer NSAIDs, the coxibs, have shown that ibuprofen has comparable therapeutic benefits and although serious gastrointestinal conditions are sometimes more frequent after short-term treatment, longer-term (several months) therapy in OA reduces the advantages of the coxibs over other NSAIDs including ibuprofen. Cardiovascular risk, though present with coxibs and some NSAIDs in OA, is lower or slightly so with ibuprofen compared with coxibs. SUMMARY: Ibuprofen is effective and relatively safe (especially at low over-the-counter doses and in the short term) for mild-to-moderate OA of the knee and hip. The PK properties of ibuprofen in OA (short plasma t½) confer advantages of this drug for OA, while evidence for clinically relevant PD benefits in joints of patients with OA, though limited, is suggestive of local anti-inflammatory activity.

Obesity and knee osteoarthritis.

BACKGROUND: The association between obesity and knee osteoarthritis, and specifically the role of obesity as a risk factor for knee osteoarthritis has been well documented. A systematic review and meta-analysis by Blagojevic et al. in Osteoarthr Cartil 18(1):24-33, (2010) examined 36 papers reporting on BMI and found that all studies demonstrated obesity and being overweight to be risk factors for knee osteoarthritis. The effect size for obesity as a risk factor for knee OA was reported to be I² = 97%, and the random effects pooled odds ratio for obesity compared to normal weight was 2.63 with a 95% CI of 2.28-3.05. OBJECTIVE: This review summarises recent findings involving the association between knee osteoarthritis and obesity: the potential mechanisms of the link between the two disease states; and the potential benefits of weight loss on obese, knee osteoarthritis patients. METHODS: Studies for inclusion in our report were identified using: MEDLINE; EMBASE; PUBMED; Cochrane Central Register of Controlled Trials; CINAHL; and reference lists of relevant articles. MAIN RESULTS: A number of recent studies involving the association between obesity and knee osteoarthritis have since been published. A large, population-based prospective study (n = 823) conducted by Toivanen et al. with a follow-up of 22 years found that the risk for knee osteoarthritis was 7 times greater for people with BMI ≥ 30 compared to the control of people with BMI <25. A prospective cohort study of the Norwegian population by Grotle et al. that followed 1,675 patients reported that BMI >30 was significantly associated with osteoarthritis of the knee, with odds ratio of 2.81, and 95% CI of 1.32-5.96. Lohmander et al. found that in a large cohort study of 27,960 patients from the Swedish population, the relative risk for knee osteoarthritis (fourth quartile compared to first quartile) was 8.1, with a 95% CI of 5.3-12.4. Finally, a case-control study from Holliday et al. with 1,042 knee osteoarthritis patients and 1,121 matched controls reported that the adjusted odds ratio for knee osteoarthritis in patients with BMI >30 was 7.48 with 95% CI of 5.45-10.27. CONCLUSION: Recent prospective studies demonstrate obesity as a primary risk factor for incident knee osteoarthritis. The potential mechanisms to link obesity and knee osteoarthritis, as both a biomechanical and metabolic condition are strongly linked. It has been established that weight loss for obese patients with knee osteoarthritis is clinically beneficial, for pain reduction, and for improved function. The exact mechanism linking obesity and osteoarthritis is complex; however, it is our opinion that further evidence supporting the link between the two diseases will be useful in providing clinicians and researchers with targets for physical therapy and pharmacological management of obese patients with knee osteoarthritis.