Rheumatoid arthritis

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Overview
Rheumatoid arthritis (RA) is traditionally considered a chronic, inflammatory autoimmune disorder that causes the immune system to attack the joints. It is a disabling and painful inflammatory condition, which can lead to substantial loss of mobility due to pain and joint destruction. RA is a systemic disease, often affecting extra-articular tissues throughout the body including the skin, blood vessels, heart, lungs, and muscles.

The name is derived from the Greek rheumatos means "flowing", and this initially gave rise to the term 'rheumatic fever', an illness that can follow throat infections and which includes joint pain. The suffix -oid means "resembling", i.e. resembling rheumatic fever. Arthr means "joint" and the suffix -itis, a "condition involving inflammation". Thus rheumatoid arthritis was a form of joint inflammation that resembled rheumatic fever. Rheumatoid arthritis appears to have been described in paintings more than a century before the first detailed medical description of the condition in 1800 by Landre-Beauvais.

History
To delineate the history of rheumatoid arthritis a researcher must rely on scanty and ambiguous data from old medical literature and buried skeletons. The current consensus is too speculative for the taste of some scholars. Nevertheless a tentative best guess has emerged.

The first known traces of arthritis date back at least as far as 4500 BC. A text dated 123 AD first describes symptoms very similar to rheumatoid arthritis. It was noted in skeletal remains of Native Americans found in Tennessee In the Old World the disease is vanishingly rare before the 1600s. and on this basis investigators believe it spread across the Atlantic during the Age of Exploration. In 1859 the disease acquired its current name.

A anomaly has been noticed from investigation of Precolumbian bones. The bones from the Tennessee site show no signs of tuberculosis even though it was prevalent at the time throughout the Americas. Jim Mobley, at Pfizer, has discovered a historical pattern of epidemics of tuberculosis followed by a surge in the number of rheumatoid arthritis cases a few generations later. Mobley attributes the spikes in arthritis to selective pressure caused by tuberculosis. A hypervigilant immune system is protective against tuberculosis at the cost of an increased risk of autoimmune disease.

The art of Peter Paul Rubens may depict the effects of rheumatoid arthritis, for it is presumed that he used his own hands as a model. In his later paintings, his rendered hands show increasing deformity consistent with the symptoms of the disease.

Epidemiology
The incidence of RA is in the region of 3 cases per 10,000 population per annum. Onset is uncommon under the age of 15 and from then on the incidence rises with age until the age of 80. The prevalence rate is 1%, with women affected three to five times as often as men. It is 4 times more common in smokers than non-smokers. Some Native American groups have higher prevalence rates (5-6%) and black persons from the Caribbean region have lower prevalence rates. First-degree relatives prevalence rate is 2-3% and disease genetic concordance in monozygotic twins is approximately 15-20%.

It is strongly associated with the inherited tissue type Major histocompatibility complex (MHC) antigen HLA-DR4 (most specifically DR0401 and 0404) — hence family history is an important risk factor.

Causes
The cause of RA is still unknown to this day. In considering possible causes, it is important to distinguish between the cause(s) that trigger the inflammatory process, and those that may permit it to persist and even progress from milder to more severe forms of inflammation. Thus, it has long been suspected that certain infections could be triggers for this disease. As in other autoimmune diseases, the "mistaken identity" theory suggests that an offending organism causes an immune response that leaves behind antibodies that are specific to that organism. The antibodies are not specific enough, though. They begin an immune attack against, in this case, the synovium, because some molecule in the synovium "looks like" a molecule on the offending organism that created the initial immune reaction - this phenomenon is called molecular mimicry. Some infectious organisms mentioned in this context have been Mycoplasma, Erysipelothrix, Epstein-Barr virus, parvovirus B19 and rubella, but these associations have never been supported in epidemiological studies. Nor has convincing evidence been presented for other types of triggers such as food allergies.

There is also no clear evidence that physical and emotional effects, stress and improper diet could be a trigger for the disease. The many negative findings suggest that either the trigger is different from patient to patient, or that the trigger might in fact be a chance event.

The factors that allow the inflammation, once initiated, to become permanent and chronic, are much more clearly understood. The genetic association with HLA-DR4 is believed to play a major role in this, as well as the newly discovered associations with the gene PTPN22 and with two additional genes, all involved in regulating immune responses. It has also become clear from recent studies that these genetic factors may interact with the most clearly defined environmental risk factor for rheumatoid arthritis, namely cigarette smoking Other environmental factors also appear to modulate the risk of acquiring RA, and hormonal factors in the individual patients may explain some features of the disease, such as the higher occurrence in women, the not-infrequent onset after child-birth, and the (slight) modulation of disease risk by hormonal medications.

Autoimmune diseases require that the affected individual have a defect in the ability to distinguish foreign molecules from the body's own. There are markers on many cells that confer this self-identifying feature. However, some classes of markers allow for RA to happen. 90% of patients with RA have the cluster of markers known as the HLA-DR4/DR1 cluster, whereas only 40% of unaffected controls do. Thus, in theory, RA requires susceptibility to the disease through genetic endowment with specific markers and an infectious event that triggers an autoimmune response.

Once triggered, B lymphocytes produce immunoglobins, and rheumatoid factors of the IgG and IgM classes that are deposited in the tissue, this subsequently leads to the activation of the serum complement cascade and the recruitment of the phagocytic arm of the immune response, which further exacerbates the inflammation of the synovium, leading to edema, vasodilation and infiltration by activated T-cells (mainly CD4 in nodular aggregates and CD8 in diffuse infiltrates). Early and intermediate molecular mediators of inflammation include tumor necrosis factor alpha (TNF-α), interleukins IL-1, IL-6, IL-8 and IL-15, transforming growth factor beta, fibroblast growth factor and platelet-derived growth factor. Synovial macrophages and dentritic cells further function as antigen presenting cells by expressing MHC class II molecules, leading to an established local immune reaction in the tissue. The disease progresses in concert with formation of granulation tissue at the edges of the synovial lining (pannus) with extensive angiogenesis and production of enzymes that cause tissue damage. Modern pharmacological treatments of RA target these mediators. Once the inflammatory reaction is established, the synovium thickens, the cartilage and the underlying bone begins to disintegrate and evidence of joint destruction accrues.

Rheumatoid arthritis: clinical features
Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disorder affecting the joints and sometimes other organs as well. It is by definition polyarticular; that is, it affects many joints. Most commonly, the small joints in the hands and feet are affected, but larger joints (shoulders, knees etc) can also be affected; the pattern of joint involvement can differ from patient to patient.

Rheumatoid arthritis affects women three times more often than men, and it can first develop at any age. The risk of first developing the disease (the disease incidence) appears to be greatest for women between 40 and 50 years of age, and for men somewhat later. RA is a chronic disease, and although a spontaneous remission may occur in a very small number of patients, the natural course is almost invariably one of persistent symptoms, waxing and waning in intensity, and a progressive deterioration of joint structures leading to deformations and disability.

The small joints of the cervical spine can also be involved.

Inflammation in the joints manifests itself as a soft, "doughy" swelling, pain, tenderness to palpation and movement, local warmth, and functional impairment. Morning stiffness is often a prominent feature and may last for more than an hour. These signs help distinguish rheumatoid and other inflammatory arthritides from non-inflammatory diseases of the joints such as osteoarthritis (sometimes referred to as the "wear-and-tear" of the joints). In RA, the joints are usually affected in a fairly symmetrical fashion although the initial presentation may be asymmetrical.

Deformity
As the pathology progresses the inflammatory activity leads to erosion and destruction of the joint surface, which impairs their range of movement and leads to deformity. The fingers are typically deviated towards the little finger (ulnar deviation) and can assume unnatural shapes. Classical deformities in rheumatoid arthritis are the Boutonniere deformity (Hyperflexion at the proximal interphalangeal joint with hyperextension at the distal interphalangeal joint), swan neck deformity (Hyperextension at the proximal interphalangeal joint, hyperflexion at the distal interphalangeal joint). The thumb may develop a "Z-Thumb" deformity with fixed flexion and subluxation at the metacarpophalangeal joint, and hyperextension at the IP joint.

Images courtesy of RadsWiki

Extra-articular (elsewhere)
Patients with RA usually exhibit signs of systemic inflammation, that is, the inflammatory process in the joint leaves its marks on other organs as well (and this may also help distinguish it from osteoarthritis). Examples are a general tiredness and lassitude, sometimes low-grade fever, and some abnormalities on blood tests such as an elevated erythrocyte sedimentation rate (ESR), and anemia, which is often seen as a consequence of the disease itself (anaemia of chronic disease) although it may also be caused by gastrointestinal bleeding as a side effect of drugs used in treatment, especially NSAIDs used for analgesia. Extra-articular manifestations (manifestations outside the musculoskeletal system) occur in about 15% of patients with rheumatoid arthritis. Examples are Hepatosplenomegaly which may occur with concurrent leukopenia and is then referred to as Felty's syndrome), lymphocytic infiltration affecting the salivary and lacrimal glands (Sjögren's syndrome), Pericarditis, pleurisy, alveolitis, scleritis, and subcutaneous nodules.

Cutaneous manifestations

 * 1) The rheumatoid nodule is the cutaneous (strictly speaking subcutaneous) feature most characteristic of rheumatoid arthritis. The initial pathologic process in nodule formation is unknown but is thought to be related to small-vessel inflammation. The mature lesion is defined by an area of central necrosis surrounded by palisading macrophages and fibroblasts and a cuff of cellular connective tissue and chronic inflammatory cells. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal joints, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF titer and severe erosive arthritis. They can rarely occur throughout the body in internal organs.
 * 2) A variety of forms of vasculitis is also a cutaneous manifestation associated with rheumatoid arthritis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin due to the presence of an obliterative cutaneous capillaropathy. (This rash is also otherwise associated with the antiphospholipid-antibody syndrome, a hypercoagulable state linked to antiphospholipid antibodies and characterized by recurrent vascular thrombosis and second trimester miscarriages.

Other, rather rare, cutaneous features include:
 * pyoderma gangrenosum, a necrotizing, ulcerative, noninfectious neutrophilic dermatosis.
 * Sweet's syndrome, a neutrophilic dermatosis usually associated with myeloproliferative disorders
 * viral infections
 * drug reactions (6)
 * erythema nodosum
 * lobular panniculitis
 * atrophy of digital skin
 * palmar erythema
 * diffuse thinning (rice paper skin), and skin fragility.

Other
In addition to articular and cutaneous features, rheumatoid arthritis has a multitude of other, rare, features:


 * Pulmonary: The lungs may become involved as a part of the primary disease process or as a consequence of therapy. Fibrosis may occur spontaneously or as a consequence of therapy (for example methotrexate). Caplan's nodules are found as are pulmonary effusions.


 * Renal: Amyloidosis can occur.


 * Cardiovascular: Possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. The risk of cardiovascular, specifically myocardial infarction (heart attack) or congestive heart failure are greater in individuals with RA. Over 1/3 of deaths of people with RA are directly attributable to cardiovascular death.


 * Ocular: Keratoconjunctivitis sicca (dry eyes), scleritis, episcleritis and scleromalacia.


 * Gastrointestinal: Felty syndrome, anemia


 * Neurological: Peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome due to compression of the median nerve by swelling around the wrist. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. At first the patient experiences clumsiness but without due care this can progress to quadriplegia.


 * Vasculitis: Vasculitis in rheumatoid arthritis is common. It is typically presents as vasculitic nailfold infarcts.


 * Osteoporosis: Osteoporosis classically occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines.


 * Lymphoma: The incidence of lymphoma is increased in RA as it is in most autoimmune conditions.

Diagnostic criteria
The American College of Rheumatology has defined (1987) the following criteria for the classification of rheumatoid arthritis:
 * Morning stiffness of >1 hour most mornings for at least 6 weeks.
 * Arthritis and soft-tissue swelling of >3 of 14 joints/joint groups, present for at least 6 weeks
 * Arthritis of hand joints, present for at least 6 weeks
 * Symmetric arthritis, present for at least 6 weeks
 * Subcutaneous nodules in specific places
 * Rheumatoid factor at a level above the 95th percentile
 * Radiological changes suggestive of joint erosion

At least four criteria have to be met for classification as RA.

It is important to note that these criteria are not intended for the diagnosis of patients for routine clinical care. They were primarily intended to categorize patients for research. For example: one of the criteria is the presence of bone erosion on X-Ray. Prevention of bone erosion is one of the main aims of treatment because it is generally irreversible. To wait until all of the ACR criteria for rheumatoid arthritis are met may sometimes result in a worse outcome for the patient. Most patients and rheumatologists would agree that it would be better to treat the patient as early as possible and prevent bone erosion from occurring, even if this means treating patients who don't fulfill the ACR criteria. The ACR criteria are, however, very useful for categorising patients with established rheumatoid arthritis, for example for epidemiological purposes.

Blood tests
When RA is being clinically suspected, immunological studies are required, such as rheumatoid factor (RF, a specific antibody). A negative RF does not rule out RA; rather, the arthritis is called seronegative. During the first year of illness, rheumatoid factor is frequently negative. 80% of patients eventually convert to seropositive status. RF is also seen in other illnesses, like Sjögren's syndrome, and in approximately 10% of the healthy population, therefore the test is not very specific.

Because of this low specificity, a new serological test has been developed in recent years, which tests for the presence of so called anti-citrullinated protein antibodies (ACPA). Like RF, this test can detect approximately 80% of all RA patients, but is rarely positive in non-RA patients, giving it a specificity of around 98%. In addition, ACP antibodies can be often detected in early stages of the disease, or even before disease onset. Currently, the most common test for ACP antibodies is the anti-CCP (cyclic citrullinated peptide) test.

Also, several other blood tests are usually done to allow for other causes of arthritis, such as lupus erythematosus. The erythrocyte sedimentation rate (ESR), C-reactive protein, full blood count, renal function, liver enzymes and other immunological tests (e.g. antinuclear antibody/ANA) are all performed at this stage. Ferritin can reveal hemochromatosis, which can mimic RA.

Treatment
There is no known cure for rheumatoid arthritis. However, many different types of treatment can be used to alleviate symptoms and/or to modify the disease process.

The goal of treatment in this chronic disease must be two-fold: to alleviate the suffering of the patient here and now, and to prevent the future destruction of the joints and resulting handicap if the disease is left unchecked. These two goals may not always coincide: while pain relievers may achieve the first goal, they do not have any impact on the long-term consequences. For these reasons, most authorities believe that RA should be treated, in the vast majority of patients, by at least one specific anti-rheumatic medication, also named DMARD (see below), to which other medications and non-medical interventions can be added as needed.

Cortisone therapy has offered relief to many patients in the past, but its long-term effects have been deemed undesirable. . However, cortisone injections can be valuable adjuncts to a long-term treatment plan, and using low dosages of daily cortisone (e.g., prednisone or prednisolone, 5-7.5 mg daily) can also have an important benefit if added to a proper specific anti-rheumatic treatment.

Pharmacological treatment of RA can be divided into disease-modifying antirheumatic drugs (DMARDs), anti-inflammatory agents and analgesics. DMARDs have been found to produce durable remissions and delay or halt disease progression. In particular they prevent bone and joint damage from occurring secondary to the uncontrolled inflammation. This is important as such damage is usually irreversible. Anti-inflammatories and analgesics improve pain and stiffness but do not prevent joint damage or slow the disease progression.

There is an increasing recognition amongst rheumatologists that permanent damage to the joints occurs at a very early stage in the disease. In the past the strategy used was to start with just an anti-inflammatory drug, and assess progression clinically and using X-rays. If there was evidence that joint damage was starting to occur then a more potent DMARD would be prescribed. Tools such as ultrasound and MRI are more sensitive methods of imaging the joints and have demonstrated that joint damage occurs much earlier and in more patients than was previously thought. Patients with normal X-rays will often have erosions detectable by ultrasound that X ray could not demonstrate.

There may be other reasons why starting DMARDs early is beneficial as well as prevention of structural joint damage. In the early stage of the disease, the joints are increasingly infiltrated by cells of the immune system that signal to one another and are thought to set up self-perpetuating chronic inflammation. Interrupting this process as early as possible with an effective DMARD (such as methotrexate) appears to improve the outcome from the RA for years afterwards. Delaying therapy for as little as a few months after the onset of symptoms can result in worse outcomes in the long term. There is therefore considerable interest in establishing the most effective therapy in patients with early arthritis, when they are most responsive to therapy and have the most to gain.

Treatment also includes rest and physical activity. Regular exercise is important for maintaining joint mobility and making the joint muscles stronger. Swimming is especially good, as it allows for exercise with a minimum of stress on the joints. Heat and cold applications are modalities that can ease symptoms before and after exercise. Pain in the joints is sometimes alleviated by oral acetaminophen (paracetamol). Other areas of the body, such as the eyes and lining of the heart, are treated individually. However, there is no diet that has been shown to alleviate rheumatoid arthritis, although fish oil may have anti-inflammatory effects.

Disease modifying anti-rheumatic drugs (DMARDs)
The term Disease Modifying Anti-Rheumatic Agent was originally introduced to indicate a drug that reduced evidence of processes thought to underly the disease, such as a raised erythrocyte sedimentation rate, reduced haemoglobin level, raised rheumatoid factor level and more recently, raised C-reactive protein level. More recently, the term has been used to indicate a drug that reduces the rate of damage to bone and cartilage. DMARDs can be further subdivided into traditional small molecular mass drugs synthesised chemically and newer 'biological' agents produced through genetic engineering.

Traditional small molecular mass drugs:
 * azathioprine
 * ciclosporin (cyclosporine A)
 * D penicillamine
 * gold salts
 * hydroxychloroquine
 * leflunomide
 * methotrexate (MTX)
 * minocycline
 * sulfasalazine (SSZ)

The most important and most common adverse events relate to liver and bone marrow toxicity (MTX, SSZ, leflunomide, azathioprine, gold compounds, D-penicillamine), renal toxicity (cyclosporine A, parenteral gold salts, D-penicillamine), pneumonitis (MTX), allergic skin reactions (gold compounds, SSZ), autoimmunity (D-penicillamine, SSZ, minocycline) and infections (azathioprine, cyclosporine A). Hydroxychloroquine may cause ocular toxicity, although this is rare, and because hydroxychloroquine does not affect the bone marrow or liver it is often considered to be the DMARD with the least toxicity. Unfortunately hydroxychloroquine is not very potent, and for most patients hydroxychloroquine alone is insufficient to control symptoms.

Many rheumatologists consider methotrexate to be the most important and useful DMARD, largely because of lower rates of stopping the drug through toxicity. Nevertheless, methotrexate is often considered by patients and even other doctors as a very "toxic" drug. This reputation is not entirely justified, and at times can result in patients being denied the most effective treatment for their arthritis. Although methotrexate does indeed have the potential to suppress the bone marrow or cause hepatitis, these effects can be monitored using regular blood tests, and the drug withdrawn at an early stage if the tests are abnormal, before any serious harm is done (typically the blood tests return to normal after stopping the drug). In clinical trials in which patients with RA were treated with one of a range of different DMARDs, patients who were prescribed methotrexate were those who stayed on their medication the longest (the others stopped theirs because of either side-effects or failure of the drug to control the arthritis). Lastly, methotrexate is often preferred by rheumatologists because if it does not control arthritis on its own then it works well in combination with many other drugs, especially the biological agents. Other DMARDs may not be as effective or safe in combination with biological agents.

Biological agents
Biological agents (biologics include:
 * tumor necrosis factor alpha (TNFα) blockers - etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)
 * Interleukin 1 blockers - anakinra
 * monoclonal antibodies against B cells - rituximab (Rituxan)
 * T cell activation blocker abatacept (Orencia)

Anti-inflammatory agents and analgesics
Anti-inflammatory agents include:
 * glucocorticoids
 * Non-steroidal anti-inflammatory drug (NSAIDs, most also act as analgesics)

Analgesics include:
 * acetaminophen (Paracetamol outside US)
 * opiates
 * diproqualone
 * lidocaine topical

The Prosorba column blood filtering device was approved by the FDA for treatment of RA in 1999 However, in most patients the results have been very modest.

Historic treatments for RA have also included: RICE, acupuncture, apple diet, nutmeg, some light exercise every now and then, nettles, bee venom, copper bracelets, rhubarb diet, rest, extractions of teeth, fasting, honey, vitamins, insulin, magnets, and electroconvulsive therapy (ECT). . Most of these have either had no effect at all, or their effects have been modest and transient in some individual patients, while not being generalizable.

Pain relief
Recent research indicates that cytokines, a group of chemicals that are produced by various cells in the body, may be responsible for generating the response of chronic pain associated with Rheumatoid Arthritis. Medications that affect the release of cytokines or block the action of cytokines may reduce the response of chronic pain. Various anti-cytokine medications are now being used to treat painful disease states such as Rheumatoid Arthritis, and Crohn's Disease. In addition, research using the anti-cytokine medication, Thalidomide, is being evaluated for its effect in treating chronic pain associated with Arachnoiditis. Food (vegetables) with higher water content should be avoided.

Specific desensitization
An experimental treatment known as enzyme potentiated desensitization (EPD) is now under development for the treatment of rheumatoid arthritis and other autoimmune diseases. EPD uses dilutions of allergen (in this case type 2 collagen) and an enzyme, β-glucuronidase, to which T-regulatory lymphocytes respond by favouring desensitization, rather than sensitization. Initial results are encouraging but the treatment is still at an early stage of development.

Other therapies
Other therapies are weight loss, occupational therapy, podiatry, physiotherapy, joint injections, and special tools to improve hard movements (e.g. special tin-openers).

Severely affected joints may require joint replacement surgery, such as knee replacement.

Prognosis
The course of the disease varies greatly from patient to patient. Some patients have mild short-term symptoms, but in most the disease is progressive for life. Around 20%-30% will have subcutaneous nodules (known as rheumatoid nodules); this is associated with a poor prognosis.

Disability

 * Daily living activities are impaired in most patients.
 * After 5 years of disease, approximately 33% of patients will not be working
 * After 10 years, approximately half will have substantial functional disability.

Prognostic factors

 * Poor prognostic factors include persistent synovitis, early erosive disease, extra-articular findings (including subcutaneous rheumatoid nodules), positive serum RF findings, positive serum anti-CCP autoantibodies, carriership of HLA-DR4 "Shared Epitope" alleles, family history of RA, poor functional status, socioeconomic factors, elevated acute phase response (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), and increased clinical severity.

Mortality
Estimates of the life-shortening effect of RA vary; most sources cite a lifespan reduction of 5 to 10 years; the National Institutes of Health has estimated a lifespan reduction of 10 to 20 years. According to the UK's National Rheumatoid Arthritis Society, "Young age at onset, long disease duration, the concurrent presence of other health problems (called co-morbidity), and characteristics of severe RA – such as poor functional ability or overall health status, a lot of joint damage on x-rays, the need for hospitalisation or involvement of organs other than the joints – have been shown to associate with higher mortality". Positive responses to treatment may indicate a better prognosis. A 2005 study by the Mayo Clinic noted that RA patients suffer a doubled risk of heart disease, independent of other risk factors such as diabetes, alcohol abuse, and elevated cholesterol, blood pressure and body mass index. The mechanism by which RA causes this increased risk remains unknown; the presence of chronic inflammation has been proposed as a contributing factor.

Clinical Summary
A 57-year-old white female had suffered from rheumatoid arthritis for 20 years. During this period, many joints were involved, some seriously. Because of the severe pain of this arthritis the patient was placed on steroids and was given analgesics, some of which contained acetaminophen. The patient also took additional analgesics (aspirin and/or acetaminophen) to help control the pain. The patient was admitted to the emergency room for weakness and hematemesis. On admission the patient's hematocrit was 21%. Endoscopy demonstrated a large bleeding ulcer and fresh blood in the stomach and proximal duodenum. The sites of bleeding were cauterized; however, shortly after the procedure the patient became hypotensive and died despite aggressive resuscitation.

Autopsy Findings
There were numerous erosions and ulcers in the gastrointestinal tract and a large quantity of fresh blood in the gastrointestinal tract. There was also significant swelling and deformation in multiple joints. On the medial aspect of the right foot there was a firm, irregular, rubbery subcutaneous nodule measuring 2 x 1.5 cm. The cut surface was whitish-yellow and fibrous.

Histopathological Findings
Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology