RHEUMATOLOGY / ORTHOPAEDICS
Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune disease that primarily affects the joints and is associated with autoantibodies that target various molecules including modified self-epitopes. Rheumatoid arthritis is more common in women than in men. It often begins between the ages of 40 and 60.
The identification of novel autoantibodies has improved diagnostic accuracy, and newly developed classification criteria facilitate the recognition and study of the disease early in its course. New clinical assessment tools are able to better characterize disease activity states, which are correlated with progression of damage and disability, and permit improved follow-up.
In addition, better understanding of the pathogenesis of RA through recognition of key cells and cytokines has led to the development of targeted disease-modifying antirheumatic drugs. Altogether, the improved understanding of the pathogenetic processes involved, rational use of established drugs and development of new drugs and reliable assessment tools have drastically altered the lives of individuals with RA over the past 2 decades.
Current strategies strive for early referral, early diagnosis and early start of effective therapy aimed at remission or, at least, low disease activity, with rapid adaptation of treatment if this target is not reached. This treat-to-target approach prevents progression of joint damage and optimizes physical functioning, work and social participation.
A high-risk genetic background, in combination with epigenetic marks and environmental exposures, leads to a cascade of events inducing synovitis and consequent destructive arthritis. The clinical picture of joint involvement in RA is the result of chronic inflammation of the synovium, characterized by interactions of resident cells such as fibroblast-like synoviocytes (FLS) with cells of the innate (e.g. macrophages, dendritic cells, mast cells and NK cells, neutrophils) and adaptive immune system (e.g. B and T lymphocytes). Currently, the understanding of the role of innate and adaptive immunity in the pathogenesis of RA is expanding.
The main symptoms of rheumatoid arthritis are pain, stiffness, and swelling in the joints of the hands, wrists, elbows, feet, ankles, knees, or neck. The disease usually affects both sides of the body at the same time. In rare but severe cases, it may affect the eyes, lungs, heart, nerves, or blood vessels.
The following joint symptoms are common to RA:
• Joint pain, tenderness, swelling or stiffness for six weeks or longer
• Morning stiffness for 30 minutes or longer
• More than one joint is affected
• Small joints (wrists, certain joints of the hands and feet) are affected
• The same joints on both sides of the body are affected
• Along with pain, many people experience fatigue, loss of appetite and a low-grade fever.
Diagnosis of rheumatoid arthritis may be difficult in the early stages, because symptoms may be very subtle and go undetected on X-rays or blood tests. In addition to a complete medical history and physical examination, diagnostic procedures for rheumatoid arthritis may include the following:
• Joint aspiration – Involves a removal of fluid from the swollen bursa to exclude infection or gout as possible causes
• Biopsy (of nodules tissue) – A procedure in which tissue samples are removed (with a needle or during surgery) from the body for examination under a microscope
• Blood tests – To detect certain antibodies, called rheumatoid factor, and other indicators for rheumatoid arthritis
Specific treatment for rheumatoid arthritis will be determined by the Rheumatologist based on:
• Patient’s age, overall health, and medical history
• Extent of the condition
• Tolerance for specific medications, procedures, and therapies
• Expectation for the course of the condition
• Patient’s opinion or preference
The earlier a diagnosis is made and treatment is started, the more joint damage and impairment can be prevented. Treatment can range from simple therapies, such as diet and rest, to more aggressive therapies, including medications.
Without treatment, the underlying inflammatory process leads to joint destruction, pain, deformity, disability and accelerated cardiovascular disease. Disease-modifying antirheumatic drugs will attenuate the inflammation. Their benefits are seen at all stages of the disease; however, the best outcomes are achieved when they are used shortly after the onset.
Treatment may include:
• Resting affected joints regularly
• Nonsteroidal anti-inflammatory medications, such as ibuprofen
• Disease-modifying anti-rheumatic drugs (DMARDS), such as slow-acting medications
• Immunosuppressive medications, such as methotrexate
• Physical therapy
• Heat or cold application to the joints
• Surgery (to repair, replace, or fuse together an affected joint)
• Special devices that provide support for the affected joint
Optimal management of rheumatoid arthritis requires an understanding of the therapeutic goals, the options available to attain them and the associated potential complications. Drugs are only one part of the management of the patient.
Methotrexate is the backbone of rheumatoid arthritis treatment. Monotherapy consistently reduces radiographic progression and improves quality of life. Approximately 40% of patients will respond to monotherapy. Limited comparative data suggest that other conventional DMARD monotherapies are as effective as methotrexate.
Combining DMARDs is frequently used as a first-line strategy, particularly for those with poor prognostic factors. Meta-analyses have shown that most biologic DMARDs combined with methotrexate are superior to methotrexate alone for controlling disease activity. However, the benefits of combining methotrexate with conventional synthetic DMARDs are uncertain. The combination of methotrexate with sulfasalazine and hydroxychloroquine, so called ‘triple therapy’, has greater efficacy than monotherapy.
Systemic lupus erythematosus (SLE) or simply lupus, is a disease that is characterized by periodic episodes of inflammation of and damage to the joints, tendons, other connective tissues, and organs, including the heart, lungs, blood vessels, brain, kidneys, and skin. Lupus affects each individual differently and the effects of the illness range from mild to severe. Lupus can potentially be fatal.
The majority of people who have lupus are young women (late teens to 30s). This may be due to the fact that estrogen (a female hormone) seems to be associated with lupus. Lupus affects more African-Americans, Asian Americans, Latinos, and Native Americans than Caucasian Americans. Lupus in children occurs most often at the age of 10 and older; lupus is rare in children younger than 5 years of age.
The disease is known to have periods of flare-ups and periods of remission (partial or complete lack of symptoms). Children with lupus can have a large degree of kidney involvement. The severity of the kidney involvement can alter the survival rate of patients with lupus. In some cases, kidney damage is so severe it leads to kidney failure.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by an aberrant autoimmune response to self-antigens that can virtually affect any organs and tissues. The effects of environmental factors in genetically predisposed individuals, lead to the breaking of self-tolerance and to the activation/expansion of innate immune cells and autoreactive lymphocytes.
A variety of non-HLA genes have emerged as possible candidates of genetic susceptibility to SLE but the majority of studies focused on specific ethnic groups thereby large scale data are rather few. Among the large family of cytokines, SNPs of IL-6, IL-10, IL12B, IL-17F, IL-31, IL-32 and IL-33 are associated with higher risk to develop SLE.
SLE patients display a higher death rate compared to the general population, and such rate is higher in men than in women. While the most common cause of death, in patients aged 20–39 years is musculoskeletal and lupus-related, on the contrary in those aged over 40 years the most common causes of death were malignancy and cardiovascular disease.
In the last decades the survival of patients with SLE has improved, due both to prompt early diagnosis and to more effective treatment strategies of the disease and of its comorbidities. SLE complications and comorbidities can be caused both by disease activity and by the adverse events of immunosuppressant drugs.
• Malar rash – A rash shaped like a butterfly that is usually found on the bridge of the nose and the cheeks.
• Discoid rash – A raised rash found on the head, arms, chest, or back.
• Raynaud’s phenomenon – A condition in which the blood vessels of the fingers and toes go into spasm when triggered by factors such as cold, stress, or illness.
• Inflammation of the joints
• Sunlight sensitivity
• Hair loss
• Mouth ulcers
• Fluid around the lungs, heart, or other organs
• Kidney problems
• Low white blood cell or low platelet count
• Weight loss
• Nerve or brain dysfunction
Lupus is difficult to diagnose because of the vagueness of the symptoms each person might have. There is no single test that can diagnose lupus. A diagnosis is usually confirmed based on a complete medical history, reported symptoms, and a physical examination that may include the following:
• Blood test – To detect for certain antibodies that are present in most people with lupus
• Blood and urine tests – To assess kidney function
• Complement test – To measure the level of complement, a group of proteins in the blood that help destroy foreign substances; low levels of complement in the blood are often associated with lupus)
• Erythrocyte sedimentation rate (ESR or sed rate) – A measurement of how quickly red blood cells fall to the bottom of a test tube. When swelling and inflammation are present, the blood’s proteins clump together and become heavier than normal. Thus, when measured, they fall and settle faster at the bottom of the test tube. Generally, the faster the blood cells fall, the more severe the inflammation.
• C-reactive protein (CRP) – A protein that is elevated when inflammation is found in the body. Although ESR and CRP reflect similar degrees of inflammation, sometimes one will be elevated when the other is not. This test may be repeated to test your response to medication.
Further, the American College of Rheumatology created a set of criteria to assist physicians in making a diagnosis of lupus. The individual must have four of the 11 specific criteria to be diagnosed with lupus. It is important to remember that having some of the following symptoms does not mean that lupus is the diagnosis. The criteria include the following:
• Malar rash – A rash shaped like a butterfly that is usually found of the bridge of the nose and the cheeks.
• Discoid rash – A raised rash usually found on the head, arms, chest, or back.
• Sunlight sensitivity
• Mouth ulcers
• Inflammation of the joints
• Heart or lung involvement
• Kidney problems
• Seizures or other neurological problems
• Positive blood tests
• Changes in normal blood values
Thanks to a better understanding in SLE pathogenesis, today new immune-modulating drugs are currently administrated in patients resistant to conventional treatments.
Besides the FDA-approved B lymphocyte stimulator (BLyS) inhibitor, belimumab, interferon-α represents a promising treatment target, albeit with modest effectiveness primarily in non-renal SLE. Preclinical and early-phase clinical trials using biologics and small molecules targeting B and T cell activation as well as the cross-talk between these cells also show promise. BLyS and interferon targeting show the most promising results in challenging the current treatment status in non-renal SLE.
Belimumab is a human monoclonal antibody specific for B-cell activating factor (BAFF) that is approved in the USA, Canada and Europe to treat adult patients with autoantibody-positive SLE whose disease is active despite receiving standard therapy. BAFF was originally identified as a target for SLE because of its required role in mature B-lymphocyte survival. Along with another family member named a proliferation-inducing ligand (APRIL), BAFF promotes plasma cell survival, and it also regulates naïve B-lymphocyte repertoire selection. Overexpression of BAFF leads to SLE-like symptoms in transgenic mouse models, including anti-DNA autoantibody production. BAFF concentrations are elevated for patients with SLE and correlated with lupus disease activity.
Type I IFNs are a class of cytokines that play a protective role against viral infections. IFN-α, a member of the type I IFN family, promotes the stimulation and differentiation of various immune cells, including the differentiation of autoreactive B lymphocytes to immunoglobulin-secreting plasma cells, maturation of myeloid dendritic cells and inducing their expression of BAFF and APRIL, upregulation of T-cell costimulatory molecules and inactivation of T-regulatory cells (Tregs).
Anifrolumab is a fully human, IgG1 κ monoclonal antibody in phase III clinical development for SLE. Anifrolumab binds to and neutralizes the IFN-α receptor, in effect blocking type I IFN-dependent cell signaling.
Atacicept is a fusion protein composed of the TACI receptor with the modified Fc portion of human immunoglobulin that binds BAFF and APRIL. In a phase II/III trial for patients with moderate-to-severe SLE, no difference was observed in the flare rates (primary endpoint) or time to first flare (secondary endpoint) between treatment and placebo groups.
Abatacept is a cytotoxic T lymphocyte-associated antigen 4-IgG1 fusion protein that inhibits T-cell activation by modulating T-cell costimulatory events. In a phase II/III trial of patients with lupus nephritis, no difference was observed between abatacept-treated patients and placebo-treated patients in the time to confirmed complete response (the primary endpoint) or the percentage of patients who achieved confirmed complete response at the end of treatment (52 weeks).
Rituximab is a chimeric anti-CD20 monoclonal antibody that is considered a treatment option in published guidelines for patients with lupus nephritis who are not responsive to first-line therapy.
Primary Sjögren’s syndrome, a chronic inflammatory process, is among the most commonly occurring rheumatologic diseases. The clinical hallmark of this disease is exocrine gland dysfunction, resulting predominately in dry eyes and dry mouth. However, the disease often extends beyond the exocrine glands to seriously affect other organs systems, such as the lungs, kidneys, and nervous system. Moreover, patients with primary Sjögren’s syndrome develop non-Hodgkin’s B cell lymphoma at a substantially higher rate than the general population.
Primary Sjögren’s syndrome is among the most common of the systemic autoimmune diseases, ranging in prevalence from 0.1 to 0.6%; it is much more common in women than in men2. The disease is termed an “exocrinopathy” because of its predominant effects on the lacrimal and salivary glands, as well as other exocrine glands in the larynx (hoarseness), trachea (cough), skin (pruritus), and vagina (dyspareunia).
Primary Sjögren’s syndrome results from a complex interplay of several factors, including genetic and epigenetic controls of immune homeostasis and gene expression, age and gender, and environmental insults. It follows a typical multistep model of human autoimmune diseases characterized by loss of immunologic tolerance to self-antigens, the permissive production of autoantibodies, and the subsequent emergence of disease. Studies of labial salivary glands reveal the contribution of a panoply of cell types, including T cells, B cells, macrophages, dendritic cells, and epithelial cells, that combine to orchestrate a persistent chronic inflammatory response.
• Dry eyes
• Dry mouth
• Dry skin
• Vaginal dryness
• Muscle or joint pain
• Swollen salivary glands
The clinical diagnosis of primary Sjögren’s syndrome is based on the presence of symptoms of dry eyes and dry mouth, often with objective evidence of keratoconjunctivitis sicca and/or decreased salivary flow, and a positive test for serum anti-Ro antibodies or rheumatoid factor or, in the absence of these autoantibodies, a labial salivary gland biopsy showing focal lymphocytic infiltrates.
Treatment is designed to lessen the most bothersome symptoms. Dry eyes usually respond to artificial tears applied regularly during the day or to gels applied at night. Other measures, such as plugging or blocking tear ducts, can be used in more severe cases. Eye drops that reduce inflammation in the glands around the eyes, such as cyclosporine (Restasis), may be used to increase tear production. Drinking water, chewing gum, or using saliva substitutes may relieve dry mouth. Some patients benefit from using prescription medications that stimulate saliva flow, such as pilocarpine (Salagen) or cevimuline (Evoxac).
If patients develop yeast infections, anti-fungal therapies may be used. Humidifiers and nasal saline irrigation may improve nasal dryness. Medications that reduce gastric acid (such as proton-pump inhibitors and H2 blockers) may lessen symptoms of acid reflux. Treatments may help relieve some of the dryness, but usually some dryness persists.
All patients should receive regular dental care to prevent cavities and tooth loss that may occur as a complication of Sjögren’s. Patients with dry eyes should see an ophthalmologist (eye doctor) regularly for signs of damage to the cornea. Patients with excessive redness and pain in the eyes should be evaluated for infections.
Hydroxychloroquine (Plaquenil), an antimalarial drug used in lupus and rheumatoid arthritis, may be helpful in some patients with Sjögren’s syndrome by reducing joint pain and rash experienced by some patients. Patients with rare but serious systemic symptoms, such as fever, rashes, abdominal pain, or lung or kidney problems, may require treatment with corticosteroids such as prednisone (Deltasone and others) and/or immunosuppressive agents like methotrexate (Rheumatrex), azathioprine (Imuran), mycophenolate (Cellcept) or cyclophosphamide (Cytoxan). In addition, researchers are evaluating rituximab (Rituxan) and other biological therapies to treat cases of Sjögren’s that affect the entire body.
Osteoarthritis (OA), the most common form of arthritis, is a chronic, degenerative joint disease that affects mostly middle-aged and older adults. Osteoarthritis is characterized by the breakdown of joint cartilage. Although it can occur in any joint, usually it affects the hands, knees, hips, or spine. The disease is also known as degenerative arthritis or degenerative joint disease.
The definition of OA was long centered on the changes in the articular cartilage. This concept has evolved and OA is now considered a disease of the whole joint, including alterations in the articular cartilage, subchondral bone, ligaments, capsule and synovial membrane, ultimately leading to joint failure. Among the structural damages to the joint (that is, structural OA) are loss of cartilage, osteophyte formation, subchondral bone changes and meniscal alterations, some of which can be visualized using radiography, whereas all the above-mentioned can be seen using MRI. These alterations could be accompanied by joint pain (that is, symptomatic OA). Disease evolution in OA is usually slow and can take several years to develop. In turn, this disease could also undergo phases or demonstrate a progressive evolution over time, leading to a worsening of disease severity and symptoms.
The most common symptom of osteoarthritis is pain after overuse of a joint or prolonged inactivity of a joint. The most common joints affected by osteoarthritis include the hips, knees, fingers, feet, and spine. Symptoms of osteoarthritis usually develop slowly over many years. The following are the most common symptoms of osteoarthritis. However, each individual may experience symptoms differently.
• Joint pain
• Joint stiffness, especially after sleeping or inactivity
• Limited joint movement as the disease progresses
• Grinding of joints when moved (in more advanced stages of osteoarthritis) as the cartilage wears away
Osteoarthritis can be classified as primary or secondary. Primary osteoarthritis has an unknown cause, while secondary osteoarthritis is caused by another disease, infection, injury, or deformity. Osteoarthritis is characterized by the breakdown of cartilage in the joint. As the cartilage wears down, the bone ends may thicken, forming bony growths or spurs that interfere with joint movement.
In addition, bits of bone and cartilage may float in the joint space and fluid-filled cysts may form in the bone, limiting joint movement. Several risk factors are associated with osteoarthritis, including the following:
• Hereditary: Slight joint defects or double-jointedness (laxity) and genetic defects may contribute to the development of osteoarthritis.
• Obesity: Excessive weight can put undue stress on such joints as the knees over time.
• Injury/Overuse: Significant injury to a joint, such as the knee, can later result in osteoarthritis. Injury may also result from repeated overuse or misuse over a period of time.
X-rays – X-rays are the most useful test to confirm osteoarthritis. They may show changes such as bony spurs or narrowing of the space between the bones.
Magnetic resonance imaging (MRI) scans – Rarely, an MRI scan of the knee can be helpful. This will show the soft tissues (cartilage, tendons, muscles) and changes in the bone that can’t be seen on a standard x-ray.
The goals of treatment for osteoarthritis are to reduce joint pain and stiffness, and improve joint movement. Treatment may include:
Exercise: Regular, aerobic exercise, and stretching and strengthening exercises may help reduce the symptoms of and pain associated with osteoarthritis.
Heat treatment: Treating the affected joint with heat may help reduce pain.
Physical and occupational therapy: Physical and occupational therapy may help to reduce joint pain, improve joint flexibility when performing daily activities, and reduce joint strain.
Weight maintenance: Maintaining your recommended weight or losing weight (if overweight) may help prevent or reduce the symptoms of osteoarthritis.
Medication: Medication for specific symptoms may include pain relievers and anti-inflammatory medications, if inflammation is present. Conventional and biologic disease-modifying anti-rheumatic drugs (DMARDS) do not offer clinically significant pain relief above placebo in OA. This poor efficacy indicates that inflammation may not be a prime driver for OA pain.
Injections of thick liquids into the joints: These liquids mimic normal joint fluid.
Joint surgery: Surgery may be necessary to repair or replace a severely damaged joint.
The spondyloarthopathies (SpA), which encompass related diseases that were originally viewed as autoimmune, are now known to have a strong innate immune or autoinflammatory initiation phase characterized by disease localization to tissue-specific sites based on the microanatomy and immunology of those sites.
Spondyloarthritis is an autoinflammatory rheumatic disease in which arthritis and osteoproliferation lead the patients who suffer from it to chronic disability. The role of cytokines beyond tumor necrosis factor (TNF) continues to grow with support for the interleukin (IL)-23/17 axis being key to disease and emergent evidence for the importance of the IL-36 pathway.
Symptoms present in two main ways. The first is inflammation causing pain and stiffness, most often of the spine. Some forms can affect the hands and feet or arms and legs. The second type is bone destruction causing deformities of the spine and poor function of the shoulders and hips.
The most common condition of SpA is the ankylosing spondylitis, which affects mainly the spine. Others include:
• axial spondyloarthritis (axSpA), a chronic disease affecting primarily the spine and the sacroiliac joints
• peripheral spondyloarthritis, affecting mostly the arms and legs
• reactive arthritis
• psoriatic arthritis
• enteropathic arthritis/spondylitis associated with inflammatory bowel diseases (ulcerative colitis and Crohn’s disease).
Ankylosing spondylitis is hereditary. Many genes can cause it. Up to 30 of these genes have been found. The major gene that causes this disease is HLA-B27. Almost all white people with ankylosing spondylitis are carriers of HLA-B27.
Enteropathic arthritis is a form of chronic, inflammatory arthritis. The two most common types are ulcerative colitis and Crohn’s disease. The cause of enteropathic arthritis is unclear. It may be due to bacteria that enter the bowel. People with HLA-B27 are more likely to have this form of arthritis than those without the gene.
Correct diagnosis requires a physician to assess the patient’s medical history and do a physical exam. The doctor also may order imaging tests or blood tests. Imaging studies in SpA continue to add support for the pivotal role of enthesitis in disease initiation and expression. X-ray changes of the sacroiliac joints, known as sacroiliitis, are a key sign of spondyloarthritis. If X-rays do not show enough changes, but the symptoms are highly suspicious, a magnetic resonance imaging should be ordered.
A test for the HLA-B27 gene may also be ordered. However, having this gene does not mean spondyloarthritis will always develop. Some people have the HLA-B27 gene but do not have arthritis and never develop arthritis.
All patients should get physical therapy and do joint-directed exercises. Most recommended are exercises that promote spinal extension and mobility.
There are many drug treatment options. The first lines of treatment are the NSAIDs, such as naproxen, ibuprofen, meloxicam or indomethacin. No one NSAID is superior to another. Given in the correct dose and duration, these drugs give great relief for most patients.
For localized joint swelling, injections of corticosteroid medications into joints or tendon sheaths can be effective quickly.
For patients who do not respond to the above lines of treatment, DMARDs such as sulfasalazine (Azulfidine) might be effective. These drugs relieve symptoms and may prevent damage to the joints. This class of drugs is helpful mainly in those with arthritis that also affects the joints of the arms and legs.
Although they may be effective, corticosteroids taken by mouth are not advised. This is because the high dose required will lead to many side effects.
Antibiotics are an option only for patients with reactive arthritis.
TNF alpha blockers (a newer class of drugs known as biologics) are very effective in treating both the spinal and peripheral joint symptoms of spondyloarthritis. TNF alpha blockers that the FDA has approved for use in patients with ankylosing spondylitis are:
• infliximab (Remicade), which is given intravenously (by IV infusion) every 6-8 weeks at a dose of 5 mg/kg;
• etanercept (Enbrel), given by an injection of 50 mg under the skin once weekly;
• adalimumab (Humira), injected at a dose of 40 mg every other week under the skin;
• golimumab (Simponi), injected at a dose of 50 mg once a month under the skin.
However, anti-TNF treatment is expensive and not without side effects, including an increased risk for serious infections. Biologics can cause patients with latent tuberculosis (no symptoms) to develop an active infection. Therefore, you and your doctor should weigh the benefits and risks when considering treatment with biologics. Those with arthritis in the knees, ankles, elbows, wrists, hands and feet should try DMARD therapy before anti-TNF treatment.
Certolizumab pegol (CZP) is a pegylated humanized tumor necrosis factor-α inhibitor (TNFi) approved for the treatment of ankylosing spondylitis (AS) in the USA and for AS and non-radiographic axial spondyloarthritis (nr-axSpA) in Europe and in some Latin American countries. CZP lacks Fc region, preventing complement fixation and cytotoxicity mediated by antibody; CZP does not actively cross the placenta, unlike other TNFi.
Surgical treatment is very helpful in some patients. Total hip replacement is very useful for those with hip pain and disability due to joint destruction from cartilage loss. Spinal surgery is rarely necessary, except for those with traumatic fractures or to correct excess flexion deformities of the neck.
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