Differential diagnosis of systemic connective tissue diseases and systemic vasculitis in children.
Systemic connective tissue disorders – a group of diseases characterized by systemic lesions of connective tissue, including fiber-containing collagen: systemic lupus erythematosus, scleroderma, dermatomyositis, periarteritis nodosa, rheumatic fever and rheumatoid arthritis.
Juvenile rheumatoid arthritis.
Etiology
The causes leading to the development of rheumatoid arthritis are unknown.
The following possible etiological factors are currently discussed:
Ø -Genetic factors. Patients with rheumatoid arthritis have a genetic predisposition to a breach of immune reactivity. There is proved a close correlation between the development of rheumatoid arthritis and HLA antigens DR1 DR4, DRW4, DW4, DW14. The presence of these antigens may change the cellular and humoral immunity to various infectious agents and contribute to the development of rheumatoid arthritis. Family-genetic predisposition to the development of rheumatoid arthritis is proved by increased frequency of disease among relatives of patients, especially monozygotic twins.
Ø -Infectious agents. Revealed several infectious agents, claiming to be the etiological factor in rheumatoid arthritis. There are Epstein-Barr virus, retroviruses (including T-lymphotropic virus type I human), rubella virus, herpes, parvovirus B19, cytomegalovirus, mycoplasma, etc. Most researchers are paying attention to Epstein-Barr virus.
The available evidence of the role of this virus in the development of rheumatoid arthritis is:
· elevated antibody titers to Epstein-Barr virus is detected in 80% of patients
· B-lymphocytes of patients with rheumatoid arthritis are more infected with Epstein-Barr virus than B-lymphocytes of healthy people, the virus can induce the synthesis of rheumatoid factor
· revealed antigenic similarities between the components of the virus and the size of the beta-chain molecules HLA DW4, DW14, DR.
Risk factors for rheumatoid arthritis are:
• female
• genetic predisposition
• availability of HLA-antigens
• co-morbidities (nasopharyngeal infection, congenital defects of bones and joints).
Pathogenesis
The pathological process in juvenile rheumatoid arthritis begins in the synovial membrane of joints, microcirculation disturbances and destruction of cells of the synovial membrane. In response to this changes in the patient the modified IgG is formed, which is perceived by their own immune system as autoantigens. Immunocompetent cells, including plasma cells of the synovial membrane of the joint, produce antibodies in response – anti-IgG (CIC). These antibodies, called rheumatoid factor, in the presence of complement interact with autoantigens, and form immune complexes. CIC damage both the vascular endothelium and the surrounding tissue. Synovium of the joint is primarily affected, resulting in developing arthritis. Cytokines of macrophage origin – interleukin-1 and interleykin-6, tumor necrosis factor (TNF-a) are formed in the synovial fluid and joint tissues. Interleukin-1 induces inflammation and destroys cartilage. The same property has tumor necrosis factor (TNF-a). Interleukin-6 promotes the overproduction of acute phase proteins of inflammation – C-reactive protein and fibrinogen. There is the further activation of enzyme systems that destroy cartilage. Increased tumor blood vessels, or angiogenesis, arises the action on the tissue cytokines, also enhances the degradation of cartilage.
Electron micrograph Electron micrograph of bone
normal bone tissue of patient with JRA (osteoporosis)
Changes in lymphatic nodes of patient with JRA
Muscular atrophy of patient with JRA
Mucoid and fibrinoid edema of cartilage
JRA is the most common form of arthritis in children. It may be a mild condition that causes few problems over time, but it can be much more persistent and cause joint and tissue damage in other children. JRA can produce serious complications in more severe cases. Arthritis is best described by four major changes in the joints that may develop. The most common features of JRA are: joint inflammation, joint contracture (stiff, bent joint), joint damage and/or alteration or change in growth.
Other symptoms include joint stiffness following rest or decreased activity level (also referred to morning stiffness or gelling), and weakness in muscles and other soft tissues around involved joints. However, because JRA affects each child differently, your child may not experience all of these changes. Children also vary in the degree to which they are affected by any particular symptom.
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From the left side – health joint, from the right – affected joint.
The signs and symptoms of JRA vary from child to child, and even from day to day in the same child. This is an important fact for parents, caretakers and teachers (especially gym teachers) to keep in mind when working with children who have JRA.
Diagnostic criteria of JRA:
Clinical signs:
1. Arthritis more than 3 months (in Europe), more than 6 weeks (in USA).
2. Next joint arthritis in 3 months and more after the first joint affection.
3. Symmetrical affection of small joints.
4. Effusion in joint cavity (under the capsule).
5. Joint contracture.
6. Tendosynovitis or bursitis.
7. Muscular atrophy.
8. Morning stiffness of joints.
9. Rheumatoid eye disease.
10. Rheumatoid nodules.
X-ray signs:
1. Osteoporosis.
2. Articular cavities narrowing.
3. Bone growth disturbances.
4. Bone erosion, ankylosis.
5. Lesion of the cervical spine.
Laboratory:
1. Positive rheumatoid factor.
2. Positive data of the synovial membrane biopsy.
X-ray data in RA
• Stage IA: The bony elements of the joints without any changes, swelling of periarticular soft tissue
• Stage IB: Initial osteoporosis in the joints
• Stage II: Narrowing of the joint cavity and the initial destruction of the
subcortical bone (erosions and cysts)
• Stage III: The destruction of the joint without ankylosis
• Stage IV: Phase repair without destroying the joint with sclerosis, ankilostosis, as well as the formation of osteophytes
USD signs of arthritis (presence of fluid in a joint)
PECULIARITIES OF JRA IN CHILDREN
• frequent lesion of the knee, cervical spine, mandibular joints;
• relatively rare involvement in the pathological process of small hand joints;
• more often than in adults, the asymmetry of joint damage;
• more frequently observed mono-and oligoarthritis.
There is no single test to diagnose JRA. The diagnosis is made when there has been persistent arthritis in one or more joints for at least 6 weeks after other possible illnesses have been ruled out. Sometimes, a variety of tests may be necessary to come to a firm diagnosis. Once your child’s physician suspects or makes this diagnosis, your child may be referred to a pediatric rheumatologist. This is a physician who specializes in the diagnosis and treatment of children with arthritis and arthritis-related conditions.
The type of arthritis is usually determined based on the symptoms your child has had during the first 6 months of the illness. The 3 major types of JRA are: pauciarticular which affects 4 or fewer joints; polyarticular JRA which affects 5 or more joints; and systemic onset JRA which affects at least one joint but causes inflammation of internal organs as well.
Types of Juvenile Rheumatoid Arthritis
Pauciarticular JRA
Pauciarticular means “few joints.” This form of JRA affects 4 or fewer joints. About 50% of all children with JRA have this type. Usually, large joints (knees, ankles or elbows) are most often involved. Other joints such as wrists, spine and even small finger or toe joints can also be affected but less commonly. Pauciarticular JRA often affects a particular joint on one side of the body rather than both sides at the same time (both sides involved is called “symmetrical arthritis”).
There are two different types of pauciarticular JRA: one type usually affects little girls under age 7 and is associated with the development of eye inflammation (chronic iridocyclitis or uveitis) in about 1/3 of these children. These children should be tested for antinuclear antibodies (ANA). This tells the rheumatologist and the ophthalmologist (eye doctor) whether your child has a higher risk of developing uveitis (when the ANA is positive the risk is higher). Unfortunately, this eye condition is silent so only proper monitoring by an eye doctor who is familiar with this complication of JRA may find the changes in the eyes.
Uveitis in patients with JRA
The second type of pauciarticular JRA usually affects boys who are somewhat older, typically after age 8 and tends to involve the lower spine (sacroiliac joints), hips, knees, ankles and tendons. Sometimes, the spots at which tendons and ligaments attach to bones are also inflamed (enthesitis). These children may also develop eye problems, but this is usually acute uveitis (rather than chronic uveitis) and often causes redness and pain in the eyes. This type of JRA may be the first sign of another arthritis-related condition, such as one of the spondyloarthropathies. This group of diseases usually affects the spine, tendons, and eyes, and is associated with a genetic factor, HLA-B27 in some people.
Long-term problems due to pauciarticular JRA are seen in some of the children affected. Many children have no long-term consequences due to this illness. However, chronic damage can occur in the eyes and the eye problems may be much more persistent than any joint problems. On the other hand, some children develop chronic joint problems. This can include: decreased range of motion of a joint, shortening or lengthening of a limb or digit, damaged cartilage and/or enlargement of a joint. In some children, the arthritis spreads to other joints. These children are said to have “extended pauciarticular JRA” which is similar to polyarticular JRA. Speak to your doctor if you have questions or concerns about any of these issues.
Polyarticular JRA
Polyarticular means many joints; this form of arthritis affects five or more joints. Girls are affected by polyarticular JRA more frequently than boys. When polyarticular JRA affects teenagers, it often resembles RA.
Polyarticular arthritis usually affects the small joints of the fingers and hands; it can also affect weight-bearing joints (including the knees, hips and ankles) as well as the neck and jaw. Polyarticular JRA often affects the same joints on both sides of the body (symmetrical arthritis). Other possible symptoms might include: low grade fever, a positive blood test for rheumatoid factor (RF), and/or nodules (bumps on an elbow or other point of the body that receives a lot of pressure from chairs, shoes or other objects). Less often, inflammation of internal organs may occur. Anemia (low red blood cell count) is a common problem for these children.
Polyarthritis. This young girl has polyathritis. There is involvement of the ankles, knees, wrists and fingers and swelling of the right shoulder. Both temperomandibular joints are involved, as are her hips and cervical spine.
Oligoarthritis involving the right knee joint in a 3 year old boy. There is swelling of the knee due to an effusion in association with synovial proliferation. There is also increased growth of the right leg. This is the result of epiphyseal overgrowth secondary to the increased vascular supply to the area of inflammation.
Children with polyarticular JRA, especially the younger girls with a positive ANA, are at risk to develop chronic uveitis just like those with pauciarticular disease. Ophthalmologists should evaluate these children too.
Children with polyarticular JRA may develop damage to some of their joints. For example, slower growth may occur in the jaw due to arthritis in the TMJ (temporomandibular joint). This may cause jaw pain and discomfort with chewing. It may also affect dental care and eating habits. This may affect how well your child grows.
In the spine, neck stiffness and difficulty turning the head side to side may occur. Special x-rays can help your doctor determine if arthritis has developed in these areas.
Since polyarticular JRA affects many more joints than is seen with pauciarticular JRA, your doctor may need to use several different medications (often taken together) to treat your child successfully.
Disability due to JRA.
Systemic Onset JRA
A systemic illness is one that affects the entire person or body systems. This is the least common form of JRA. Boys and girls are equally likely to have systemic onset JRA. This type of JRA is associated with high fevers, a rash, arthritis and, in some children, inflammation of internal organs. For some children the systemic symptoms of the disease and the fever may go away completely after the first few months of the illness, although the joint-related symptoms of arthritis may remain for a longer period of time.
Rash in a patient with systemic form of JRA
Symptoms of systemic onset JRA usually include: daily high spiking fevers (103 degrees or higher) that may last for weeks or even months; a rash of pale red or pink spots that appear on the child’s chest, thighs and sometimes other parts of the body (the rash may accompany the fever and may come and go for many days in a row); joint pain and inflammation that may accompany the fever or begin weeks or months later. Joint problems can become a major long-term symptom. Other possible features of this form of arthritis include inflammation of the outer lining of the heart (pericarditis) or the lungs (pleuritis); anemia and high white blood cells and platelets (cells that help with clotting); and enlarged lymph nodes, liver or spleen. Blood work is usually checked frequently in the first few weeks and months of this illness to watch your child closely.
This form of juvenile rheumatoid arthritis has two main options – Still syndrome, usually occurs in children of preschool age, and Wisler-Fanconi syndrome, usually observed in schoolchildren.
Variants of systemic JRA
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Main clinical signs |
Still syndrome |
Wisler-Fanconi syndrome |
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Acute onset |
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Moderate febril temperature |
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– |
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High constant febril temperature |
– |
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Polyarthritis of small joints |
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– |
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Polyarthritis of big joints |
– |
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Long arthralgia |
– |
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Lymphoadenopathy |
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Hepatosplenomegaly |
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Polyserositis |
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Myocarditis |
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Anemia |
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– |
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Hyperleucocytosis |
– |
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High ESR |
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In about half the children with systemic JRA, the illness seems to disappear within 1 year of onset. Flare-ups, or a return of the illness, can happen without warning or after some viral infections (mononucleosis and chicken pox, for example). In most children with systemic JRA, medications must be used for months to years to control both parts of this illness – the systemic part (fever, rash, anemia, etc.) as well as the arthritis.
Long term problems due to systemic JRA are similar to polyarticular JRA. Uveitis, however, is uncommon, so the eyes only need to be checked only once a year in these children.
The palms become reddened (palmar erythema) – non-specific sign of JRA.
Rheumatoid nodules on the external surface of the elbow.
Violations of the II-III metacarpophalangeal, proximal interphalangeal and wrists at rheumatoid arthritis.
Diagnosis.
Physician may have to go through many steps to find out if a type of juvenile arthritis or a related condition is present. Other possible diagnoses are reviewed in detailed pamphlets available through the Arthritis Foundation. The main processes involved in making a diagnosis usually include:
· A complete health history to help determine the length of time symptoms have been present, to rule out other possible causes such as viral infections, and to find out if other family members may have had a form of arthritis that possibly could have been inherited (family history).
· A physical examination to look for joint inflammation, rashes, nodules, signs of internal organ inflammation and/or eye problems that may suggest the presence of juvenile arthritis.
· Laboratory tests to help rule out other diseases. These may include erythrocyte sedimentation rate (ESR), ANA, RF, HLA-B27 typing, hemoglobin and blood count testing and urinalysis (UA).
· X-rays or other specialized x-ray procedures of joints, bones and organs to check for infections, tumors or fractures.
· Tests of joint, blood and tissue fluids to check for infections or inflammation.
For example, an illness such as systemic lupus erythematosus may be similar to JRA in its symptoms (fever, rash arthritis) or fibromyalgia may seem similar, too (joint and muscle pain, fatigue). Further testing will help exclude these and other diagnoses.
Treatment of JRA.
Early diagnosis and appropriate treatment provides children with the best possible opportunity for a favorable outcome. Your child’s treatment will be based on the kind of arthritis he/she has and on their specific symptoms.
The goals of any treatment program for juvenile arthritis are: control inflammation, relieve pain, prevent or control joint damage and maximize joint and body function.
Sick child’s treatment program will usually include medication, exercise, eye care, dental care and healthy eating practices. Treatments such as surgery may be necessary for special long-term problems. Some physicians have also found that pain can be lessened by combining medical treatment with techniques such as progressive muscle relaxation, meditative breathing and guided imagery.
Because so many techniques are used to treat children with JRA, the ideal type of care is sometimes called team care or coordinated care. Your child’s health-care team will include many different specialists who work together to offer your child a complete treatment program. These may include a pediatric rheumatologist, nurse clinician, physical or occupational therapist, dietitian, ophthalmologist, psychologist, nephrologist, neurologist, gastroenterologist, cardiologist, pulmonologist, dentist, social worker or orthopaedic surgeon.
Pediatric rheumatology centers in many major medical centers offer this care in one location. If you do not live near a pediatric rheumatology center, your child’s physician will refer you to the specialists he/she needs.
Medications
The immediate goal of drug therapy is to reduce inflammation, relieve pain and swelling, and maximize function. Long-range goals are to alter the progress of the disease and the prevent damage to bone, cartilage and soft tissues such as muscles, tendons and joint capsules. It must be remembered that medication dosages in children must be carefully calculated based on their weight and body size. Medication doses should be adjusted regularly as the child grows to make sure the proper dosages are used. In addition, it is well known that children metabolize some medications differently than do adults. Therefore, drug dosages may be much higher than one would expect based just on the child’s smaller body size. Side effects may be different in children, or occur rarely compared to adults taking the same medication.
The following medications may be used to treat children with arthritis and related conditions.
NSAIDs
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first line of medication used in juvenile arthritis and are the mainstay of the initial therapy. NSAIDs must be taken for at least three to four weeks to tell whether they are helping control pain and inflammation. Laboratory tests may be done a few times a year to monitor medication side effects. These medications come in liquid or pill form and are taken from one to four times per day, depending on the drug prescribed. Some common NSAIDs on the market approved for children include: ibuprofen, naproxen, tolmentin, aspirin, choline magnesium trisalicylate and indomethacin.
Possible side effects of NSAIDs include: occasional stomach pain, nausea and vomiting; anemia; headache; and uncommonly, blood in the urine; fluid retention; thinning and scarring of the skin (especially with naproxen); difficulty concentrating; and rarely, stomach ulcer.
Aspirin
Aspirin is a rarely prescribed NSAID these days. If chosen by your doctor, it may be used to control joint pain and swelling and to reduce fever just like the other NSAIDs. It is prescribed in large amounts and is given three or four times a day. Young children should not suck or chew on the aspirin because this may damage the chewing surfaces of the teeth and irritate the gums. Instead, try crushing the dose and having the child swallow it in a small amount of a favorite food such as applesauce or yogurt.
Possible side effects of aspirin include stomach pains or stomach bleeding; toxic reactions can occur from too a high dose built up in your child’s system (rapid or deep breathing, ringing in the ears, decrease in hearing, drowsiness, nausea, vomiting, irritability, unusual behavior and black stools). A rare complication called Reye’s syndrome can occur in children who have the chicken pox or the flu and are taking aspirin. Symptoms include frequent vomiting, very painful headaches, unusual behavior, extreme tiredness and confusion. The different NSAIDs should never be combined together without your doctor’s instructions.
Skin rash associated with the use of a non steroidal anti-inflammatory medication. The rash in this child was due to the use of naproxen, and occurred in sun exposed areas of the skin. It resolved gradually over several years after cessation of the naproxen.
Slow Acting Anti-Inflammatory Drugs
These drugs do not relieve pain or inflammation right away; instead, they are given to change the progress of joint disease (such as joint erosions or cartilage and bone destruction) weeks to months after therapy is begun. Therefore, they are referred to as slow-acting anti-rheumatic drugs (SAARDs) or disease modifying anti-rheumatic drugs (DMARDs). These drugs are often used in combination with NSAIDs. Because they are more powerful medications, children will need to have more frequent laboratory tests for monitoring of possible side effects. Some of these medications are described below.
Hydroxychloroquine
Hydroxychloroquine (Plaquenil) is a pill used to control joint pain and swelling. It may take 3 to 6 months to work. While not helpful in all cases, it may be useful when methotrexate or gold have not been completely effective and can be used alone or in combination with other drugs.
Side effects of hydroychloroquine include upset stomach, skin rash and a rare complication, eye damage. A child who takes this drug should have his/her eyes examined at least every six months by an ophthalmologist familiar with this medication.
Sulfasalazine
Sulfasalazine (Azulfadine) is given in pill form. This medication helps the joint pain, stiffness and swelling. It can sometimes have more side effects in children with systemic onset JRA, so should be used with caution in this type of JRA. It takes 6-12 weeks to work.
Side effects may include stomach upset, achiness, diarrhea, dizziness, headache, light sensitivity, itching, appetite loss, liver abnormalities, lowered blood count, nausea, vomiting or rash. Blood work is checked within a few weeks of starting this medication then every few months to check for these changes.
Gold Compounds
Gold compounds (Auranofin, Ridaura, Myochrysine and Solganol) are used to ease morning stiffness and control joint swelling and pain. The oral form is taken daily. Injections are usually given every week for five or six months, then one or twice a month for as long as necessary. These medications are only occasionally used in JRA any more. They take 3-6 months to work.
Side effects may include skin rash, mouth sores, kidney problems, a low blood count or anemia. Blood and urine tests are checked every 1 to 4 weeks while taking gold compounds.
Penicillamine
Penicillamine (DePen and Cuprimine) is given in pill form. This medication is rarely used for JRA but more often for scleroderma, an arthritis-related condition. It takes up to 6 months to work.
Side effects include diarrhea, skin rash, hives or itching, low blood counts, mouth sores, nausea or vomiting, stomach pain, loss of taste or appetite, swollen glands, unusual bleeding or bruising, or weakness.
Immune System Medications
Methotrexate
Methotrexate (Rbeumatrex) is given weekly either orally as a liquid or in pill form, or by injection. It is one of the most commonly prescribed SAARDs for children with JRA. It can help the arthritis as well as the systemic illness in many children. It can help control uveitis in more severe cases. It takes 4-8 weeks to work.
Few side effects have been reported at the low doses at which methotrexate is usually prescribed (typically 7.5 to 25 mg a week), but regular laboratory monitoring is still important. Blood tests are usually checked every month at first then every 6-8 weeks later on. This is also a cancer chemotherapy drug but the dosages used in children with JRA are much lower. Therefore, the side effects are less frequent.
Side effects may include nausea, mouth sores, moodiness, diarrhea, low white blood cell count, lung irritation, infections and liver irritation. Avoid all alcohol intake and smoking while on this medication.
Azathioprine
Azathioprine (Imuran) is given in pill form. This is an immune system suppressing medication. It is not commonly used to treat JRA. It is saved for children that have failed or cannot take methotrexate. It takes about 3 months to work.
Side effects can include cough, fever and chills, loss of appetite, nausea or vomiting, skin rash, unusual bleeding or bruising, unusual tiredness or weakness, or possibly, sterility.
Cyclophosphamide
Cyclophosphamide (Cytoxan) is given in pill form daily or intravenously in a single dose, usually monthly. This drug is rarely used for JRA but often given in children with systemic lupus erythematosus, an arthritis-related condition. It may take several months to work.
Side effects include blood in the urine or burning on urination, confusion or agitation, cough, dizziness, fever and chills, infertility, loss of appetite, nausea or vomiting, unusual bleeding or bruising, unusual tiredness or weakness, and an increased risk for cancer.
Cyclosporine
Cyclosporine (Sandimmune) is given in liquid or pill form. This drug helps the joint inflammation as well as the systemic symptoms of systemic onset JRA. It may take a 1-2 months to work. Blood levels are often checked to determine the best dosage for your child.
Side effects include bleeding, tender or enlarged gums; fluid retention; high blood pressure; increased hair growth; kidney problems; loss of appetite; or trembling or shaking of hands.
Biologic Agents
Biological agents are a new class of medications made of synthetic proteins. These drugs may be made of antibodies that block high levels of inflammatory proteins in patients with arthritis. The drugs available include etanercept (Enbrel) which blocks the protein TNF, and was approved in 1998 by the FDA for RA treatment in adults, and in 1999 for the treatment of JRA. Infliximab (Remicade) is another anti-TNF medication that is approved to treat RA and has begun testing in JRA.
Intravenous immunoglobulin (IVIG) is used to treat several childhood rheumatic diseases. It is usually given intravenously once a month. It is sometimes used as part of the treatment of systemic JRA. Side effects include the risk of allergic reactions, headaches, stomachache and flu-like symptoms.
Researchers are developing other experimental biologic therapies that are aimed at specific proteins to control a variety of different diseases.
Glucocorticoid Drugs
Glucocorticoid medications (Dexamethasone, Methylprednisolone, Cortef, Prednisolone and Prednisone) are the most potent anti-inflammatory agents. These drugs are used to treat a variety of rheumatic diseases when the disease is severe or has not responded to other drugs. Sometimes glucocorticoids are used for a few weeks until other slower medications can become effective in controlling the arthritis.
Because of their many side effects, glucocorticoids must be used with caution. If these drugs are prescribed, the lowest possible dose should be used for the shortest length of time. Usually the drug is given by mouth as a pill or liquid. It can also be given as an injection into the joint itself, or into a muscle, or vein (IV).
Possible side effects of these medications include high blood pressure, osteoporosis (brittle bones), Cushing’s syndrome (weight gain, moon face, thin skin, muscle weakness) cataracts, slowed growth rate, reduced resistance to infection, sudden mood swings, increased appetite and weight gain, or increased risk for ulcers. Many of these side effects occur only when the dose is more than 7.5 to 10 mg a day (dose for an average size adult who is taking prednisone).
Glucocorticoids should never be stopped suddenly if they have been taken for more than a month. Your child’s owatural gluco-corticoids may not be produced enough after using these drugs for a month or more. A schedule to slowly discontinue or taper these medications will be given to you by your doctor and will prevent this problem. A child taking glucocorticoids should wear a medical alert bracelet or necklace. This will alert emergency medical personnel to give extra medication if the child has surgery or is seriously injured.
Cushing’s syndrome
Analgesics
Analgesics (acetaminophen [Tylenol, Panadol], tramadol [Ultram]) do not relieve inflammation, but provide pain relief. They should be taken only under a physician’s advice in conjunction with other medications. Acetaminophen has few side effects when taken in small doses; very high doses (overdoses) can cause liver damage. Side effects of tramadol may include dizziness, nausea, constipation, headache and sleepiness.
Exercise
Exercise is a very important part of treatment for juvenile arthritis. For children with arthritis, exercise helps keep joints mobile; keep muscles strong; regain lost motion or strength in a joint or muscle; make everyday activities like walking or dressing easier; and improve general fitness and endurance.
Therapeutic Exercise
While medications reduce pain and inflammation, only therapeutic exercise can restore lost motion in a joint. These exercises can make it easier for children to walk and perform other activities of daily living such as walking, eating and writing.
Range-of-motion exercises keep joints flexible and are especially important for children who have lost motion in a joint, or whose joints have become fixed in a bent position. Strengthening exercises build muscles.
A physical or occupational therapist will teach the child how to perform these exercises at home. Most of these must be done daily. The therapist will show to the child how to use hot baths, hot packs and/or cold treatments before exercise to make the therapy easier.
Sports and Recreational Activities
Recreational activities help to the sick child exercise joints and muscles, develop important social skills and have fun. But remember that recreational activities cannot take the place of therapeutic exercise.
Participating in sports and recreational activities helps children with arthritis develop confidence in their physical abilities. Encourage activities that exercise the joints and muscles without putting too much stress on them, like swimming.
Strong muscles and joint protection are the keys to participating in sports. Although contact sports are never recommended, even aggressive sports like soccer and basketball may not be off-limits for sick child. Special exercises and protective equipment can further reduce the risk of injury, and help to the child play sports she likes.
Splints
Splints help keep joints in the correct position and relieve pain. If a joint is developing a contraction (bent in the wrong position), a splint may help stretch that joint gradually back to its normal position. Commonly used splints include knee extension splints, wrist extension splints and ring splints for the fingers.
Splints help keep joints in the correct position.
An occupational or physical therapist usually makes the splint. Arm and hand splints are made from plastic; leg splints are sometimes made of cast material. The therapist custom-makes the splint for your child and can adjust the splint as your child grows, or as the joint position changes.
Morning Stiffness Relief
Many children experience a period of stiffness when they get up each day. This morning stiffness can be one of the best measures of disease activity; the longer the stiffness lasts, the more active the disease. Taking a hot bath or shower, sleeping in a sleeping bag or warm bed, doing range-of-motion exercises, or using a hot or cold pack can help relieve it. Although most children do better with warmth, there are a few who respond to cold treatments (a plastic bag filled with ice or frozen vegetables works well).
Surgery
Surgery is rarely used to treat juvenile arthritis in the early course of the disease. However, surgery can be used to relieve pain, release joint contractures and replace a damaged joint.
In joint replacement surgery, the entire joint is replaced with an artificial joint. This procedure is used mainly in older children whose growth is complete or almost complete and whose joints are badly damaged by arthritis. This operation is usually used to replace the hip, knee or jaw joints. It can reduce pain and improve function.
Soft tissue release may sometimes help to improve the position of a joint which has pulled out of line by a contracture. In this operation, the surgeon cuts and repairs the tight tissues that caused the contracture, allowing the joint to return to a normal position.
Eye Care
Several forms of eye inflammation are associated with various forms of juvenile arthritis. However, frequent eye exams can identify inflammatory problems early and reduce the potential for serious eye complications.
Chronic iridocyclitis occurs most commonly in young girls with pauciarticular JRA whose blood contains an antibody protein called the ANA. This inflammation of the eyes may occur without obvious signs or symptoms. Therefore, it is important for all children with JRA to have their eyes checked by an ophthalmologist as soon as the diagnosis is suspected. This allows the doctor to detect any eye problems early and to begin proper treatment to avoid serious problems. Children diagnosed before 7 years old with pauciarticular JRA and a positive ANA are at the greatest risk of developing chronic uveitis. Their eyes should be checked every 3 months for several years. Acute or sudden onset of eye inflammation is called iritis. This may occur particularly in the spondyloarthropathies.
The ophthalmologist will give to the child a complete medical eye evaluation, including a slit lamp test. This simple and painless procedure can spot problems before symptoms are present. Children should continue to get periodic eye exams, since eye inflammation may occur when the joint disease is inactive. The frequency of eye exams will depend on sick child’s risk for developing eye problems.
Dental Care
Children with arthritis may have limited jaw movement, which can make brushing and flossing their teeth difficult. Your child’s dentist may suggest various toothbrush handles, electric toothbrushes, floss holders, toothpicks and rinses that will help your child maintain healthy teeth and gums.
Medications may also affect your child’s oral health and development. Always inform your dentist about the status of your child’s disease and the medications she is taking. The dentist will consider these when planning any treatment, general anesthesia, sedation or oral surgery. Older children who have had joint replacements may require an antibiotic before dental treatment.
The joint in front of the ears, where the lower jaw connects to the base of the skull, is called the temporomandibular joint (TMJ). Arthritis may affect this joint in the same way it does others, by causing pain, stiffness and altered growth. Jaw exercises and therapy may be recommended for the pain and stiffness. If the lower jaw does not develop properly, it may create an overbite. Your child’s dentist may recommend an early consultation with an orthodontist if this occurs. Surgery is also sometimes necessary for this condition.
A child with active arthritis may not always have the stamina for even routine dental work. If possible, schedule appointments when your child has the most stamina, or schedule shorter appointments.
Diet
Children with arthritis sometimes have poor appetites, leading to weight loss and poor growth; medication side effects may cause excessive weight gain.
Chronic disease places increased demands on a child’s body and creates a need for additional calorie intake. Children may have little appetite when they feel ill, or may have a difficult time eating when they have painful joints or limited mobility. Some children with arthritis might feel too sick or too tired to eat. Encourage him/her to eat a well-balanced diet at regular meal times and include planned snacks even when he/she may not feel like eating. Try to reduce the amount of food he/she needs to eat by increasing the nutrient content of each bite of food or drink. For example, add melted cheese, gravies, margarine and dips to foods, and offer whole milk. This can help prevent weight loss and poor growth.
At the opposite end of the spectrum, children with arthritis may gain too much weight due to medication side effects or limited activity. Excess weight puts more stress on joints such as knees, hips and ankles. Appropriate exercise combined with eating a well-balanced diet based on the basic four food groups can help your child keep a normal body weight. A registered dietitian can teach you ways to improve your child’s diet.
Many children with arthritis need additional calcium and vitamin D to help strengthen their bones. Giving your child a multivitamin with breakfast is usually worth the effort.
Medications for Juvenile Rheumatoid Arthritis
|
Drug Type/Name(s) |
Dosage |
Possible Side Effects |
Cautions |
|
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) |
Taken one to four times per day in pill or liquid form. Must be taken three to four weeks to determine if helping to control pain and inflammation. |
Possible side effects include occassional stomach pains, nausea and vomiting, anemia, headache, blood in the urine, fluid retention, thinning and scarring of the skin (especially with naproxen), difficulty concentrating, stomach ulcer. Aspirin |
Young children should not suck or chew on aspirin as this may damage the chewing surfaces of the teeth and irritate the gums. Instead, try crushing the dose and having the child swallow it in a small amount of a favorite food such as applesauce or yogurt. The different NSAIDs should never be combined without doctor’s instructions.
|
|
Disease-Modifying Anti-Inflammatory Drugs(DMARDS) |
Hydroxychloroquine Sulfasalazine Gold Compounds Penicillamina |
Hydroxychloroquine Sulfasalazine Gold Compounds Penicillamina |
Hydroxychloroquine eyes checked every six months by an opthalmologist familiar with this medication. Sulfasalazine more side effects in children with systemic onset JRA. |
|
Immune System Medications |
Methotrexate Azathioprine Cyclophosphamide Cyclosporine Leflunomide |
Methotrexate Azathioprine Cyclophosphamide Cyclosporine Leflunomide |
Methotrexate intake and smoking while on this medication. |
|
Glucocorticoids |
If prescribed, the lowest possible dose should be used for the shortest length of time. Normally administered orally in pill or liquid form but can also be administered intravenously. |
Possible side effects include high blood presssure, osteoporosis (brittle bones), Cushing’s syndrome (weight gain, moon face, thin skin, muscle weakness) cataracts, slowed growth rate, reduced resistance to infection, sudden mood swings, increased appetite and weight gain, increased risk for ulcers. Many of these side effects only occur when the dose is more than 7.5 to 10 mg a day (dose for an average size adult). |
Glucocorticoids should never be stopped suddenly if they have been taken for more than a month. A schedule to slowly discontinue or taper these medications should be given by your doctor. A child taking glucocorticoids should wear a medical bracelet or necklace. |
|
Analgesics |
Should be taken only under a physician’s advice in conjunction with other medications. |
Acetominophen Tramadol |
|
SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)
Background: Systemic lupus erythematosus (SLE) is a rheumatic disease characterized by autoantibodies directed against self-antigens, immune complex formation, and immune dysregulation resulting in damage to essentially any organ, including the kidney, skin, blood cells, and the CNS.
Causes: The specific causes of SLE remain undefined. Research suggests that many factors, including genetics, hormones, and the environment (eggs, sunlight, drugs), contribute to the immune dysregulation observed in lupus.
Pathophysiology: Within the healthy population, a subset of individuals exist who have small amounts of low titer antinuclear antibody (ANA) or other autoantibody. In lupus, much greater production of autoantibodies leads to immune complex formation and tissue damage due to direct binding and/or immune complex deposition in tissues. Whether these antibodies are produced in reaction to exposure of normally nonexposed self antigens or as a consequence of a broad spectrum of immune dysregulation resulting in excessive production of many antibodies without regard to prior stimulation is unclear. Patients with SLE make antibodies against DNA, other nuclear antigens, ribosomes, platelets, erythrocytes, leukocytes, and other tissue-specific antigens. Thus, the resulting immune complexes result in widespread tissue damage. Cell-mediated autoimmune responses also play a pathophysiologic role.
Haemotoxil bodies in connective tissue
Hyperceratosis and infiltration of skin
Morphology of lupus nephritis has different variations – both in different glomeruli, and within a single one. Specific (though not pathognomonic) are considered manifestations of fibrinoid necrosis of capillary loops, hyaline thrombi in the lumen of capillaries, the nuclear pathology (karyorexis and karyopyknosis), a sharp focal thickening of glomerular basal membrane in the form of wire loops.
Cell vacualization and thickening of glomerular basal membrane
Trombomikroangiopathy in SLE: A pronounced capillary-arteriolotrombosis in glomeruli, edema and necrosis of endothelial cells, infiltration by
neutrophils, red blood cell stasis with no signs of immune reactions in immunofluorescence
Histologic sings in kidney in SLE
Frequency: Incidence rates among children younger than 15 years have been reported to be between 0.5 and 0.6 per 100,000 persons.
Mortality/Morbidity: The 5-year survival rate for children with SLE is more than 90%. Most deaths of children with SLE are the result of infection, nephritis, renal failure, CNS disease, or pulmonary hemorrhage.
Sex: Prevalence rates are higher in females than in males. A female-to-male ratio of approximately 2:1 occurs before puberty, and a ratio of 4:1 occurs after puberty.
Age: Approximately 20% of patients with SLE initially present by the second decade of life.
History: Eleven criteria are used for the classification of lupus in adults. The same criteria can serve as a guideline in children. Any 4 criteria are sufficient and should be sought in the history. Of note, ANA is almost always present. Diagnosis is not difficult in the child who presents with many manifestations, such as malar rash, pleuritic chest pain, nephritis, and a positive ANA.
Diagnostic criteria for SLE.
At least four of the following symptoms are generally present for a diagnosis to be made:
(by The American College of Rheumatology)
1. Red, butterfly-shaped (malar) rash on the face
2. Typical discoid rash on other parts of the body (neck, chest)
3. Sensitivity to sunlight
4. Mouth sores (ulcers)
5. Arthritis (pleurisy, pericarditis)
6. Serositis
7. Kidney dysfunction
8. Leucopenia, anemia, or/and trombocytopenia.
9. CNS dysfunction
10. Immunological changes (LE-cells or positive results of a blood test for antibodies to double-stranded DNA or tests for antibodies to the extractable nuclear antigens (SSA/Ro, SSB/La, Sm, and RNP) or false-positive Wassermann reaction).
11. Positive ANA test.
Le-cells
Other laboratory findings: positive ANA, Positive anti–double-stranded DNA, anti-Smith, or antiphospholipid antibody.
Clinical features:
Mucocutaneous findings include the following:
· Rash occurs in 70-80% of patients. The characteristic rash is a malar or butterfly rash, including both cheeks and the nasal bridge. The rash varies from an erythematous blush to thickened epidermis to a scaly rash.
· Other diagnostic skin findings include discoid rash, which is rare in childhood, a photosensitive rash, and mucous membrane changes that range from vasculitic erythema to large deep ulcers on the palate and nasal mucosa.
· Other common rashes include vasculitic macular eruptions, particularly on the distal extremities and often in the subungual region with visible microinfarcts from small vessel vasculitis; purpura; livedo reticularis, which is often associated with antiphospholipid antibodies; alopecia, which usually is frontal or hairline; and Raynaud phenomenon, which is characterized by sequential color changes in the fingers and toes.
Typical “butterfly” rush in SLE.
Systemic lupus erythematosus: facial rash in girls with active lupus vasculitis. There are also vasculitic lesions on both ears.
Aphthous stomatitis
Capillaritis and teleangiectases
Thickening and redness of eyelids in SLE
Musculoskeletal findings include arthritis, arthralgia, tendonitis, and myositis.
Deforming arthritis is unusual and, if present, is usually secondary to a Jaccoudlike arthropathy. This arthritis can lead to ligament damage and severely lax joints.
Avascular necrosis of bone is a frequent complication occurring in about 25% of children with SLE over time. It occurs both in children with SLE alone and in children receiving corticosteroids for conditions other than SLE, but it is much more common in children with SLE who are receiving corticosteroids.
Abdominal findings include the following:
Patients often present with lymphadenopathy and hepatosplenomegaly. Many have chronic abdominal pain secondary to recurrent vascular insults to the intestinal tract and/or chronic pancreatitis, which may result from both corticosteroids and SLE. Hepatitis on laboratory evaluation is not uncommon.
Other abdominal findings can include pain secondary to peritoneal serositis or small-vessel vasculitis.
Cardiac involvement includes pericarditis, murmurs associated with endocarditis, and cardiac failure due to myocarditis or infarction. Pulmonary auscultatory findings may be abnormal secondary to pleuritis, infiltrates, or hemorrhage.
Neurologic manifestations can include both the central and the peripheral nervous systems.
Diagnostic findings include seizure and psychosis; however, patients may present with stroke, pseudotumor cerebri, cerebral venous thrombosis, aseptic meningitis, chorea, global cognitive deficits, mood disorders, transverse myelitis, and peripheral neuropathy as well as many less commoeurologic findings.
Up to 40% of children may have CNS disease and perhaps even more when considering psychiatric manifestations, which can be associated with antiribosomal P antibodies and cognitive abnormalities. Quantification with formal neuropsychiatric testing may be advisable.
Renal disease is manifested by hypertension, edema of the lower extremities, retinal changes, and clinical manifestations associated with electrolyte abnormalities, nephrosis, or acute renal failure. Renal disease is more frequently observed in children than in adults.
Patients with lupus may present with the clinical findings of endocrine disease, such as hyperthyroidism and Addisonian crisis.
Neonatal lupus syndrome
Some infants born to mothers with serological evidence of lupus will have transient manifestations of the disorder. These are due to transplacental passage of maternal IgG autoantibody, particularly anti-Ro and anti-La antibody. The most common abnormality is a discoid lupus-like skin rash, which gradually fades as maternally acquired antibody liters decrease. The most important complication is congenital heart block, which persists throughout life and may require placement of a cardiac pacemaker.
Differential diagnosis should be performed with:
· Acute Lymphoblastic Leukemia
· Acute Poststreptococcal Glomerulonephritis
· Autoimmune Chronic Active Hepatitis
· B-Cell and T-Cell Combined Disorders
· Juvenile Rheumatoid Arthritis
· Mixed Connective Tissue Disease
· Rheumatic Fever
· Systemic Sclerosis
· Takayasu Arteritis
Lab Studies:
Initial laboratory evaluation should include a CBC with platelets and reticulocyte count; a complete chemistry panel to evaluate electrolytes, liver, and kidney function; a urine analysis; and a measure of acute phase reactants (erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).
Diagnostic laboratory studies include ANA, anti–double-stranded DNA, anti-Smith antibody, and antiphospholipid antibodies.
Quantitative immunoglobulins are useful because patients with lupus often have hypergammaglobulinemia and have a higher incidence of immunodeficiency.
Imaging Studies: Perform chest radiography and echocardiography.
Other imaging studies should be guided by clinical manifestations and may include the following:
· MRI of the brain
· Renal ultrasonography
· Nuclear medicine evaluation for renal function
· High-resolution CT scanning to evaluate for pulmonary fibrosis
· Dual-energy x-ray absorptiometry (DEXA) to evaluate bone density
Other Tests: Obtain pulmonary function tests, including diffusing capacity of the lung for carbon monoxide (DLCO), to evaluate baseline pulmonary disease.
Procedures: The most common procedure in the diagnostic evaluation of SLE is a tissue biopsy to confirm diagnosis and to evaluate disease severity. This is particularly useful in evaluating the severity of renal involvement.
Although skin biopsy is frequently used for diagnostic purposes when the diagnosis is not clear, lesional and sun-exposed skin may show positive immunofluorescence. Skin biopsy is rarely necessary to make the diagnosis of SLE.
Renal or liver biopsy is obtained more often for evaluation of disease severity and to determine the intensity of the medical regimen required for treatment.
Histologic Findings: Fibrinoid deposits are found in blood vessel walls of affected organs; the parenchyma of these organs may contain hematoxylin bodies representing degenerated cells. Other histologic manifestations are associated with the particular organ. Immunofluorescence often reveals immune complexes and complements. The most important histology related to treatment decision is renal histopathology. Location of immune complexes (ie, subepithelial, subendothelial, intramembranous) is also important in prognosis.
TREATMENT
The most important tool in the medical care of the patient with SLE is careful and frequent clinical and laboratory evaluation to tailor the medical regimen and to provide prompt recognition and treatment of disease flare, which is the cornerstone of successful intervention. Lupus is a lifelong illness, and patients must be monitored indefinitely. Specific medical interventions are listed below.
Surgical Care: The need for surgical care is dependent on the severity of organ involvement and the need for tissue diagnosis. Usually, SLE is not a surgical condition. If for any reason surgery is necessary, monitor the patient closely for healing and evidence of infection.
Diet: Diet restrictions are driven by the medical therapy. Most patients require a course of corticosteroids and should be on a no added salt, low-fat, and calcium-sufficient diet.
MEDICATION
Drug Category: Antimalarials — Rash and other minor symptoms can be treated with hydroxychloroquine (Plaquenil) 3-7 mg/kg/d, usually no more than 400 mg/d PO. Long-term use of this medication requires monitoring for retinal pigment changes every 6 months. Adverse effects are infrequent and include eye changes, GI symptoms (of which diarrhea is most prominent), and CNS changes.
Drug Category: Corticosteroids. Treat children who have evidence of severe renal, CNS, or hematologic diseases with corticosteroids. The dose varies with intensity of the organ system involved and in select individuals with serologic disease activity. Consider daily prednisone (1 mg/kg/d) or higher-dose alternate-day prednisone (5 mg/kg/d, not to exceed 150-250 mg depending on the size of the patient). Alternatively, lower-dose daily prednisone (0.5 mg/kg) may be used in conjunction with intermittent high-dose IV methylprednisolone (30 mg/kg/dose, not to exceed
Children who are systemically ill with renal, neurologic, severe hematologic, cardiac, or pulmonary disease are begun on high-dose daily prednisone 2 mg/kg/d (not to exceed 80 mg/d) in divided doses, which are consolidated after serologic disease activity is controlled and finally switched to alternate-day prednisone.
Alternatively, the patient may be treated with IV pulse methylprednisolone therapy (3 d of high-dose IV corticosteroids) and then switched to intermittent high-dose IV corticosteroids with lower daily prednisone doses depending on disease severity.
Drug Category: Immunosuppressive agents — Evaluate children with signs of active nephritis to determine the WHO classification category of their nephritis. Patients with class IV nephritis and some patients with class III nephritis should be treated with corticosteroids and cyclophosphamide. Azathioprine is used for more mild nephritis. Consider cyclophosphamide for severe systemic involvement of other vital organs, especially the brain. Other agents (eg, mycophenolate mofetil, cyclosporine, methotrexate) are considered when standard therapies have failed.
Cyclophosphamide (Cytoxan, Neosar) Pediatric Dose 500-750 mg/m2 IV q3-4wk; not to exceed 1 g/m2.
Azathioprine (Imuran) — Pediatric Dose 1-3 mg/kg/d PO qd
All patients with SLE who are on corticosteroids or who have arthritis are at increased risk for osteopenia and its complications. Diet and appropriate supplementation with vitamin D and calcium are important tools for bone health in these patients.
Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDs) — The child who presents with mild disease with no evidence of nephritis, hypocomplementemia, and elevated anti–double-stranded DNA antibodies is treated symptomatically and is monitored closely for signs of disease progression. Arthritis is treated with NSAIDs.
Naproxen (Aleve, Naprelan, Naprosyn)
Pediatric Dose 7-20 mg/kg/d PO divided bid/tid; not to exceed adult dose
Tolmetin (Tolectin)
Pediatric Dose 15-30 mg/kg/d PO divided tid/qid; not to exceed adult dose
Diclofenac (Voltaren, Cataflam
Pediatric Dose <12 years: Not recommended
>12 years: 2-3 mg/kg/d PO divided bid; not to exceed adult dose
Further Inpatient Care: Further inpatient care is required for severe hematologic, nephrologic, neurologic, or psychiatric disease or for complications from these (eg, severe anemia, renal failure, stroke, seizure), including the use of intravenous high-dose corticosteroids or chemotherapy as required.
Hospitalization may also be required for severe hypertension.
Inpatient care is appropriate for the patient with unexplained fever in order to provide a sepsis evaluation and treatment, as well as to evaluate the patient for disease flare and to treat accordingly.
Further Outpatient Care: Patients with SLE have a chronic often persistent disease and need constant monitoring of disease activity and modification of medical regimen according to fluctuations in disease status.
Complications
SLE is a high-risk disease with the possibility of end-organ damage to any organ, vital or otherwise. This damage can severely affect organ function and can lead to decreased quality of life.
Some patients with SLE have increased thrombosis, which result in severe complications.
Treatment of SLE is also fraught with potential complications from steroid adverse effects, infection from immunosuppression, and cardiovascular disease leading to early myocardial infarction.
Necrosis as a result of microthrombosis
Gangrene as a result of microthrombosis
Prognosis: Current mortality figures suggest that patients have a 95% rate of survival at 5 years. Some clinicians report a 98-100% survival rate at 5 years. These figures depend on disease severity and compliance with therapy.
JUVENILE DERMATOMYOSITIS
Defininition
Juvenile dermatomyositis is one of the conditions in a group of conditions called the dermatomyositis/polymyositis complex. The conditions in this complex are characterized by muscle damage due to an inflammatory process of the blood vessels that lie under the skin and muscles. Skin changes around the eyelids and over the knuckles and finger joints are also seen. Juvenile dermatomyositis is the condition most often seen in children.
Juvenile dermatomyositis is rare, and it affects girls more often than boys.
Etiology
The cause of juvenile dermatomyositis has not yet been determined. However, factors which are thought to be associated with dermatomyositis include dysfunction of the immune system, resulting in infections.
Muscular biopsy: inflammation cells attack muscular tissue
Clinical features
The symptoms of juvenile dermatomyositis often appear gradually. At times, there may be a more acute, or intense, onset of symptoms. The following are the most common symptoms of juvenile dermatomyositis. However, each child may experience symptoms differently. Symptoms may include:
· fever
· rash around the eyelids and/or knuckles and finger joints; a rash may also occur on the elbows, knees, and ankles
· muscle weakness
· fatigue
· malaise
· muscle pain and tenderness
· irritability
· weight loss (due to difficulty swallowing)
· joint pain and inflammation
· calcium deposits under the skin (calcinosis)
· mouth ulcers
Onset is insidious with muscular weakness, or may be abrupt.There is bilateral muscular weakness in most cases. Stiffness, pain, tenderness of muscles, easy fatigability, weight loss, arthralgia, Raynaud phenomenon and constitutional disturbances are seen. The skin around the upper eye-lips often has violaceous colour with dermatitis and swelling around eyes. On the face butterfly rash is evident. Erythematous rash, dark pigmentation, urticarial patches and scaling may be seen elsewhere on skin.
Gottron symptom: red and pink rash with scaling or patches on external surface
of joints
Classical heliotropic rash on face sometimes with eye-lips edema
Changes around knee joint
Xeroderma, ceratosis and fragility of nails
“Mechanics hands” in JDM
Atrophy, contractures develop later and calcinosis along the tendons, ligaments and muscles in the later stages.
Deformation of fingers in forms of swaeck
Calcinosis of humerous and knee in JDM
Symptoms of juvenile dermatomyositis may resemble other medical conditions or problems.
For a definitive diagnosis 3 or 4 of the following criteria are required:
1) symmetrical limb girdle weakness; 2) muscle biopsy evidence of myositis and muscle necrosis; 3) elevation of muscle enzymes; 4) electromyographic changes of myositis; 5) heliotropic rash and periorbital edema on the face.
Phases of juvenile dermatomyositis:
The course of juvenile dermatomyositis is often divided into four phases, based on symptoms and findings on examination. The four phases are briefly described below:
· Prodromal period
This phase can last for weeks or months. The symptoms seen during this period are nonspecific (general symptoms which can indicate many different conditions).
· Progressive muscle weakness and rash
In this phase, muscle weakness increases for days and weeks and then stabilizes. Once the stabilization occurs, it may last from one to two years before recovery.
· Persistent muscle weakness, muscle inflammation, and rash
During this phase, symptoms include persistent muscle weakness, active inflammation of the muscles, and rash lasting up to two years.
· Recovery
Recovery may occur without any apparent consequences, or may occur after two or more years with residual muscle weakness, atrophy (wasting), or contractures (a condition in which muscles in a particular location may become permanently paralyzed as a result of lack of use).
Diagnostics
In addition to a complete medical history and physical examination, diagnostic procedures for juvenile dermatomyositismay include:
· laboratory tests – to assess the presence of antibodies, muscle enzymes, and indicators of inflammation in the blood.
· Electromyography (EMG) – an electrical test to determine nerve or muscle damage.
· Muscle biopsy – removal of a small piece of muscle for microscopic examination.
· x-rays – a diagnostic test which uses invisible electromagnetic energy beams to produce images of internal tissues, bones, and organs onto film.
· Magnetic resonance imaging (MRI) – a diagnostic procedure that uses a combination of large magnets, radiofrequencies, and a computer to produce detailed images of organs and structures within the body.
Treatment
Juvenile dermatomyositis cannot be cured. However, with supportive therapy and a multidisciplinary team approach to treatment, remission of the disease may be achievable in time. Treatment may include:
· medications such as glucocorticosteroids and methotrexate (to treat the inflammatory process) and hydroxychloroquine (to help treat the skin disease of dermatomyositis)
· physical and occupational therapy (to improve muscle function and strength)
· liberal use of sunscreens (to prevent further irritation or damage to the skin)
· nutritional support (to ensure an adequate diet)
Polyarteritis Nodosa
Definition
Polyarteritis nodosa is a rare autoimmune disease (immune system attacking its own body) characterized by spontaneous inflammation of the arteries (arteritis) of the body. Because arteries are involved, the disease can affect any organ of the body. The most common areas of involvement include the muscles, joints, intestines (bowels), nerves, kidneys, and skin. Poor function or pain in any of these organs can be a symptom. Poor blood supply to the bowels can cause abdominal pain, local bowel death, and bleeding. Fatigue, weight loss, and fever are common.
Polyarteritis nodosa is most common in middle age persons. Its cause is unknown, but it has been reported after Hepatitis B infection. Polyarteritis is not felt to be an inherited condition.
Introduction
In 1866, Kussmaul and Meier first described polyarteritis nodosa (PAN), a disease of small-sized and medium-sized arteries. Although any organ can be affected, PAN most commonly involves the skin, joints, peripheral nerves, gastrointestinal (GI) tract, and kidney. Disease manifestations are diverse and complex, ranging from a benign cutaneous form to a severe disseminated form. PAN is also observed as a complication of hepatitis B (HB) and hepatitis C (HC) infection.
In the literature, PAN has often been described along with microscopic polyangiitis (MPA). The Chapel Hill consensus conference defines these 2 different disorders with differing prognoses. According to the new nomenclature, PAN causes necrotizing inflammation of medium-sized or small-sized arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Conversely, MPA causes necrotizing vasculitis with few or no immune deposits affecting small vessels (capillaries, venules, arterioles). Necrotizing arteritis involving small-sized and medium-sized arteries may be present. Necrotizing glomerulonephritis and pulmonary capillaritis often occur in MPA.
Frequency
United States
PAN is a rare condition. Incidence in the general population is 0.7 per 100,000 people, and prevalence is 6.3 per 100,000.
International
PAN is a rare condition worldwide. In the United Kingdom, annual incidence of MPA is 3.6 per million people; incidence of PAN is 2.4 per million people. In Kuwait, combined annual incidence is 45 per million people.
Mortality/Morbidity
The mortality rate can be as high as 20-30%, despite aggressive therapy.
Race
No racial predilection exists.
Sex
A slightly higher incidence is found in males. Male-to-female ratio is 1.6:1 to 2:1.
Age
PAN has been described in all age groups.
· PAN is rarely found in children. Mean age of 9.05 +/- 3.57 years.
· PAN predominantly affects individuals aged 40-60 years.
Causes
· HBV
· HC virus
· HIV
· Cytomegalovirus
· Parvovirus B19
· Human T-lymphotrophic virus
· Streptococcus species infection
Pathogenesis
Immunopathogenetic mechanisms leading to vascular injury are incompletely understood and are probably heterogeneous. Some of the possible mechanisms follow.
Immune complexes
The origin of the immune complex is unknown. Various infections and superantigens have been implicated as causes of persistent antigenemia that subsequently leads to immune complex formation. The resultant immune complex activates the complement cascade, which activates and attracts neutrophils.
Antineutrophil cytoplasmic antibodies
Antineutrophil cytoplasmic antibodies (ANCA) appear to play a significant role in causing endothelial damage. However, ANCA are not present in all patients with PAN. In vitro, ANCA can activate neutrophils to adhere more to endothelial cells and to stimulate neutrophils that have been primed with tumor necrosis factor (TNF) to lyse-cultured endothelial cells. Two types of ANCA exist. Perinuclear ANCA (P-ANCA; antimyeloperoxidase) are often found in patients with microscopic polyarteritis or MPA. Cytoplasmic ANCA (C-ANCA; antiproteinase- 3) have also been described in patients with PAN.
Adhesion molecules
Cytokine-induced expression of adhesion molecules (leukocyte function-associated antigen-1 [LFA-1]), intercellular adhesion molecule-1 [ICAM-1], and endothelial-leukocyte adhesion molecule-1 [ELAM-1]) allows close contact between polymorphonuclear (PMN) and endothelial cells. The coexistence of cytokine-primed neutrophils, endothelium, and circulating ANCA permit ANCA to initiate a cascade of events leading to vasculitis.
Antiendothelial cell antibodies
Antiendothelial cell antibodies (AECA) are directed against surface endothelial antigens and have been proposed as a pathogenic factor in vasculitis. AECA are not disease specific; they are found both in autoimmune vasculitis and systemic vasculitis. AECA can cooperate in the endothelial injury by increasing endothelial adherence of granulocytes or monocytes through their Fc-gamma–receptor–mediated binding.
Cytokines
Cytokines are potentially involved in the pathogenesis of vasculitis. A marked increase in alpha interferon and interleukin (IL)-2 and a moderate increase in TNF- and IL-1- have been reported in persons with PAN. IL-1 and TNF- enhance endothelial damage by activating endothelial and PMN cells. Serum basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are angiogenic cytokines that have been shown to be elevated in patients with PAN.
Pathology
PAN causes transmural necrotizing inflammation of small-sized or medium-sized muscular arteries. Kidneys, heart, liver, GI tract, pancreas, testes, skeletal muscular system, central nervous system (CNS), and skin are involved. The lesions are segmental and may involve partial circumference only. The associated inflammation process may cause weakening of the arterial wall, aneurysmal dilatation, and localized rupture. This is perceived clinically as a nodule, which is also demonstrated by radiology. The area supplied by the involved vessels may slow impaired perfusion, leading to ulceration, infarct, or ischemic atrophy. Occasionally, the lesion may be excessively microscopic and produce no gross changes.
Diagnosis
The diagnosis is supported by tests that indicate inflammation including elevation of blood sedimentation rate and C-reactive protein. The white blood cell count and platelet count can be elevated, while the red blood count is decreased (anemia). The Hepatitis B virus tests (antigen and antibody) can be found in 10-20% of patients. Urine testing can show protein and red blood cells in the urine. In patients with nerves affected, nerve function tests are abnormal.
The diagnosis of polyarteritis nodosa is confirmed by a biopsy of involved tissue which reveals the inflamed blood vessels (vasculitis). Examples of tissues that are sometimes biopsied include nerves, muscle, kidneys, and bowel. The vasculitis of the bowel and kidneys can often be detected with an angiogram (x-ray testing while contrast “dye” is infused into the blood vessels).
The American College of Rheumatology established criteria for the classification of polyarteritis nodosa in 1990. For classification purposes, a patient is said to have polyarteritis nodosa if at least 3 of the following 10 criteria are present:
1. Weight loss greater than/equal to
2. Livedo reticularis (a mottled purplish skin discoloration over
the extremities or torso).
3. Testicular pain or tenderness. (occasionally, a site biopsied
for diagnosis).
4. Muscle pain, weakness, or leg tenderness.
5. Nerve disease (either single or multiple).
6. Diastolic blood pressure greater than 90mmHg (high blood pressure).
7. Elevated kidney blood tests (BUN greater than 40 mg/dl or
creatinine greater than 1.5 mg/dl).
8. Hepatitis B virus tests positive (for surface antigen or antibody).
9. Arteriogram (angiogram) showing the arteries that are dilated (aneurysms) or constricted by the blood vessel inflammation.
10. Biopsy of tissue showing the arteritis (typically inflamed arteries).
Nonspecific signs and symptoms are the hallmarks of polyarteritis nodosa (PAN). In 1990, the American College of Rheumatology (ACR) developed the criteria for the classification of PAN. The primary purpose of these guidelines was to allow for a more homogeneous patient population in research studies and treatment protocols.
Note: For classification purposes, PAN is diagnosed in a patient PAN if at least 3 of these 10 criteria are present. The presence of any 3 or more criteria yields a sensitivity of 82.2% and a specificity of 86.6%.
Consider PAN whenever the following symptoms present independently or in combination:
· General
· Fever
· Malaise
· Weight loss
· Anorexia
· Organ specific
Central nervous: Peripheral (mononeuritis multiplex, cranial nerve palsy) and central (motor deficits, strokes, brain hemorrhages) symptoms are observed.
Skin: Vascular purpura, subcutaneous nodules, livedo reticularis, distal gangrene, and ischemic atrophy are symptoms of PAN.
Musculoskeletal: One half of patients with PAN have myalgia. The arthritis is an asymmetric, episodic, nondeforming polyarthritis, which predominantly affects the larger joints, especially in the lower extremities, early in the course of disease in 20% of patients. Later in the course of illness, a larger percentage of patients have a more involved polyarticular distribution.
Renal: Rapid renal failure as a consequence of multiple infarcts, renin dependent hypertension, nephritic syndrome, nephrotic syndrome, rapidly progressive glomerulonephritis (RPGN), and ureteral stenosis is a symptom of PAN. PAN seldom leads to renal failure. RPGN is more characteristic of MPA.
Gastrointestinal: GI symptoms of PAN are abdominal pain, digestive tract bleeding, bowel perforation, and malabsorption.
Cardiac and pulmonary: Cardiomegaly, pericarditis, coronary artery involvement leading to ischemia and infarction, pneumonopathy and infiltrates, and pleural effusions (PEs) are symptoms of PAN.
Reproductive: Orchitis is a symptom in males.
Ocular: Amblyopia and eye pain are symptoms of PAN.
Limited forms of PAN
Skin: Cutaneous PAN manifestations are well known. Lower extremities are involved most frequently with palpable purpura, painful nodes surrounded by livedo reticularis, and necrotic lesions. Histologic lesions are identical to those observed in persons with systemic PAN. The outcome is favorable, relapses are frequent, and systemic PAN may develop.
Other organs: Organs such as appendix, gallbladder, uterus, testes, and peripheral nervous system can be involved without systemic involvement.
Laboratory Studies
Nonspecific inflammatory changes commonly observed in individuals with polyarteritis nodosa (PAN)
CBC may reveal normochromic anemia, polymorphonuclear leucocytosis, and thrombocytosis. Although it occurs in PAN, eosinophilia greater than 1.5 X 109/L commonly accompanies pulmonary involvement in persons with MPA (14%), predominantly in Churg-Strauss syndrome (allergic angiitis and granulomatosis).
Erythrocyte sedimentation rate (ESR) is elevated (usually >60 mm/h) and follows disease activity.
C-reactive protein is increased.
Antivisceral epithelial cell antibody may be present.
· Serum albumin (a reverse acute-phase reactant) may be decreased.
· Creatinine
· Urinalysis
· 24-hour urine collection: Increased protein loss is more characteristic of MPA than classic PAN.
· Creatine phosphokinase
· Cryoglobulins: These are associated with rheumatoid factor and hypocomplementemia.
· Serum complement: C3 and/or C4 levels are depressed in 25% of patients with PAN but may be elevated or within reference range in patients with MPA.
· Rheumatoid factor: Rheumatoid factor is usually present in low titer in individuals with PAN but may occur in 40-50% of patients with MPA.
· Antiphospholipid antibodies
· Antiglomerular basement antibodies (differential for Goodpasture syndrome)
· Angiotensin converting enzyme (differential for sarcoidosis)
· Low titer circulating immune complexes
· Increased platelet activating factor levels
· Increased factor VIII-related antigen (von Willebrand factor antigen)
Imaging Studies
· Chest radiography reveals interstitial infiltrates in patients with hypoxemia and respiratory distress.
· Sinus radiography may be obtained to exclude a granulomatous vasculitis such as Wegener granulomatosis.
· Consider arteriography when involved organs are not accessible. Angiographic abnormalities include the following:
Long segments of smooth arterial stenosis alternating with areas of normal or dilated arteries (fusiform or saccular aneurysm)
Smooth tapered occlusions
Thrombosis
Absence or nondominance of arterial plaques, irregularities, and ulcerations
Multiple intraparenchymal microaneurysms: These are considered pathognomonic. In patients with clinical PAN, 60% have aneurysms, and, in most cases, more than 10 aneurysms per patient are present.
· Doppler studies reveal arterial narrowing and dilatations.
Other Tests
· Electromyography and/or nerve conduction studies
Procedures
· A single biopsy procedure followed by angiography is calculated to have 85% sensitivity and 96% specificity.
Histologic Findings
Histopathologic examination demonstrates transmural inflammation of the arterial wall with a heavy infiltrate of polymorphs, eosinophils, and mononuclear cells. This inflammation frequently is accompanied by fibrinoid necrosis of the inner half of the vessel wall. Thrombus can be observed (see Images 2-4). The lesion can be segmental with normal arterial walls between diseased areas with a predilection for bifurcations. The acute inflammatory infiltrate disappears at a later stage and is replaced by fibrous thickening of the vessel wall. Later, only marked fibrotic thickening is noted. All stages of activity in different vessels or within the same vessel at a particular time are characteristic findings in PAN.
Treatment
Medical Care
Steroids and immunosuppressive medications form the backbone of therapy. Choice of agents depends on severity of the disease. Severity and outcome of polyarteritis nodosa (PAN) has been demonstrated to be dependent on the following 5 factors, known as the 5-factor score (FFS):
1. Proteinuria greater than1 g/d
2. Renal insufficiency (creatinine >140 µmol/L)
3. Cardiomyopathy
4. GI manifestations
5. CNS involvement
Although the idea that treatment should be chosen as a function of such criteria has not been demonstrated, these criteria probably should be considered in the therapeutic strategy. Patients without poor prognostic factors can be treated with prednisone alone. Cyclophosphamide can be administered as a second-line medication in the presence of persistent disease activity or relapse despite steroid therapy.
Steroids: Wheo bad prognostic factors are present, prednisone can be administered as a single agent. As the patient’s clinical status improves and the ESR returns to normal (usually within 1 mo), tapering of the prednisone dosage can begin. The schedule for tapering should be progressive. In the absence of relapses, steroids can be stopped after 9-12 months. For severe systemic disease, starting “pulse” methylprednisolone as 30 mg/kg (not to exceed 1 g ) IV over 60 minutes repeated in 24-hour intervals for 1-3 days is prudent.
These agents elicit anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body’s immune response to diverse stimuli.
Prednisone (Deltasone, Orasone, Sterapred)
Most commonly prescribed oral corticosteroid. Metabolized in liver to its active form, prednisolone. Relative to hydrocortisone, prednisone is approximately 4 times as potent as a glucocorticoid. Glucocorticoids are naturally occurring hormones that prevent or suppress inflammation and immune responses when administered at pharmacologic doses (decreased lymphocyte volume and activity, decreased PMN migration, decrease or reversal of capillary permeability). High doses, especially over periods >2-3 wk, suppress adrenal function.
PediatricDosing
1 mg/kg PO every am or in divided doses; preferable to start with high dose and taper as clinical condition improves and as ESR decreases
Methylprednisolone (Solumedrol)
Initial management of PAN should include high doses of corticosteroids. It has been used widely as first-line agent in patients with severe PAN. Half-life is approximately 2 h, which contributes to decreased short-term and long-term adverse effects and complications. There may be used at weekly or every-other-week intervals to facilitate rapid taper of daily oral steroids.
Dosing
15-30 mg/kg IV over 60 min, not to exceed 1000 mg, repeated at 24-h intervals for 1-3 d
Cyclophosphamide (Cytoxan, Neosar)
Cell cycle phase nonspecific antineoplastic agent and immunosuppressant. Chemically is related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA and possible protein modification, which may interfere with growth of normal and neoplastic cells.
When cyclophosphamide is indicated for a FFS>0, consider pulse therapy over daily PO therapy because of rapid clinical response. Even though it increases acute adverse effects, fearsome long-term complications (eg, bladder cancer) are lesser issues. Low incidence of bladder cancer in pulse therapy has been linked to lower cumulative dose. Adjust dose and frequency to disease severity, renal function, hematologic profile, and response to previous therapies.
Dosing
1-2 mg/kg/d PO, not to exceed 150 mg
Can be administered as long as absolute lymphocytes are at least 300-500 and absolute neutrophil count is at least 1500-2000
IV pulse administration:
Initial doses: 0.5-
Protocol of French Cooperative study group for PAN: Pulse dose: 0.6 g/m2 every mo for 1 y
Azathioprine (Imuran)
Oral and parenteral immunosuppressive agent is chemical analog of endogenous purines (adenine, guanine, hypoxanthine) and is metabolized to 6-mercatopurine. Antagonizes purine metabolism and may inhibit synthesis of proteins, RNA, and DNA.
PediatricDosing
1-3 mg/kg/d PO
· Cyclophosphamide is indicated for patients with poor prognostic factors
(FFS >0).
Daily oral dosing remains the established therapy.
Intravenous route may provide a more rapid clinical response with less toxicity than the oral route. To date, studies of comparative efficacy have included too few patients to be conclusive in favor of either route.
Intravenous pulse cyclophosphamide increasingly is being used to treat systemic vasculitis. Use intense hydration and mesna to prevent hemorrhagic cystitis during both oral and pulse cyclophosphamide.
Treatment duration with corticosteroids and cyclophosphamide usually does not exceed 1 year. Patients with immune dysregulation and autoimmunity often benefit from immunosuppression.
· Plasma exchange is not recommended as a first-line therapy for individuals with PAN without HBV infection; however, plasma exchange is useful as a second-line treatment in PAN refractory to conventional therapy.
Therapeutic plasma exchange
The HF400 & HF440 provide a rising by flush (Dr Branger’s method)
Double Filtration Plamapheresis
· Considering the high frequency of renal involvement, consider all patients with MPA to have poor prognostic factors, and treat such patients with high-dose steroids and cyclophosphamide.
Cyclophosphamide pulse has been demonstrated as superior to azathioprine in inducing remission. Once remission is induced, azathioprine can be used for maintenance.
Plasma exchanges are useful for patients with renal failure (creatinine >500 µmol/L), patients dependent on dialysis, or patients with lung hemorrhage.
In patients with symptoms refractory to these treatments, intravenous immunoglobulin can be considered.
· PAN with HB infection: In individuals with chronic HB infection, corticosteroids and immunosuppressive agents had deleterious effects and were demonstrated to enhance viral replication. Thus, combination therapy involving antiviral drugs and steroids is used in patients with HB infection.
Corticosteroids are used initially to rapidly control the most severe life-threatening manifestations of PAN, which are common during the first weeks of the disease; then, plasma exchanges are used to control the course of PAN.
Antiviral drugs used include vidarabine or interferon alpha-2b. In most patients, antiviral treatment can be stopped after 3 months.
Surgical Care
· Surgery is necessary during diagnostic evaluation to perform biopsies.
· Surgery is required therapeutically in patients with peripheral gangrene and acute abdomen.
Consultations
· Consult with a nephrologist in the presence of renal involvement.
· Consult with a surgeon for severe GI bleeding, bowel perforation, and vascular catastrophes.
· Consult with a cardiologist for cardiac involvement in the form of atrioventricular block, pericarditis, and myocarditis.
· Consult with a rheumatologist for short-term and long-term follow-up care.
Diet
No restriction is necessary except as indicated for patients with hypertension, cardiac failure, and renal failure. Low sodium intake is recommended during courses of high-dose steroids.
Activity
Activity is unrestricted, except in patients with joint and cardiac involvement, for whom appropriate activity restrictions apply.
Antibiotics
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.
Sulfamethoxazole and trimethoprim (Bactrim, Septra)
DOC is used for prophylaxis of Pneumocystis carinii. It inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.
Pediatric Dosing
Dose based on trimethoprim component; 5-10 mg/kg/d or 150 mg/m2/d PO divided bid administered 3 times/wk, not to exceed 320 mg/d trimethoprim
Follow-up
Further Inpatient Care
· Because of maximal immunosuppression at the beginning of treatment, prevention of opportunistic infections, such as P carinii infection, may be necessary with oral trimethoprim-sulfamethoxazole.
· ACE inhibitors can be used to control hypertension.
· Unexplained abdominal pain may indicate silent bowel infarction.
Further Outpatient Care
· Look for evidence of relapse by both physical examination and laboratory means.
· Look for adverse effects of drugs.
· Advise patients to avoid exposure to contagious disease.
· Prevent opportunistic infections that may emerge during therapy.
Inpatient & Outpatient Medications
· Continue or taper the steroids and immunosuppressive drugs according to the response.
· Consider therapy to inhibit platelet aggregation.
Transfer
· Transfer to a tertiary care center for patients who require renal replacement therapy.
Transfer to an emergency department if patients present with any of the following:
§ Respiratory distress
§ Acute abdomen
§ Disseminated infections
§ Acute CNS insults such as stroke or intracranial hemorrhages
Deterrence/Prevention
· Avoid abrupt cessation of drugs, especially steroids.
· Avoid exposure to contagious diseases.
Complications
ü Multiple mononeuropathies
ü Strokes
ü Brain hemorrhages
Skin
ü Ischemia
ü Gangrene
ü Ulcers
Kidney
ü Renal failure
ü Hypertension
ü Renal or perirenal hematomas
ü Ureteral stenosis
Gastrointestinal
ü Digestive tract bleeding
ü Bowel perforation
ü Malabsorption
ü Pancreatitis
ü Appendicitis
ü Cholecystitis
ü Liver infarction and hematomas
Cardiac and pulmonary
ü CVF
ü Atrioventricular block
ü Hypertension
ü RF and pneumonopathy
Miscellaneous
ü Retinal detachment
ü Orchitis
Prognosis
· Prognosis for individuals with polyarteritis nodosa (PAN) varies, and the mortality rate can be as high as 20-30% despite aggressive therapy.
· The most frequent causes of death in individuals with PAN are GI hemorrhage and perforation, CVF, and infection.
· Even with histologic evidence of effective control of inflammation, occlusion can result from fibrosis.
· The 1-year survival rate for individuals with PAN who tested positively for HB surface antigen was 70%; the rate for individuals with PAN without infection was 85.
Differential diagnosis of polyarteritis nodosa (PAN) and microscopic polyangiitis (MPA)
Histopathology of kidney of individual with polyarteritis nodosa demonstrating transmural inflammation of the arterial wall with a heavy infiltrate of polymorphs, eosinophils, and mononuclear cells and fibrinoid necrosis of inner half of vessel wall.
Histopathology of lung of individual with polyarteritis nodosa demonstrating arterial wall with a heavy infiltrate of polymorphs, eosinophils and mononuclear cells and fibrinoid necrosis of vessel wall.
Histopathology of kidney of individual with polyarteritis nodosa demonstrating transmural inflammation of the arterial wall with a heavy infiltrate of polymorphs, eosinophils, and mononuclear cells: fibrinoid necrosis of inner half of vessel wall; and thrombus.
Infantile polyarteritis nodosa. Bilateral axillary aneurysms.
Infantile polyarteritis nodosa. Multiple aneurysms on arteriogram and autopsy specimen.
Infantile polyarteritis nodosa. Gangrene of the forearm in a 3-month-old infant.
Pediatric Scleroderma
Scleroderma means hard (sclero) skin (derma). It is a rare autoimmune disease in which normal tissues are replaced with dense, thick scar tissue. Scleroderma can affect the skin or other organ systems. In children, scleroderma most frequently affects only the skin. The term “scleroderma” was applied by G. Gintrac (1847). Scleroderma is characterized by multicentric structural and morphofunctional fibrotic pathological processes with severe chronic course and irreversible foci seal skin, in which there is progressive fibrosis with obliterative arteriolar lesions.
There are two types of scleroderma:
· Localized scleroderma — most common in children. This form of scleroderma does not change into the generalized forms of scleroderma.
· Systemic scleroderma (sclerosis) — rare in children.
No less important factors in the pathogenesis of scleroderma are microcirculatory disorders caused by the lesions of the vascular wall and intravascular changes, plasma and cellular elements of blood.
Etiology and pathogenesis.
The etiology is unknown. The provoked factors are stressors, acute and chronic infectious disease, physical stimuli (cooling, insulation, vibration, radiation), chemicals (vaccines, serums).
Pathogenesis of scleroderma is complex, integrated, with a probability of genetic conditions, but not yet established precisely defined genotypes of HLA. Scleroderma is a multifactorial disease with polygenic inheritance. Its pathogenesis belongs to the functional disorder of fibroblasts and other collagen cells. In the development of dermatosis the particular importance have autoimmune reactions to collagen in connection with a high level of antigenic “collagen” stimulation.
Pathophysiology
Systemic sclerosis is a systemic disease that affects many organ systems. It is most obvious in the skin; however, the GI tract; the respiratory, renal, cardiovascular, and genitourinary systems; and numerous vascular structures are frequently involved. The symptoms result from inflammation and progressive tissue fibrosis and occlusion of the microvasculature by excessive production and deposition of types I and III collagens. The levels of other macromolecules (eg, glycosaminoglycans, tenascin, fibronectin) found in the connective tissue are also increased.
The vascular alterations show a predilection for the small arteries and arterioles. Vascular dysfunction is one of the earliest alterations of systemic sclerosis and may represent the initiating event in its pathogenesis. Severe alterations in small blood vessels of skin and internal organs, including fibrosis and perivascular cellular infiltration with activated T cells, are almost always present in systemic sclerosis.
Localized scleroderma
Localized scleroderma is the most common type of scleroderma in children and it usually affects the skin, only occasionally spreading to the underlying muscles.
There are two main types of localized scleroderma: linear scleroderma and morphea.
When the areas of affected skin appear in a band, it is called linear scleroderma. Linear scleroderma most often occurs on an arm or leg and occasionally on the face or neck. It can result in cosmetic problems, growth abnormalities of the affected area and if it crosses joint lines, limitation of joint motion and contractures (inability to straighten the joint).
Skin changes that appear in patches — either as a single patch or in a group — are called morphea. Morphea appears waxy and usually has an ivory or white color. In both linear scleroderma and morphea, the skin may change to appear white with purple borders.
Limited (patch) scleroderma
Several pockets of patchy scleroderma with marked dermatosclerosis; on the edge of some of these there is fringe pink-brownish color.
Patch scleroderma with dermatosclerosis
Often a sign of scleroderma is the intense staining of the skin, limited or widespread, with areas of hypo-or depigmentation (“salt and pepper”).
Linear (ribbon-like) scleroderma occurs mainly in children. The process also begins with erythematous patches with a gradual transition to the stage of edema, compression and atrophy. The process is usually represented by one lesion, spreading linearly from the scalp on the forehead, back of the nose, as a scar from a sword blow (sclerodermia en coup de Sabre).
Atrophodermia Pasini – Perini, combined with linear form in the lumbar region.
Hemisclerodermia – unilateral skin lesions along the vascular-nerve bundle.
SYSTEMIC SCLEROSIS
In addition to skin changes, a child with systemic sclerosis may also develop problems with internal organs (such as the kidneys, heart, lungs and gastrointestinal tract). Children with systemic sclerosis have more widespread skin changes that can result in limited joint movement.
Raynaud’s phenomenon (white, blue and red color changes of the fingers and/or toes upon exposure to cold or stress) is present early in a child with systemic sclerosis, as well as fatigue, joint pain, difficulty swallowing, abdominal pain, heartburn, diarrhea and shortness of breath.
Children with systemic sclerosis should be checked often for high blood pressure, as well as lung, kidney, gastrointestinal and heart problems, to detect and treat potential internal organ involvement.
The skin changes of systemic sclerosis may include:
· Loss of the skin’s ability to stretch
· Light or dark discoloration of the skin
· Thinning of the skin
· Curling of the fingers (contractures)
· Decreased hand function because of skin tightening on fingers and hand
The skin changes of systemic sclerosis Raynaud’s phenomenon
Initially, the skin of the hands and feet appears swollen. Over time, the skin tightens and hardens and may appear to have ridges, depressed areas, or small pits that are seen mostly at the fingertips. Since there is not much pain, it is common for scleroderma to be present for quite some time before a parent or child becomes concerned.
Other signs and symptoms of systemic sclerosis may include:
· Joint inflammation with stiffness and pain
· Raynaud’s phenomenon — abnormal sensitivity to cold, which is usually seen in the hands. Signs include color changes in the hands (white, blue, red), tingling, discomfort, and decreased sensation.
· Sores (ulcers), mostly on the finger tips
· Digestive problems (heartburn, trouble swallowing, diarrhea, stomach cramps)
· Itching
· Fatigue (easily becoming tired)
· Muscle weakness
· Lesions of internal organs
Raynaud’s phenomenon
Vascular disorders on toes
Muscular disorders
Diffuse pneumosclerosis in patient with systemic scleroderma
Diagnostics
The American College of Rheumatology (ACR) criteria for the classification of systemic sclerosis require one major and two minor criteria, as follows:
· Major criteria: Proximal scleroderma is characterized by symmetric thickening, tightening, and induration of the skin of the fingers and the skin that is proximal to the metacarpophalangeal or metatarsophalangeal joints. These changes may affect the entire extremity, face, neck, and trunk (thorax and abdomen).
· Minor criteria:
ü Sclerodactyly is characterized by thickening, induration, and tightening of the skin, limited to only the fingers.
ü Digital pitting scars or a loss of substance from the finger pad: As a result of ischemia, depressed areas of the fingertips or a loss of digital pad tissue occurs.
ü Basilar pulmonary fibrosis includes a bilateral reticular pattern of linear or lineonodular densities most pronounced in basilar areas of the lungs on standard chest roentgenography. These densities may assume the appearance of diffuse mottling or a honeycomb lung and are not attributable to primary lung disease.
Tightening of the skin in a face with the characteristic beaklike facies and paucity of wrinkles.
Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair.
A radiograph of the distal digits demonstrates calcinosis and distal phalanx reabsorption (acral osteolysis).
Lung biopsy demonstrates severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of a pulmonary arteriole compatible with pulmonary hypertension.
The diagnosis of scleroderma is often made by a rheumatologist or dermatologist and is based on a combination of factors:
· Presence of symptoms and physical signs
· Characteristic skin changes (including location, size, shape, color)
· Results of a complete medical history and physical exam
Other tests may be used to confirm the diagnosis or to determine the severity of the disease, such as:
· Skin biopsy of affected skin, in which a small tissue sample is removed for evaluation under a microscope
· Blood tests in which autoimmune proteins and kidney function are measured in a laboratory
Additional tests for systemic sclerosis
· X-rays which can show changes in the skin, bones and internal organs such as the lungs and intestines
· Tests to evaluate the swallowing function of the esophagus (tube leading from the mouth to the stomach)
· Pulmonary function test (breathing test) to make sure the lungs are working properly
· Echocardiography (ultrasound of the heart) to look at the heart function
No single test or X-ray will prove the diagnosis of scleroderma, and not all children will need all these tests.
Treatment
There is no cure for scleroderma, but with proper diagnosis, it can be treated and controlled.
Treatment of children begins with the use of vitamins A, E, C, contributing to the normalization of the connective tissue. In connection with the suppression of hyaluronidase activity enzymes are using – lidasa, ronidaza and vitreous body. In all forms of scleroderma antibiotics, mainly penicillin, is prescribed for up to 5000000 – 6000000 units per course according to age and body weight of the child.
Intramuscular injections of crystalline trypsin or chymotrypsin are used for 5-10 mg in 2 ml of isotonic sodium chloride solution after 1 day, at the rate of 10-15 injections. Proteolytic enzymes are also introduced with the help of ultrasound or electrophoresis (alone or in combination with parenteral administration).
Treatment is specialized for each child, based on his or her overall health, medical history, type of scleroderma, severity, and presence of other symptoms.
For systemic sclerosis, a team of specialists, including various physicians (dependent on involvement of internal organs), nurses, physical and occupational therapists, psychologists and other health care professionals, provide comprehensive care for your child in a compassionate setting.
The team focuses on medically controlling the disease while decreasing the effects of scleroderma on your child’s physical growth and emotional development. The location of the skin rash, and how deep it is, will impact how the child feels the skin rash will affect his or her appearance (cosmetic impact).
Scleroderma management may include family counseling regarding cosmetic, financial, emotional, social or disability issues.
Medication for systemic form
The goal of medication is to control disease activity. Several different medications to treat the effects of scleroderma are currently being investigated.
Steroids, such as cortisone or prednisone, may be used to decrease inflammation in muscles, joints or rarely in the skin itself. Steroids can also be helpful in treating fatigue, or occasionally to treat the early stages of internal organ inflammation. Generally, steroids do not work in the later stages of systemic sclerosis.
Methotrexate is often used to treat scleroderma, especially the linear type of scleroderma.
Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen are sometimes used for children who have arthritis to decrease joint inflammation.
Medications that dilate blood vessels and improve blood flow are often used to treat Raynaud’s phenomena.
Skin protection
Protecting the skin will help maximize blood flow to the skin, hands and feet, especially for children who have Raynaud’s phenomenon. Here are some tips:
· Avoid injury to the affected areas, especially the tips of the fingers and the toes.
· Protect the child’s hands and feet from cold. Keep rooms at a warm temperature and have the child wear an extra layer of clothing in the winter, as well as a hat (ear muffs), gloves and warm socks. Wool is warmer than cotton or synthetic fabrics, and several layers of thin clothing are better than one heavy or thick layer of clothing.
· Avoid cold medications that include pseudoephedrine.
· Protect the child from excess sun exposure.
· Avoid using astringents, body or facial scrubs or harsh detergents on the skin.
· Use lotions as prescribed by the doctor to keep the child’s skin soft.
Physical therapy
Basic stretching and guided exercise programs with physical and occupational therapists help your child maintain flexibility, joint range of motion, muscle strength and blood flow to the affected areas. Therapy will also help prevent joint contractures (or bends at the joints). Splints may be recommended if necessary.
Bath therapy and ozokerit applications
Diathermia
Surgery
In rare instances orthopedic hand or cosmetic surgery may become necessary to correct severe joint contractures or skin deformities or scars. Before surgery can be performed, the disease must usually be in remission (a time when the disease is not active) for several years.
Prognosis
Scleroderma is a chronic and slowly progressive disease, lasting for months or years. The outlook depends on the type of scleroderma, where and how much skin is involved and whether or not internal organs are affected.
Localized scleroderma frequently progresses in the early stages, but often does not further change after the first 3 to 4 years. It usually resolves by adulthood. In systemic sclerosis, children who have lung, heart or kidney problems have the greatest risk for complications. In linear, morphea and systemic sclerosis, joint contractures, cosmetic changes and uneven bone growth may occur.
Although scleroderma often does not go away, it can remain at the same level without getting worse for several years.
Through current research, we hope to develop a better understanding of the cause and improve treatment options
Reference:
A – Basic:
1. Pediatrics. Textbook. / O. V. Tiazhka, T. V. Pochinok, A. N. Antoshkina et al. / edited by O. Tiazhka – Vinnytsia : Nova Knyha Publishers, 2011 – 584 pp. : il.
2. ISBN 978-966-382-355-3Nelson Textbook of Pediatrics, 19th Edition Kliegman, Behrman. Published by Jenson & Stanton, 2011, 2608. ISBN: 978-080-892-420-3.
3. Illustrated Textbook of Paediatrics, 4th Edition. Published by Lissauer & Clayden, 2012, 552 p. ISBN: 978-072-343-566-2.
4. Denial Bernstein. Pediatrics for medical Students. – Second edition, 2012. – 650 p.
