Board Review Part 1
Rheumatoid Arthritis - a chronic inflammatory autoimmune disorder of unknown etiology that is characterized by symmetric, erosive synovitis and sometimes multisystem involvement. The incidence is .2 to .4/1000 per year. If left untreated many patients will develop progressive joint destruction, deformity, disability, and premature death. More common in females than males. Though the incidence in females may be decreasing ( perhaps due to increased use of estrogens/oral contraceptives. These may modify the severity of the disease - mechanism unknown).
While the exact etiology remains undetermined, attempts to identify an immunogenetic predisposition to rheumatoid arthritis have focused on examination of the HLA alleles in affected persons. Study of the major histocompatibility complex using complementary DNA (cDNA) probes has identified a shared epitope on the third hypervariable region of DR B chains. This epitope is common to virtually all patients who develop rheumatoid arthritis, although only a small fraction of those with the epitope develop the disease. It is probable, however, that susceptibility to rheumatoid arthritis is polygenic.
Defects in T cells are inextricably linked to rheumatoid arthritis. Patients with rheumatoid
arthritis who contract the acquired immunodeficiency syndrome (AIDS) and lose functioning T cells experience lifelong remissions of the arthritis. By contrast, B cells play less of a role in initiating rheumatoid arthritis.
In RA the synovium is infiltrated with mononuclear phagocytes, lymphocytes, plasma cells and PMNs. Synovial fluid changes include increased volume, varying degrees of turbidity, and decreased viscosity. WBC around 20,000 may be higher. Most lymphoid inflammatory cells are CD4+ cells. Other inflammatory mechanisms are the finding and synthesis of RF, the expansion of T cells in the synovium, immune complexes in the serum and synovial with complement activation, and the production of various cytokines.
Rheumatoid Factors are a family of immunoglobulins with antibody specificity for the Fc region of the IgG of humans and of several animals. While normally involved in immune clearance, in RA pts they play a role in The pathogenesis. They are produced by synovial cells in RA pts. RF tests usually detect IgM rheumatoid factors only. About 80% of patients with definite RA will test positive for RF’s. Some early on will be negative but may become positive within one year. Levels may fall with therapy, and remember the diseases that can give a false positive RF older age (10-25% over age 75), SBE, other CVD, sarcoid, chronic liver diseases, hypergammaglobulinemic states, chronic parasitic, bacterial infections.
Another feature of RA pathology is neovascularization. Capillaries and postcapillary venules assume the characteristics of High Endothelial Venules (HEV's) and express adhesion molecules such as ELAM-1, ICAM-1, and VCAM-1. These enhance the ability of lymphocytes to bind to vessels and migrate into the sites of inflammatory activity.
The typical extra-articular pathologic lesions that occur in RA - the skin, sclera, pleura, pericardium resemble chronic granulomatous changes with areas of necrosis or focal vasculitis. Rheumatoid nodules are associated with more severe disease. If in a patient with pneumoniosis - Caplan’s Syndrome. Nodules may be made worse with methotrexate therapy.
Pregnancy relieves the symptoms of rheumatoid arthritis through a poorly clarified mechanism of immunosuppression. Although the risk of developing rheumatoid arthritis is lowered in women who have been pregnant, it has not been established that the use of oral contraceptives confers protection against the disease
CLINICAL FEATURES
In 1987 the ACR revised the criteria for a diagnosis of RA. 4 of the following seven are needed.
1. AM stiffness greater than or equal to one hour
2. 3 joint areas with soft tissue swelling/fluid simultaneously
3. At least one are swollen in the wrist, MCP, or PIP
4. Simultaneous bilateral involvement. MCP.PIP, MTP don't need absolute symmetry
5. Sub Q nodules along boney prominences,extensor surfaces,juxt-articular areas
6. Positive RF by a method with less than 5% false positive
7. x-ray criteria - erosions, juta-articular osteopenia
1. Deforming/erosive arthritis. common joints involved - wrists MCP, PIP (spares the DIP), elbow, hip, knee, ankle, shoulders. C-spine - A common site. There is a direct relationship between Nodular erosive disease and C-spine involvement. MRI appears to be the test of choice for evaluation of the spine/cord relationship. flexion/extensions to screen.
2. Pleuropulmonary - Pulmonary manifestations are associated with systemic rheumatoid disease; the most common form of lung involvement is pleurisy with effusions. Characteristically have a low glucose exudative effusion (less than 30 mg/dl), The condition characterized by the presence of rheumatoid nodules in both lungs in association with pulmonary fibrosis, which was originally described in coal miners, is termed Caplan’s syndrome. Interstitial lung disease may also occur
3.Cardiac - symptomatic cardiac involvement is rare. Pericardial - 50% by echo have some evidence of pericardial involvement. most asymptomatic. Myocardial/endocardial, coronary vasculitis, endocardial - nonspecific valvulitis in 20%. Rheumatoid nodules in the valves and the conduction system affect heart function. .In some instances, amyloidosis can be the cause of arrhythmia’s.
4. Neurologic - Entrapment syndromes - CTS, TTS, vasculitis
5. Skin - vasculitic infarcts rheumatoid nodules. which is often found in patients who
have progressive seropositive disease [see Figure 4]. Nodules are usually subcutaneous and
often are found in areas exposed to pressure. They are also found in viscera, such as the heart, lungs, and intestinal tract, and in the dura. Rheumatoid nodules are nontender, firm
6. Eyes - The most frequent ocular manifestations - the sicca syndrome or as part of Sjögren’s
syndrome. Symptoms of the sicca syndrome include sensations of grittiness, an
accumulation of dried mucoid material, and decreased tear formation, which can be
demonstrated by decreased wetting of a filter paper strip in a Schirmer test. Filamentous
keratitis may be demonstrated by slit-lamp examination and abnormal rose bengal staining of
the corneal surface. Additional features of Sjögren’s syndrome are dryness of the nose,
mouth, rectum, and vagina and enlargement of lacrimal and salivary gland
7. Heme - The most common abnormality is anemia of chronic disease and /or blood loss. Patients with severe arthritis usually seropositive, may develop Felty’s syndrome– rheumatoid arthritis with splenomegaly and leukopenia. Severe thrombocytopenia is uncommon. Infections, particularly in the skin, perianal region, and lungs, are frequent and are usually caused by common organisms such as staphylococci, streptococci, Hemophilus, and gram-negative bacilli. Other common findings in Felty’s syndrome include hepatomegaly, lymphadenopathy, and chronic cutaneous
ulcerations. Splenectomy is not helpful and should be avoided. Large Granular Lymphocyte Syndrome can mimic this.
6. Vasculitis- Periungal infarct - no real significance common finding. Vary in number day to day. No prognositic findings treat the disease.Systemic vasculitis - Different typically seropositive. May see cutaneous infarcts, palpable purpura,cutaneous ulcers, mononeuritis multiplex. The majority require biopsy or angiogram to confirm the diagnosis. Tx. Like other vasculitic syndromes
PROGNOSIS - Only 10 % go into a prolonged remission. Most show exacerbations and improvements. THE BEST INDICATOR OF PROGNOSIS APPEARS TO BE RF. Extra-articular manifestatons are associated with high titer RF. As a group seropositive pts have erosive disease more often. However some positives have none and some without have erosive disease.
TREATMENT - There is no known cure for RA or means of preventing it. Optimal management is seen with an early diagnosis and prompt introduction of agents that reduce the probability of irreversible joint damage. The generalist may consider more aggressive treatment after three months of rest, PT and NSAIDS. Rheumatologist tend to start earlier Studies show that patients with active, polyarticular, rheumatoid factor positive RA have a >70% probability of developing joint damage or erosions within 2 years of the onset of disease. While the ultimate goal of treating RA is to induce a complete remission, this rarely occurs.
The following baseline laboratory evaluations should be obtained - CBC, platelet count, chemistry profile, RF measurement, measurement of ESR or CRP. renal and hepatic function , initial radiographs of the hands and/or feet should be obtained since structural damage cannot be deduced by physical examination alone.
Poorer prognosis is associated with earlier age at onset , high titer of RF, elevated ESR, swelling of >20 joints, Extraarticular manifestations of RA, including rheumatoid nodules, Sjogren's syndrome, episcleritis and scleritis, interstitial lung disease, pericardial disease, systemic vasculitis, and Felty's syndrome
Medications -
Nonsteroidal antiinflammatory drugs (NSAIDs).
A. The initial D.O.C for RA is the NSAID. NSAIDs have analgesic and antiinflammatory properties but do not alter the course of the disease or prevent joint destruction. There are no significant differences in efficacy among the NSAIDs, although there are some differences in the incidence of side effects.
To reduce gastrointestinal (GI) toxicity, patients should take NSAIDs with food, rather than on an empty stomach. Patients with NSAID-induced GI intolerance or toxicity may require the concomitant use of GI-protective agents (e.g., the prostaglandin analog misoprostol). Currently, only misoprostol has been shown to reduce the frequency of NSAID-induced GI complications. Misoprostol should be considered for patients who require NSAID treatment and are elderly or have a history of peptic ulcer disease, GI bleeding, or cardiovascular disease. Sucralfate, H2 blockers, and antacids are often used to treat dyspepsia, but may not prevent ulcer formation or bleeding due to NSAIDs. Cox-2 inhibitors appear to have a significantly lower side effect profile
Older patients, patients with comorbid diseases (e.g., hypertension, diabetes, congestive heart failure, renal impairment, cirrhosis, or other states of renal hypoperfusion), and patients taking concurrent medications that reduce renal blood flow (such as diuretics) must be monitored carefully for renal insufficiency when given NSAIDs. Cox-2 inhibitors may be safer.
NSAIDs may also reversibly inhibit platelet function and prolong bleeding time. Cox-2 inhibitors may be safer. Patients with prior aspirin hypersensitivity are also at risk for developing bronchial spasms (rare), when taking NSAIDs.
DMARDS (Disease Modifying Anti-Rheumatic Drugs)- The initiation of DMARD therapy should not be delayed beyond 3 months for any patient with an established diagnosis who, in spite of adequate treatment with NSAIDs, has ongoing joint pain, significant morning stiffness or fatigue, active synovitis, or persistent elevation of the ESR or CRP level.
1. Hydroxychloroquine 200 mg bid. HCQ has the least toxicity and is the least costly to monitor. Side effects are nausea, Abd discomfort, and rash. The incidence of retinal damage for those pts taking hydroxychloroquine is extremely low, however retinal exams are still advised.
2. Methotrexate - The emerging D.O.C. is methotrexate in a single weekly dose of 7.5 mg to 10 mg. The dosage may be increased up to 25 mg each week. One advantage to MTX is it's fast acting - often improvement of both systemic and articular symptoms within one month.
The most serious toxicities of MTX include - hepatic fibrosis (rare) and cirrhosis (rare), pneumonitis (uncommon), and myelosuppression, also stomatitis, GI upset and worsening of Rheumatoid nodules. Side effects can be minimized with the concurrent administration of folic acid or folinic acid in small dosages. Folic acid at a dosage of 1 mg per day or 7 mg once a week is less expensive than folinic acid. Neither low-dose folate (1 mg per day) nor folinic acid (<=5 mg per week) interferes with the beneficial effect of MTX. ....... In patients with suspected liver disease, a pretreatment liver biopsy should be obtained. Prevention also includes advising the patient against alcohol consumption while taking MTX. .............Risk factors for myelosuppression include the use of antifolate agents such as trimethoprim, the presence of folate deficiency, and renal insufficiency...The baseline evaluation consists of a CBC with differential cell count. Monitoring consists of a CBC and platelet count performed every 4-8 weeks. Routine monitoring of renal function every 4-8 weeks is also recommended.
Male patients should wait a minimum of 3 months after discontinuation of therapy. Female patients should wait at least 1 ovulatory cycle after discontinuation of MTX therapy before attempting conception.
Intramuscular Gold - given as a single dose of 50 mg/week (aurothioglucose, aurothiomalate) until a total of 1 gram, (20 weeks ) then it is cut back to biweekly or monthly to sustain the effects. Used much less often than in past years. The major serious toxicities of gold compounds hematologic (thrombocytopenia 1-3% and aplastic anemia <1%), renal, (membranous nephropathy) and pulmonary--are rare. Skin rashes mouth sores are more common. Oral gold has GI problems (diarrhea) and is less effective Other toxicities include oral ulcers (common), rash (common), pruritus without rash (uncommon), and vasomotor reactions (with parenteral gold, especially aurothiomalate)
Sulfasalazine about 2 grams daily is another alternative Hematologic toxicities of SSZ, including leukopenia (1-3%), thrombocytopenia (rare), hemolysis in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency, agranulocytosis (rare), and aplastic anemia (rare), are the most serious potential side effects of SSZ . Except or G6PD deficiency and sulfa allergy, there are no known risk factors
Leflunamide - New . A pyrimidine base inhibitor. Its toxicities inlclude hepatic, marrow and teratogenic
Azathioprine - For the patient that does not respond to MTX or others. It may be given in a dose of 50 to 150 mg /day. Cytopenia with Azathioprine is common but mild and dose dependent. It does increase the risk of malignancies in transplant pts, however it is not clear whether it does in pts with RA. Risk factors for myelosuppression include the use of concomitant allopurinol or ACE inhibitors and the presence of renal insufficiency. Prevention consists of reducing the dosage of AZA to one-fourth the usual dosage with concomitant allopurinol, avoiding the use of concomitant ACE inhibitors, and decreasing the dosage of AZA in patients with renal insufficiency.
Penicillamine - rarely used. Started at 250 mg/day and increased in 250 mg/month increments to 750-1000 mg. . Side effects like gold. neuromuscular as well Other significant but rare toxicities include nephrotic syndrome or renal failure and induction of autoimmune syndromes such as systemic lupus erythematosus, myasthenia gravis, polymyositis, and Goodpasture's syndrome
Cyclophosphmide - is rarely used to treat RA. Risks are hemorrhagic cystitis, secondary malignancies, bone marrow suppression and pulmonary fibrosis are known side effects
TNF-soluble receptor antibodies are new and when given as an injection appear to significantly diminish pain and swelling in RA. The inhibit TNF’s binding. There are presently three. The first was a soluble receptor to TNF called etanercept. The second is a chimeric antibody (Fab is mouse, Fc is human) called infliximab. The third is a fully humanized monoclonal ab called adalimumab. The potential board question is about infection especially TB. The data on long term malignancies is less clear.
Glucocorticoids
Low dose glucocorticoids are very effective at reducing inflammation. Many rheumatologists are using prednisone at low dosages. The toxicities of low-dose systemic glucocorticoids (<=10 mg prednisone daily or equivalent) include increased appetite, weight gain, fluid retention, acne, development of cushingoid facies, hypertension, diabetes, atherosclerosis, glaucoma and cataract formation, osteoporosis, a vascular necrosis, increased susceptibility to infection, and impaired wound healing. the importance of limiting the dosage and duration of glucocorticoid use, the potential difficulty of discontinuing prednisone in a patient with active RA, and the danger of abrupt cessation of the medication after long-term use. Patients should be advised regarding smoking cessation and reduction of cholesterol intake to minimize cardiovascular risk factors.
OA
Intro - Osteoarthritis (OA) is also called degenerative joint disease. It is a patholgic condition of a synovial joint. It exists as either idiopathic or secondary OA
Epidemiology - .. It is the most common joint disease of man. Under age 35 the distribution is similar. Hip OA is more common in older men, knee is older obese females, and hand in females. there exist some racial differences as well. Hip OA is less common in asians, DIP less common in South African Blacks than whites in the same population. Genetic reasearch and OA is presently being researched.
Risk - the most powerful risk factor is age...............repetitive trauma or mechanical injury is also important.....if you exclude trauma there is no correlation between exercise and OA (ie... running)........ obesity close with knee less with hip probably not with hands ........framinham study obesity precedes hip.........stonger assoc in females. Osteoporosis is a negative association..........hip OA less freacture risk.
Hypermobility........Associated with other diseases DM (DISH, forestier's disease), Hyperuricemia, all independent of Obesity.........Mechanical factors
Pathology - OA is a disorder of the entire joint. The most obvious targert tissue is the articular cartilage. Cartilage - starts out a little thicker than normal. There are two major factors
1. - either decreased ability of the cartilage to withstand normal pressures or
2. increased mechanical forces on normal cartilage
Clinically - Pain - Often a deep ache. AM gel is less than 20 minutes. Other causes.... synovitis........... crepitus......... effusions....deformity......Specific sites - IP joints , Thumb base - squaring
Hip - loss of internal rotation occurs early. Knee - medial, lateral or patellofemoral compartments. vs chondromallacia patella Spine - apophyseal joints - OA.... Degenerative disc disease - spondylosis................Paraspinous ligaments - DISH
LAB - - x-ray 90% over 40 only 30% with symptoms
TX - Reduction of joint loading, PT, Surgery - last Pharmacologic - D.O.C. in 2003 is still Acetominophen. Though this is changing. For those with an inflammatory component, NSAIDS should be first.
MECHANISMS OF ACTON - All work primarily by inhibiting cyclooxygenase which catalyses the synthesis of cyclic endoperoxidases from arachidonic acid to form prostaglandins.
COMMON ADVERSE REACTONS TO NSAIDS
GI - nausea vomiting, dyspepsia, constipation, diarrhea, GI irritation, superficial erosions, ulceration, increased fecal blood wasting, hemorrhage, small bowel erosions liver toxicity, fulminant hepatic failure
Management of GI toxicity - If symptomatic, at high risk, erosive disease, try to stop NSAID
try non NSAIDs. H2 blockers or sucralfate have not been shown to be of benefit in gastric ulcer. They all are beneficial in the prevention of (+/- sucralfate) duodenal ulcers in those taking NSAIDS. Prophylaxis is still questionable in regard to preventing major gastroduodenal complications, drugs to heal it are better understood. Cox-2 inhibitors appear to be much safer on GI, and platelet. As of now they are probably no better than standard NSAIDS for renal.
H2 blockers - 50% of gastric ulcers healed after 4 weeks and 90% after 3 months of therapy. Omeprazole a pump inhibitor is more effective in healing gastric ulcers associated with NSAIDS than H2 blockers If the NSAID must be continued, then the duration of ulcer therapy can be extended from 8 to 12 weeks, especially if large ulcers. Sucralfate in a slurry may be more effective than pill or H2 blockers for symptoms of esophageal lesions, omeprazole may have a role in this area.
Misoprostol is effective in the treatment and prevention of gastroduodenal erosions and significant ulcerations in NSAID use. 2 big side effects are DIARRHEA, dose related and can be seen in 30-40% taking 200 mcg QID, and increased uterine contractility, and subsequent spontaneous abortion.
While Misoprostol and NSAIDS together showed a decreased rate of ulcer formation, there is no evidence the the risk of subsequent complications (bleeding, perforation etc) was improved.
Nonacetylated Salicylates like choline magnesium trisalicylate salsalate or diflunisal theoretically offer an advantage. Unfortunately in the high doses often needed prostaglandin inhibition may occur. The advantage if there is one is not clearly proven.
Renal - Glomerulopathy, interstital nephritis, decreased GFR, inhibition of renin release, edema
A recent trial has shown that patients over 65 yrs with a CrCl less than 70 ml/min can tolerate a 2 week course of naproxen at 750 mg/d. If Cr is over 2 close follow up, if over 60. UA, lytes, BUN Cr baseline, 1-2 weeks later, and q 3 months after. Substitue analgesics whenever possible.
CNS - headaches, confusion, hallucination, depersonalization reations, depresson tremor,
Aseptic menningitis, tinnitis vertigo, neuropathy, transient transparent corneal deposits.
HEME - anemia marrow suppression Coomb's positivehemolytic anemia, decreased platlet aggregation. Avoid NSAIDS in patiens with platelet defects (uremia, von willibrands disease,) or thrombocytopenia. Nonacetylated salicylates offer a therapeutic alternative.
Hypersensitivty - Asthma, urticaria, rashes, photsensitivity, Stevens-Johnson' s. For the patient with Asthma, nasal polyps and or aspirin sensitivity, the nonacetylated salicylates have been shown to be a safer alternative
OTHER -displacemet of oral hpoglycemics and warfarin from binding sites and metabolism
INTERFERENCE WITH THE ACTONS OF B BLOCKERS, ACE INHIBITORS
Pregnancy and nursing - acetomenophen or the salicylates are the safest analgesics in pregnancy and nursing. NSAIDS have been associated with fetal abnormalities. If ASA is used stop it 2 weeks before delivery. Early closure of the ductus arteriosus can occur with prostaglandin synthetase inhibitors
About .2% of the maternal dose of NSAIDS is excreted in breast milk. Salicylates given to nursing mothers are not considered harmful to nursing infants
OTHER PROBLEMS - Other important interactions include anticoagulants, oral hypoglycemic agents, phenytoin, sodium valproate, methotrexate, digoxin, aminoglycosides, antacids, probenecid, barbiturates, cafeine, cholestyramine, metoclopramide
Going for surgery??- For ASA hold off about 2 weeks. If nonacetylated only 3-5 half lives of the drug.
Viscus-supplementation – Hyaluronate ( a glycosoaminoglycan ) when injected, causes synovial cells to create a better, more viscous synovial fluid.
There is some promising data on glucosamine and chondroitin sulfate. They may infact help slow down the progression of OA. This has yet to be proven
PAGETS DISEASE
Paget's disease is a disorder of localized bone remodeling. the initial event is an increase in osteoclast mediated bone resorption with subsequent compensatory increases in new bone formation. This results in a disorganized matrix of woven and lamellar bone at affeted skeletal sites.
Its main clinical features are bone pain, brittleness and deformity. - 10% over 80. It is usually minimally symptomatic (30%) if any. Common complaints are bone pain in about (80%) (one half of which is joint pain), and skeletal deformity. The most common bones in descending order are the PELVIS, lumbar spine, femur, thoracic spine sacrum, skull, tibia, Humerus. Unpredictable course, progressive or wax and wane. Deformities can be unsightly especially facial bones (leontiasis ossea). Deafness and cranial neve involvement can occur, platybasiaat the base of the skull can lead to vertebrobasilar insufficiecy and hydrocephalus. Pagetic bones are very brittle and can fracture spontaneously. .
Pagetic bones are very vascular. Often this gives rise to hyperthermia. In the skull the increased vascularization can occur at the expense of the brain resulting in hypertrophy and tortuosity of the temporal artery in many pts, and the so called vascular steal syndrome that affects the brain, rendering patients insomnolent, withdrawn, and apathetic. Similar problems can occur at the spinal cord diversion of blood can give rise to paraplegia or quadralegia. Once Paget's affects > 35% of the skeleton, it may result in high output failure.
Osteogenic sarcoma is a rare complication (less than 1%) originating in the metaphyseal regions of long bones especially the humerus. .
DIAGNOSIS - based on characteristic findings with an elevated serum alkaline phosphatase level - parallels course Some bones give a higher AP like the skull. while the pelvis, sacrum, lumbar spine, and femoral head give lower. Osteocalcin is also elevated but is a less reliable index of disease acitivty. Once the AP goes over 200 the acid phosphatase will also rise
3. elevated urinary hydroxyproline excretion - parallels course and is more sensitive. Recently pyridinoline and deoxypyridinoline cross links have been used.
4. Bone scan - the most sensitive way to determine location of active pagetic lesion. If screening reveals an elevated AP and there are no signs of liver disease, urinary hydroxyproline is elevated, the next step is to request a bone scan. Hot spots will reveal areas to be explored by conventional radiographic and if needed CT. X-rays have the advantage of showing whether a lesion is osteolytic or blastic or both.
5. Serum calcium, urine calcium are usually normal
6. If extensive - immobilzation can lead to hypercalciuria, hypercalcemia (increased bone turnover)
The first phase is lytic
the second phase is mixed lytic blastic
The third stage is sclerotic secondary to the blastic lesions.
TREATMENT
1. ASA or NSAIDS is usually adequate
2. Osteoclast inhibiting agents is indicated in more severe cases - impingement, or extensive involvement
a. Calcitonin can decrease bone pain, reduce high output failure, decrease activity. Respoonses are seen after several months of therapy. Often 50-100 MRC units 3xs weekly may be enough. CAN CONTINUE INDEFINITELY. Occasionally high titer neutralizing antibodies may result in resistance to calcitonin.
b. Bisphosphonates - the future of paget's treatment lies in these agents. The Second generation (allendronate) are becoming drugs of choice. The first generation bisphosphonates (Sodium etidronate) produced mineralization defects at high doses, generalized osteomalacia,and focal osteomalacia at low doses Used in 6 month courses, alternating with 6 months or more without treatment.
BACK PAIN - MECHANICAL LBP
SPONDYLOTHESIS
AGE - 20-30 YEARS
WORSE WITH - STANDING AND EXTENSION
ONSET - INSIDIOUS BACK PAIN
MUSCLE STRAIN
AGE - 20-40 YEARS
WORSE WITH - STANDING AND FLEXION
ONSET - ACUTE BACK PAIN
HERNIATED DISC
AGE - 30-50 YEARS
WORSE WITH - SITIING FLEXION, POSITIVE SLR,
ONSET - ACUTE BACK PAIN
OA
AGE - > 50
WORSE WITH - STANDING, EXTENSION
ONSET - INSIDIOUS BACK PAIN
SPINAL STENOSIS -
AGE - >60
WORSE WITH - STANDING EXTENSION, POSITIVE SLR
ONSET - INSIDIOUS LEG PAIN
THE SYSTEMIC APPROACH - Red Flags - fever saddle anesthesia, and incontinence
Most are mechanical. There are two that are worrisome. Cauda equina syndrome and abdominal aneurysm.
Cauda Equina syndrome - LBP, saddle anesthesia, bilateral sciatica, and incontinence
Causes are central herniation of IVD, epidural abscesses and tumor. There are also nonmechanical causes
Abdominal aneurysm is the other. Here there is a history of lower extremity claudication. The pt may be Dizzy and older
LOCALIZED Affects 65 to 80 percent of populations sampled. ..1/3 of all rheumatic complaints.....Disc herniations account for only 5% of all back disorders. They DO NOT increase in frequency in a heavy lifting population. Low back pain does...25% of all asymptomatic people will have a disc herniation on MRI...Radicular pain relates to the spinal nerve root worsens when the root is stretched like bending and usually improves with rest. Paresthesias and numbness may be present and there may be an associated motor weakness
FACTORS THAT INFLUENCE THE ESR
Factors That Increase the ESR - Advancing age, Female sex, Pregnancy, Hypercholesterolemia, B cell neoplasm (e.g., myeloma, macroglobulinemia, cryoglobulinemia)
Factors That Decrease the ESR -Congestive heart failure, Sickle cell disease
Altered erythrocyte shape (e.g., anisocytosis, spherocytosis, acanthosis, microcytosis)
Polycythemia, Extreme leukocytosis, Cachexia
ANA's and Pathogenesis
1. We refer to antibodies to nucleic acids or nucleoproteins at any cellular location as ANA's. Antibodies to nuclear antigens are found in the sera of healthy individuals and patients with a variety of infectious, neoplastic and inflammatory diseases rheumatic diseases. Often they are named after the patient in whom they were first discovered (ie Smith) or associated diseases SCL-70, or they organelle or antigen involved.
False positives tend to be in low titer, a significant proportion in medium to high titer. Usually <1:320 homogeneous with a higher incidence in elderly and females. False negatives are rare in SLE may be seen with positive Ro (The HEP-2 substrated has improved this somewhat), also cytoplasmic antigens will not cause nuclear fluorescence. RNP, Jo-1
THE PATTERNS
A. The ANA pattern while less important then the specific antibody-antigen reactions is of value. There are four major patterns.
1. Homogeneous - seen in all the connective tissues diseases including drug-induced SLE.
2. Speckled - seen in sera from patients with SLE, Sjogren's, RA, PSS.
3. Peripheral - when found it is most frequently in SLE.
4. Nucleolar - Seen most frequently in Scleroderma, but can occur in Sjogren's and also in SLE. A subset of this pattern is the centromere pattern
These correlate with the specific antigen at which the antibody is targeted. For example a person whith an antibody to DS-DNA tends to show a peripheral staining pattern. Anti-Ro antibodies tend to produce a speckled pattern
AUTOANTIBODY -AUTOANTIGEN SYSTEMS ASSOCIATED WITH
SLE
DNA - Antibodies to both DS and SS DNA are clinically significant in SLE.
1. The presence of DS DNA is helpful in making the diagnosis of SLE. There are other disorders that may have an Anti-DS DNA however these usually have overlap features with SLE, and they titers are lower (25% of sjogren's may have positive DNA). The presence of high titers of DS-DNA with low complements is a risk factor for the development of nephritis in SLE. They may very well be pathogenic.
2. SS-DNA are ubiquitous. They are commonly seen in SLE, CAH, infectious mononucleosus, and RA. They have POOR specificity for SLE, but are present almost universally.
3. Sm and U1-RNP. Sm is in the revised criteria for SLE. found more commonly in blacks and Asians with SLE than in whites. (20-40% vs 10%). Whether or not they correlate with disease manifestations is presently being studied.
4. Ro/SSA and La/SSB - Associated with SLE and SS. Ro is 25-50% of patients (and higher is ELISA is used). If SLE with a positive Ro, there is a higher incidence of a postive RF. Ro antibodies are associated with several subsets of SLE.
"ANA negative SLE", subacute cutaneous lupus, Neonatal lupus Ro and La (complete heart block often irreversible), early onset in offspring,SLE in male children,.
5.HISTONES - the most ubiquitous proteins found in the nucleus of eukaryotic cells. Antibodies directed to histones occur in SLE, drug induced SLE, JRA, RA. They may be responsible for many of the "false positive ANAs". With regard to DILE, hydralazine and procainamide are the two biggest offenders. Followed by chlorpromazine,quinidine INH, and methyldopa, and a long list of other agents.
DETERMINING THE CAUSE OF A POSITIVE ANA
1. In patients with a suspected CTD, specific autoantibodies may help in the diagnosis
2. Careful review of medications taken by the patient to exclude drug induced ANA syndromes
3. Family history to identify ANA genetic predispositions
4. Chest exam and CXR to detect pulmonary fibrosis or pulmonary hypertension.
5. Liver enzymes and complete blood counts to look for hepatic and hematologic pathology .....ANA's may disappear after treatment.
6. Appropriate cultures in febrile patients.
SLE
Clinical Features - SLE may affect one organ system or many systems. Mild/intermittent to fulminent/persistent. < 10% ever see a true remission without meds and symptoms. Systemic constitutional symptoms are often present. Autoantibodies are present at the onset of disease.
Musculoskeletal - arthralgias, myalgias, intermittent arthritis. Pain is out of proportion to exam. Diffuse puffiness in hands and feet may occur. Tenosynovitis, 10% have a deforming arthritis, erosions are rare sub q nodules may be found, myopathy can occur secondary to meds or be inflammatory. Aseptic necrosis of the hip, shoulder, knees, especially when pts are on GC.
Cutaneous:
Malar rash is fixed raised or flat photosensitive. No scarring +/- telangiectasias. a diffuse maculopapular sun exposed rash may also occur. Pathology for SLE, DLE, SCLE similar - Hair loss, oral ulcers
DLE in 20%. (5% of DLE go on to develop SLE) these have atrophy and do scar. Also sun exposed.
SCLE is a recurring dermatitis with arthritis and fatigue mostly are positive for Ro or SS dDNA some are ANA negative. All pts can develop a vasculitic skin lesion (leukocytoclastic angiitis)
Renal - GN becomes a problem is about 50-75% of SLE patients. Asymptomatic proteinuria or hematuria is typical of mild SLE. Nephrotic syndrome and azotemia are common but Rapidly Progressive renal failure is seen in a small subset of patients........Glomerular changes include swelling and proliferation of mesangial,endothelial and epithelial cells. monocytes PMN's nfiltrations, hyalin thrombi (representing massive IC deposits, most frequently seen in severe nephritis). .
CLASSIFCATION
The World Health Organization classifies five major types.These are not discrete entities as much as they are different Stages of a continuous process. Transition can proceed in either direction. IC are found in II through V.
I normal ....II mild to moderate mesangial disease.....III focal/segmental, necrotizing/proliferative glomerulonephritis......IV Diffuse proliferative nephritis - A broad range encompassing purely proliferative to superimposed on sclerosing lesions.....V membranous nephropathy...VI - sclerosing
Renal biopsies are useful to: (1) identify unexpected severe disease (2) assess risk of progression to end stage, (3) evaluate response to Treatmen (4) verufy the cause as ative SLE (5) occasionally to confirm the diagnosis. Still There is controversy....These patients also tend to heal by sclerosis, so they are at risk for end stage renal disease. Those with a high chronicity index tend not to respond as well to therapy (the damage is already done).
Activity Index
Glomerular lesions cellular proliferation, fibrinoid necrosis, hyalinethrombi, crescents, leukocyte exudations.......................Tubulointerstital disease - mononuclear cell infiltration.
Chronicity Index
glomerular lesions sclerotic glomeruli, fibrous crescents. .............Tubulointerstitial disease tubular atrophy and interstitial fibrosis.
Treatment for a patient with a high chronicity index is determined by the extra-renal disease.
Persistent abnormal UA, DS-DNA, Decreased complement are all risk factors for renal disease.
The three strongest predictors of End stage Renal disease are Male, less than 24 years old and elevated serum creatinine
The worst prognosis is given to those with diffuse proliferative nephritis.
CNS - Any part of the CNS or PNS can be affected. There are 4 major categories
1.- Nonfocal changes - The most common is mild cognititive dysfxn (70%). .
2. - Seizures may occur. these may be of any type. This does not neccessarily imply active cerebritis.
3.- focal deficits - Infarcts, optic neuritis, transversemyelitis all can occur. The lab shows a positive EEG, increased protein in the CSF in 50%. Increased mononuclear cells in 30%. if symptoms suggest possibility of infection tap the pt. Imaging - MRI is the best but nonspecific. Tx is immunosuppression.
4. - Other - peripheral neuropathies, Myasthenia like, Guillain-Barre type..............Don't forget the influence of drugs (GC especially), evaluation should include APL antibodies and IC.
Cardiopulmonary - pericarditis is the most common. effusions are common may lead to tamponade. constrictive pericarditis is rare. Myocarditis with sudden death has occured. Valve - uncommon Libman-Sachs enodocarditis. Pleurisy and effusions are common manifestations of SLE. Pneumonitis with fever , dyspnea, cough, x-rays fleeting infiltrates. platelike atelectasis responds to GC. Most common cause of infiltrates in SLE is infections (board question). also ARDS and intravleolar hemorrhage.
GI- Nausea, vomiting, dyspepsia. Lupus peritonitis is possible. Vascultitis may infarct bowel GC is tx Some scleroderma like problems. Pancreatitis may occur
Ocular - retinal vascultis is a serious complication can result in blindness. Cytoid bodies are white exudates. Also Sicca syndrome, conjunctivitis, optic neuritis, episcleritis
Vascular - thrombosis - vascultits, APL.......or degenerative vascular changes forom IC and GC
Heme - anemia of chronic disease.................hemolysis - coombs positive high dose of GC, splenectomy is resistent to tx leukopenia, lymphopenia is common rarely associated with infection.
mild decrease is platelets, 5% severe high dose GC, or IVGG if no Increase in 2 weeks then splenectomy
LA or ACL - decreased platletes, venous/arterial clotting, recurrrent fetal loss, valvular heart disease.
Also AB to factors VIII or IX , hypoprothrombinemia (rare)...bleeding dis respond to GC and clotting doesn't.
Pregnancy - Fertility rates are normal in patients with SLE. The difficulty arises in carrying to term. Adverse fetal outcomes are reported in 40% of patients with SLE. There is a 30-50% risk of spontaneous Ab or still birth. If APL antibodies are present the risk is higher. Treatment varies; waiting, ASA until the last month of pregnancy, Heparin then ASA then Heparin, each trimester. Maternal Ro/SSA or La/SSB are associated with neonatal lupus and congenital heart block. Tx -Steroids are mostly metabolized by the placenta, they usually cause few major problems. The best immunosupressive drug to used is Azathioproine. Several recent studies are supporting plaquenil.
Treatment - No cure for SLE. Treat exacerbations and set up a maintainenece strategy.
1. Sunscreens with an SPF of at least 15 should be used.
2. There is no evidence that vaccination for influenza.hepatitis, or pneumococcal worsens disease, but severely immuosupressed patients should avoid live vaccines.
3. With no organ involvement and mild disease avoid GC if possible. Fatigue can be severe and may respond to low dose GC but NSAIDS may be helpful.
4. Caution should be used with NSAIDS in certain patients.
5. Hydroxychloroquine (plaquenil) is one of the more common second line agents. The big side effect is retinal toxicity which almost never happens at the dosages used for SLE. Neuropathy has also been reported. Retinal opthalmologic exams should be performed at least annually.
6. Severe lifethreatening or disabling manifestations of SLE should be treated with high dose GC
1-2 mg/kg. Split up 2-3 times /day when active and then daily once control is acheived. Alternated daily dosing may minimized side effects. Always give with Ca 1500 mg/day and vitamin D 400 units/day. An alternative in sick patients is to bolus with high dose GC 1 gram/day for 3-5 days and then place the pat on maintenance.
7. Estrogen therapy at menoapuse shows no increased risk of SLE activity. Oral contraceptives premenopausally have not been used however this is being re-investigated
8. In patients with serious major organ involvement cytotoxic therapy is usually indicated. The major drugs include; CYCLOPHOSPHAMIDE , AZATHIOPRINE , CHLORAMBUCIL - rarely used METHOTREXATE ( commonly used)
GOUT - encompasses a broad spectrum. Associated with obesity, HTN, hyperlipidemia,vascular disease. May present as: hyperuricemia, acute gout, tophaceous gout, urate deposition in the renal parenchyma, renal lithiasis
URIC ACID METABOLISM - U.A. is the final breakdown product of protein metabolism in humans.
Causes of hyperuricemia -
1. Diet exogenous - organ meats sweetbreads anchovies
2. Endogenous - purine synthesis and urate synthesis
a. PRPP - phosphoribosylpyrophosphate overactivity
b.HGPRT - hypoxanthinephophoribosyl transferase deficiency
3. Decreased excretion - over 95% of pts with increased uric acid have some defect in renal excretion.
4. BOTH over production and decreased excretion - G-6-PD, hereditary fructose intolerance, ETOH
DIAGNOSIS - Polarized light gout is negatively birefringent
X-RAYS- sclerotic border with overhanging edge
COMPLICATIONS -
1. Asymptomatic hyperuricemia, Acute gouty arthritis, Interval or intercritical gout , Tophaceous gout . Renal involvement
TREATMENT -
1. Asymptomatic hyperuricemia- none
2. Symptomatic hyperuricemia - treat initially then decide whether to start antihyperuricemic therapy.
3. Acute Gouty Arthritis - Uncomplicated patients or without comorbidities - Rest, NSAIDS, intrarticular steroids, IM GC, ACTH, oral corticosteroid, Colchicine
1. NSAIDS - indomethacin usual. less specific than cochicine. presently the drug of choice Side Effects
2. Colchicine -. Specific for gouty arthritis so if not certain can be a therapeutic challange. Toxicities - If certain of diagnosis then NSAID is drug of choice.
3. GC - inject larger joints can aspirate. Can give IM injecton or even oral if needed
4. ACTH - 40-80 IU to start IM may be given every 8 hours if needed x 2-3 doses. Always use colchicine to prevent rebound attack. .6-1.2 mg/day. Remember will prevent attacks but does nothing for the sequelae of hyperuricemia.
b. Complicated patients - intra-articular steroid of ACTH IM. Colchicine prophylaxis may be used or even a low dose NSAID. Remember acute gout is essentially a benign condition.
Must decide whether or not to use hypouriciemic therapy. Drugs used either decrease the formation by inhibiting xanthine oxidase (allopurinol) or increase the excretion (uricosuric agents).
ALLOPURINOL TOXICITY - 1. The severe toxic syndrome - 90% have a diffuse erythematous maculopapular to desquamative skin rash. (Like TEN) Clinically may see fever, hepatocellular injury, increased WBC, increased Eosinophils, increased creatinine 75% of pts have pre-exisitng renal insufficiency, 50% are on diuretics. Usually within 2-4 weeks of initiating treatment. There is a 20% mortality, Stop the allopurinol and treat with prednisone, hemodialysis to remove oxypurinol maybe of benefit, ...........Careful with azathiprine (decrease doese to 1/3 AZA) prolongs half life of coumadin and theophylline.must adjust for renal function
Probenicid - inhibit reabsorption of urate - Gi intolerance, fever, hypersensitivity. Sulfinpyrazone is another uricosuric It is a phenylbutazone metabolite.
CPPD - Calcium Pyrophosphate Deposition Disease
Nomenclature
1. Chondrocalcinosis Calicification of articular fibro- or hylaine catilage
2. Pseudogout - the acute synovitis associated with intra-articular CPPD deposition,
3. pyrophophate arthropathy - Structural cartilage and bone abnormality associated with CPPD deposition.
X-ray evidence of calcium pyrophosphate deposition disease is rare in
patients less than 50 yeas old. The peak is 65-75 years old. No genetic association. ubiquitous geographical distribution. The disorders which are associated with CPPD are: Hyperparathyroidism Hemochromotosis, Wilson's Disease, Hypomagnesemia, Hypophosphatemia
THE ACUTE PSEUDOGOUT ATTACK.
It is the most common cause of acute monoarthrits in the elderly. It can occur in any joint. The Knee is most common. Severe pain, stiffness, swelling, maximum within 6-24 hours after onset. This can be the worst pain ever felt (like gout). Erythema, Tenderness to the lightest touch, Triggering events for the acute attack include; Trauma to the joint, intercurrent illness (MI, CVA) Surgery - thyroid /parathyroid Transfusion of blood or fluids, starting thyroxine therapy, Joint lavage
THE CHRONIC PYROPHOSPHATE ARTHROPATHY Chronic pain, early AM, inactivity, stiffness, limited motion, can also have acute attacks. knees most common, and also most severe.
IDENTIFICATION
Can be done on compensated polarized light - mildly positively birefringent
X-RAY Condrocalcinosis found mostly on fibrocartilage (menisci, triangular is wrist) also hylaine (knee, hip, glenohumeral) catrilage. Can have changes similar to OA but there are certain distinctions....Atypical joints - glenohumeral, MCP, ankle, elbow, patellofemoral
compartment, and the radiocarpal joint.
When should we screen for metabolic disease - Early onset - arthritis <55, Polyarticular (vs Pauci), recurrent acute attacks > chronic arthrop, additional clinical or radiographic clues.
The blanket screen includes - Ca, AP, Mg, Ferritin, LFT's
MGMT.
1. Acute psuedogout - Aspiration and injection, analgesia, NSAIDS, oral steroids cochicine if warranted. identiffy triggering illness
2. Chronic arthropathy - no specific therapy reduce symtpoms.
APATITE DEPOSITION DISEASES -
Hydroxyapatite crystals are part of the spectrum of basic calcium phosphate disease. It is deposited in cartilage, and peri-articular tissues. It is associated with hypercalcemia, hyperparathyroidism, injury, bursitis, tendonitis, OA and renal disease (ESRD). Clinically it is part of two disorders:
1. Calcific peri-arthritis - deposits in the rotator cuff tendons or bursa is relatively common. >70% occur at the shoulder. Calcific depostis may rupture and inflame the surrounding tissues and tendons this can produce an acute bursitis.
2. Intra-articular apatite - these crystals have recently been found in elderly females with large joint destructive arthropathies. The most common of which is called the "Milwaukee Shoulder Syndrome" Always at least 70 y.o., with a massive cool effusion into the joint.
3. These crystals are also seen in Scleroderma patients, and childhood dermatomyositis
OXALATE CRYSTALS - Think of theses in a patient who presents with renal failure. Knees and hands may also affects intervertebral discs. Dx is made by synovial fluid analysis. CRF is also associated with gout, CPPD, BCP,,CTS, amyloidosis,
DEPOT-CORTICOSTEROID INDUCED IATROGENIC INFLAMMATION - an inflammatory reaction around 8 hours following an injection with a GC.
LIPID CRYSTALS (Cholesterol, lipid liquid crystals) - not common- may or may not be pathogenic. May be seen as a complication of effusions due to RA and other chronic arthritidies like (chronic olecranon bursitis), also in recent hemarthrosis or trauma followed by inflammation. Dx by polarized light look for a "Maltese Cross" type pattern
POLYMYOSITIS/DERMATOMYOSITIS
Polymyositis is an idiopathic inflammatory muscle disease. Like other connective tissue disorders it shares immunologic features and evidence of autoimmunity. It has an annual incidence of about 5 per million, and can affect any age group (though many view adult PM/DM and childhood as two distinct diseases). It may attack predominately striated muscle (polymyositis) or muscle and skin (dermatomyositis). There appears to be a genetic predisposition in some cases and no obvious environmental factors have been identified (with the exception of various medications capable of causing myositis) The distribution of the various types is as follows: 5-% adult PM, 20% adult DM, 10% childhood, 10% overlap, 10% malignancy. Clinically many divide PM/DM into 1) polymyositis 2) dermatomyositis and 3) inclusion body myositis
The most common initial presenting complaint is a gradual painless proximal muscle weakness usually lasting 3-6 months prior to the physicians visit. There is a small subset that will progress quickly and may involve distal extremity weakness. These are usually men with Inclusion body myositis. Also involved are oropharynx, esophagus, diaphragmatic, neck flexors. Ocular and facial muscles are essentiallly never involved.
The clinical features vary Constitutional features - fatigue is common fever occurs occasionally. Skeletal muscle - proximal muscle weaness. May see bulbar weakness witrh hoarseness,dysphonia. Muscle pain may be present in up to 50% but is usually not severe. Swelling may be present, and atrophy is present only if the illness is longstanding. Skin - the lesions of dermatomysoitis are classical. Gottron's sign - scaling red raised papules on the hand. Gottron's rash as well. May see a dusky rash along the shoulders or the "V" of the neck. The Heliotrope rash a violaceous /erythematous rash over the eyelids and around the face. Mechanics hands are scaling cracked areas of skin along the distal fingertips. Joints - arthritis if it occurs is early in the disease. A distribution like RA but mild and transient. Calcinosis - is rare in adult onset disease , but very common in the childhood illness. Predilection for areas of microtrauma. Seen in subcutaneous, fascial, and intracutaneous sites. Respiratory - a common presenting complaint is dyspnea. Ventilatory dysfunction from muscle weakness (diapragm or intercostal muscles) may occur and can be a serious problem. Other causes of dyspnea include Cardiac, interstitial lung disease, recurrent aspiration pneumonia, or bacterial pneumonia. Cardiac - While very common cardiac involvement is seldom symptomatic unless the disease is very advanced. Arrhythmias may occur, aslo rarely myocarditis or fibrous replacement of cardiac tissue. It is not uncommon to see positive MB % in patients with active myosistis. this is probably not due to direct cardiac damage but due to the regenerating myofibrils in damaged skeletal muscle. GI - Pharyngeal dysphagia may occur and result in aspiration. Smooth muscle involvement in the GI tract is uncommon unless there is overlap with systemic sclerosis. Lower espophageal dysfunction may lead to reflux and esophagitis. Childhood DM may result in vasculitis and intestinal ischemia. Vasculature Raynaud's may occur especially if there is an overlap with PSS or SLE. Renal disease - is rare unless an overlap. Malignancy - This relatonship remains controversial. There does appear to be a three times greater risk of Malignancy with Dm when compared to PM. This appears to be greatest for those with new onset illness over the age of 40. Malignancy is often obvious and rarely occult. The evaluation should include a careful History and physical with initial blood work and evaluation of any abnormalities in depth (ie Iron deficiency anemia)
DDX - The differential is extensive and includes
DRUGS - Colchicine, D-penicillaine, cimetidine, antimalarials, AZT, lovastatin, clofibrate, ipecac, amphetamines, ethanol, steroids, heroin,cocaine, pentazocine
ENDOCRINE DISORDERS - Hypothyroidism, hyperthyroidism/thyroiditis, hypopara, acromegally, cushings, addison's
ELECTROLYTES -hypokalemia, hypercalcemia, hypocalcemia, hypomagnesemia
INFECTIONS -
VIRAL coxsackieB, adeno 2, hepatitis B, influenza A,B HIV, echoviruses, rubella
BACTERIAL - legionnaires, pyomyositis staph, strept, clostridia
FUNGI PARASITES - Borrelia, trichinosis,mycobacterium, Toxo.
METABOLIC - glycogen storage diseases - deficiencies of phophorylase (Mc ARdle's Disease) complete or partial deficiencies, deficiencies of phophofructokinase, acid maltase, Disorders of muscle lipid metabolism - carnitine palmityltransferase deficiency
MITOCHONDRIAL - cytochrome oxidase, reductaste, ubiquinone reductase
NEUROMUSCULAR DISORDERS - Gulliane Barre and other polyneuropathies, MG, Eaton Lambert, ALS, myotonic Dystrophy, Familial periodic paralysis, spinal MD
It also may be secondary to disorders of SLE, or Systeic Sclerosis, and Sjogren's syndrome
Evaluation -
Lab - In general most lab tests are normal. The ESR may be slightly elevated. Various muscle enzymes are elevated. The CPK is considered the best choice. In order of sensitivity they are Creatine Kinase, aldolase, AST, ALT, and LDH. These may rise before clinical myositis is present, and may fall weeks prior to improvement. There are rare exceptions when the CPK's are negative with biopsy proven myositis. (circulating CPK inhibitor, or "burned out" myositis)
Serum autoantibodies - About 80% of patients of ANA's and half of these are directed at muscle tissue. The identification of these antibodies is relatively new. The most common of these is the ANTI-Jo-1 antibody. this is found in about 20% of all myositis patients (may be ANA negative). A syndrome seen in many of these patients "the anti-synthetase syndrome" consists of myositis, ILD, raynauds and arthritis
Prognosis - Until recently the 5 year survivial was 50% . More recent studies have shown it to be approximatley 80%. Older age, associated malignancy, myocardial involvement, delayed treatment with GC, and aspiration are all poor prognoistic signs.
EMG - classic finding show irritability of myofibrils (fibrillation potentials) on needle insertion and at rest, short duration low amplitude, complex polyphasic potentials.
Biopsy - Biopsy should be performed in all cases to confirm the diagnosis of inflammatory myopathy. Choose a site free of trauma and recent needle sticks
Management - Glucocorticoids are still the mainstay of management in PM/DM. However because of the relapsing course many patients follow, other immunosuppressive drugs are often used. Methotrexate is the most popular (the average dose being 7.5mg-30-mg/week), Azathioprine, oral cyclophosphamide, cyclosporine, and hydroxychloroquine have all be used with varied success.
VASCULITIS
A. This is a diverse group of diseases manifested by inflammatory cell filtration and necrosis of the walls of blood vessels or perivascular regions. The different syndromes are characterized by the size and type of vessel, qualitative differences in inflammation, and the different clinical features that accompany the vasculitis.........Vasculitis may occur as a primary disease or a secondary manifstation of other diseases. (RA, dermatomyositis, SLE, MCTD, PSS)
C. Classification has proved extremely difficult. In 1990 the ACR devised classification criteria for seven types of vasculitis. These are listed. These are used for classification. They don't include all of the manifestations of a given disease and cannot be used for diagnosis of individual patients. These seven major subtypes are
1. Temporal arteritis/giant cell arteritis - large/medium vessel
2. Takayasu's arteritis - large vessel
3. PAN - small/medium vessel also called periarteritis
4. Churg-Strauss - large-small
5. Wegener's Graulomatosis -small/medium
6. Hypersensitivity vasculitis - a small vessel (leukocytoclastic), venules arterioles
7. Henoch Schonlein Purpura - small vessel (leukocytoclastic), venules arterioles There are several other vasculitic disorders. Also often a necortizing vasculitis doesn't fit into any one category and is named polyangiitis overlap.
PATHOGENESIS - Much is unknown about the causes of vasculitis. There are three mechanisms by which inflammation may occur. 1. Direct noxious attack by and agent -chol emboli 2. Involvement in a process directed specifically at components in vascular tissue.(antiendothelial antibodies) 3. Passive involvement secondary to an inflammatory process not predominately directed toward vascular tissue. (Hep B)
D. Investigations - Most initially are diagnostc dilemmas First step would be to try to determine the type of vascultits one is dealing with.........some vasculitities are benign and self limited (HSP or drug induced) While occasionally they can be life threatening to treat aggressively may not be appropriate...... some syndromes may require other treatment modalities other than steroids. (antibiotics for SBE, surgery for atrial myxoma).....identifying associated conditions (renal disease in SLE)
There are several nonvasculitic conditions which can mimic vasculitis
large arteries (aorta and its primary branches)
Fibromuscular dysplasia - noninflammatory, any artery (renal in 60-75%) most common types are in females hypertension renal function is usually preserved. May show ischemic signs in other affected tissues.
Radiation fibrosis - after surgery months to years
Neurofibromatosis
Congenital coarctation of the aorta
Thoracic outlet syndrome
MEDIUM/SMALL ARTERIES
Ergotism (vasoconstriction) - ergotamines are used to treat migraine headaches. Ischemic pain and burning sensationof the limbs is known as St. Anthony's Fire. Ischemic changes in extremities
Cholesterol Embolization - spontaneous or after surgery, arteriography, or anticoagulation can be catastophic to nonspecific symptoms, livedo reticularis, if renal involvement, renal failure, HTN. ESR and C-reactive protein may be elevated. Complements may be low. Biopsy is the most effective way to make the diagnosis
Atrial Myxoma- symptoms vary with locations usually mitral sounding murmur symtpoms change with change in position
Malignancy (Lymphomatoid granulomatosis,
polymorphic reticulosis)
antiphospholipid antibodies
SMALL VESSELS
Mycotic aneurysms and embolization
Bacteremia/septicemia
Infective Endocarditis
Thrombocytopenia and other Purpuric Dis
VARIOUS VASCULITIC DISORDERS
1. PAN - Acute necrotizing vasculitis involving medium sized and small muscular arteries. Classically progressive frequently fatal toxic multisystem disease. Associated with hepatitis B, recently C, and hairy cell leukemia. 2 males:1 female all races kids-elderly average age is 40-60's. Can be limited to one or several organs, muscle or skin
1990 ACR Criteria for the classification of PAN (3 of 10 for classification, 3 or more yields sensitivity of 82.2% and specificity of 86.6%).
1. weight loss >4 kg - since illness began not due to other factors (dieting)
2. Livedo reticularis - palpable purpura, ischemia, ulcerations.
3. Testicular pain or tenderness - not due to other causes
4. Myalgias weakness or polyneuropathy -
5. Mononeuropathy - or polyneuropathy (mononeuritis, symmetric polyneuropathy ,sensory/motor)
6. Diastolic BP > 90 mm Hg -
7. Elevated BUN or Creatinine - (>40 mg/dl 0r Cr > 1.5 not due to dehydration or obstruction) 70% proteinuria to GN
8. Hepatitis B virus - Hep B S Ag or antibody in serum
9. arteriographic abnormality - aneurysms or occlusions of visceral arterieis not due to ASVD, fibromusc dysplasia or noninflammatory causes. Abd mensenteric thrombosis
10. Biopsy of small or medium sized arteries consistent with PAN
Dx - best made by biopsy of the symptomatic area - muscle, sural nerve, skin, testis
Positive results typically show an acute panmural focal necrotizing process with PMN invading the arterial walls.
If organs are not available for biopsy or suspected intra-abdominal involvement. Biopsies show; multiple aneurysms, narrowing, and luminal irregularities. Kidney biopsies are not helpful.
Management - varies with clinical picture. Initially Steroids 40-60 mg q day - the pt may respond. If patient fails - Cyclophosphamide 100-150 mg/day - orally if needed, or may use I.V. cyclophosphamide 500-1000mg q 3-4 weeks. Anitviral therapy may be useful in pts with associated hepatits viral infection Mortality highest during first year (GI infarcts, renal insufficiency, are the most common causes). Infection cardiovascular later. Drug side effects.The five year survival recently has been 75% !!!
2. Churg -Strauss - Allergic vasculitis angiitis and granulomatosis - systemic vasculitis that occurs with the triad of Asthma, eosinophilia, and allergic rhinnitis. may be 3 phases; a predominate URI, then a Loffleur's syndrome then systemic vasculitis. Skin common cardiac may be seeen.Renal and GI disease on occasion
1990 ACR Critieria for Classification
1. Asthma -
2. Eosinophilia - >10% of Diff
3. Mononeuropathy or polyneuropathy - moneuro or glove stocking or others
4. pulmonary infiltrates nonfixed - loffleur's like, may have fixed as well
5. Paranasal sinus abnormality - acute or chroninc sinus pain or tenderness or x-ray
6. Extravascular eosinophils - biopsies of vessels. bx - necrotizing granulomas as well as necrotizing vasculitis
TX - usually respond to GC 40-60.day
WEGENER'S - GRANULOMATOSIS - a multisystemic diseases characterized by necrosis, granuloma formation, vasculitis of the upper and the lower respiratory tracts and glomerulonephritis. Female= male, rare in kids, generalized or limited. Arthralgia arthritis, fever common. May be chronic/limited initially to the nasal structure subglottic region, lungs, Almost any organ can be affected. Progressive and fatal if not treated. 15% ocular (proptosis most common), fever 35% presentation, weight loss 35% overall (>10% body weight)
1990 ACR Criteria for the Classification of WG
1. nasal or oral inflammation - painful or painless oral ulcers, purulent or bloodynasal discharge.
2. abnormal CXR - nodules infiltrates or cavities
3. Urinary sediment abnormalities- microhematuria or RBC casts (18% Gn at presentation 75% eventually develop GN)
4. Granulomatous inflammation on biopsies - granulomatous changes within artery/arteriole or perivascular region
LAB
ANCA - Wegnener's patients develop antibodies to a serine protease found in the granules of neutrophils and mast cells. In Wegener's this cytoplasmic protein is expressed on the cell surfaces as well. Antibodies are created to the protein and are called "Antineutrophilic Cytoplasmic Antibodies" or ANCA. Now the principle antigen (PR3) can be tested for with ELISA. Both IIF and ELISA when positive for C-ANCA have a specificity of 98% for WG. These also tend to vary with disease activity.They may also themselves be pathogenic.
The C-ANCA pattern needs to be distinguished from the P-ANCA pattern. Here the principle antigen is myleoperoxidase (MPO) and tends to show a perinuclear appearance when looked at under IIF. P-ANCA is not specific for Wegener's. This is seen in many types of glomerulonephritidies, non-WG vasculitidies, and Goodpasture's disease. P-ANCA reactions are usually directed at MPO, but other antigens have been implicated (such as elastase). A P-ANCA not asscoiated with MPO has been described in Ulcerative Colitis and Crohn's disease.
Tx - Management -Cytoxan and Prednisone can give a 90% remission. Prednisone d/c'd after remission, cytoxan continued for one year. 100-150 mg each AM, pred is 40-60 q day. Increasing fluids will help protect bladder. MESNA a detoxifying agent may help prevent hemorrhagic cystitis. IV pulse cytoxan 500 to 1000 mg per 3-4 weeks may be an alternative less toxic but may not be as effective. Prednisone d/c'd after 1-3 months and cytoxan tappered and stopped after 12-15 months. Relapses of Wegener's may occur several months to years after cytoxan therapy. Trimethoprin-sulfamethoxazole is helpful (especially in limited WG) it role is not defined
Giant Cell Arteritis - Also referred to as cranial arteritis, temporal arteritis, and granulomatous arteritis. Usually involving the cranial branches of the arteries originating from the aortic arch. It is a generalized vasculitis of medium and large vessels. It is frequently associated with Polymyalgia Rheumatica (PMR). The nature of this assocation is not clearly understood. PMR is a clinical syndrome manifested by achiness and stiffness in the extremtiies and upper torso. (Shoulder girdle, hip girdle, neck)., plus evidence of inflammation. 50% of pts with TA have PMR, 10-20% of pts with PMR have a positive BX for TA. PMR is 3x's as prevalent as TA. Other diseases should be excluded (RA, thyroid, PM, chronic infections, malignacy).
Pathology - Inflammation tends to be patchy, long portions may be involved. The highest degree of involvement is found in the temporal arteries, also involved are the vertebral, opthalmic and posterior ciliary.
Clinically - Average age is 70 years rare under age 50. constititional symptoms are found. Onset is abrupt or insidious. May present as an FUO. females : males 2:1.Headaches are found in at least 66%. Usually localized to the temple, may be occipital. Can go away when disease is still active. Scalp tenderness is common and may occur around the vessels. Ocular pathology occurs. blindness is the most serious and irreversible. Jaw claudication is found in up to 66%. deafness, depression, peripheral neuropathy, abnormalities of transaminases (70% with elevated alk phos in one study), abnormal thyroid studies as well upper respiratiory symptoms in about 10% of patients.
Investigation - ESR is elevated and helps to follow treatment. Anemia (mild hypochromic may occur), WBC are usually normal SPEP may show an alpha2 globulin spike. Other acute phase reactants are no more helpful than the ESR Biopsy is the gold standard. A symptomatic or clinically abnormal area should be chosen for study. Several cm is size is often needed and often the other side should be biopsied if the first side in normal.
1990 ACR Criteria for the Classification of Giant Cell arteritis
1. Age of onset > or = 50 years
2. New Headache
3. Temporal artery abnormality - tenderness to palpation or a decreased pulsation unrelated to ASVD
4. Elevated ESR>= 50 per hour
5. Abnormal temopral biopsy
Treatment - Once diagnosis is suspected start treatment. High dose glucocorticoids 40-60 mg or prednisone /day is the usual starting does. This will alter the pathologic changes but biopsy can be done several days after the prednisone is started. The prednisone should be tapered at a maximum of about 10 % every 1-2 weeks. At times higher dosages may be needed and/or a second line agent used. (methotrexate, imuran). giant cell arteritis runs a self limited course over several years and eventually the GC can be reduced and stopped.
PMR requires less of a dose of steroid usually 5-15 mg of prednisone. If there are no other symptoms present. NSAIDS may be helpful in early disease
Amyloidosis
Intro- A syndrome characterized by the extracellular deposition of a highly soluble protein complex whixch may affect multiple organs....Generalized nonheredtiary forms occur in association with chronic inflammatory diseases (AA amyloid) and monoclonal gammopathies (AL amyloid)
CLINICALLY - involvement in vitals organs in particular the kidneys (AA) and the heart (AL). The disease generally runs a progressive course unless the production of the amyloid precursor protein can be successfully eliminated.
AA AMYLOID - This is a potentially fatal complicaton of chronic inflammatory diseases. . It is seen as a complication of RA, JCA, TB Osteomyelitis and other chronic inflammatory diseases.
the clinical manifestations are determined by the renal involvement. from mild proteinuria to the nephrotic syndrome. Renal function becomes disturbed results in ARF. Hepatomegaly may be part of the picute Infiltrative cardiomyopathy is RARE in AA amyloid (5%).
Typically persistent elevations of acute phase reactants can lead to amyloid devlopment
AL AMYLOID - The clinical picture of AL amyloid is more DIVERSE than that of AA. Here the main features are nephropathy and cardiomyopathy.. these are responsible for its poor prognosis. After clinically significant heart disease is diagnosed the average survivial is 7 months. Cardiomyopathy is the most frequent cause of death. Right sided failure and arrhythmia occur. Increased wall thickness restrictive cardiomyopathy.This type can be associated with multiple myeloma or the benign monoclonal gammopathy. If AL is suspected then a search should be made for a monoclonal gammopathy including serum immunoelectrophoresis, immunofixation of the urine, and immunofluorescence of bone marrow plasma cells. Amyloid cardiomyopathy is best detected by echocardiography
Para-articular deposition of amyloid is responsible for the AL amyloid arthropathy which can be found in 1-5% of cases of AL amyloid. Shoulders, knees, wrists, MCP, and IP. Characterisitic features also include shoulder-pad arthropathy, and carpal tunnel syndrome.
B2- Microglobulin amyloidosis - In patients who have been receiving HD for a long time (>50% over 5 years), some will devlop arthropathy due to depositon of B2 microglobulin amyloid. these patients classically show Pannus like swelling around the joints, tenosynovitis, and the devlopment of large cysts and eroisions of bone. CTS and spntaneous fractues also occur.
INVESTIGATIONS -
1. Identify the presence or absence of precursor proteins
2. Establish whether there is a major organ dysfunction
3. obtain evidence of amyloid deposition.
So if AA amyloid is suspected, look for inflammations with the ESR, CRP, and an assessment of renal function including 24 hour urinary protein excretion, and endogenous creatinine clearance.
Histological evidence of amyloid deposition can be obtained by
1. a general approach - sub Q fat aspirate of by rectal biopsy. These have an 80% true positive rate.
2. Or by a directed approach such as a renal or an endomyocardial biopsy with a true positive result of 90%. Amyloid should be identified using congo red staining and polarized microscopy (showing an aple green birefringence
DDX - The arthropathy associated with amyloid can mimic RA. A biopsy of para-articular tissue may be needed to establish the cause of joint swelling. In AA small deposits can be found in synovial vessel walls. CTS may be due to peritendinous synovitis or to amyloid deposits of either the AL of AH type.
In AA amyloid complicating RA either the disease itself of the concomitant antirheumatic medication may cause prtoeinuria. In about 15% of RA with proteinutria and a negative renal bx a positive rectal bx can be found.
MGMT - Reduction of the precursor protein appears to be the best approach to the mgmt of amyloid.
In AL, by reducing the monclonal component with melphalan/prednisone as in multiple myeloma is usefule. In "primary" amyloid the production of monclonal light chains is so small that they cannot be used to assess treatment.
In AA, amyloid treatment should be directed toward reducing the acute phase response including SAA synthesis. Elimination of the associated inflammatory disease or a nonspecific suppresson of inflammatory activity may favorable alter the course of the amyloidosis. the use of steroids and cytotoxic drugs to decrease the inflammatory response is indicated. In established AA amyloid prolonged infectons or surgical procedures may accelerate amyloid depositon. Careful monitoring is essential.
1. Adult Still's disease (ASD) is an inflammatory disorder characterized by daily, spiking high fevers, arthritis, and an evanescent rash. First described in children by George Still in 1896, "Still's disease" became the eponymous term for juvenile rheumatoid arthritis and is now called systemic onset juvenile rheumatoid arthritis ETIOLOGY – The etiology of ASD is unknown EPIDEMIOLOGY – equal sex distribution. There is a bimodal age distribution, with one peak between the ages of 15 and 25 and the second between the ages of 36 and 46. However, occasional patients present with ASD after the age of 70.
DIAGNOSTIC CRITERIA – There is no specific test or combination of tests that can be used to establish the diagnosis of ASD. Thus, a number of different classification criteria have been proposed. To establish a diagnosis of ASD requires the presence of certain major or minor criteria or a combination of both and the absence of certain exclusions. Major criteria – The proposed major criteria include
1. Fever of at least 39°C lasting one week or longer The fever of ASD is usually quotidian or "double- quotidian" with a brief peak in the late afternoon or early evening.
2. Arthralgias or arthritis lasting two weeks or longer The most commonly involved joints, in descending order, are the knees, wrists, ankles, elbows, proximal interphalangeal joints and shoulders. The synovial fluid is usually inflammatory, with a mean leukocyte count of 13,000 cells/µL but a range from 100 to 48,200 cells/µL
3. Characteristic rash which is a macular or maculopapular, nonpruritic salmon-pink eruption, usually apparent over the trunk or extremities during febrile episodes
4. Leukocytosis (10,000/µL or greater) with 80 percent or more granulocytes.
Minor criteria – Minor criteria include:
• Sore throat .. Pharyngitis – A severe, nonsuppurative pharyngitis frequently occurs. One review of 341 cases noted sore throat, which can recur with disease relapses, in 69 percent
• The recent development of significant lymph node swelling
• Hepatomegaly or splenomegaly
• Abnormal liver function studies, particularly aminotransferases and lactate dehydrogenase
• Negative tests for antinuclear antibody and rheumatoid factor.
Exclusions – The following findings must not be present in ASD:
• Infection, such as infectious mononucleosis or parvovirus B19 • Malignancy, particularly lymphoma
• Other rheumatic diseases such as polyarteritis nodosa, systemic lupus erythematosus, or rheumatoid vasculitis with extraarticular features.
LABORATORY FINDINGS – A number of laboratory findings are characteristically seen in patients with ASD. None is specific for ASD, but the constellation of the clinical features listed above plus the presence of these laboratory features should alert the clinician to the possibility of ASD.
An elevated erythrocyte sedimentation rate (ESR) is seen in virtually all patients. It is typically accompanied by a leukocytosis, with the peripheral white blood cell count exceeding 15,000 cells/µL. There is a predominance of granulocytes and the presence of immature forms, including bands, may suggest a septic process. A normocytic, normochromic anemia with a hemoglobin less than or equal to 10 g/dL is seen in the majority of patients, and a reactive thrombocytosis is common.Liver function studies – Elevations in the serum aminotransferases and lactate dehydrogenase are seen in 75 percent of patients with ASD. A wide range of values has been observed, from minimally abnormal to fulminant hepatic necrosis and death. The liver biopsy findings are nonspecific .Serum ferritin - ASD has been associated with markedly elevated serum ferritin concentrations in as many as 70 percent of patients. This is probably an acute phase response since hepatocytes responding to inflammatory cytokines can increase ferritin synthesis. The elevations correlate with disease activity, and have been suggested as a serologic marker to monitor response to treatment. Serum ferritin concentrations exceeding 3000 ng/mL (normal 40 to 200 ng/mL) have been observed in ASD, with patients having values above 10,000 ng/mL
It has been suggested that serum ferritin values above 3000 ng/mL in a patient with compatible symptoms should lead to suspicion of ASD in the absence of a bacterial or viral infection. Glycosylation of ferritin also may help distinguish ASD from other rheumatic diseases. In one study, the percentage of glycosylated ferritin in patients with the ASD was markedly lower than in other inflammatory diseases. (3.7 versus 30 percent).
COURSE – The clinical course of ASD can be divided into three main patterns. Approximately one-third of patients fall into each group.
1. A self-limited or monophasic pattern usually lasts less than one year, with complete resolution of symptoms. 2. A polycyclic or intermittent course in which there are one or more flares of disease with complete remission between episodes. Although subsequent flares cannot be predicted, they tend to be less severe and of shorter duration. 3. A chronic course of ASD is characterized by persistently active disease, usually due to a chronic, destructive arthritis. Although some patients require total joint arthroplasty, about one-quarter of patients in this group eventually improve after many years.
TREATMENT – Therapeutic decisions should be based upon the organ involvement and the severity of the disease. The choices are nonsteroidal antiinflammatory drug (NSAIDs) and aspirin, corticosteroids, and immunomodulating drugs.
There are a variety of rheumatic disorders that have been associated with HIV infection. They involve both infectious and noninfectious causes
1.Increased risk for infections - Septic Arthritis - Joint infection has been well documented (especially in IVDA). Staph Aureus remains the number one bug. Also cultured have been Strep pneumoniae, various Mycobacterial species, Nocardia and others. Considering the degree of immune suppression the prevalence is less than one might expect.2. Increased immunologic disorders Myositis - Both HIV and the medications used ( AZT induced mitochondrial myopathy) have been associated with myositis Also Toxoplasmosis may be the causative agent. HIV itself might induce and immune inflammatory response rather than directly attacking the muscle. Pyomyositis has also been reported. 3. Sjogren’s like syndrome - also called Diffuse Infiltrative Lymphocytosis Syndrome (DILS) has been reported. Dry mouth (less often dry eyes) and generalized lymphadenopathy have been reported. DILS has extraglandular features (like interstitial pneumonitis), shows infiltration with CD8 cells as opposed to CD 4 in SS, has a lower association with antibodies and is HLA-DR5 associated. (SS is B8, DR2, DR3, and DR4) Steroids appear to be tolerated fairly well as treatment in these patients 4. Reactive Arthritis - Both the HIV patient and the nonHIV patient will show an association with HLA-B27 and reactive arthritis. In HIV infected patients the risk of developing Reiter’s syndrome is 144 to 312 fold that of the normal population. In those of high risk there has been an aggressive form described. The greatest risk is unprotected homosexual contact. Reiter’s syndrome may precede Symptomatic HIV infection by up to 12 months. . These patients classically have a large joint lower extremity, oligoarthritis that is often associated with achilles tendonitis (enthesopathy) and dactylitis. They also show less conjunctivitis and uveitis. They may show keratoderma blenorrhagicum a psoriatic like skin rash. About ½ will show radiographic changes. Because of the overlap between these two disorders some have suggested calling both of them undifferentiated spondyloarthropathy.5. Psoriatic Arthritis - HIV patients show a diverse number of psoriatic disorders. The arthritis is also common and tends to resemble that of Reiter’s syndrome. Nail changes are common.
6.Arthralgias - this is the most common rheumatic manifestation of HIV infection. 10-35% of patients will complain of arthralgias. On occasion these can be severe and disabling. These may also occur during the time of seroconversion. As a rule arthralgias tend to be intermittent and involve large joints.7. Fibromyalgia - Several studies have reported fibromyalgia in 10-20% of patients with HIV. This may be increased in those that are depressed.
Treatment - treatment in HIV related Rheumatic disease becomes a risk vs benefit issue. NSAIDS are the first line of drugs for those with articular disease. Most patients show a good response. There is limited data on steroids in HIV articualr disease sort courses appear to be OK. They may be safer than previously thought. DMARDS need to be used very cautiously
SERONEGATIVE SPONDYLOARTHROPATHIES
This is a group of related multisystem disorders that affect the spine, peripheral joints, periarticular structures and also may show extraarticular manifestiations. clinically these may show the following:
a. involvement of the SI joints
b. peripheral inflammatory arthropathy
c. The absence of Rheumatoid factor
d. Enthesopathy - inflammation at the site of ligamentous insertions into bone. These changes can also affect the aortic valve, the lung parenchyma (often apicies), the eye (anterior inflammation) and the skin.
e. There exists clinical overlap between these seronegative spondyloarthropathies. A pt with Psoriatic arthropathy can develop uveitis and sacroiliitis while pt with inflammatory bowel disease can develop mouth ulcers and spinal involvement.
f. familial involvement
g. antecedent infection - genital or intestinal
h.The presence of HLA-B27 (Though this is not necessary nor does it mean the development of these disorders)
1. Ankylosing spondylitis "bent spine" involves the SI joints and progresses upwards with varying degrees to the rest of the spine. Clinically you see
a. insidious onset, less than 20 years old, persistent for more than 3 months, morning stiffness, improves with exercise. male 3:1 females
b. radiologically there is squaring of the vertebral bodies early on and the classic bamboo spine later in the disease caused by marginal syndesmophytes secondary to endochondral ossification of the superficial layers of the annulus fibrosis.
c. 90% are HLA-B27 positive. Do not however use this as a screening test it is expensive and the wrong answer on the boards. 7% of North American Caucasians are + HLA-B27. HLA-B27 has a 1-2% of HLA-B27 have AS. The concordance rate of identical twins is 60% (environmental factors probably involved).
d. peripheral joint involvement - especially the lower limbs is seen in 20-30%, ...uveitis in 25%
e. Severe cases can get apical pulmonary fibrosis. Also aortic incompetence, and conduction defects. Anterior uveitis is the most common extraarticular manifestation. microscopic inflammatory ileocecal valve and colonic lesions have been found in many with AS. Amyloidosis may be present in up to 10 percent of patients, although it appears to be of little clinical significance in most cases Amyloidosis may be present in up to 10 percent of patients, although it appears to be of little clinical significance in most cases. IGA nephropathy has also been reported.
f. The most common presenting complaint is back pain, and stiffness.
g. screening test is the Schober test. 5 cm below the PSIS and 10 cm above. Flerx forward should increase by 5cm or more. Also pain over the SI joints.
H. Tx.-Indomethacin is the drug of choice. Treat complications. PT is helpful. Avoid smoking. Sulfasalazine is used often as a second line drug. Anti-TNF therapies show tremendous promise.
I. Differentiate it from DISH
2. Reactive Arthritis/Reiter's Syndrome - In a cavalry officer in 1916 Hans Reiter described the case of a soldier with arthritis, nongonococcal urethritis, and conjunctivitis. Now often grouped as a “reactive arthritis”.Chlamydia trachomatous and Ureaplasm are associated infectious agents. Can also be caused by infectious diarrhea (SSYC) Other features are:
a. male to female ratio 5:1 for venereal but closer to 1:1 for enteric
b. onset is sudden 2-6 weeks after infectious episode
c. three classic musculoskeletal findings
1. sausage digits
2. lower extremity/achilles tendon insertion involvement
3. low back pain
d.GU - nongonococcal urethritis. In women may not see this easily. May give hx of PID, cervicitis.
e. conjunctivitis - can get uveitis iritis, scleritis
f. skin - balanitis circinata small shallow painless ulcers on glans penis or urethral meatus. Keratoderma blennorhagica - hyperkeratotic skin lesions mostly on the soles of the feet
g. sacroiliitis - often asymmetric
h. enthesopathy - can see erosions at insertion sites
i. Syndesmophytes - asymmetric, skip disc spaces (as opposed to AS)
j. HLA-B27 in 80% pts
k. Tx - Again NSAIDS are most important with Indomethacin being most active. Systemic steroids are of no effect. Severe cases can use MTX, Azathioprine, and sulfasalazine.
l. the first rheumatic disease to be associated with HIV.
3. Psoriatic arthritis 5-20% of psoriasis pts develop arthritis. Also HLA-B27 associated.(50% with axial)
a Joint involvement varies. 95% have peripheral involvement...40% have spondylitis, 20% with sacroiliitis...5% have only spinal involvement. Most often a combination is observed.
b. Enthesopathy occurs
c. The "sausage digit" occurs here also.
d. Arthritis can precede the rash.
e NAIL PITTING and ridging are found. Associated more with arthropathy than without 80% vs 20%.
f. Associated diseses like the other variants (uveitis commonly 30%)
G. Lab - mildly elevated ESR, hyperuricemia can occur, Inflammatory synovium,
h. radiographically - can see distal erosive disease. With a PENCIL and CUP deformity, can see severe osteolysis with complete joint destruction "arthritis mutilans". can see sacroiliitis
Tx. - PT, move joints full ROM each day. NSAIDS are first line drugs. Indomethacin often used. Of the second line agents MTX is the best. It helps skin and joints. Psoralen and UVA may help peripheral but not axial arthritis. Other immunosupressives are also used. Though presently used off label, the anti-TNF drugs show tremendous promise in treating both psoriasis and psoriatic arthritis
4. Enteropathic arthritis - Seen with UC and Crohn's. Typically it is transient, oligoarticular, nondestructive arthritis that is found more in increased bowel disease
activity. Knees and ankle most commonly involved.
a. peripheral arthritis is not associated with HLA-B27.
b. axial arthritis is associated with HLA-B27 (50%)
5.Undifferentiated Spondyloarthropathy - the term reserved for those with clinical findings suggestive of a spondyloarthropathy but not enough criteria to fit the Diagnosis
Scleroderma: Systemic sclerosis is a connective tissue disease that is characterized by fibrosis of skin and various organs.There is overproduction and the accumulation of collagen and other extracellular proteins in the skin and other organs. This results in three basic abnormalities 1) a vasculopathy 2) increased fibroblastic activity, 3) thickening of skin and internal organs.It is associated with various autoantibodies, the activation of fibroblasts and microvascular disturbances. Its etiology is unknown. F:M is 4:1 peaks in the 5th and 6th decade, 1/100,000 B>W. Suggestions of a hereditary predisposition.
Pathogenesis:
1.An early vascular finding is Raynaud’s Phenomena. (often the initial symptom in scleroderma) Intimal hyperplasia is the major vascular cause of structural narrowing. The capillary loss may be viewed by nailfold capillaroscopy.
2. When compared to a normal person, the fibroblasts of SSc patients have aberrant growth regulation. They appear to be in a state of permanent activation.
3. TGF-B plays a large role in stimulating fibroblasts, PDGF (platelet derived growth factor) also is a fibroblast stimulator, while IL-1 ( from macrophages) and IL-2 (from activated T Cells) also promote fibroblast function.
Types: Scleroderma may exist in various forms.:
1. Localized skin SSc. - there are two forms
Morphea - single or multiple plaques of skin induration
Linear scleroderma which involves an extremity or the face.
2. Limited Scleroderma: a form which involves distal extremities and the face. This subset frequently shows features of the CREST syndrome. The CREST syndrome is an acronym for Calcinosis, Raynaud’s phenomena ( an early clinical expression of small vessel damage), Esophageal dysmotility, Sclerodactyly and Telangiectasias. This may also feature other GI involvement and Pulmonary disease.
3. Diffuse Scleroderma. - this features the development of SSc involving the proximal and distal extremities, and the trunk. It has a higher risk for organ involvement.
4. Overlap syndrome describes those with features of Scleroderma with another CTD
5. UDCTD - is saved for those who do not have classic features of any one Rheumatic disorder
6. MCTD - features of various connective tissues disorders (RA,SLE,PM/DM SSC etc. ) along with high titers of RNP.
Clinically -a closer look at the various clinical features
1. Raynaud’s - 95% don’t need the classic three colors of white, blue then red. If present for years less likely to develop SSc. small arteries and arterioles. define acrocyanosis. Treatment - dress warm, no tbbc, decrease stress avoid ergotamines, beta blockers +/-, amphetamines. Drugs that vasodilate such as calcium channel blockers (dihydropyridine derivatives seem to be the best ie..nifedipine) are the best initial choices. Also those that block sympathetic peripheral vasoconstriction (reserpine, prazosin, alpha-methyldopa) may be used. Topical nitrates are sometimes used. Iloprost a prostacyclin analogue. Biofeedback has also been used, Surgical sympathectomy and nerve blocks have also been used.
2. Musculoskeletal - pain swelling and puffiness in over half. Can develop a RA like symmetric arthritis. CTS may develop. Crepitations along several joints. muscle weakness or myositis if overlap. Tendon friction rubs
3. Skin - early on edematous phase weeks-months years. hands face fingers swollen spares lower extremities. Skin then becomes firm thickened indurated May stop or go to a progression involving trunk. If rapid associated with visceral involvement. Skin may soften later on in life. Flexion contractures later in hands. Ulcerations, pitting scars of the volar pads, boney resorption of terminal phalanges.May see areas of hyperpigmentation. Calcific deposits in the intra and subcutaneous tissues. microstomia, Capillaries - ectasias seen in limited. Drop out is seen with ectasias in diffuse scleroderma. Not seen in isolated Raynaud’s.
4. GI - After Raynaud’s and skin this is the third most common manifestation of scleroderma.50% esophageal decreased tone of the LES and dilated distal esophagous. May see peptic esophagitis with stricture. Reflux esophagitis - small meals, elevation of the head of the bed, avoid coffee, tea, chocolate. H2 antagonists, Pump inhibitors, and prokinetic agents are useful. Hypomotility of stomach, and small intestine may also occur. Malabsorption syndromes. Chronic constipation or intermittent diarrhea. Malabsorption can be corrected with antibiotics and if needed, hyperalimentation. (dx with d-xylose or quantitative fecal fat). In the colocn hypomotility also pseudo-obstruction. Also wide-mouth diverticuli (uncommon source of bleeding)
5. Pulmonary - 2/3 affect lungs. Leading cause of death .Exertional dyspnea most common. May see symptoms w/o pulm fibrosis. . Increased frequency of alveolar cell and bronchogenic CA in pulm fibrosis. Abnormal PFTs. These are the mainstay of making the diagnosis.Low DLCO low pO2 with exercise. May develop Pulmonary hypertension. <10% This is a poor prognosis Avg survival is 2 years. Worse for Limited with isolated Pulmonary Hypertension. Uncertain as to the role of preventing inflammation in the lung so as to slow the progression of fibrosis.
6. Cardiac - Most with diffuse. some with myocardial fibrosis (<10%). A high prevelance of both supraventricular and ventricular tachycardia arrhythmias. Right sided changes . Patchy areas of involvement in about 80%. pericarditis is uncommon as is tamponade.
7. Renal - Diffuse worse. Malignant hypertension rapidly progressive renal insufficiency, microangiopathic hemolysis, and consumptive thrombocytopenia in the setting of hyperreninemia constitute the scleroderma renal crisis. This can progress to renal failure. HTN encephalopathy, seizures, headaches, retinopathy and LV failure may occur. Proteinuria and hematuria may occur. Caused by activation of the renin-angiotensin system. Remember ACE inhibitors if HTN renal crisis. Propranolol, clonidine, minoxidil have also been used.
8. Others - Dry eyes and dry mouth could be Sjogren’s or periglandular fibrosis. A biopsy of the lip and SSA/SSB are consistent with Sjogren’s. An association with hypothyroidism (fibrosis) is also reported
LAB - May see increased ESR, anemia of chronic disease, GI bleeding with anemia, B12.folated deficiency, MAHA caused by intravascular fibrin in the renal arterioles. Hypergammaglobulinemia (Gig in most) 50%, RF 25% (low titer) ANA with (hep-2) is about 95% Ana’s are anti-topoisomerase I (Recognizes DNA topoisomerase originally called SCL-70 (seen in 20% , with diffuse , with ILD). Anti-nucleolar (RNA polymerase I (higher prevalence of renal and cardiac disease) Anti- U3 nucleolar RNP highly specific for SSc. and anti-centromere antibodies which react with proteins in the kinetochore region of the chromosome. (By IIF)Course and prognosis - variable prognosis. Estimates show a 5 year survival of about 70%. Most common causes of death is secondary to pulmonary disease. Poorer prognosis with pulmonary, cardiac, GI, and Renal disease.
Treatment - Cannot be cured. Try to control symptoms and organ involvement. Other modalities include
1. Penicllamine – never been shown to be.
2. Antiplatelet therapy appears to be helpful but no study has proven its worth. Low doses of ASA block Thromboxane A2 (a powerful vasoconstrictor and platelet aggregator). Dipyridamole has not been shown to be helpful though it may help raynaud’s.
3. Glucocorticoids - best with inflammatory myositis or pericarditis. Small dose <10 mg/day in those with arthritis. Not otherwise indicated in treating SSc. Big doses may exacerbate renal crisis
4. Methotrexate and cyclosporin A.
5. It is important to maintain flexibility, and local care of digital infections is crucial.
6.Yearly vaccinations, supplemental O2 if hypoxic
7. Iloprost - a prostacyclin analogue. Bosetan an endothelin receptor antagonist. Works for Pulmonary HTN
.
Other Scleroderma Like Illnesses
There are some environmental pathogens associated with SSc like disorders. These are caused by a variety of factors. They include disorders that result in edematous changes and/or fibrotic changes in the skin and subcutaneous tissues. These can mimic scleroderma. They are accompanied by eosinophilia, constitutional symptoms and soft tissue changes of the extremities.
A. As a rule they do not involve Raynaud's (present in 75% of initial scleroderma and 95% of established scleroderma), Sclerodactyly, Fingertip ulceration and no evidence of nail fold capillary dilatation or capillary drop-out.
2. Some suggestion of silica dust in gold and coal miners. (no proven association with breast implants) polyvinyl chloride, benzene, bleomycin produces skin changes fibrotic skin nodules, linear hyperpigmentation, alopecia, pulmonary fibrosis
3. Eosinophilic fasciitis - A scleroderma like illness seen in adults, and associated with vigorous exercise followed by swelling and eventual thickening/induration of the skin. May resolve spontaneously. Tx is steroids.