MOLECULAR ABNORMALITIES OF COLLAGEN AND FIBRILLIN 477 Table 16.14 Clinical features and genetics of EDS Type Inheritance Genetic defect Common Clinical picture Hyper-lax skin. Profound bruising and scarring Classical (type I and II) AD Abnormal pro-alpha 1 and 2 encoded by COL5A1 and A2 gene Hypermobility (Type III) AD Not known. ? Tenascin X insuf \201 ciency See BJHS, Table 16.16 Vascular (Type IV) AD Abnormal pro-alpha 1 encoded by COL3A1 gene Characteristic facies \200\224wide spaced eyes, lobeless ears. Vascular rupture Kyphoscoliosis (Type VI) AR De \201 ciency of lysyl hydroxylase Severe hypotonia. Scoliosis. Scleral fragility Atherochalasia (Type VII subtype) AD Abnormal pro-alpha 1 and 2 encoded by COL1A1 and A2 Severe dislocations. Skin laxity. Bruising. Hypotonia Dermatospraxis (Type VII subtype) AR De \201 ciency of procollagen 1 peptidase Severe, sagging skin. Bruising. Hernias Rare forms: X-linked (Type V) X-linked ? Milder version of Classical type Periodontal (Type VIII) AD ? Classical with gum fragility Type X ?AR ? Milder version of classical type with platelet aggregation AD-autosomal dominant; AR-autosomal recessive CHAPTER 16 Metabolic bone diseases 478 Treatment of hypermobility syndrome \200 Although hypermobility diminishes with age, the symptoms tend to continue and may worsen. It is important to remember that older patients may have been previously more mobile and that the Beighton score may not be an appropriate measure. A his tory of joint laxity should be sought. \200 Hypermobility extends beyond the joints highl ighted in the Beighton scale. The clinician should look at the \201 ngers, shoulders, nec k, hips, patellofemoral joint, and skin laxity. Analgesics are often unhelpful for chronic pain but have their place for the treatment of a cute symptoms. Pain and fatigue cause signi \201 cant morbidity. Joint stabilizing exercises with particular reference to core stability, posture and propri oception are bene \201 cial, as may be advice on avoiding overuse injuries and practical w ays of managing day-to-day activities. A global approach to joint stability and function, a s opposed to just treating regional symptoms, is effective. Pain management should be considered in chronic pain cases. This might include for example, cognitive behavioral therapy and the process is similar to that used in \201 bromyalgia (see Chapter 18). \200 The role of serotonergic/noradrenergic agents in these patients is unclear. In part there may be effective control of depression, however, there may also be d irect analgesic properties to these agents. Neuroleptic agents for neuropathic pain have not been studied in this group of patients. Ho wever, gabapentin or pregabalin and other similar agents may have a role. Table 16.15 Beighton hypermobility rating Subject has the ability to: Right Left 1. Passively dorsi \202 ex the \201 fth metacarpophalangeal joint to (cid:2) 90 1 1 2. Oppose the thumb to the volar aspect of the ipsilateral Forearm 1 1 3. Hyperextend the elbow (cid:2) 10 1 1 4. Hyperextend the knee (cid:2) 10 1 1 5. Place hands \202 at on the \202 oor without bending the knees 1 Possible total score 9 MOLECULAR ABNORMALITIES OF COLLAGEN AND FIBRILLIN 479 Table 16.16 The Brighton (1998) criteria for benign joint hypermobility syndrome Major criteria A Beighton score of 4 out of 9 or greater (current or historical) Arthralgias for > 3 months in four or more joints Minor criteria A Beighton score of 1, 2, or 3 out of 9 Arthralgias in one to three joints or back pain, either for longer than 3 months, spondylos is/spondylolisthesis Dislocation/subluxation in > one joint, or one joint on > one occasion Soft tissue rheumatism in three or more sites Marfanoid habitus Abnormal skin: striae, hyperextensibility, papyraceous scars Eye signs: drooping eyelids, myopia, Varicose veins, hernias, uterine/rectal prolapse Rare chondrodysplasias and storage disorders There are >150 distinctive chondrodysplasias r epresenting autosomal dominant, recessive, and X-linked patterns of inheritance. The \201 rst identi- \201 ed mutations were found in the collagen 2A1 gene, and are associated wi th premature osteoarthrosis. Such conditions include achondrogenesis, Kniest syndrome, spon dyloepiphyseal dysplasia, and the Stickler syndrome. Clinical features in the latter three conditions include premature joint destruction, joint/bone deformity, short stature, and pr ogressive myopia (with or without retinal detachment). Stickler syndrome patients are also prone to hernias and cardiac valvular and conduction disorders. Storage diseases associated with progressive skeletal dysplasia include: Mucopolysaccharidoses, e.g., Hurler, Hunter, Scheie \200 Mucolipidoses \200 Sphingolipi doses \200 Gaucher \200\231s disease \200 Fabry \200\231s disease. The detail and compl exities of these conditions is beyond the scope of this book. This page intentionally left blank 481 Chapter 17 Infection and rheumatic disease Introduction 482 Pyogenic nongonococcal and gonococcal arthritides 486 Pyogenic nongonococc al & gonococcal arthritides 488 Mycobacterium tuberculosis 490 Osteomyelitis 492 Lyme disea se 494 Rheumatic fever 496 CHAPTER 17 Infection and rheumatic disease 482 Introduction Infectious agents have been linked directly and indirectly (through organ- ism -speci \201 c and autoimmune responses) to a number of acute and chronic in \202 ammatory rheumatic diseases. This chapter will introduce some exam- ples of in \202 ammatory mecha nisms (see Table 17.1) and infectious agents (see Table 17.2) linked to rheumatic disease, and then discuss septic arthri- tis, osteomyelitis, Lyme disease, and rheumatic fever. Table 17.1 Pathogenesis of rheumatic disease associated with infection In \202 ammatory process Basic process Example Susceptibility Local infection at musculoskeletal sites Infection. Tissue in \202 ammation and direct damage Pyogenic septic arthritis Structural damage to joint replacement Diabetes, complement and immunoglobulin de \201 cie ncies Pathogen and pathogen-speci \201 c immune response Infection and organism-speci \201 c response. Immune response to intact organismor fragmen ts, probable immune complex- mediated tissue injury Syndromes associated with viral hepatitis, e.g., Sj gren \200\231s syndrome Not generally established Pathogens, immuneresponse, and auto immunity i. Cross-reactive immune response Rheumatic fever Rheumatoid arthritis Juvenile idiopathic arthritis Systemic lupus erythemat osus Certain MHC class I and II genes Receptor genes MHC class I and II genes T-cell receptor ge nes ii. Infection inferred but not established autoreactivity I N T R O D U C T O N I 4 8 3 CHAPTER 17 Infection and rheumatic disease 484 Table 17.2 Selected pathogens associated with arthritis Class Examples Disorder Bacteria Staphylococcus and Streptococcus Non-gonococcal arthritis Septic monoarthritis Osteomyelitis Neisseria spp Gonococcal arthritis Brucella Septic monoarthritis Spondylarthropathy Chlamydia Reactive (formerly, Reiter \200\231s) Mycobacteria M. tuberculosis Osteomyelitis Spinal disease Monoarthropathy Atypical mycobacteria M. avium complex M. malmoense Septic arthritis in immunosuppressed patients Spirochete Borrelia burgdorferi Lyme disease Viruses Parvovirus B19 Fifth disease Rubella Polyarthropathy Hepatitis B Polyarteritis nodosa Hepatitis C Cryoglobulinemia Sj gren \200\231s syndrome HIV Polyarthralgia and myopathy Vasculitis Sicca syndrome Protozoa Toxoplasma Polyarthritis Giardia Oligoarthritis Small-vessel vasculitis Trypanosoma Myopathy Helminths Toxocara All cause myositis and arthritis Dracunculus Schistosoma Fungi Histoplasma Can cause monoarthropathy Cryptococcus This page intentionally left blank CHAPTER 17 Infection and rheumatic disease 486 Pyogenic nongonococcal and gonococcal arthritides \200 Septic arthritis caused by a pyoge nic bacterium is a medical emergency. Incidence in the general population is 2 \200\22310 p er 100,000, rising to 30 \200\22370 per 100,000 in those with autoimmune rheumatic disease or prosthetic joint replacements. Most cases are due to hematogenous seeding during transient bacteremia, but septic arthriti s can also be caused by direct penetration through the skin or by local spread from a conti guous infected site. Joints damaged by chronic arthritis (e.g., RA, OA) and prosthetic joints are at increased r isk of infection. Immunode \201 ciency states and diabetes are added risk factors. Transient synovitis, particularly of the hip, is not uncommon in children, and generally occurs after upper respiratory tract infection. The presence of thr ee of the following favors the diagnosis of septic arthritis: an elevated serum white blood cell count, inability to bear weight, recent history of fever, and elevated erythrocyte se dimentation rate. The most common pathogens are Staphylococcus aureus, Streptococcus spp and Neisseria gonorr hoeae in adults. Prior to the development of the vaccine, Haemophilus in \202 uenzae was a common cause of septic arthritis. The clinical features and natural history of gonococcal and nongonococcal arthritis are suf \201 ciently distinct to discuss them separately (see Table 17.3). Unusual organisms may be involved in patients with a current history of IV drug abuse, or those who are immunosuppressed. Salmonella may cause septic arthritis among patients with sickle cell disease. Management of pyogenic joint infection Three principles determine outcome: prompt diagnosis , immediate institution of appropriate antibiotics, and adequate drainage of joint. \200 Speci \201 c tests for infection should include joint aspiration, Gram stain, and culture of synovial \202 uid; blood cultures, and (if relevant) skin/rash swabs and oral and urethral swabs. Surgical drainage and washout or daily arthrocentesis may be required for nongonococcal septic arthritis. Plain radiographs in early disease are unhelpful, since they show only soft tissue swelling . In later untreated disease, joint space narrowing and erosion will be seen. Ultrasound ma y show a joint effusion. \200 An affected joint should be rested and nonweight-bearing un til the in \202 ammation and pain have subsided enough to allow passive mobilization. Mobiliza tion should be encouraged as soon as possible. Empiric therapy with a third-generation cephalosporin should be started while waiting for culture data. Consider vancomycin in areas where community acquir ed MRSA is prevalent. Pseudomonas spp. should be suspected in intravenous drug users. PYOGENIC NONGONOCOCCAL & GONOCOCCAL ARTHRITIDES 487 Table 17.3 Clinical features of gonococcal and nongonococcal arthritis Gonococcal arthritis Nongonococcal arthritis Causative agents: Causative agents: Neisseria gonorrhoeae Neisseria meningitidis Staphylococcus aureus (50% of cases) Staphylococcus epidermis (15% of cases) S treptococcus pyogenes/pneumoniae (20% of cases) Gram-negative bacteria (10% of cases) anaerobes (5% of cases) Most often in young, healthy adults Most often in the elderly, or underlying joint or medical condition Women > men Men > women Hip disease uncommon Hip disease common (20% of cases) Migratory polyarthritis common Polyarthritis uncommon Monoarthritis very common Rash, skin blisters/pustules, tenosynovitis common Extra-articular manifestations common Synovial \202 uid analysis: Synovial \202 uid analysis: Gram \200\231s stain is positive in 25% Culture positive, 50% Lactate normal Gram \200\231s stain is positive in 60% Culture positive, 90% Lactate raised Rapid response to therapy Often slow response, may require surgery Full recovery in most cases 10% mortality; one-third residual damage Duration of therapy should be based on the organism and response to therapy. One general ap proach is to treat with IV antibiotics for 7 to 14 days (until the swelling subsides and bl ood cultures are negative), followed by another 2 \200\2234 weeks of an appropriate oral an tibiotic. \200 There are no studies comparing long and short courses of antibiotics. \200 Septic arthritis involving a prosthetic joint should be treated in a stepwise fashion . First, the prosthetic should be removed and replaced with an antibiotic-impregnated space r; the patient should receive intravenous antibiotics for six weeks. Two to four weeks afte r antibiotics are \201 nished, the joint should be aspirated; if there continues to be ev idence of infection, intravenous antibiotics should be administered for another six weeks. When the aspirate shows no evidence of infection, the joint can be replaced, using antibiot ic- impregnated cement. CHAPTER 17 Infection and rheumatic disease 488 Under no circumstances should a joint be injected with corticosteroid if intra-articular in fection is suspected, or if there is super \201 cial infection over the skin covering a jo int, e.g., cellulitis/psoriasis. Likewise, there is no bene \201 t from intra-articular an tibiotics; indeed, these drugs may cause a chemical synovitis. Management of septic bursitis \200 The two most common sites of bursal infection are the olecranon and prepatellar bursae. These are usually managed with serial aspiration and oral antibiotics. Those who do not respond will need IV antibiotics and surgical incision and d rainage. Osteomyelitis is a potential complication of chronic infected bursitis. This page intentionally left blank CHAPTER 17 Infection and rheumatic disease 490 Mycobacterium tuberculosis \200 Until 1985, the United States and Europe saw a decline in the number of tuberculosis (TB) cases. The appearance of acquired immune de \201 ciency syndrome halt ed that trend. More recently, the recurrence of TB has become an important complication of new disease modifying antirheumatic therapies. It is estimated that one-third of the world \200\231s population is infected with TB. In in dustrialized countries <5% of cases of TB develop infection of bone or joints. Tuberculosis of bone is usually a low grade and slow progressive infection associated with a variable degree of local and systemic symptoms such as fatigue, weight loss, or night swe ats. The onset is insidious and usually mono-articular or mono-osseous. Predisposing factor s include pre-existing arthritis, alcoholism, prolonged use of corticosteroids, and immunos uppression. TB can affect any part of the musculoskeletal system. The spine is a common site, whether within a vertebral body, disc, or a paravertebral abscess. Spinal-cord compression due to vertebral destruction and/ or soft tissue swelling due to an abscess is a serious complication and must be treated emergently, with review by a neurosurgeon. Spin al stabilization procedures carry a good prognosis in preventing neurological sequelae. Mon oarticular disease is seen most often in the weight-bearing joints of the hip, knee, ankle or sacroiliac joint, in that order. The wrist and shoulder are less commonly affected. Oste omyelitis may affect any long bone and is associated with either solitary or multifocal cys ts. The diagnosis of TB is made by identifying acid-fast bacilli from a lesion or by histopatho logical changes in excised tissue. Occasionally, a high level of clinical suspicion, in the absence of other identi \201 ed pathology, will lead the physician to treat empirically. Standard anti-TB regimens should be used for treatment and surveillance for 1 year after th e end of treatment is recommended. Surgical intervention may be necessary; this may take th e form for example of tissue biopsy, debridement of necrotic tissue, or stabilization of a joint or long bone. Because of the association between TNF- A inhibitors and disseminated tuberculosis, the ide nti \201 cation of latent TB has become increasingly important. This is accomplished using a tuberculin skin test (PPD). Induration of greater than 5 mm should be considered positiv e in patients who are immunosuppressed. This is true whether or not the patient has receive d the BCG vaccine in the past. Two blood-based interferon-gamma release assays have been approved by the FDA for the diagnosis of Mycobacterium tuberculosis infection, including la tent disease. This is the test of choice in patients who have a history of BCG vaccination, or are unlikely to return to have their tuberculin skin test read. MYCOBACTERIUM TUBERCULOSIS 491 Atypical mycobacterial infection \200 Patients with autoimmune rheumatic diseases on immu nosuppressant medication are at risk of developing atypical infections. These infections are usually chronic in nature and can mimic an in \202 ammatory \202 are of rheumatic disease, which can make diagnosis dif \201 cult. M. malmoense has been described causing tensoynovitis and septic arthritis of the knee. M. avium complex and M. chelonae osteoarticular infections have also been described. Atypical infections should be considered in patients with autoimmune rheumatic disease who present with musculoskeletal symptoms that do not respond to conservative treatment. CHAPTER 17 Infection and rheumatic disease 492 Osteomyelitis \200 This term is used to describe any infection involving bone or marrow. \200 A number of general, local, and systemic factors need to be taken into account when managing osteomyelitis (see Table 17.4). Staphylococcus aureus is the most common cause of osteomyelitis, but in the immunosuppresse d host, it is also important to consider tuberculosis, pseudomonas, and salmonella. Diagnostic procedures \200 No single laboratory test is reliable enough to be used routin ely for the diagnosis of osteomyelitis. An elevated white cell count and ESR may not be see n despite infection. Imaging plays an important part in establishing the diagnosis. Whether a particular imaging technique is successful at picking up osteomyelitis depends partly on the stage of the infective process. Once the pathogen has reached bone, a suppurative reaction and marrow edema occurs. This ca n be seen using MR imaging. The next stage, vascular congestion, ischemia, thrombosis, and soft tissue swelling, is readily detected by CT. After 2 \200\2233 weeks, bone reactions in cluding new periosteal bone formation and decalci \201 cation can be seen on plain \201 lms. Plain \201 lms should always be taken if the clinical setting is appropriate, even in ass umed early disease, as they may be highly informative. \200 Vertebral osteomyelitis is of ten seen early on plain \201 lms. Erosion of the vertebral body or disc, and paravertebra l abscesses and vertebral collapse, are common complications. Isotope bone scanning may be helpful in localizing an area of abnormality. 99 Tcm-labeled scans are, however, not speci \201 c, and the negative predict ive value is often greater than the positive predictive value in this scenario. 67 Ga- or 1 11 Indium-labeled leukocyte scans may be helpful in localizing infection. Treatment \200 Initial treatment in the acute phase is the same as that for septic monoarthritis (see above). In general, antibiotics are needed for 6 weeks, although chronic infection may require long-term (in excess of 3 months) treatment. In addition to the comm on IV antibiotics discussed above, an anti-staphylococcal penicillin (such as oxacillin or nafcillin) should be considered. Clindamycin and \202 uoroquinlones are also used to trea t osteomyelitis. Surgery is required early in the acute phase especially if there is necrotic tissue, an abs cess, or spinal involvement. Chronic osteomyelitis implies that dead bone is present and th is will require surgical debridement. Hyperbaric oxygen has also been used successfully in the treatment of air embolism, osteone crosis, myonecrosis, and burn patients with infection. OSTEOMYELITIS 493 Table 17.4 Factors relevant to the management of osteomyelitis Factors Examples General Age: neonates tend to harbor S. aureus, enterobacteriaceae, and B -hemolytic streptococci. In children > 4 years, H. in \202 uenzae is common, and in adults S. aureus Bone: long bones (especially lower limb) are more susceptible than short bones. Pelvic and cranial bones are infrequently involved Local Chronic lymphedema Venous stasis Arterial disease with poor \202 ow Scars Sensory neuropathy Prosthetic material Systemic Malnutrition Renal and liver failure Immunode \201 ciency Diabetes Malignancy Extremes of age Chronic hypoxia Parenteral drug use CHAPTER 17 Infection and rheumatic disease 494 Lyme disease \200 Lyme disease is a tick-borne infection caused by the spirochete Borreli a burgdorferi . Cases of Lyme disease have been reported from most states in the United States as well as throughout Europe, the former USSR, China, and Japan. The highest incidence is in children under the age of 15 years and middle-aged adults, with seasonal variation, being most common in the summer months of June and July. The tick vector, Ixodes , is found on rodents mainly and in wooded, brush, or grassy areas. A history of potential exposure in an endemic country within the la st 30 days is an important fact to establish in considering the diagnosis. A clear history of a tick bite is not necessary to make this diagnosis. The diagnosis is approached clinically, partly based on epidemiological history as well as on classical clinical features (see Table 17.5), and con \201 rmed with laboratory tests. Laboratory tests \200 Con \201 rmation of Lyme disease may be by: isolation of the spirochete from tissue or body \202 uid \200 detection of diagnostic l evels of IgM or IgG antibodies in the serum or CSF detection of changes in antibody levels between acute phase and convalescent paired sera. False-positive results occur in other infections such as syphilis and treponema, as well as in RA and SLE. Western blotting is available as a con \201 rming tes t, distinguishing between true seroreactivity and false positivity. Serologies may be negative in early in the disease course, when erythema migrans is present . Note that erythema migrans is sometimes called the \200\234bull \200\231s eye rash \200 \235, although it does not always take on this appearance. Treatment Treatment of Lyme disease is summarized in Table 17.6. LYME DISEASE 495 Table 17.5 The clinical features of Lyme disease System affected Symptoms Skin Erythema migrans (EM). Begins as a red macule/ papule expanding over days or weeks to a lar ge round lesion often with partial central clearing. The lesion should measure 5 cm or more . There may be smaller secondary lesions* An expanding lesion is often accompanied by general symptoms: fever, fatigue, arthralgias, myalgias, headache Months later a chronic lesion, acrodermatitis chronicum atrophicans (ACA), can appear (viol aceous in \201 ltrated plaques or nodules) Musculoskeletal system Recurrent, brief attacks of joint swelling in one or a few joints (may become chronic \200 \22460% of untreated cases weeks to years after infection). A post-Lyme syndrome of fatigue, arthralgias, and myalgias has been reported. Ongoing infec tion has been dif \201 cult to prove, and this may represent a \201 bromyalgia/chronic p ain syndrome. Nervous system Lymphocytic meningitis Cranial neuritis (especially facial nerve palsy) Radiculoneuropathy (differential Guillain \200\223Barr ) Encephalomyelitis Cardiovascular Acute second- or third-degree atrioventricular conduction defects often associated with myo carditis. Resolve in days to weeks Carditis \200\224rare and remits spontaneously A similar lesion occurring within hours of a tick bite is usually a hypersensitivity reacti on and does not qualify as EM. Table 17.6 The treatment of Lyme disease Clinical feature Treatment Skin disease Doxycycline 100 mg twice daily for 3 weeks or Cefuroxime 500 mg twice daily for 3 weeks Septic arthritis As for skin disease except may require treatment for up to 30 days Neurologic disease: Meningitis, Cranial nerve palsy IV Ceftriaxone 2 g daily or Penicillin G 3 \200\2234 million units every 4 hours or cefotax ime 2 g every 8 hours Carditis As for neurologic disease, above. Both meningitis and carditis should be treated with 2 \200\2233 weeks of parenteral antibiotics CHAPTER 17 Infection and rheumatic disease 496 Rheumatic fever \200 Rheumatic fever is a delayed, nonsuppurative sequel to a pharyngeal infection with Lance \201 eld group A B -hemolytic streptococci. There is a latent period of 2 \200\2233 weeks before the appearance of an illness. A sympto matic pharyngitis is seen in 60% cases; migratory arthritis (typically of the large joints) , myocarditis and valvulitis, and central nervous system disease (chorea) are all associate d with this diagnosis. While the infection is often self-limiting, chronic and progressive damage to cardiac valves occur leading to cardiac decompensation and death. The use of penicillin within 10 days after a S. pyogenes infection decreases the risk of rh eumatic heart disease signi \201 cantly. Although there has been a dramatic decline in the United States and Europe, the disease sti ll occurs in these areas, and is common in developing countries. There are an estimated 10 \200\22320 million cases per year in these areas, with an annual incidence of 100 \200\2232 00 per 100,000. Associations have been described with HLA DR2, 3, and 4. The clinical features may be summa rized in the revised Jones criteria (see Table 17.7). Clinical manifestations and treatment of rheumatic fever Arthritis \200 Joint involvement is more common and often more severe inteenagers and young adults. It tends to start in th e large joints of the lower limbs and migrate. Arthropathy tends to occur early and the pai n can be severe in the absence of objective signs of in \202 ammation. It lasts 2 \200\223 3 weeks and is self-limiting. NSAIDs are the main treatment for the condition. \200 Where one draws the line between th e phenomenon of post- streptococcal reactive arthritis (seen in the absence of carditis) and rheumatic fever is d if \201 cult. Most patients will ful \201 ll the Jones criteria and, therefore, should be considered as having rheumatic fever. Cardiac disease \200 Rheumatic heart disease is the most severe outcome of acute rheumatic fever. It remains the major cause of acquired valvular heart disease in the world . The mitral valve (stenosis) is involved more frequently than the aortic valve. When left unchecked, cardiomegaly and cardiac failure secondary to valvular disease develops. Carditis may also occur and is associated with cardiomyopathy and conduction defects includ ing second- or third-degree heart block. Chorea \200 Sydenham \200\231s chorea (St. Vitus dance) is a neurological disorder consisting of abrupt, purposeless movements, muscle weakness, and emotional disturbance. Th e hands and face are usually the most obviously affected parts. The movements are not prese nt during sleep RHEUMATIC FEVER 497 Table 17.7 The revised Jones criteria for the diagnosis of acute rheumatic fever (diagnosis requires 2 major, or 1 major and 2 minor criteria) Major manifestations Carditis Polyarthritis Chorea Erythema marginatum Subcutaneous nodules Minor manifestations Fever Arthralgia Previous rheumatic fever or rheumatic heart disease Laboratory tests Raised ESR or CRP Normochromic normocytic anemia Prolonged PR interval on ECG Supporting evidence Raised ASO titer* Positive throat cultures for group A streptococci Recent scarlet fever ASO = antistreptolysin O antibodies (titers peak at about 4 weeks, which is about 2 weeks i nto the clinical onset of rheumatic fever; they fall off rapidly over the following 2 \200 \2233 months). but do occur at rest, and may be more marked on one side of the body. Chorea may be the sole feature suggesting rheumatic fever (beyond observing new cardiac mur murs) and may occur weeks to months after onset of an arthropathy. Skin \200 The subcutaneous nodules of rheumatic fever are \201 rm and painless. They are located over bony surfaces or near tendons, and are present for 2 \200\2234 weeks only, and more often in patients with carditis. \200 Erythema marginatum is an evanescent , nonpurpuric rash, usually affecting the trunk and proximal part of the limbs, but sparing the face. Because the rash often appears to make a ring, it is also called erythema annula re. The lesions come and go in a matter of hours and heat may make them appear, or become w orse. Again, it is more common in association with carditis. They resolve spontaneously. Erythema nodosum is rare. Diagnosis \200 There is no diagnostic investigation. \200 Raised in \202 ammatory mark ers are seen, often with a mild anemia. CHAPTER 17 Infection and rheumatic disease 498 Serial rises in antistreptolysin O titers may be seen if measured every 14 days. Chest radiograph and ECG to look for conduction defects/ cardiomegaly. Treatment of rheumatic fever \200 The mainstay of treatment is an anti-in \202 ammatory agent, usually aspirin. If carditis is present, steroids should be started (2 mg/kg/day oral prednisone for 1 \200\2232 weeks followed by steroid taper over 2 weeks). \200 Penicillin should be taken for 10 days, even in the absence of ongoing pharyngitis. Chorea can be treated with haloperidol 1 \200\2232 mg/kg/day, often given with prednisone, although there is little evidence that this gives added bene \201 t. Recurrence is most common within the \201 rst 2 years; however, recurrence rates seem to be low, and the risk of recurrence declines with age at \201 rst attack. Prophylaxis in those who have had rheumatic fever should probably continue for life, though some clinicians would recommend up to 10 years with antibiotic therapy to cover any dental or invasive procedure. Prophylaxis can be given either as oral penicillin V, 250,000 units twice daily, or as penicillin G, 1.2 million units IM once every 3 \200\2234 weeks. Erythr omycin at 250 mg daily may be used if there is an allergy to penicillins. 499 Chapter 18 Miscellaneous conditions Beh et \200\231s disease 500 Sarcoidosis 504 Miscellaneous skin conditions associated wi th arthritis 508 Chronic regional pain syndrome 514 Relapsing polychondritis 516 Miscellane ous disorders of synovium 518 Amyloidosis 520 Fibromyalgia and chronic widespread pain 524 CHAPTER 18 Miscellaneous conditions 500 Beh et \200\231s disease \200 Beh et \200\231s disease is a systemic in \202 ammat ory disorder of unknown etiology. It is most common in the Mediterranean basin, the Middle East, and Asia. The usual onset of the syndrome is in the third or fourth decade. \200 Onset is rare in c hildren, and after the age of 45 years. \200 The male: female ratio is approximately equa l, but the syndrome tends to run a more severe course in men and the young. Based on registries, the prevalence is about 1 in 300,000 in Northern Europe, 1 in 10,000 in Japan, and 40 in 10,000 in Turkey. The syndrome is classically associated with HLA B5 \200\224its presence associated with gre ater disease severity. However, there are geographical variations. Patients from Mediterran ean countries and Japan show this association with B5, but patients in the United States do not. In patients of Israeli origin, there is an association with HLA B51. The full-blown syndrome might be easy to identify, but there are conditions that mimic the incomplete picture, including reactive arthritis, in \202 ammatory bowel disease, and majo r aphthous ulcers. \200 There are no laboratory \201 ndings speci \201 c to the condit ion. The ESR and CRP are often only moderately raised. Clinical features and their management Skin and mucosa involvement (see Table 18.1) \200 Oral aphthous ulcers are always present, and may precede other features by several years. Idiopathic oral aphthous ulcers are common, and by themselves do not imply the presence of Beh et \200\231s. The ulcers associated with Beh et \200 \231s are indistinguishable from ordinary ulcers, but tend to be multiple, more frequent, a nd may heal with scarring. Genital ulceration in men is most prominent over the scrotum (90%). Urethritis is not seen unless there is a meatal ulcer. In women, the labia are commonly affected. Cervical ulcers are rare. Skin lesions may be nodular (resembling erythema nodosum), acneiform, or vasculitic. The pathergy reaction, a hyperreactivity of the skin to a needle prick, is peculiar to this syndrome and pyoderma gangrenosum. After skin puncture with a needle, a papule or pustule forms in 24 \200\22348 h. The reaction is seldom found in patients from Northern Europe or the United States, but is positive in 60% and 70% of patients from Japan and Turkey, respec tively. Mild oral and genital ulceration may respond to oral colchicine 0.6 mg po bid. More severe disease may require AZA 2.5 mg/kg/day. Nonsteroidal anti-in \202 ammatory drugs can help c ontrol pain. Eye disease \200 This is a serious complication and a negative prognostic factor. Eye dis ease is more common in men and patients <25 years of age. \200 Disease is bilateral in 90 % of cases and is usually a chronic relapsing panuveitis. The presence of a hypopyon (cells in the anterior chamber) BEH \207ET \200\231S DISEASE 501 Table 18.1 The clinical \201 ndings in Beh et \200\231s disease Lesion Prevalence (%) Aphthous ulcers 97 \200\223100 Genital ulcers 80 \200\22390 Skin lesions 80 Eye lesions 50 Arthritis 40 \200\22350 Thrombophlebitis 25 Neurological disease 1 \200\22315 Gastrointestinal disease 0 \200\22325 is almost always associated with severe retinal vasculitis, after which there is almost alw ays some structural damage despite treatment. The extent of this damage determines the cour se of eye disease in Beh et \200\231s syndrome. Topical steroids and mydriatics with close supervision may be suf \201 cient in mild disease, but severe disease requires the addition of AZA 2.5 mg/kg/day or anti-TNF- A therapy to the topical regimen. Musculoskeletal system involvement \200 Joint involvement is seen in about 50% of patient s. \200 It is usually mono- or oligoarticular, but can be symmetric, mimicking RA. Chronic synovitis is rare, nonerosive, and nondeforming. \200 In general, knees, ankles, wrists, and elbows are involved (in descending order of frequency). Back pain is rare. \200 Pain may respond to NSAIDs. In \202 ammatory disease often requi res the introduction of methotrexate 20 \200\22325 mg PO/SQ weekly. Cardiovascular and pulmonary involvement \200 Endocarditis, myocarditis, pericarditis, co ronary vasculitis, and ventricular aneurysms can all occur but are rare. Venous involvement is one of the main features of Beh et \200\231s syndrome. Thrombophlebitis occurs in 25% of all patients. Limb venous thrombosis is often o bserved. Occlusion of the suprahepatic veins \200\224Budd \200\223Chiari syndrome \200\224c arries a high mortality. Pulmonary embolism is rare despite high rates of thrombophlebitis. It might be explained by the difference in architecture of thromboses seen in Beh et \200\231s syndrome versus normal (e.g., postoperative) thromboses. The former tends to adhe re throughout its length to the vein wall; the latter tends to have a long, nonadherent and potentially embolic tail. Arterial lesions can occur anywhere. Aneurysms may develop and rupture. This is frequently fatal. CHAPTER 18 Miscellaneous conditions 502 The pulmonary pathology of Beh et \200\231s disease is related to arterial vasculitis. A neurysms, thromboses, and infarcts may be found. \200 Aspirin and NSAIDs can be used to r elieve the symptoms of phlebitis. Aneurysms and arterial occlusion require cytotoxic therap y with cyclophosphamide 2.5 mg/kg/day and prednisone 1 mg/kg/day; surgery may also be indic ated. There remains debate about whether to use heparin or oral anticoagulants for the thro mbophlebitis, although most physicians will choose to treat with anticoagulation in additio n to immunosuppression. Neurological involvement \200 Prospective surveys suggest a prevalence rate of 5% for neu rological disease in the condition. Pyramidal signs are the most common, followed by cerebellar and sensory symptoms and signs. The most common site is the brainstem. Meningeal irritation and dementia may also occur. As is the case with eye disease, central nervous involvement is o ften more severe in men. In contrast to other vasculitides, peripheral neuropathy is unusual. \200 CNS disease sho uld be treated with IV methylprednisolone, and cyclophosphamide should be considered. Gastrointestinal involvement \200 While seen in up to one-third of patients in Japan, gas trointestinal disease is rare in patients from the Mediterranean basin. The basic pathology is mucosal ulceration, seen most often in the ileum and cecum. The course is one of relapse and remission, with a distinct tendency to pe rforate. Ulceration may respond to prednisone 0.5 \200\2231 mg/kg/day, sulfasalazine 2 \200\2233 g/d ay, or in \202 iximab. Surgical evaluation may be necessary to manage severe sequelae. Renal involvement \200 This is seen much less than might be expected in a systemic vascul itis. There are occasional reports of glomerulonephritis. Amyloidosis usually presents with nephrotic syndrome. About 5% of men develop epididymitis. Treatment focuses on symptom control. Treatment of Beh et \200\231s disease \200 Colchicine 0.6 mg po bid should be used to treat orogenital ulceration; dapsone (25 \200\223100 mg PO daily), thalidomide, and anti-TN F- A therapy all have demonstrated ef \201 cacy. Azathioprine 2.5 mg/kg/day should be considered for the treatment of the systemic manifesta tions of Beh et \200\231s. Methotrexate 20 \200\22325 mg/week may also be effective, par ticularly for articular symptoms. Arteritis and other life-threatening manifestations shoul d be treated with cyclophosphamide 2.5 mg/kg/day. In \202 iximab (e.g., 5 mg/kg IV every 4 weeks) or rituximab (e.g., 375 mg/m 2 IV weekly for 4 weeks) may be effective for treating ocular manifestations of Be h et \200\231s that do not respond to topical therapy. \200 Warfarin should be used in the usual way for thrombotic episodes. If thrombosis occurs in the setting of disease \202 are, immunosuppression may be required as well. This page intentionally left blank CHAPTER 18 Miscellaneous conditions 504 Sarcoidosis \200 Sarcoidosis is a multisystem disease of unknown etiology, characterized by the presence of multiple, noncaseating granulomas in involved tissue. It occurs worldwide, but the prevalence, clinical features, and outcome varies. It is seen more often in developed versus underdeveloped, Western versus Eastern, and in Northern vers us Southern European countries. Sweden and Denmark have prevalence rates of 60 per 100,000: the United Kingdom 20 per 100,000. In the United States, sarcoidosis is 10 \200\22315 time s more prevalent in the African American population than in Caucasians; African Americans m ay also present with a more severe form of this disease. There is also an increased inciden ce of sarcoidosis in families. Recent studies have suggested a link between HLA B8, DR3, an d acute sarcoidosis with arthritis.