In this patient an enthesitis related to an inflammatory spondyloarthropathy needs to be co nsidered in view of his chronic low back pain and morning stiffness. Less than 30% of patie nts with psoriatic arthritis are positive for HLA B27. 2. What further information might be helpful in making a diagnosis? It is important to ascertain whether he had back symptoms prior to his motor vehicle accide nt. It is also pertinent to ask about other symptoms which might sug- gest spondyloarthriti s such as peripheral arthritis, dactylitis, psoriasis, palmar plantar pustulosis, balanitis , nail changes, other recurrent tendon problems, iritis, or inflammatory bowel symptoms. En quiries should be made about a family his- tory of psoriasis and inflammatory arthritis. 3. Are there any other investigations you would like to perform? How would these help? Consider imaging the sacroiliac joints and lumbar/thoracic spine with an MRI scan. Features of sacroiliitis (bone oedema, synovitis, erosion, and sclerosis) may 101 CASE 17 be visible on MRI if the underlying etiology is psoriatic arthritis or ankylosing spondylit is. Romanus lesions at the corners of the vertebral body may be present in the lumbar or th oracic spine. These appear as bright signal on STIR MRI sequences and indicate enthesitis o f the spinal ligament insertion to the vertebral body. Ultrasound of the tendon is useful t o monitor improvement over time, but is unlikely to differentiate between insertional mecha nical overuse tendinopathy and enthesitis from a spondyloarthropathy. Thickening of the ten don insertion, calcific deposits, periosteal changes, and vascularization (seen by Doppler ultrasound) can be found in both settings. 4. How would you manage this patient? Treatment will be guided by whether or not the insertional tendinopathy is thought to be me chanical or inflammatory in etiology: Mechanical overuse i) Relative rest from activities causing the problem (in this case time off from running). ii) Eccentric calf raises. This is a well-established therapy for mid-portion Achilles tend inopathy but has not been very successful in insertional tendinopathies. In the original st udies with eccentric training the patient did the exercise on a step and the heel went lowe r than the rest of the foot, causing dorsiflexion at the ankle. It is now thought that dors iflexion causes impingement between ten- don, bursa, and bone at the insertion, resulting i n a compressive force, and hence is the reason for treatment failure in those with insertio nal tendinon- opathy. It has been demonstrated that eccentric calf raises done on flat grou nd with no dorsiflexion at the ankle improves insertional tendinopathy. Three sets of 15 re petitions with knee straight and three sets of 15 repetitions with knee bent twice a day fo r 12 weeks are the minimum treatment course. iii) Correct any biomechanical abnormality. In this patient, correction of over- pronation is important, either by using support shoes or by referral for orthotics to have medial arc h supports made to fit his running shoes. iv) A variety of \200\230novel \200\231 treatments are currently used but they have little or no evidence base at present. Sclerotherapy has been used to reduce the \200\230neovasc u- larization \200\231 which is thought to contribute to the pain. Dry needling, autologous blood, and platelet-rich plasma (PRP) injections are also in use. The rationale is that th e trauma and blood/PRP provides the growth factors necessary for tendon repair. Extracorpor eal shock wave therapy and high-volume tenotomy are also occasionally offered, but the reco mmendation for these second-line therapies is anecdotal rather than evidence-based. Inflammatory spondyloarthropathy i) Education about disease and symptomatic treatment. ii) Physiotherapy to maintain range of back flexibility. iii) Anti-inflammatories. 102 CASE HISTORIES IN RHEUMATOLOGY iv) Consider corticosteroid injection into sacroiliac joint if there is sacroiliitis on MRI. v) Anti-TNF therapy for refractory disease. There is no proven benefit of traditional DMARD therapy in the setting of spinal inflammation or enthesitis. DMARDs can be used if there i s an associated peripheral arthritis. Further reading Alfredson H ( 2005 ). The chronic painful Achilles and patellar tendon: research on basic biology and treatment . Scand J Med Sci Sports ; 15 : 252 \200\223 9 . Antoni CE , Kavanaugh A , Kirkham B , et al . ( 2005 ). Sustained benefits of infliximab th erapy for dermatologic and articular manifestations of psoriatic arthritis: results from th e Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT) . Arthritis Rheum ; 52 : 1227 \200\223 36 . Jonsson P , Alfredson H , Sunding K , et al . ( 2008 ). New regimen for eccentric calf-musc le training in patients with chronic insertional Achilles tendinopathy: results of a pilot stu dy . Br J Sports Med ; 42 : 746 \200\223 9 . 103 CASE 18 Case 18 A 26-year-old healthy landscape gardener attended the rheumatology clinic com- plaining of a year \200\231s history of intermittent wrist discomfort, numbness, and pins and needles i n his hands. His symptoms had started during a period of heavy gardening. His past medical history included an injury to his upper spine 6 years previously, which ha d occurred while using a sledgehammer. These symptoms resolved over a 6-month period. He ha d a more recent 2-year history of stiffness across his shoulders and upper back. On examination he had a forward protruding neck at the cervico-thoracic junction, with some restriction of thoracic and scapular mobility. He had a full range of pain- free movement at the wrists and fingers with no swollen or tender joints. Power, tone, reflexes, and sens ation in the upper and lower limbs were normal. Tapping the palmar aspect of the wrist over the carpal tunnel to elicit paraesthesia in the distribution of the median nerve (Tinel \200\231s test) was negative. However, he reported mild paraesthesia 1.5 minutes into Phale n \200\231s test where the wrist is held in a fully flexed position for 2 minutes. The physiotherapist was able to reproduce his symptoms by stressing the brachial plexus on both sides. The upper thoracic joints were described as hypomobile. Questions 1. What are the possible causes of the symptoms in his hands? 2. What clinical tests are useful in confirming the diagnosis? 3. How would you manage this patient? 104 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What are the possible causes of the symptoms in his hands? \227\206 Musculoskeletal soft tissue symptoms related to adverse neural dynamics (AND) are the most likely cause of his symptoms in view of his age, neck posture, the intermittent n ature of his symptoms, and the absence of other neurological signs. \227\206 Central cervical disc prolapse at C5 \200\2236 or C6 \200\2237 should be consider ed in view of his previous history of injury and his symptoms during a period of heavy gard ening. \227\206 Bilateral median nerve entrapment is a possible diagnosis in view of his occupa- tion and use of heavy equipment. \227\206 CNS disorders such as demyelination are less likely. 2. What clinical tests are useful in confirming the diagnosis? \200\230Adverse neural dynamics \200\231 may cause symptoms of pain, paraesthesia, or numb - ness due to the restriction of movement or irritation of the nerve through its course fro m spine to distal origin. This is seen, for example, with the straight-leg raise and \200 \230slump tests \200\231. Upper-limb neural mobilization tests, usually used by physiothera - pists, are used to identify which nerves of the brachial plexus are predominantly affecte d where upper limb symptoms occur. The patient is examined in the supine position with the hand of the untested side resting on the patient \200\231s abdomen. The patient reports any pain, stretching, tingling, or numbness. Figures 18.1 \200\223 18.3 describe the sequence s of testing for median, ulnar, and radial nerves, respectively. A test is deemed positive if the patient \200\231s symptoms are at least partially recreated specifically during the mobilization. These symptoms and signs are often present in work-related upper-limb disorde rs related to repetitive use or overuse activities, such as excessive keyboard work. They c an also be seen in patients who suffer whiplash injuries or any musculoskeletal impairment, as in this patient, where soft tissue damage compromises the nerve in its pathway. The symptoms of AND are common, especially in individuals who use a compu- ter for prolonge d periods. It affects men and women equally and can occur at any age. 105 CASE 18 a b c d e f Fig. 18.1 Testing sequence for the median nerve. (a) the shoulder girdle is fixed. (b) the shoulder is abducted. (c) the wrist is extended. (d) the shoulder is externally rotated. (e ) the elbow is extended. (f) the head is laterally flexed away from the side being tested. Adapted from Mobilization of the Nervous System , Butler, DS, p. 149, Copyright Churchill L ivingstone (1991). 106 CASE HISTORIES IN RHEUMATOLOGY a b d c e f Fig. 18.2 Testing sequence for the ulnar nerve (a) the wrist is extended. (b) the arm is pr onated. (c) the elbow is flexed. (d) the shoulder is depressed. (e) the shoulder is externa lly rotated. (f) the shoulder is abducted. Adapted from Mobilization of the Nervous System, Butler, DS, pp. 158 \200\2239, Copyright Churchill Livingstone (1991). 3. How would you manage this patient? A patient with AND should be managed with physiotherapy and home posture exer- cises. This will include correction of posture and muscle balance to improve biome- chanics, spinal joi nt mobilization, soft tissue massage, and exercises and skin taping in order to offload str uctures and improve local proprioception. 107 CASE 18 a b c d Fig. 18.3 Testing sequence for the radial nerve (a) the shoulder is depressed and elbow ext ended. (b) the shoulder is internally rotated. (c) the wrist is flexed. (d) the shoulder is abducted. Adapted from Mobilization of the Nervous System, Butler, DS, p. 155, Copyright C hurchill Livingstone (1991). It is important to address activities that aggravate symptoms, including assess- ment of th e patient \200\231s work environment and posture. They may need advice on pacing, splitting repetitive tasks, and reduction of upper-limb use with voice recog- nition software in the case of keyboard users. He may need to liaise with his employ- ers or managers to ensure t hat he takes regular breaks at work and may need to change to lighter jobs. If these measur es do not resolve his symptoms, he may have to make significant changes to his work. Further reading Butler DS ( 1991 ). Mobilization of the Nervous System . Melbourne : Churchill Livingstone . Schmid AB , Brunner F , Luomajoki H , et al . ( 2009 ). Reliability of clinical tests to evaluate nerve function and mechanosensitivity of the upper limb peripheral nervous system . BMC Mus culoskelet Disord ; 10 : 11 (available from : http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC 2653029/?tool=pubmed ). Turl SE , George KP ( 1998 ). Adverse neural tension: a factor in repetitive hamstring stra in? J Orthop Sports Phys Ther ; 27 : 16 \200\223 21 . 108 CASE HISTORIES IN RHEUMATOLOGY Case 19 A 47-year-old nurse was referred with a 3-month history of dry eyes and mouth and aching up per-arm muscles, and a 3-day history of left-sided facial weakness. For the previous year s he had been suffering from fatigue, poor sleep, and non-specific joint pains. Six months pr eviously she had developed a pustular psoriatic rash on her palms and feet, resistant to to pical treatments. She had no antecedent history of infection, arthritis, colitis, or recent foreign travel. S he had last visited her family in Nigeria 5 years previously. She was married with two chil dren aged 8 and 10. She had lived in the UK for 5 years. On examination she had palmar pustular psoriasis, tender deltoid muscles, swollen parotids, and a left lower motor neuron facial nerve palsy. Joint examination was normal with full r ange of movement and no synovitis. Schirmer \200\231s test was positive. Investigations showed the following: \227\206 Normal FBC \227\206 Normal liver and renal function \227\206 CPK 500 IU/L \227\206 RF and ACCP negative; ANA negative; ENAs negative; ANCA negative; HLA B27 negative; serum ACE normal \227\206 CXR clear. 109 CASE 19 Questions 1. Suggest a unifying diagnosis. 2. What further information is needed to establish the underlying diagnosis? 3. What treatments are available? 4. What are the implications for her occupation and her family? 5. What musculoskeletal complications may occur in response to treatment? 110 CASE HISTORIES IN RHEUMATOLOGY Answers 1. Suggest a unifying diagnosis Multisystem inflammatory automimmune conditions like SLE, primary Sj gren \200\231s syndro me, and antisynthetase syndrome are important differential diagnoses. However, her professi on and travel from an HIV-endemic area means that HIV/ AIDs must be considered. HIV/AIDS wo uld account for the chronic fatigue, late- onset aggressive palmar pustular psoriasis, myos itis, and parotid enlargement with facial nerve involvement (diffuse infiltrative lymphocyt osis syndrome (DILS)). Some patients develop symptoms in association with seroconversion. Unexplained arthralgias occur in 5 % of HIV-positive patients who also suffer from fibromyalgia-like symptoms. Join t pain may occur in the absence of synovitis. A lower-limb, self-limiting, non-erosive mono arthritis can occur. Psoriasis, myositis, and DILS can all be initial presentations of HIV infection. Psoriasis may be dramatic and intractable, with poor response to topical treatments. Myositis is usua lly subacute and progressive. Skin involvement is rare. EMG studies can be normal or show n on-specific, short-duration, polyphasic, motor- unit potentials with abnormal spontaneous a ctivity. Muscle biopsy may show infiltrate of inflammatory cells in necrotic and non-necrot ic fibers. Often the lesions are ill-defined. In HIV-positive patients it is important to r ule out oppor- tunistic infections such as toxoplasmosis, which can occur during immune com - promise and also presents with muscle weakness and raised muscle enzymes. DILS occurs in 3 \200\2234 % of HIV-positive patients. Proposed diagnostic criteria for DIL S include HIV seropositivity with either bilateral salivary gland enlargement or xerostomia for > 6 months. Histology shows lymphocytic infiltration of salivary or lacrimal glands in the absence of granulomatous or neoplastic enlargement. Gadolinium-67 scintigraphy of sali vary glands is positive. Inflammatory myopathy and DILS can be associated with infiltrative peripheral neuropathy, lymphocytic hepatitis, and lymphocytic infiltrative pneumonia. This woman \200\231s facial palsy may have been secondary to the parotid gland infiltration. 2. What further information is needed to establish the underlying diagnosis? A careful history for HIV risk factors includes needle stick injury (UK or abroad), intrave nous drug use with needle sharing, and sexual contact with persons at risk of HIV or from H IV-endemic areas. \227\206 The most important test is an HIV test. Combined antigen/antibody tests currently used for screening will detect patients within 4 weeks of exposure. Patients need appropri ate counseling and consent before testing. \227\206 50 % of HIV-infected patients in the UK are ignorant of their diagnosis. \227\206 CD4 count is helpful in tracking progress, but it is expensive and should not be used to confirm diagnosis. Assessment for other sexually transmitted diseases and infective hepatitis screening are also needed. 111 CASE 19 This woman was HIV positive with a CD4 count of 200. Her potential risk factor was her husb and who traveled regularly to Africa on business. He refused HIV testing. 3. What treatments are available? Treatment of HIV is highly specialized and should be conducted under expert super- vision. Current standard therapy is highly active antiretroviral therapy (HAART). Low to moderate-dose steroids may be used to treat glandular swelling and inter- stitial pn eumonia but immunosuppressive therapies, including steroids, need to be used with caution a s they may increase viral load and worsen the illness. Sicca symptoms of dry eyes and mouth are treated symptomatically. The facial palsy may not respond to treatment and may be perm anent. Psoriasis associated with HIV is often resistant to topical treatments. Methotrexate and ciclosporin may improve skin lesions, but there is increased risk of systemic infectio n. Hydroxyurea is generally considered a safer alternative. The psoriasis usually settles w ith HIV treatment. Explosive reactive arthritis can occur which is difficult to treat with conventional therap y. The association with HLA B27 is less strong, particularly in African popu- lations where the HLA B27 prevalence is low. 4. What are the implications for her occupation and her family? The patient \200\231s immediate family, husband and children, should be tested for HIV. If her children test negative, then their future risk of transmission from her is neg- ligible . Her husband refused HIV testing. Whatever his HIV status, counseling about safe sex and c ontact tracing is important. There are implications for future pregnancies, primarily around time of delivery. Strategie s taken in the UK and other developed countries have reduced the risk of vertical transmiss ion of HIV from mother to infant to <2 % . These strategies involve universal HIV screening of all pregnant women, treating pregnant HIV-positive patients with HAART to make viral lo ad undetectable before delivery, elective Cesarean section; avoidance of breastfeeding, and 6 weeks zidovudine prophylaxis for the infants. In resource-poor countries the advice on b reastfeeding is different. Implications for her employment depend on her workplace. She is safe to work in all environments apart from an \200\230exposure-prone environment \200\231 where she is unable to see her hands and may catch them on a spike of bone or surgical ins tru- ment (e.g. assisting some operations in theater). She should not work where there is high exposure to tuberculosis. She should have antibody testing for varicella and CMV. 5. What musculoskeletal complications may occur in response to treatment? Complications of HAART include metabolic abnormalities with lipid abnormalities, insulin re sistance, and changes in body fat distribution. Although (low BMD) osteopenia 112 CASE HISTORIES IN RHEUMATOLOGY and osteoporosis are frequent in HIV-positive patients, it is still unclear whether this is a direct consequence of the viral infection or of the antiretroviral drugs. Treatment is w ith bisphosphonates plus calcium and Vitamin D supplementation. Zidovudine-induced myopathy Zidovudine (a nucleoside analog) has been first-line treatment for AIDS since 1987 and is associated with myopathy in 2 \200\22318 % patients. Patients pr esent with myalgia and muscle weakness and an associated rise in CK. Incidence is minimized by using low- dose zidovudine and monitoring CK levels during treatment. Treatment is to w ith- draw zidovudine, and add corticosteroids and possibly carnitine. Immune reconstitution inflammatory syndrome (IRIS) Conditions driven by CD4 lymphocytes (e. g. RA, SLE, and sarcoidosis) are rarely seen with HIV. Symptoms can regress with the develo pment of HIV/AIDS and recur after treatment with HAART. This is termed immune reconstitutio n inflammatory syn- drome (IRIS). In addition, new-onset RA, SLE, and sarcoidosis can occur in associa- tion with increasing CD4 + T-cell counts. During immune reconstitution there a ppears to be an increased risk of developing these symptoms above the pre-existing risk for that individual. CD8 + driven conditions such as psoriasis, reactive arthritis, and DILS may be initial manifestations of HIV infection and should settle with HIV treatment. Other opportunistic infections of muscle and bone may occur, especially atypical mycobacter ial infections; Mycobacterium haemophilum and Mycobacterium kansasii are the two most frequ ent. Mycobacterium tuberculosis is no more frequent in HIV AIDS, but may emerge during immu ne reconstitution. Disseminated histoplasmosis, cryptococcosis, sporotrichosis, and blastomycosis, leading to osteomyelitis, septic arthritis, or bursitis may also occur. Avascular necrosis is seen in 3 \200\2235 % of HIV patients. The hips are most commonly aff ected, but more than three joints are involved in 70 % of affected patients. Possible contr ibutory risk factors, in addition to HIV itself, are hyperlipidaemia, alcohol excess, use o f high-dose steroids, and a hypercoagulable state. There may be an association with the use of HAART. The whole spectrum of vasculitis has been reported, from small-vessel vasculitis to aortiti s. Vasculitis has been described in early stage HIV when patients have preserved CD4 counts , as well as later in patients with severe immunosuppression. Patients commonly present wit h rash and peripheral neuropathy. HIV-associated cryoglobuli- naemia, polyarteritis nodosa (PAN), and large-vessel complications such as strokes have been reported. Osteoporosis There are a number of reasons why patients with HIV are at increased risk of l ow bone mass. HAART treatment itself may contribute to low bone mass. In addition, HIV pati ents suffer from anorexia with associated vitamin D insufficiency, reduced lean body mass, and limited weight-bearing exercise. Smoking and excessive alcohol con- sumption is more co mmon in HIV-infected patients. 113 CASE 19 Further reading Medina Rodriguez F ( 2003 ). Rheumatic manifestations of human immunodeficiency virus. Rheum Dis Clin North Am ; 29 : 145 \200\223 61. Plate A-M , Boyle B ( 2003 ). Musculoskeletal manifestations of HIV infection . AIDS Read ; 13 : 62 , 69 \200\223 70 , 72, 76. 114 CASE HISTORIES IN RHEUMATOLOGY Case 20 A 3-year-old Caucasian girl was referred to a pediatric rheumatology clinic with a 6-month history of a swollen right knee. She had not complained of any pain but her parents had not iced that she had stopped jumping on her trampoline. She had no history of injury. She was apyrexial and had no rashes. Her knee was warm with a boggy swelling and a reduced range of movement. The other joints and spine were normal. Slit-lamp ophthalmic assessment is shown in Fig. 20.1. Fig. 20.1 (See also Plate 10) Slit-lamp examination of eye. 115 CASE 20 Questions 1. What is the differential diagnosis of a swollen joint in a child? 2. What further investigations would be helpful? 3. What is the most likely diagnosis? 4. What do the arrows in Fig. 20.1 indicate? What is the significance of the ophthalmologist \200\231s findings? 5. How would you manage this case? 116 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis of a swollen joint in a child? The differential includes the following: \227\206 Septic arthritis including chronic infection (e.g. tuberculosis) \227\206 Trauma including non-accidental injury: \227\206 Malignancy: leukemia primary bone tumor \227\206 JIA \227\206 Hematological causes: hemophilia (in a boy) \227\206 Internal structural abnormalities: discoid meniscus (knee) osteochondritis dissecans \227\206 Sarcoidosis (rare) \227\206 Villonodular synovitis (rare). 2. What further investigations would be helpful? Investigations in a young child should be performed where necessary but without causing und ue distress. In this case they may include the following: \227\206 FBC and blood movie \227\206 Inflammatory markers (e.g. CRP) \227\206 ANA \227\206 CXR if TB, sarcoid, or lymphoma are possibilities \227\206 Ultrasound scan of the affected joint \227\206 MRI scan of the affected joint \227\206 Examination of joint aspirate \227\206 ASOT if recent sore throat \227\206 ELISPOT or QuantiFERON if at risk of tube rculosis. The FBC and inflammatory markers were normal and ANA was positive. An ultra- sound scan of the knee demonstrated synovitis and an effusion. Inflammatory synovial fluid was aspirated under general anesthesia and there was no evidence of infection. 117 CASE 20 3. What is the most likely diagnosis? This child had oligoarticular disease and was systemically well. The presence of fever, sev ere pain, weight loss, or abnormalities of the blood movie would raise con- cerns about mal ignancy or chronic infection which were unlikely in this case. The risk of tuberculosis was low. More detailed imaging with MRI would be indicated if bone tumor or intra-articular st ructural abnormalities were suspected on clinical grounds. Ultrasound demonstration of synovitis with a good response to intra-articular steroid injec tion supported a diagnosis of JIA. Tests for ANA are positive in up to 85 % of children wit h oligoarthritis, especially in girls and those children with uvei- tis. FBC and inflammato ry markers are generally normal but may show signs of inflammation. Rheumatoid factor is no t a useful test as it is almost always negative. A biopsy may be considered if sarcoid, vil lonodular synovitis, or chronic infection were suspected, or if there was an inadequate res ponse to intra-articular steroids, leading to review of the diagnosis. JIA is a chronic inflammatory disease beginning before the 16th birthday. The prevalence in the UK is 65 in 100 000 and the annual incidence is 10 in 100 000. Arthritis in children i s different from that in adults both clinically and in pathogen- esis. The different types of JIA (Table 20.1 ) can occur in any age group, but tend to peak at certain ages. Oligoart icular JIA tends to occur in toddlers and is associated with inflammatory eye disease. The child is usually systemically well. A child has oligoarticular JIA if four or fewer joints are affected during the first 6 mont hs of the disease. If more joints become affected, it is termed extended oli- goarticular J IA. Generally the joints affected are lower limb; knee, ankle, and mid- foot. Leg-length di fference may result from increased bone growth around an affected knee relative to the norm al side. Mid-foot and subtalar joint involvement may cause an everted foot posture and a sm aller foot. The peak incidence is between 2 and 4 years old, and it is more common in girls than boys w ith a female-to-male ratio of 3:1. The etiology is poorly understood. Genome-wide studies h ave identified JIA susceptibility loci in the HLA region involved in T-cell receptor signal ing and activation pathways. 4. What do the arrows in Fig. 20.1 indicate? What is the significance of the ophthalmologist \200\231s findings? Slit-lamp examination showed early band-shaped keratopathy of the cornea (thin arrow), flar e, cells in the anterior chamber, and synechiae (thick arrow) between the iris margin and t he lens. Intra-ocular pressures were measured at a later date when full cooperation had bee n achieved and were found to be in the normal range. There was no posterior segment disease . The opthalmologist \200\231s findings were consistent with a diagnosis of anterior uveiti s in keeping with JIA. 118 CASE HISTORIES IN RHEUMATOLOGY Table 20.1 International League of Associations for Rheumatology (ILAR) classification of j uvenile idiopathic arthritis 2004 Category Features Oligoarthritis: \227\206 Persistent \227\206 Extended Arthritis in 4 or fewer joints during the first 6 months of disease \227\206 Never more th an 4 affected joints \227\206 More than 4 joints affected after the first 6 months Exclusi ons 1, 2, 3, 4, 5 Polyarthritis (rheumatoid factor positive) Arthritis affecting 5 or more joints during the first 6 months of disease RF test is positi ve Exclusions 1, 2, 3, 5 Polyarthritis (rheumatoid factor negative) Arthritis affecting 5 or more joints during the first 6 months of disease RF test is negati ve Exclusions 1, 2, 3, 4, 5 Systemic arthritis Arthritis in any number of joints with fever of at least 2 weeks \200\231 duration, documen ted to be quotidian for at least 3 days, accompanied by one or more of: \227\206 Evanescen t rash \227\206 Generalized lymphadenopathy \227\206 Enlargement of liver or spleen \227 \206 Serositis Exclusions 1, 2, 3, 4 Psoriatic arthritis Arthritis and psoriasis, or arthritis and at least 2 of: \227\206 Dactylitis \227\206 Nai l pitting or onycholysis \227\206 Psoriasis in first-degree relative Exclusions 2, 3, 4, 5 Enthesitis- related arthritis Arthritis and enthesitis, or arthritis or enthesitis with at least 2 of: \227\206 Sacroili ac joint tenderness and/or inflammatory lumbosacral pain \227\206 The presence of HLA-B27 antigen \227\206 Onset of arthritis in boy > 6 years old \227\206 Anterior uveitis (sympt omatic) \227\206 Family history of HLA-B27 associated disease Exclusions 1, 4, 5 Undifferentiated arthritis \227\206 Fits no other category \227\206 Fits more than one category Exclusions 1. Psoriasis or a history of psoriasis in the patient or a first-degree relative. 2. Arthritis in an HLA-B27 positive male after the 6th birthday. 3. Ankylosing spondylitis, enthesitis-related arthritis, sacro-iliitis with IBD, reactive arthritis, or acute anterio r uveitis or a history of one of these disorders in a first-degree relative. 4. The presence of IgM RF on at least 2 occasions, at least 3 months apart. 5. The presence of systemic JIA in the patient. 119 CASE 20 Uveitis is caused by inflammation in the anterior chamber of the eye and occurs in up to 20 % of children with oligoarticular JIA. Inflammatory eye disease associ- ated with JIA is t he most common cause of chronic anterior uveitis in childhood and usually occurs in the oli goarticular subset. Uveitis is usually asymptomatic in children under 12 years old, and new -onset inflammatory eye disease rarely presents over this age. Although uveitis is five tim es more common in girls, boys are more likely to have severe disease. A child may present with uveitis at the time of diagnosis and up to 7 years later, but eye inflammation precedes joint disease in 5 % of cases. The severity of uveitis at presentatio n is a major factor in determining its outcome and in 70 \200\22380 % cases is bilateral. A positive ANA is a risk factor in children, but those who have uveitis with a negative ANA are more likely to have severe disease. Regular screening is essential, and protocols are a vailable depending on the type of arthritis and age of onset. Children under the age of 8 y ears have a particularly high risk of developing severe eye disease and should be very clos ely monitored for the first 2 years after diagnosis of JIA. Complications include cataract formation, glaucoma, and cystoid macular oedema, all of which are sight threatening. Amblyo pia (lazy eye) can develop with even mild disease in children under 7. Band keratopathy is caused by calcium deposition in the cornea and is evidence of inflammation. 5. How would you manage this case? Both disease course and management of eye and joint disease may differ in the same patient. The aim of management of JIA is to control synovitis, restore muscle strength, and encoura ge normal growth and movement. A multidisciplinary approach is required, including rheumato logy, opthalmology, physiotherapy, occupational therapy, orthotics, and psychology. Medications that may be used include the following: \227\206 NSAIDs such as ibuprofen 30 mg/kg/day or diclofenac 1 \200\2233 mg/kg/day in divi ded doses provide symptomatic relief. \227\206 Intra-articular joint injections with triamcinolone hexacetonide 1 mg/kg per join t. In young children this should be under a general anesthetic and in older children the us e of Entonox may help. \227\206 Methotrexate is used when joint inflammation recurs despite intra-articular injec - tion. This is prescribed orally or as subcutaneous injections at 15 \200\22320 mg/m 2 /we ek. \227\206 Children with five or more swollen joints and three or more joints with limitatio n of movement who have not responded to subcutaneous methotrexate 20 mg/m 2 may be consider ed for anti-TNF therapy. Steroid eye drops are the mainstay of treatment of uveitis and can be instilled up to two-h ourly in the first instance. The frequency should be slowly tapered over sev- eral months a s the inflammation subsides. Short-acting cycloplegic (dilating) drops 120 CASE HISTORIES IN RHEUMATOLOGY should also be applied to prevent progression of synechiae. Periocular injection of steroid under general anesthetic is an option for severe or non-responsive cases. Treatment with o ral or subcutaneous methotrexate is considered when uveitis is uncontrolled by these measur es. Ciclosporin, azathioprine, mycophenolate mofetil, and leflunomide may also be effective . The results from anti-TNF treat- ment are conflicting, but infliximab and adalimumab may be effective. This patient was managed with intra-articular steroid injections under general anesthetic, physiotherapy, and hydrotherapy. Her joint disease was rapidly con- trolled by steroid inje ction. The eye disease was initially treated with dexametha- sone and 1 % cyclopentalate dr ops but did not show a significant response. After 6 months she had developed severe bilate ral anterior uveitis. Methotrexate therapy was commenced and the uveitis settled. Screening every 2 \200\2233 months will continue during childhood and monitoring will continue for l ife. She found the routine blood monitoring for methotrexate very upsetting and the help of the team psy- chologist was enlisted to support the family with strategies to reduce her d istress. Further reading Cassidy JT , Petty RE ( 2005 ). Textbook of Pediatric Rheumatology ( 5 th edn). Philadelphi a, PA : Elsevier Saunders . Edelsten C ( 2007 ). Reconsidering treatment options in childhood uveitis . Br J Ophthalmol ; 91 : 133 \200\223 4. Edelsten C , Lee V , Bentley CR , Kanski JJ Graham EM ( 2002 ). An evaluation of baseline r isk factors predicting severity in juvenile idiopathic arthritis associated uveitis and oth er chronic anterior uveitis in early childhood . Br J Ophthalmol ; 86 : 51 \200\223 6. Petty RE , Southwood TR , Manners P, et al . ( 2004 ). International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonto n, 2001 . J Rheumatol ; 31 : 390 \200\223 2. Ravelli A , Martini A ( 2007 ). Juvenile idiopathic arthritis . Lancet ; 369 : 767 \200 \223 78 . 121 CASE 21 Case 21 A 19-year-old male with a history of recurrent fractures from birth was seen in the rheumat ology department. He had sustained more than 40 fractures leading to pain- ful skeletal def ormity and he had been wheelchair-bound from the age of 10 years. His father was also affec ted by \200\230brittle bones \200\231 and was restricted to a wheelchair. He was treated with cyclical intravenous pamidronate from the age of 10 years, which result ed in reduced bone pain. A baseline DEXA scan at age 14 years showed a T-score of \200\223 7.0 SD below the mean at the lumbar spine, which increased to \200\2235.1 after 4 years of therapy (osteoporosis is defined as a T-score less than \200\2232.5 SD below the mean for peak age). The infusions were discontinued at age 17 years when his family moved district. He developed increasing back and limb pain, which he attributed to cessation of the bispho sphonate, and required regular opiates and baclofen. He also reported troublesome morning h eadaches. On examination, he was below the third centile for height with a severe thoracolum- bar sco liosis. His teeth were translucent, with scalloped borders. His sclerae appeared normal. Th ere was no objective muscle weakness. Questions 1. What is the most likely diagnosis? 2. What is the pathogenesis? 3. What are the common clinical manifestations? 4. What investigations may be useful? 5. How would you manage this patient? Why might he have morning headache? 122 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the most likely diagnosis and what is the classification? The most likely diagnosis is osteogenesis imperfecta type III. Osteogenesis imperfecta (OI) is a genetic condition characterized by bone fragility. This p atient has OI type III on the basis of the autosomal dominant inheritance, severe disease r esulting in multiple fractures at birth, progressive deformity through childhood, and short stature. Extra-skeletal manifestations include abnor- mal dentition (dentinogenesis imperf ecta), but the sclera may appear normal (Table 21.1 ). Currently, eight subtypes of OI are recognized (Table 21.1 ). Types I \200\223IV are based on the Sillence clinical classification and are due to mutations in type I collagen genes ( COL1A1 or COL1A2) with autosomal dominant inheritance. Affected indi- viduals may have extr a-skeletal manifestations. Type I is the most common sub- type and may result in mild disea se, type II is lethal in the perinatal period, and types III and IV range from moderate to severe. The Sillence classification has been extended to include types V \200\223VIII, which are ph enotypically severe and lack extra-articular manifestations. Types VII and VIII are recessi vely inherited, and are due to genetic mutations affecting proteins involved in post-transl ational processing of type I collagen (CRTAP/LEPRE genes). The genetic bases of types V and VI have yet to be fully characterized. 2. What is the pathogenesis? Most cases of OI are due to gene mutations in type I collagen which is the predomi- nant co llagen component of the bony organic matrix. Type I collagen is composed of a triple helix of polypeptide chains, with glycine positioned regularly within the peptide sequence cross- linking the chains together. Two major genetic mechanisms are responsible for bone fragility in OI. \227\206 Milder disease (particularly OI type I) may be due to an extra stop codon or fram eshift mutation within the type I collagen gene. The abnormally truncated polypeptide chain s are removed by the cell and are not incorporated into the triple helix. As the condition is autosomal dominant, some normal polypeptides are formed and the patient is left with red uced production of normal collagen helices. \227\206 In OI types II \200\223IV mutations typically code for amino acid substitutions o f a glycine residue. This alters the stability of the triple helices by interfering with cr oss-linking between the normal and abnormal polypeptide chains. Severe disease may result i f the affected glycine is at a crucial position. 3. What are the common clinical manifestations? The defining characteristic of OI is bone fragility resulting in susceptibility to fracture . Although typically diagnosed in childhood, OI type I may be mild and therefore 123 CASE 21 may present at any age. It is crucial to exclude non-accidental injury in a child presentin g with recurrent fracture. Extra-skeletal manifestations may be present in patients with OI types I \200\223IV. These may be subtle and difficult to detect. They include the following: \227\206 Blue sclera: the pigmented choroid is visible through an abnormally translucent s clera. This can be difficult to recognize as it is relatively common in non- Caucasian chil dren with or without OI. \227\206 Dentinogenesis imperfecta ( \200\230shell teeth \200\231): discolored translucent teeth which are susceptible to damage resulting in scalloped borders.