 \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. \227\206 Conductive hearing loss: this is due to fractures and subsequent fibrosis of the ossicles of the middle ear. Hearing impairment is particularly common in adults over the ag e of 50 years. 4. What investigations may be useful? In the presence of a positive family history of fracture and typical extra-skeletal manifes tations such as blue sclera or dentinogenesis imperfecta, no further investi- gations are r equired. However, in equivocal cases the following may be helpful. \227\206 X-ray: although not pathognomonic, a mosaic appearance on skull X-ray may be seen due to numerous wormian bones. Wormian bones are irregular bony plates that form between t he cranial sutures. \227\206 Limb X-ray: a hypertrophic callus or calcified forearm interosseous membrane may indicate OI type V. OI types VII and VIII may be indicated by \200\230popcorn epiphyses \200\231. \227\206 DEXA scan: bone density is reduced. \227\206 Genetics/proteomics: samples of serum or saliva can be collected and screened for mutations in the type I collagen or CRTAP/LEPRE genes (Table 21.1 ). Alternatively, fibrob lasts isolated from a skin biopsy can be cultured and assessed for the quantity and quality of type I procollagen protein. Approximately 90 % of cases affecting collagen type I genes can be detected by these methods (OI types I \200\223IV). However, they are less helpful f or OI subgroups V \200\223VIII. \227\206 Bone biopsy: in most cases, biopsy will show a reduced cortical thickness of bone in association with reduced trabecular density and size. This is an invasive test but may be diagnostic, particularly in OI types V and VI (Table 21.1 ). 5. How would you manage this patient? Management of severe cases should be coordinated in a specialist center. Treatment includes physiotherapy, rehabilitation, orthotics, and surgery to minimize disabil- ity. Bisphospho nates may improve bone density, mobility, and grip strength, and reduce the incidence of fr acture and bone pain. Treatment in severe OI is most effective when given in the growth pha se, and cyclical intravenous pamidronate is the most commonly used regimen in children. The long-term safety of bisphos- phonate therapy in children is unclear, and there may be theo retical risks of 124 CASE HISTORIES IN RHEUMATOLOGY impaired postoperative bone healing. In the longer term there is also concern about prior p amidronate administration in women of childbearing age which may reduce the availability of skeletal calcium for fetal bone formation. This patient should probably re-start bisphosphonate therapy. Options include regular intra venous pamidronate or zoledronate. Alternatively, as an adult, he may tolerate oral prepara tions such as alendronic acid or risedronate. It is essential to ensure an adequate intake of calcium and vitamin D. Management of the extra-skeletal manifestations of OI and monitoring for com- plications is important. This patient should be referred to a maxillofacial surgeon for optimal care of the dental abnormalities. Severe kyphoscoliosis may result in a restrictive respiratory def icit. The symptoms of morning headache may indicate nocturnal hypoventilation; a referral t o the respiratory team would be warranted for consideration of nocturnal non-invasive venti lation. Table 21.1 Classification of osteogenesis imperfecta Type Gene Inheritance Severity Clinical features I Abnormal stop codon or frameshift mutation in COL1A1 or COL1A2 gene AD \227\206 Most common and mildest OI subtype \227\206 Increased fracture \227\206 Normal height \227\206 Minimal deformity \227\206 Vertebral wedge risk fractures common especially in puberty \227\206 Non-deforming \227\206 May present at any \227\206 Blue sclera age including elderly II Typically due to point mutations in COL1A1 or COL1A2 AD \227\206 Lethal perinatally due to multiple fractures and respiratory complications \227\206 Multiple fractures at birth \227\206 Gray sclera \227\206 Wormian bones on skull X-ray III AD \227\206 Severe \227\206 Wheelchair-bound \227\206 Progressive deformity throughout chil dhood \227\206 Respiratory compromise \227\206 Multiple fractures at birth \227\206 Short stature \227\206 White/gray sclera \227\206 Severe dentinogenesis imperfecta \227\206 Triangular facies \227\206 Early hearing loss \227\206 Wormian bones on skull X-ray \227\206 Moderate short stature \227\206 Dentinogenesis imperfecta IV AD \227\206 Moderate to severe \227\206 Progressive deformity throughout childhood \227\206 Early hearing loss 125 CASE 21 Table 21.1 (Contd.) Type Gene Inheritance Severity Clinical features V Not characterized AD \227\206 Moderate to severe \227\206 Moderate short stature \227\206 Calcified interroseous membrane causing radial h ead dislocation \227\206 Hypertrophic callus after fracture \227\206 Mesh-like appearance of bone lamellae histologically VI Not characterized AR \227\206 Moderate to severe \227\206 Moderate short stature \227\206 Scoliosis \227\206 Fish-scale appearance of bone lamellae and increased osteoid histologically AR \227\206 Moderate to severe VII Reduced expression of cartilage- associated protein (CRTAP) involved in post-translational modification of collagen type I \227\206 Mild short stature \227\206 Limb length discrepancy \227\206 Coxa vara \227 \206 \200\230Popcorn epiphyses \200\231 AR \227\206 Severe VIII Mutations in prolyl-3- hydroxylase-1 (LEPRE1) involved in post-translational modification o f collagen type I \227\206 Marked short stature \227\206 Reduced mineralization of fractures \227\206 Barrel-shaped chest \227\206 \200\230Popcorn epiphyses \200\231 AD: autosomal dominant; AR: autosomal recessive. Data from Basel D, Steiner RD (2009). Oste ogenesis imperfecta: recent findings shed new light on this once well-understood condition. Genet Me d ; 11 : 375 \200\22385. Further reading Basel D , Steiner RD ( 2009 ). Osteogenesis imperfecta: recent findings shed new light on t his once well-understood condition . Genet Med ; 11 : 375 \200\223 85 . Cheung MS , Glorieux FH ( 2008 ). Osteogenesis Imperfecta: update on presentation and management . Rev Endocr Metab Disord ; 9 : 153 \200\223 60 . Phillipi CA , Remmington T , Steiner RD ( 2008 ). Bisphosphonate therapy for osteogenesis imperfecta . Cochrane Database Syst Rev ; 8 : CD005088 . 126 CASE HISTORIES IN RHEUMATOLOGY Case 22 A 25-year-old male presented with a 4-week history of right anterior shin pain. He was an o ffice worker who had recently commenced running regularly in order to compete in the London Marathon for a charitable organization. The marathon was 3 months away. He had been a comp etitive long-distance runner as a teenager, but had led a sedentary lifestyle in recent yea rs. His symptoms had initially been a mild ache in his right anterior shin towards the end of a 10 mile run, but this had gradually worsened over the past 2 weeks to the point where he n ow had pain with any weight-bearing activity and was unable to run. There was occasional ni ght pain. He had tried paracetamol and NSAIDs but had received no symptomatic benefit. Examination revealed an antalgic gait. He was unable to hop on the right leg because of pai n. There was point tenderness and subtle swelling over a 3cm region in the distal third of the tibia on the medial aspect. He had weak hip abductors and poor core stability. A plain radiograph of his right tibia was normal. 127 CASE 22 Questions 1. What is the differential diagnosis? 2. How would you manage this patient acutely? 3. What further imaging would you do to help clarify the diagnosis? 4. Are there any other investigations that may be useful? 5. What advice should you give him regarding returning to running? 6. Will he be able to compete in the marathon? 128 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis? The differential diagnoses in order of probability in this patient are as follows. \227\206 Tibial stress fracture: the inability to hop (especially if this is due to impact pain) and the point tenderness suggest the diagnosis of a stress fracture. \227\206 Medial tibial stress syndrome (MTSS): this remains a strong possibility. MTSS is due to a traction periostitis where tendons attach to the tibia and is the most common caus e of anterior shin pain. It commonly occurs in runners who suddenly increase their frequenc y or intensity of training, or who use worn-out shoes. Swelling and tenderness over the dis tal portion of the tibia are consistent with this diagnosis. Pain with resisted plantar fle xion could be the reason for the inability to hop. \227\206 Chronic exercise-induced anterior compartment syndrome: this diagnosis is very un likely in the current scenario, but is listed here because it is a differential diagnosis o f shin pain. Patients with chronic exercise-induced compartment syndrome do not usually pre sent acutely and do not usually have point tenderness or impact pain. Common symptoms are a nterolateral shin pain of gradual onset that becomes progressively worse with exercise and improves within a few minutes of rest. There may be exercise-associated foot drop, or senso ry symptoms in the distribution of the deep peroneal nerve. \227\206 Osteoid osteoma: the limited night pain and lack of response to anti-inflammatori es are against the diagnosis of osteoid osteoma, but it should be considered in this age gr oup, especially if night pain were a major feature. Osteoid osteomas are small (<2 cm) beni gn prostaglandin-producing tumors that can occur in any bone, but the femur and tibia are t he most common sites. Males under the age of 30 are the highest risk group. Prostaglandin p roduction by the tumor causes local bone pain which is responsive to anti-inflammatory medi cation. 2. How would you manage this patient acutely? The working diagnosis is tibial stress fracture. The initial management is to make the pati ent non-weight-bearing. Options would be to put on an Aircast boot or plaster of Paris an d provide him with crutches. He should be encouraged to do non- weight-bearing exercise, su ch as swimming, to maintain his fitness and muscle tone. This is called \200\230relative r est \200\231. A decision on how long he should be non-weight-bearing will depend on imaging results and improvement in symptoms. 129 CASE 22 3. What further imaging would you do to help clarify the diagnosis? There are three options for imaging. \227\206 MRI is the imaging option of choice. MRI will usually be able to identify bone st ress, demonstrate fracture lines, identify areas of periosteal reaction and soft tis- sue p athology. \227\206 Nuclear bone scan will show a hot spot in the context of a stress fracture, incre ased bone turnover, or a periosteal reaction. Bone scans are good at identifying the presen ce of abnormal pathology, but not at discriminating the etiology of the underlying problem. A positive bone scan will need to be followed up with a CT of the abnormal area. \227\206 A CT scan will evaluate the bony architecture and therefore demonstrate a cortica l breach, fracture lines, cortical thickening due to new bone formation (Fig. 22.1), or a nidus in the case of an osteoid osteoma. The main drawbacks of CT are the lim- ited soft t issue information and the radiation dose. Fig. 22.1 CT scan of tibia. The arrow is pointing to cortical thickening of the anterior ti bia. This is consistent with bone stress or a healing stress fracture. 130 CASE HISTORIES IN RHEUMATOLOGY 4. Are there any other investigations that may be useful? Vitamin D levels should be checked, and replaced if low. A large proportion of patients pre senting with stress fractures are vitamin D deficient. It is uncertain whether low vitamin D directly contributes to the development of stress fracture or if it is simply an observed association. In a female patient the female athlete triad of amenorrhea, anorexia, and ost eoporosis should be considered and appropriately managed. The weak hip abduction may be par t of the vitamin D deficiency. Physiotherapy will be helpful in addressing this when he has replenished his stores. 5. What advice should you give him regarding returning to running? A tibial stress fracture requires the patient to be non-weight-bearing for 2 \200\2234 week s and in a boot for approximately 4 weeks. Partial, followed by full, weight-bearing will b e guided by symptoms and clinical improvement. Clinical improvement is gauged by the abilit y to hop pain free on the affected leg and resolution of tibial tenderness. Once fully weig ht-bearing, return to running will need to be done in a slow stepwise manner. This should s tart with a gentle walk \200\223jog program, with the intensity and duration of jogging slo wly increasing over a period of months. Any biomechanical abnormalities which may have cont ributed to the stress frac- ture such as over- pronation, weak hip abductors, and poor core stability should be addressed. This man had a tibial stress fracture which was demonstrated on MRI scan. The area of bone stress correlated with his local pain on the medial aspect of the distal third of the tibia . His 25OH-vitamin D levels were 15 nmol/L, which is low. He was given 50 000 IU of vitamin D daily for 7 days and thereafter one capsule per week for 6 weeks. He worked with the phy siotherapist, and his pain resolved in 8 weeks and his muscle power returned to normal afte r 4 months. 6. Will he be able to compete in the marathon? No, he will not be able to compete in a marathon in 3 months. He should be advised that he will need a much longer period to increase his running distance and intensity slowly in ord er to compete safely. He could aim to compete in the London Marathon the following year. 131 CASE 23 Case 23 A 51-year-old man presented with a 2-day history of increasing exertional breathless- ness and cough productive of a moderate amount of fresh blood. Over the preceding 3 weeks he had felt very fatigued and noticed migratory joint and muscle pains. On further enquiry, he ha d seen his GP several times in the last year for a recurrent blocked nose which had been tr eated as allergic sinusitis. In the past month his nasal symp- toms had changed to a foul-s melling discharge. He had no significant past medical history. On examination he had a fever of 37.9 C, blood pressure of 160/100 mmHg, and O 2 saturat ions of 89 % on air. There was diffuse nasal mucosal swelling and redness with some areas o f ulceration and crusting. Bronchial breath sounds were heard in the mid and lower zones of both lung fields. Neurological examination revealed conduc- tive hearing loss in his left ear. The remainder of the cardiovascular system, gastroin- testinal, and musculoskeletal ex amination was normal. Investigations showed the following: \227\206 Hb 9.4 g/dL; WCC 13.2 \227 10 9 /mL; neutrophils 9.1 \227 10 9 /mL; platelets 6 23 \227 10 9 /L \227\206 Serum creatinine 488 mol/L \227\206 Urea 32 mmol/L \227\206 CRP > 160 mg/L \227\206 CXR \200\224 see Fig. 23.1 \227\206 Urine microscopy: red cell casts present. 132 CASE HISTORIES IN RHEUMATOLOGY Fig. 23.1 CXR showing pulmonary hemorrhage. 133 CASE 23 Questions 1. What is the differential diagnosis? 2. What tests will help to differentiate between the possible diagnoses? 3. How should this man be managed in the acute setting? 4. What is his prognosis? 5. What can be done to reduce the risk of relapse? 134 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis? The differential diagnosis includes the pulmonary renal syndromes. Red cell casts in the urine indicate glomerular damage. The most common cause of glomerular damage is glomerular inflammation but other causes include renal infarction and bacterial endocarditis. The elevated serum creatinine and hyperten- sion support severe renal involve ment. The CXR showed bilateral air space opacity with some apical sparing. Diffuse pulmonar y hemorrhage is the most likely cause of the CXR findings. Infection is less likely because it is bilateral, but needs to be excluded. The main differentials for a pulmonary renal sy ndrome are as follows. \227\206 Wegener \200\231s granulomatosis (WG): WG is a necrotizing vasculitis of small an d medium-sized blood vessels in which granulomatous inflammation of the respi- ratory tract occurs. The newer nomenclature for this condition is granulomatosis with polyangiitis (GPA ). Lung capillaritis, which can result in pulmonary haem- orrhage and necrotizing glomerulo nephritis, is a common feature. \227\206 Microscopic polyangiitis (MPA): MPA is a necrotizing vasculitis with few or no im mune deposits, predominantly affecting small-caliber vessels. Necrotizing glomerulonephriti s and pulmonary hemorrhage from capillaritis are the char- acteristic features. The lack of granulomatous inflammation of the respiratory tract is the main distinguishing clinical fe ature between MPA and WG. \227\206 Goodpasture \200\231s syndrome (anti-glomerular basement membrane disease): This is a rare autoimmune condition where antibodies against the 3 -subunit of type IV collag en found in the lung and kidney cause pulmonary hemorrhage and glomerulonephritis. \227\206 Systemic lupus erythematosus (SLE): SLE is an autoimmune connective tissue diseas e with a wide spectrum of presentations including multisystem disease involving the lung an d kidney. It typically affects women between the ages of 15 and 50 years. The history of nasal congestion, crusting, and conductive deafness favors a diagno- sis of WG. These items are not typical features of the other differential diagnoses, and the patie nt \200\231s gender and age make SLE unlikely. 2. What tests will help to differentiate between the possible diagnoses? \227\206 Anti-neutrophil cytoplasm antibodies (ANCA) are present in most patients with WG and MPA and are helpful in confirming the diagnosis in the appropriate clinical context. Ho wever, they should not be used as a screening test. ANCA can be detected in two ways. Indirect immunofluorescence assay to identify specific staining patterns on human neutrophi ls by the antibodies. A cytoplasmic (c-ANCA) staining pattern is observed in most patients with WG, whereas a perinuclear pattern (p-ANCA) is seen with MPA (Fig. 23.2 ). 135 CASE 23 Fig. 23.2 (See also Plate 11). Antineutrophil cytoplasm antibodies as seen with indirect im munofluorescence: (a) perinuclear staining pattern (p-ANCA); (b) cytoplasmic staining patte rn (c-ANCA). Source: private collection of Raashid Luqmani. Enzyme-linked immunosorbent assay (ELISA). Antibody directed against proteinase 3 (PR3) is strongly associated with WG (and c-ANCA). Antibodies against myeloperoxidase (MPO) are asso ciated with MPA (and p-ANCA), but can also be found in other vasculitic syndromes and IBD. \227\206 Anti-glomerular basement membrane (GBM) antibodies are diagnostic of Goodpasture \200\231s syndrome. ANCA tests can be positive in around 20 % of patients with Goodpasture \200\231s syndrome and in those patients there is a more favorable prognosis. \227\206 Anti nuclear antibody (ANA) tests can be performed to rule out a diagnosis of SLE . Over 95 % of patients with SLE will have a positive ANA, but the test is not specific for the diagnosis. In this clinical setting, a negative test would be helpful. \227\206 Nasal mucosal biopsy showing necrotizing granulomatous vasculitis is strongly suggestive of WG. \227\206 Renal biopsy: all the differential diagnoses mentioned above may show evidence of a rapidly progressive crescentic glomerulonephritis on histology. IgG deposits visible alo ng the glomerular basement membrane on microscopy with immun- ofluorescence staining is sug gestive of Goodpasture \200\231s syndrome. Immune com- plexes directed against immunoglobul ins or complement can be seen in patients with lupus nephritis. \227\206 Other tissue biopsies such as lung or nerve may be useful in different settings, but the above-mentioned tests should be sufficient to make the diagnosis in this patient. 3. How should this man be managed in the acute setting? This patient has organ- and life-threatening disease as demonstrated by diffuse alveolar he morrhage and renal failure. He is probably best managed in an intensive care unit/high-depe ndency unit where his respiratory function can be closely monitored and mechanical ventilat ion can be provided if required. Treatment includes plasma exchange (to remove circulating autoantibodies and immune complexes which may be driving this process) and immunosuppressiv e therapy 136 CASE HISTORIES IN RHEUMATOLOGY with cyclophosphamide and glucocorticoids. The MEPEX trial showed that plasma exchange impr oved the renal outcome for patients with severe renal vasculitis. In addition, there is a c onsensus that plasma exchange should be used for pulmonary hemorrhage, with evidence from r etrospective case series. However, randomized trial evidence is not yet available. Intraven ous pulse cyclophosphamide at a dose of 15 mg/kg every 3 weeks is given for up to 6 months in conjunction with oral pred- nisolone at a dose of 1 mg/kg daily (the dose of steroid is slowly tapered). Intravenous cyclophosphamide is favored over continuous oral cyclophospham ide as it has similar efficacy but lower cumulative dose and thus lower long-term toxicity. This treatment strategy is applicable to all the differential diagnoses, although the dose of cyclophosphamide is usually lower (10 mg/kg) for SLE because of the higher risk of infe ctive complications associated with this disease. This patient was found to have a c-ANCA > 160 IU. A diagnosis of WG was made. He was treate d with 60 mg of prednisolone daily and given cyclophosphamide 1g intravenously every 3 week s for six cycles. He was given co-trimoxazole 960 mg three times a week as pneumocystis pro phylaxis and to reduce nasal carriage of Staphylococcus aureus , alendronate 70 mg weekly, and omeprazole 20 mg daily. His hypertension was treated with amlodipine. His renal functio n stabilized at creati- nine 190 mmol/L by 3 months. 4. What is his prognosis? The mortality rate for patients with a diagnosis of WG or MPA and renal failure at presenta tion is approximately 25 % in the first year and highest in the first 3 months when the vas culitis is most active and immunosuppressive therapy is maximal. The mortality rate is even higher for patients requiring admission to an intensive care unit. The main causes of deat h are infection, pulmonary hemorrhage, and complications of severe renal failure. The risk of death is higher in those who remain dialysis-dependent than in those who regain renal fu nction and are dialysis- independent. Those who do not regain renal function probably have severe disease and/or a delay in receiving appropriate therapy. If patients survive the ini tial 12 months, the prognosis improves, but there is increased long-term morbidity and mort ality from the results of renal or other organ damage and increased risk of malignancy from cyclophosphamide exposure. This patient had a relatively uneventful course. He had one episode of presumed pulmonary s epsis which was treated with antibiotics. He went onto mycophenolate mofetil 2 g daily afte r the cyclophosphamide therapy was completed at 22 weeks. His BP was treated with amlodipin e and doxazocin. 5. What can be done to reduce the risk of relapse? Once the disease activity is controlled with cyclophosphamide (i.e. the patient is in remis sion), treatment should be changed to less toxic immunosuppressive therapy. Azathioprine is the most common medication used for maintenance of remission and should be continued for a minimum of 18 months but often for up to 5 years. Other options for maintenance therapy ar e methotrexate, leflunomide, and 137 CASE 23 mycophenolate mofetil. Earlier withdrawal of maintenance therapy is associated with a high rate of relapse. In addition, chronic nasal carriage of Staph.aureus has been associated wi th higher rates of relapse. Prophylactic use of co-trimoxazole may be useful in this settin g. Prednisolone should ideally be tapered and stopped by the time maintenance therapy is co mmenced, but if this is not possible owing to persistent low-grade disease, it should be co ntinued at the lowest possible dose. Patients with WG are at two- to threefold increased ri sk of cardiovascular morbidity, so modifiable risk factors such as smoking, dyslipidaemia, and hypertension should be addressed. Bone protection with calcium, vitamin D, and bisphosp honates should be considered in patients at increased risk of osteoporotic fracture, especi ally those who require ongoing glucocorticoid therapy, are post-menopausal, and/or have low baseline BMD. Additional Reading Jayne D , Rasmussen N , Andrassy K , et al . ( 2003 ). A randomized trial of maintenance th erapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies . N Engl J M ed ; 349 ( 1 ): p. 36 \200\223 44 . Jayne DR , Gaskin G , Rasmussen N , et al . ( 2007 ). Randomized trial of plasma exchange o r high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis . J Am S oc Nephrol ; 18 : 2180 \200\223 8 . Jennette JC , Falk RJ , Andrassy K , et al . ( 1994 ). Nomenclature of systemic vasculitide s. Proposal of an international consensus conference . Arthritis Rheum ; 37 : 187 \200\223 92 . Hudson BG , Tryggvason K , Sundaramoorthy M , et al . ( 2003 ). Alport \200\231s syndrome, Goodpasture \200\231s syndrome, and type IV collagen . N Engl J Med ; 348 : 2543 \200\223 56 . Koldingsnes W , Nossent H ( 2002 ). Predictors of survival and organ damage in Wegener \200 \231s granulomatosis . Rheumatology ; 41 : 572 \200\223 81 . Mukhtyar C , Flossmann O , Hellmich B , et al . ( 2008 ). Outcomes from studies of antineut rophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force . Ann Rheum Dis ; 67 : 1004 \200\223 10 . 138 CASE HISTORIES IN RHEUMATOLOGY Case 24 A 31-year-old woman presented to the rheumatology department with a 2-year history of arthr algia of her hands, wrists, and ankles, associated with early morning stiffness. Her past m edical history included mild asthma and depression. She smoked 15 cigarettes a day. There w as no family history of arthritis or autoimmune disease. On examination, she had swelling of the small joints of her hands and wrists, with wasting of the intrinsic muscles and reduced grip strength. There was a small nodule at her left el bow. The CXR was unremarkable, and her hand X-rays suggested carpal crowding and periarticu lar osteopenia, with possible small erosion at the distal end of her proximal phalanx. The diagnosis of rheumatoid arthritis was made, and she was treated with intramuscular steroid, methotrexate, and hydroxychloroquine. The following year, she presented with shortness of breath on exertion. Her meth- otrexate was stopped, but the shortness of breath progressed and she developed orthopnoea. On admiss ion, she was found to be tachycardic and hypertensive. The CXR (Fig. 24.1 ) demonstrated an increase in the cardiac silhouette. An echocardiogram demonstrated a pericardial effusion, as well as a severely dilated left atrium, mitral regurgitation, and a reduced ejection fr action at 49 % . An MRI gadolinium cardiac scan showed left ventricular hypertrophy, a dila ted left atrium, a pericardial effusion, moderate mitral regurgitation, and a thrombus in t he left apex. It also demonstrated endomyocardial inflammation or fibrosis (Fig. 24.2 ). Fig. 24.1 CXR showing increased cardiac silhouette. 139 CASE 24 Questions 1. Give a differential diagnosis at her initial presentation with joint pains. 2. What are the current recommendations for management of rheumatoid arthritis (RA)? 3. What are the causes of shortness of breath in RA? Give a differential diagnosis based on the CXR findings. 4. What is the differential diagnosis for the endomyocardial inflammation or fibrosis? 5. What are the current NICE guidelines for starting biological therapy in RA? Fig. 24.2 The echocardiogram: (a) asterisk, left ventricular hypertrophy; arrow, pericardia l effusion; (b) thin arrow, thrombus in apex; thick arrow, endomyocardial enhancement demon strating inflammation or fibrosis; (c), (d), (e) arrows show the endomyocardial enhancement pattern. The patient had a coronary angiogram which was normal, excluding an ischaemic cause. The patient was commenced on warfarin for the apical thrombus. Her hematology data was reviewed and she was found to have an eosinophilia of 37 % (normally <5 % ). Oral corticosteroids were given and an infliximab infusion commenced because of ongoing high DAS and lack of efficacy of multiple DMARDs. 140 CASE HISTORIES IN RHEUMATOLOGY Answers 1. Give a differential diagnosis for the initial presentation of joint pains The most likely diagnosis is nodular rheumatoid arthritis because there was a sym- metrical small-joint polyarthritis with wrist involvement, wasting of the intrinsic muscles, and a nodule at the elbow. There is periarticular osteopenia on X-ray. These are consistent with a the diagnosis of RA. Other causes of a polyarthritis include the following: \227\206 Psoriatic arthritis \227\206 Reactive arthritis \227\206 Osteoarthritis \227\206 Connective tissue disease (e.g. SLE) \227\206 Vasculitis \227\206 Sarcoidosis \227\206 Malignancy (e.g. leukemia). These are less likely given the absence of other supporting features such as a rash, histor y of preceding infection, family history, erythema nodosum, or marked constitutional upset. 2. What are the current recommendations for management of rheumatoid arthritis? The BSR guidelines for the management of new-onset disease suggest the following: \227\206 Refer patients with suspected persistent synovitis of undetermined cause for spec ialist opinion. Patients should be offered ongoing access to the multidisci- plinary team, including specialist physiotherapist and occupational therapist. \227\206 Offer a combination of DMARDs, including methotrexate and at least one other DMAR D, plus short-term glucocorticoids as first-line treatment as soon as possible. \227\206 To monitor disease, use CRP and the key components of DAS. The DAS is a combined index that was developed in Nijmegen in the 1980s to measure the dise ase activity in patients with RA. It has been validated for use in clinical trials in combi nation with the EULAR response criteria. There are DAS calculators that make it easy to use , and thus it is possible to collect information about the disease activity and response to treatment. The DAS takes into account the number of swollen and tender joints, the ESR or CRP, and a V isual Analog Score (VAS) of perceived patient disease activity. The score is between 0 and 10 and indicates how active the RA is at the time of measurement. The DAS has been used to define thresholds for disease activity: high disease activity (>3.7); moderate (2.4<DAS<3.7); low (<2.4); remission (<1.6) 141 CASE 24 3. What are the causes of shortness of breath in RA? What does the CXR in Fig. 24.1 show? Give a differential diagnosis based on the CXR finding s The causes of shortness of breath in rheumatoid arthritis are as follows. \227\206 Pulmonary: non-specific interstitial pneumonia (NSIP) idiosyncratic allergic alveolitis associated with drugs such as methotrexate, leflunomide, salazopyrine pulmonary fibrosis pleural effusion pulmonary hypertension. \227\206 Cardiac: pericarditis pericardial effusion cardiac amyloid.