 \227\206 Sweetened soft drinks and drinks high in fructose are associated with increased risk of gout in men. \227\206 Dietary advice is the same as the general advice given for the associated meta- b olic syndrome. In addition, patients should avoid foods rich in purines such as red meat, g ame, offal, and shellfish. \227\206 Alcohol enhances urate production, decreases renal urate clearance, decreases sol ubility of urate crystals, and can be relatively dehydrating. Beer, even non- alcoholic bee r, is purine rich. Avoid beer and binge drinking. Limit alcohol intake per week to <21 unit s (men) and <14 units (women). It is important to monitor renal function and general metabolic state. The patient \200\231 s metabolic syndrome may be a much more serious cause of mortality and morbid- ity than the ir gout. The lipid-lowering drugs atorvostatin and fenofibrate, and the antihypertensives l osartan and amlodipine, have mild uricosuric effects. This may be helpful when treating the comorbid conditions associated with gout. Further reading Jordan KM , Cameron JS , Snaith M, et al . ( 2007 ). British Society for Rheumatology and B ritish Health Professionals in Rheumatology guideline for the management of chronic gout . Rheumatology ; 46 : 1372 \200\223 4. Rider T , Jordan K ( 2010 ). The modern management of gout . Rheumatology ; 49 : 5 \200 \223 14. Zhang W , Doherty M , Bardin T , et al . ( 2006 ). EULAR evidence based recommenda tions for gout . Ann Rheum Dis ; 65 : 1301 \200\223 11. 31 CASE 6 Case 6 A 17-year-old Caucasian male was seen urgently in outpatients with a 3-week history of inte rmittent pain and swelling of his right knee. He had a past history of heel pain when he wa s 12 years old which had settled spontaneously. He was otherwise healthy, with no recent tr auma and no significant past medical history. A paternal uncle had psoriasis. On examination his height and weight were on the 60th centile and he was apyrexial with nor mal pulse and blood pressure. Examination of skin and musculoskeletal system was normal apa rt from a tense effusion of his right knee: 150 mL of straw- colored fluid was aspirated fr om his knee and 80 mg of Depo-Medrone was injected. Investigations showed the following: \227\206 Hb 12.4 g/dL; MCV 74 fL; WCC 12.4 \227 10 9 /L; neutrophils 6.9 \227 10 9 /L; p latelets 488 \227 10 9 / L; CRP 89.2 mg/L \227\206 Renal and liver functions were normal \227\206 Synovial fluid: no organisms; no crystals; 2 + WCC; 0 RBC; no growth. Questions \200\224Part 1 1. What is the differential diagnosis? 2. What further information is needed to make the diagnosis? 32 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis? In a young person, the most important differential diagnoses to consider are septic arthrit is (see p. 208), trauma, and reactive arthritis. A travel history and sexual his- tory are essential. With teenagers, it may be important to interview the patient without their paren ts to obtain an accurate history. The differential diagnosis is wide and includes enthesiti s-related juvenile idiopathic arthritis (JIA), early seron- egative inflammatory arthritis (psoriatic or enteropathic), undifferentiated spond- ylarthritis with peripheral joint invo lvement, atypical presentation of rheumatoid arthritis, and rarer conditions such as BD and acute sarcoidosis. In older patients a crystal arthritis should be considered. Enthesitis-related JIA would fit with the previous history of heel pain and knee swelling, more common in human leucocyte antigen (HLA) B27-positive patients (his first rheumatologic al presentation was at age 12). The heel pain may represent an enthesopathy; these are freq uently associated with spondyloarthritis but, as their symptoms are short-lived, they are o ften forgotten by patients and therefore need direct enquiry and examination. The MCV of 74 fL is significant. Blood loss due to NSAID use, iron-deficiency anae- mia due to malabsorption, inadequate diet, and blood loss should be considered. This patient had n ormal growth and was on the 60th centile for height and weight, which would not support a d iagnosis of long-standing malabsorption. However, undiag- nosed coeliac disease is known to be present in 0.5 % of the population, and should be screened for. There is an association with muscle pain, probably related to low-grade vitamin D insufficiency. There is no assoc iation with inflammatory arthritis. His low MCV might suggest a diagnosis of asymptomatic enteropathic arthritis. A careful GI history, particularly noting mouth ulcers, weight loss, and systemic malaise should be obtained. A history of psoriasis in a second-degree relative is of borderline significance, given the background population frequency of psoriasis; however, it does lend weight to a diagnosis of psoriatic arthritis. In younger children, a history of psoria- sis in a first-degree rel ative (psoriatic diathesis) may be enough for a diagnosis of psoriatic arthritis, as the ar thritis may precede the skin disease by many years, par- ticularly in children. 2. What further information is needed to make the diagnosis? A personal or family history of iritis, psoriasis, or colitis should be established. Clinic al examination should include all joints, especially the spine and sacroiliac joints. Skin, nail, and eye examination should be documented. This patient \200\231s diagnosis was enteropathic arthritis, with microcytosis due to gas- trointestinal blood loss. Six weeks later he was admitted with a 3-day history of severe abdominal pain associated wi th vomiting. He underwent laparotomy where he was found to have a 50cm segment of inflamed ileum proximal to the ileocaecal junction. Histology confirmed Crohn \200\231s disease (Fig s 6.1 \200\223 6.3 ). 33 CASE 6 Fig. 6.1 (See also Plate 6) Linear fissuring ulcer formed by granulation tissue on either s ide, and containing neutrophils. Fig. 6.2 (See also Plate 7) Granulomatous inflammation and giant cells. 34 CASE HISTORIES IN RHEUMATOLOGY Fig. 6.3 (See also Plate 8) Distorted acutely inflamed colonic crypts (crypt abscesses). 35 CASE 6 Questions \200\224Part 2 3. What are the treatment options? 4. How are his joint symptoms related to his Crohn \200\231s disease? 36 CASE HISTORIES IN RHEUMATOLOGY Answers 3. What are the treatment options? First-line treatment for the joint disease is aspiration and intra-articular steroid inject ion to the affected joint(s). The effect of drugs on the bowel needs to be considered in any treatment regime. Many patie nts are intolerant of NSAIDs, which can precipitate a flare of inflamma- tory GI symptoms. If joint symptoms do not settle with local steroid injections, sulfasalazine, methotrexate, or azathioprine are options. Anti-TNF treatments such as infliximab or adalimumab are curr ently used for severe Crohn \200\231s disease and enteropathic arthritis. 4. How are his joint symptoms related to his Crohn s disease? The peripheral arthritis may be mono-, oligo-, or polyarticular. Some authorities suggest a classification into two groups. Type I is a large joint oligoarticular pattern, primarily affecting the knees and ankles, with self-limiting episodes often mirroring bowel activity. Type II is a symmetrical peripheral polyarthritis, involv- ing both upper and lower limb. The clinical course of arthritis may run independ- ently of the IBD, although in some patie nts a flare of arthritis can signal a flare of IBD. The prevalence and pattern of arthritis is similar in Crohn \200\231s disease and ulcer- ative colitis. Approximately 20 % of patients with IBD have inflammatory joint disease during the course o f their illness. Symptoms are often episodic and variable, with 9 % suf- fering inflammator y back pain, 2 % having classical ankylosing spondyloarthritis (AS), and 5 % having asympto matic radiographic sacroiliitis. Up to 5 \200\22310 % of patients with spondyloarthritis have coexistent IBD. Between 30 % a nd 60 % of unselected spondyloarthritis patients have histological evidence of intestinal i nflammation. Changes vary from an acute neutrophilic infiltrate of the lamina propria with intact architecture to more chronic changes with mononuclear cell infiltration of the lamin a propria, aphthoid ulceration, and distortion of the villi and crypts. It is not yet known how frequently these changes progress to symp- tomatic IBD or whether treatment of arthrit is alters the natural history of the gut changes. Ankylosing spondylitis (AS) can precede IBD by many years and runs an inde- pendent clinica l course. Peripheral arthritis, with associated dactylitis and enthesopa- thies, can again precede bowel symptoms. It is rarely erosive or deforming. HLA B27 and CARD 15 Whilst over 90 % of patients with isolated AS carry the HLA B27 gene, i t is only carried by 70 % of those with coexisting IBD and 20 \200\22350 % of those with ps oriatic spondylitis. Only 15 % of individuals with IBD are HLA B27 positive. (HLA B27 posit ive patients are more likely to develop iritis, dactylitis, and sacroiliitis, but the assoc iation is much weaker than with AS). Polymorphisms in the CARD 15 gene on chromsome 16 are associated with suscep- tibility to C rohn \200\231s disease, with homozygotes being at 38 times increased risk. 37 CASE 6 Thirty per cent to 46 % of patients with Crohn \200\231s disease carry one of three mutatio ns. The background population prevalence of these mutations is 20 % . An increased rate of CARD 15 mutations is not found in isolated AS. However, there is an increased rate of CARD 15 mutation in those patients with a spondyloarthritis and histological evidence of gut inf lammation, with 38 % having a CARD 15 mutation. Further reading Brophy S , Pavy S, Lewis P, et al . (2001). Inflammatory eye, skin, and bowel disease in spondyloarthritis: genetic, phenotypic, and environmental factors . J Rheumatol ; 28 : 2667 \200\223 73. Laukens D , Peeters H, Marichal D , et al . (2005). CARD15 gene polymorphisms in patients w ith spondyloarthropathies identify a specific phenotype previously related to Crohn \200 \231s disease . Ann Rheum Dis ; 64 : 930 \200\223 5. Palm \230 , Moum B, Jahnsen J, Gran JT ( 2001 ). The prevalence and incidence of periphera l arthritis in patients with inflammatory bowel disease, a prospective population-based study (the IBSEN study) . Rheumatology ; 40 : 1256 \200\223 61. Steer S , Jones H, Hibbert J , et al . ( 2003 ). Low back pain, sacroiliitis, and the relat ionship with HLA-B27 in Crohn \200\231s disease . J Rheumatol ; 30 : 518 \200\223 22. Taurog JD ( 2006 ). Enteropathic arthritis . In: Fauci AS , Langford CA (eds). Harrison \200\231s Rheumatology ( 16 th edn). New York : McGraw-Hill ; 152 \200\223 3 . 38 CASE HISTORIES IN RHEUMATOLOGY Case 7 A 49-year-old Caucasian male presented with a 10-week history of bilateral swelling and sti ffness of his MCP joints. His hands were stiff for 15 minutes every morning. He had a 10-ye ar history of mechanical back pain and was on the waiting list for left hip replacement. He had had a right total knee replacement at age 40 years. He had previ- ously been a high-le vel rugby player. Family history was unremarkable. On examina- tion he had tender swelling of the second and third MCP joints of both hands. He had painless restriction of left ankle and subtalar joint movement. Normal investigations included: \227\206 FBC \227\206 urea and electrolytes, liver function \227\206 fasting glucose, calcium, uric acid \227\206 ESR and CRP. RF and ACCP antibody were negative. Radiographs of the patient s hands, left ankle, and wri st are shown in Figs 7.1 \200\2237.4. Fig. 7.1 Radiographs of patient s hands. 39 CASE 7 Fig. 7.2 Ankle X-ray showing severe osteoarthritic changes with almost complete loss of joi nt space, subchondral cysts, and sclerosis. 40 CASE HISTORIES IN RHEUMATOLOGY Fig. 7.3 Ankle X-ray showing severe osteoarthritic changes with almost complete loss of joi nt space, subchondral cysts and sclerosis, and large osteophytes (arrows). Fig. 7.4 Calcium pyrophosphate deposition in the wrist (arrow). 41 CASE 7 Questions 1. What is the differential diagnosis? 2. What specific laboratory investigations would you request? 3. What are the most likely diagnosis and clinical features of this condition? 4. What are the treatment strategies for the patient? 5. What are the implications for his relatives? 42 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis? \227\206 Osteoarthritis (OA), especially secondary to trauma \227\206 Early inflammatory arthritis \227\206 Haemochromatosis \227\206 Other causes of secondary chondrocalcinosis (hyperparathyroidism, hypomag- nesaemia) \227\206 Acromegaly. The most likely diagnosis in a 49-year-old male presenting with mechanical hand pain and sh ort-lived early morning stiffness is OA. The history of previous joint replacement and regu lar high-impact exercise may suggest accelerated OA second- ary to trauma. However, the spe cific radiographic changes (Figs 7.1 \200\223 7.4 ) prompt consideration of other underlyi ng diagnoses. Early inflammatory arthritis needs to be considered because of the MCP joint involvement an d joint swelling. The short duration of early morning stiffness (less than 30 minutes), lac k of an inflammatory response and absence of rheumatoid factor and ACCP antibodies make thi s diagnosis unlikely. The presence of chondrocalcinosis on the radiographs means that the patient should be scree ned for diseases associated with calcium pyrophosphate deposition (CPPD) such as haemochrom atosis, hyperparathyroidism, and hypomagnesaemia. His normal calcium is against a diagnosis of hyperparathyroidism. Acromegaly (see p. 253) should be included in the differential diagnosis in the context of premature OA. Patients with acromegaly complain of non-specific arthral- gia of the hands a nd large joints (shoulders, knees, spine, hips). Other clinical features (skin thickening a nd enlarged hands and feet, prominent forehead, and supra-orbital ridge) may help to diagno se the condition. Increased insulin like growth factor 1 will provide definite diagnosis. R adiographs in acromegaly may show widening of joint spaces due to cartilage overgrowth, or established OA in later stages. 2. What specific laboratory investigations would you request? \227\206 Transferrin saturation (ratio of iron to total iron-binding capacity) is used for screening for haemochromatosis. \227\206 If transferrin saturation is > 50 % , ferritin should be measured. In haemochroma - tosis, ferritin levels exceed 200 g/L in pre-menopausal women and 300 g/L in post-m enopausal women and men. \227\206 Both ferritin and transferrin act as acute phase reactants and levels may be high due to inflammatory disease elsewhere. Hence confirmation of diagnosis may require liver b iopsy. Studies are exploring the use of CT and MRI to aid diagnosis. \227\206 Genetic testing: haemochromatosis is an autosomal recessive disorder. It is due t o mutations of the HFE gene located in the short arm of chromosome 6. HFE codes 43 CASE 7 a protein that acts in conjunction with 2 -microglobulin to regulate intestinal iron abs orption. The most common mutation is C282Y, and 90 % of haemochro- matosis patients are hom ozygous for HFE C282Y. Heterozygotes have increased iron stores but rarely develop clinical disease. 3. What are the most likely diagnosis and clinical features of this condition? The most likely diagnosis is haemochromatosis. Clues to the diagnosis are symptoms of accelerated osteoarthritis in a relatively young pat ient and hook osteophytes in the MCP joints. Repeated trauma related to his rugby playing c areer does not account for all these features. Patients with OA can experience morning stif fness, but not usually prolonged for more than 20 minutes. Haemochromatosis is the most common autosomal recessive genetic disorder in people of North ern European extraction, particularly Celtic populations. One in 225 white Caucasian and 1 in 85 Irish are homozygous for the HFE C282Y gene. The prevalence of the disease is 30 \200 \22360 in 10 000, with an estimated male-to-female ratio of 1.5:1. The disease presents in adult life, rarely before age 30, and men present on average 15 years before women. This is largely due to the protective effect of menstrual blood loss, although sex-specific differ ences in gene expression may be involved. Excess intestinal absorption of iron with iron deposition in the parenchymal cells of many organs, including joints, liver, pituitary, heart, pancreas, and skin, leads to the clinica l manifestation of the condition: arthritis (in 40 % of patients), cirrhosis, hypogonadis m, cardiomyopathy, hypothyroidism (rare), diabetes melli- tus, skin pigmentation, and bronz e or slate-gray pigmentation. In the early stages patients may be asymptomatic or present n on-specifically with lethargy, arthralgia, and loss of libido. Haemochromatosis-associated arthritis affects the small joints of the hands (especially the second and third MCP joints) with hook-shaped osteophytes, as well as accelerating large-j oint OA (hips, knees, ankles, and shoulders). Patients present with osteoarthritic symptoms between the ages of 30 and 60 but may present earlier. Haemochromatosis should always be s uspected in young adults with OA even in the absence of other symptoms. Radiographs show su bchondral sclerosis and cyst formation, space narrowing, and hook-like osteophytes. In 50 % of cases there is evidence of calcium pyrophosphate deposition disease (CPDD), typically i n the wrist, knee, intervertebral disc, and symphysis pubis, and patients may experience ps eudo-gout attacks. 4. What are the treatment strategies for this patient? Treatment strategies for this patient are to treat the iron overload, treat the arthritis, and assess for underlying organ damage, particularly liver disease. The aims of treatment of iron overload are to rid the body of excess iron, main- tain norma l iron stores, and minimize dietary iron intake. Initially this requires 44 CASE HISTORIES IN RHEUMATOLOGY once- or twice-weekly phlebotomy until serum ferritin is \211 20 g/L. Subsequent maint enance phlebotomy (approximately four times per year) is needed to maintain this ferritin l evel. General dietary advice includes minimizing oral iron intake, particularly red meat. Vitamin C increases intestinal iron absorption and supplements should be avoided. Alcohol also inc reases iron absorption; red wine has a high iron content and alcohol can accelerate liver d amage. Therefore patients should avoid alcohol or limit intake to less than one unit per da y. Treatment of arthritis is symptomatic with analgesia, intra-articular steroid injections, o rthotics, physiotherapy, exercise, and, in later stages, surgery. Any flares of associated chondrocalcinosis are treated symptomatically. Disease- modifying anti-rheumatic drugs (DMA RDs) are unhelpful, and the arthropathy does not respond to iron removal. The most important prognostic factor is the presence or absence of hepatic fibro- sis or ci rrhosis. Patients without liver disease have a normal life expectancy. The patient can have liver involvement with normal blood tests, and a liver biopsy is undertaken if the ferriti n level is > 1000 g/L or the patient has abnormal LFTs. There are changes due to iron ov erload on both CT and MRI, but these cannot define fibrosis or cirrhosis. Patients with cir rhosis have a 200-fold increased risk of develop- ing hepatocellular carcinoma and are scre ened by regular testing for -fetoprotein levels plus liver ultrasound. Pancreatic involvement is rare without cirrhosis, but patients with cirrhosis are at high r isk of developing insulin-dependent diabetes. Hypogonadism from pitui- tary involvement is usually a late feature, although impotence is often an early feature. Cardiac involvement c an lead to arrhythmias and cardiomyopathy. Patients can develop a slate-gray pigmentation w hich is caused by a combination of mela- nin and iron deposition. Excess mortality is usual ly from complications of cirrhosis, hepatocellular cancer, cardiomyopathy, or complications of diabetes. Regular venepuncture leads to iron removal from tissues and prevents disease progression, p articularly in early disease before irreversible parenchymal damage has occurred. This patient \200\231s transferrin saturation was 60 % and his serum ferritin level was 145 0 g/L. He was found to be homozygous for HFE C282Y. His alcohol intake was modest. He ha d regular venepuncture and he maintained normal liver function and low ferritin levels. He noted that his energy levels improved but his arthritis symptoms remained troublesome. He u nderwent a left total hip replacement, and took colchicine for episodes of wrist chondrocal cinosis flares. 5. What are the implications for his relatives? First-degree relatives should be screened with transferrin saturation, serum ferri- tin, li ver enzymes, and genotyping for the HFE mutation. Early diagnosis and treatment before orga n damage occurs is associated with normal life expectancy. The patient \200\231s only son was C282Y heterozygote with normal iron studies. His asympto matic younger brother was also C282Y homozygous with significantly 45 CASE 7 raised transferrin saturation and ferritin levels, and was referred for venepuncture treatm ent. Further reading Adams PC , Barton JC ( 2007 ). Haemochromatosis . Lancet 2007 ; 370 : 1855 \200\223 60 . C ush J , Kavanaugh A , Stein CM ( 2005 ). Rheumatology: Diagnosis and Therapeutics ( 2 nd ed n). Philadelphia, PA : Lippincott \200\223Williams & Wilkins . Timms A , Sathananthan R , Bradbury L , Athanasou N , Wordsworth BP ( 2002 ). Genetic testi ng for haemochromatosis in patients with chondrocalcinosis . Ann Rheum Dis ; 61 : 745 \200 \223 7 . Zhang W , Doherty M , Bardin T , et al . ( 2011 ). European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: Terminology and diagnosis . A nn Rheum Dis ; 70 : 563 \200\223 70 . 46 CASE HISTORIES IN RHEUMATOLOGY Case 8 A 32-year-old man presented with a 6-month history of pain and swelling affecting both ankl es and his left wrist. His past history included hemophilia A diagnosed at the age of 1 yea r after a bleeding episode from a cut lip. He had moderately severe disease with a baseline factor VIII level of 3 % . At the age of 18, he was found to have acquired hepatitis C fro m contaminated blood products. At the age of 22 he was diagnosed with a large B-cell non-Ho dgkin \200\231s lymphoma. He underwent treatment with chemotherapy and an autologous bone m arrow transplant and was currently in remission. On examination he had swelling of his wrist and both ankles and severe widespread plaque psoriasis. He had normal spinal movement. 47 CASE 8 Questions \200\224Part 1 1. What is the differential diagnosis of his joint disease? 2. What further information would be helpful? 48 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis of his joint disease? This is a case of oligoarthritis on a background of hemophilia, hepatitis C, psoria- sis, a nd lymphoma. Leukemia can present with joint swelling in the absence of hematological abnor malities, but arthritis is extremely rare as a presenting feature of lymphoma and is unlike ly to be the underlying cause of his joint symptoms. The differential diagnosis includes: \227\206 hemophiliac arthropathy (HA) \227\206 psoriatic arthritis \227\206 viral arthritis \227\206 reactive arthritis. Hemophilia A is an X-linked recessive disorder of a deficiency or functional defect of coag ulation factor VIII. Mild, moderate, and severe forms are defined by plasma coagulation fac tor levels. Joint disease affects 90 % of people with severe haemo- philia and occurs most commonly in the ankles, knees, and elbows. Coagulation levels of 5 % or less are associated with recurrent haemarthrosis which can be spon- taneous or due to trauma. Recurrent hemorr hage stimulates synovial hypertro- phy and haemosiderin deposition, which in turn leads to further synovitis. The inflamed synovium is friable and prone to further hemorrhage. Subacu te arthrop- athy follows repeated haemarthrosis affecting one or more target joints, especi ally ankles, knees, and elbows. Development of a target joint is indicated by a persistent boggy synovitis with chronic joint effusion and pain in the absence of recent hemorrhage. M uscle weakness and joint laxity increase the likelihood of further bleeding. The hyaline ca rtilage is eroded by both the inflamed synovium and direct toxic effects of iron deposition . A chronic HA may result, and may be severe with structural abnormalities, joint contractu res due to fibrosis, and ankylosis. HA was the most likely cause of this patient \200\231s recurrent ankle pain and swelling. H owever, the recent development of wrist swelling and the presence of psoriasis raised the p ossibility of psoriatic arthritis. A preceding history of bowel or geni- tourinary infectio n may indicate a reactive arthritis, and would be more likely to persist in patients who ar e positive for HLA B27. A further complicating feature of his case was his previous infecti on with hepatitis C. Prior to 1992, hepatitis C and HIV were transmitted to many hemophiliacs from contaminated blood products, leading to chronic infection. Several viruses are associated with the devel opment of inflammatory arthritis including the hepa- titis viruses, HIV, and the parvovirus B19. The most common cause of arthritis in patients infected with hepatitis C is an unrela ted inflammatory disease. Rarely, patients with chronic hepatitis C develop a directly rela ted inflammatory arthritis. This is usually a symmetrical non-deforming non-erosive polyart hritis involving small joints, but may be a mono- or oligoarthritis. Fewer than 5 % of patients with hepatitis C develop mixed cryoglobulinaemia. This may prese nt with intermittent polyarthralgia involving the hands and knees, 49 CASE 8 immune-mediated purpura, neuropathy, membrano-proliferative glomerulone- phritis, and skin ulcers. The diagnosis is confirmed by the presence of type II or III cryoglobulins, low C4, and a positive rheumatoid factor. 2. What further information would be helpful? i) Laboratory tests FBC, viral serology for HIV, hepatitis B and E, and liver function test s. If further features of a mixed cryoglobulinaemia were present, it would be appropriate t o measure cryoglobulins, renal function, rheumatoid factor, and urinalysis. The patient had a normal FBC, CRP 52 g/dL, ALT 53 IU/L, and HIV serology was negative. ii) Imaging The early X-ray changes in HA include periarticular soft tissue swelling, bone dem- ineralization, and increased radiodensity of the thickened synovium due to haemo- side rin deposition. Where joint damage occurs in children, there may be Harris lines due to gro wth arrest and epiphysial widening. Some changes are specific to certain joints, for exampl e squaring of the inferior border of the patella, tibiotalar slant, and enlargement of the proximal radial head. Established arthropathy is evi- dent by loss of joint space, subartic ular sclerosis, osteophytes, cysts, joint disor- ganization, and bony ankylosis. However, p lain films underestimate the degree of joint pathology. Ultrasound is useful in assessing s oft tissue and synovial changes, and joint effusions in acute episodes. MRI is the most sensitive examination for suspected HA, demonstrating syno- vial thickening , bleeding, and cartilage damage at an earlier stage than X-rays. A T 1 -weighted sequence can be used to reveal early structural changes. A short T 1 inversion recovery (STIR) seque nce will demonstrate bone oedema. Gradient echo sequences can be used to improve visualizat ion of deoxyhaemoglobin in acute bleeds or haemosiderin deposition in chronic HA, and in th is case would aid the differentiation between HA and psoriatic arthritis. However, when the re is a sig- nificant amount of haemosiderin in a joint, visualization of joint structure m ay be impaired by susceptibility artifacts. iii) Biopsy Histological examination of a synovial biopsy may demonstrate a hemophiliac syn - ovitis with hypertrophy, monocytic infiltration, and deposition of haemosiderin. 50 CASE HISTORIES IN RHEUMATOLOGY Fig. 8.1 Left ankle X-ray. Fig. 8.2 MRI of ankle. 51 CASE 8 Fig. 8.3 MRI of wrist. Questions \200\224Part 2 3. Radiological images from this patient are shown in Figs 8.1 \200\2238.3. What do the arrows show and what is (are) the most likely diagnosis(es)? 4. How should his joint problems be managed? What is the role of factor VIII treatment in haemophilic arthropathy? 52 CASE HISTORIES IN RHEUMATOLOGY Answers 3. Radiological images from this patient are shown in Figs 8.1 \200\223 8.3 . What do the arrows show and what is (are) the most likely diagnosi s(es)? The ankle X-ray (Fig. 8.1 ) demonstrates haemosiderin deposition in the soft tissues. A sus ceptibility artifact caused by haemosiderin deposition along the tendon sheaths is shown by the arrow in Fig. 8.2 (ankle MRI). The wrist MRI (Fig. 8.3 ) shows evidence of synovitis w ith little haemosiderin deposition. This patient was diagnosed with new-onset psoriatic arthritis on a background of HA. 4. How should his joint problems be managed? What is the role of factor VIII treatment in h aemophilic arthropathy? Management of an acute haemarthrosis in hemophilia includes 48 hours of synthetic factor VI II, and local measures to manage the joint swelling and pain (ice packs, analgesia, and phy siotherapy). The development of a \200\230boggy synovitis \200\231 indicates potential irr eversible joint damage and preventative treatment may be started with secondary prophylaxis using factor VIII replacement three times weekly for 6 \200\2238 weeks to controlling blee ding. Muscle strength is improved with physiotherapy. NSAIDs should be used with caution, a nd there is no benefit from DMARDs. Intra-articular steroids can produce short-term benefit . This patient was administered factor VIII injections at the onset of ankle swelling but did not respond to treatment. He was diagnosed with psoriatic arthritis on the basis of psoria sis, raised inflammatory markers, and MRI evidence of wrist synovi- tis without haemosideri n. He was treated with intra-articular joint injections under factor VIII prophylaxis and p hysiotherapy. In view of his history of hepatitis C, his treatment with medications such as methotrexate and subsequently leflunomide was planned in collaboration with a hepatologist. In patients without advanced liver disease and with stable liver func- tion, these medications can be u sed safely with close monitoring. Studies looking at the safety of anti-TNF agents in patie nts with chronic hepatitis C are under way. The patient \200\231s joints improved on methot rexate but, unusually, his psoriasis dete- riorated. Treatment was changed to leflunomide w hich improved both psoriasis and joint symptoms. Primary prophylaxis by regular long-term administration of clotting factor con- centrate is the first choice of treatment in children with severe hemophilia. This is implemented eith er before the age of 2 years and prior to any joint bleeding, or after no more than one joi nt bleed. The Joint Outcome Study in 2007 was the first randomized controlled trial of prop hylaxis versus on-demand treatment. It showed an 85 % reduction in the risk of joint damage by MRI assessment in children on prophylaxis (25 IU/kg every other day) compared with thos e using intensive on-demand treatments. In some patients, a secondary prophylaxis regimen is prescribed for short peri- ods to redu ce the frequency of bleeds in target joints. Published evidence on the 53 CASE 8 benefits of long-term secondary prophylaxis in young adult hemophiliacs has been from small retrospective studies. They show that severe hemophiliac adults switching from on-demand t o secondary prophylaxis used more concentrate but had fewer joint bleeds. Secondary prophyl axis has not yet been shown to slow the progression of HA in patients with established join t damage. Various radiologi- cal scoring systems have been developed to monitor disease pro gression by MRI and are important in measuring response to prophylactic factor VIII treatme nt. Further reading Coppola A , Di Capua M, Simone CD ( 2008 ). Primary prophylaxis in children with hemophilia . Blood Transfus ; 6 (Suppl 2 ): s4 \200\223 11. Jelbert A , Vaidya S , Fotiadis N ( 2009 ). Imaging and staging of haemophilic arthropathy . Clin Radiol ; 64 : 1119 \200\223 28. Tagliaferri A , De Perna C , Rivolta GF ( 2008 ). Secondary prophylaxis in adolescents and adult hemophiliacs . Blood Transfus ; 6 (Suppl 2 ): s17 \200\223 20. Vassilopoulos D , Calabrese LH ( 2008 ). Virally associated arthritis 2008 : clinical, epid emiologic, and pathophysiologic considerations . Arthritis Res Ther ; 10 : 215. 54 CASE HISTORIES IN RHEUMATOLOGY Case 9 A 30-year-old female with a 10-year history of systemic lupus erythematosus (SLE) was revie wed in clinic. She had recently married and was keen to start a family. At diagnosis she ha d presented with a photosensitive rash, fleeting arthralgia, migraine, depression, and prot einuria. A renal biopsy had confirmed membranous glomeru- lonephritis, consistent with clas s V lupus nephritis. She was initially treated with prednisolone and azathioprine, but ongo ing active renal disease necessitated escalation to cyclophosphamide and subsequent mainten ance therapy with mycophenolate mofetil 1g twice daily. Examination was normal, including a blood pressure of 120/80 mmHg. Dipstick urinalysis was normal. 55 CASE 9 Questions \200\224Part 1 1. How would you assess her disease activity? What other tests would you consider in preparation for pregnancy? 2. What pre-conception counseling would you provide with regard to the following? i. Medication and contraception. ii. Renal disease. iii. Pregnancy-related risks? What additional monitoring may be required during pregnancy? 56 CASE HISTORIES IN RHEUMATOLOGY Answers 1. How would you assess her disease activity? What other tests would you consider in prepar ation for pregnancy? Pregnancy outcome is better if conception occurs during a period of remission, or 6 months after control of a flare or a change in maintenance therapy. Disease activity in SLE can be assessed using the SLE Disease Activity Index, a global dise ase activity score (DAS) validated against experienced clinical judge- ment used to quantif y organ involvement and guide therapeutic management. Pre-conception all patients with SLE should be screened for a lupus anticoagu- lant, antiph ospholipid, and anti-Ro and anti-La antibodies. Anticoagulants includ- ing aspirin and hepa rin have been shown to improve pregnancy outcome in women with antiphospholipid syndrome (A PS) (see p. 75). Ds DNA, anti-Ro antibodies, and anti-La antibodies may result in neonatal lupus which requires further moni- toring (see Answer 2). 2. What pre-conception counseling would you provide with regard to the following? i. Medication and contraception. ii. Renal disease. iii. Pregnancy-related risks. What additional monitoring may be required during pregnancy? i. Patients taking teratogenic medications should be advised regarding contracep- tion, avo iding estrogen-containing preparations due to the risk of flare. Animal studies suggest tha t mycophenolate mofetil is associated with an increase in congenital malformations and shou ld be avoided in pregnancy. It is standard practice to switch to azathioprine and hydroxych loroquine, as was done in this case, which are considered safe in pregnancy. ii. There is a risk of deterioration in renal function due to the change in medication or a s a result of pregnancy. The risk is higher with pre-existing hypertension, proteinuria ( > 1 g/24 h), or high baseline serum creatinine ( > 125 mol/L). iii. Lupus itself does not usually affect fertility, but NSAIDs, previous cyclophospha- mid e treatment, and ongoing disease activity may prevent conception. There are increased risks of early miscarriage, intra-uterine fetal death, pre-eclampsia, intra-uterine growth retar dation, and pre-term delivery. Pregnancy may increase the risk of flare both antenatally an d in the puerperium. Patients with active lupus, particularly if nephrotic, are at increase d risk of venous thromboembo- lism (VTE) in pregnancy. Therefore it is imperative that a de tailed history is taken of previous history of clots or other risk factors, and thromboprop hylaxis should be considered. Women with APS are at increased risk of VTE and fetal loss, a nd low-dose aspirin and low molecular weight heparin are recommended throughout pregnancy a nd 6 weeks post-natally. Such patients should be man- aged under collaborative care of obst etrics and hematology. 57 CASE 9 Increased maternal and fetal surveillance is required during pregnancy, particularly in wom en with hypertension, renal disease, APS, and Ro antibodies. Ro antibodies are associated w ith congenital heart block in 1 \200\2232 % of cases; early cardiac fetal monitoring is imp ortant in detecting this as it can result in intra-uterine death. Ro and La antibodies can cross the placenta and 5 % of babies may suffer a neonatal lupus syndrome which is transien t. She conceived 8 months later and was initially well, but at 21 weeks \200\231 gestation was noted to have deteriorating renal function and hypertension (BP 170/110 mmHg). Investigati ons showed: \227\206 urea 18 mmol/L \227\206 creatinine 171 mol/L \227\206 albumin 16 g/dL \227\206 urinary protein 10 g/24 h. Questions \200\224Part 2 3. There are two main causes of this presentation, what further investigations would you request in order to differentiate between the two? 58 CASE HISTORIES IN RHEUMATOLOGY Answer 3. There are two main causes of this presentation. What further investigations would you re quest in order to differentiate between the two? Deteriorating renal function, hypertension, and proteinuria suggest a flare of her lupus ne phritis, pre-eclampsia, or both. These conditions are potentially life- threatening to both mother and baby. The features distinguishing a lupus flare and pre-eclampsia are shown in Table 9.1 . Steroids are first-line therapy for lupus flare during pregnancy. Prednisolone is inactivat ed by placental 11 -hydroxysteroid dehydrogenase 2 so that only 10 % of the active drug reaches the fetus. High-dose steroids increase the risk of maternal gestational diabetes, h ypertension, infection, and osteoporosis. Other immuno- suppressive agents that are conside red to be safe in pregnancy include azathioprine, hydroxychloroquine, ciclosporin, tacrolim us, and intravenous immunoglobulin. There are few data for the use of biological agents suc h as anti-TNF therapy, but so far there is no suggestion of adverse maternal or fetal outco me. In rare severe cases, cyclophosphamide has been used in pregnancy. Table 9.1 Features distinguishing a lupus flare from pre-eclampsia Lupus flare Pre-eclampsia Hypertension Yes Yes Urine analysis Proteinuria Red cell casts and proteinuria Platelet count Low Low Abnormal LFTs Unusual Common Creatinine Raised Raised Serology Raised dsDNA and low C3/C4 Normal Uric acid Normal High Further reading Bombardier C , Gladman DD , Urowitz MB , Caron D , Chang CH ( 1992 ). Derivation of the