 \227\206 Early-stage Lyme disease with arthritis is treated with doxycycline plus amoxicil lin for 30 days. \227\206 Brucellosis requires prolonged combination antibiotic therapy for 6 weeks to 3 months. This patient \200\231s throat swab grew -haemolytic streptococcus and her sequential ser ological testing showed a rise in both ASOT and anti-DNAseB titres. ECG, CXR, and echocardi ogram showed structurally normal heart valves with a rim of pericar- dial fluid. This was s hown to resolve over the following 3 weeks. The systolic mur- mur was thought to be physiol ogical. The diagnosis was of acute rheumatic fever. The childhood episode of irritable hip may have been a previous attack of rheu- matic fever. The transient rash may have been eryt hema multiforme. Although rheumatic fever usually occurs in childhood, 15 % of first attack s occur in adults. The risk of carditis is > 30 % in the first attacks and increases with s ubsequent attacks. Treatment is 2 \200\2234 weeks of full-dose oral penicillin followed by long-term low-dose penicillin prophylaxis to prevent recurrent attacks with subsequent card itis. The duration of penicillin prophylaxis depends on the risk of future group A streptococcal infection. In her case this would for as long as she was in contact with small children, wh ich may be up to 10 years or even lifelong. Some consider post- streptococcal reactive arth ritis a forme fruste of rheumatic fever, and even though the carditis risk is lower they ad vocate similar penicillin prophylaxis regimes. Further reading Bardin T ( 2003 ). Gonoccocal arthritis. Best Pract Res Clin Rheumatol ; 17 : 201 \200\223 8 . Cilliers AM ( 2006 ). Rheumatic fever and its management. BMJ ; 337 : 1153 \200\223 6 . Jansen T , Janssen M , van Reil P ( 1998 ). Acute rheumatic fever or post-streptococcal reactive arthritis: a clinical problem revisited. Br J Rheumatol ; 37 : 335 \200\223 40 . Medina Rodriguez F ( 2003 ). Rheumatic manifestations of human immunodeficiency virus Rheum Dis Clin North Am ; 29 : 145 \200\223 61. Moore T ( 2000 ). Parvovirus-associated arthritis. Curr Opin Rheumatol ; 12 : 289 \200\223 94. Pappas G , Akritidis N , Bosilkovski M , Tsianos E ( 2005 ). Brucellosis. N Engl J Med ; 352 : 2325 \200\223 36 . Schnarr S , Franz J , Krause A , Zeidler H ( 2006 ). Lyme borr eliosis. Best Pract Res Clin Rheumatol ; 20 : 1099 \200\223 1118. 253 CASE 44 Case 44 A 55-year-old woman presented with a 5-year history of pain and swelling in her hands and f eet with bilateral numbness and tingling in the median nerve distribution. She had gained 1 0 kg in weight over the same period of time and developed type 2 diabetes. She attributed i ncreasing fatigue to poor sleep quality because of backache and to snoring. On examination, she weighed 80 kg with a BMI of 35.2 kg/m 2 . Her BP was 150/100 mmHg. She had a kyphosis and painful spinal movements. She had hand joint tenderness with generalized hand swelling and coarse thickened skin. Her wrists, knees, and ankles were hypermobile. Investigations showed the following: \227\206 Normal FBC and inflammatory markers \227\206 R12 IU/ml; ACCP <6 U/ml \227\206 Na 136 mmol/L; K 4.2 mmol/L; creatinine 70 mol/L; total calcium 2.7 mmol/L; phosphate 1.04 mmol/L; ALT 30 IU/L; ALP 68 IU/L; albumin 40 g/L \227\206 TSH 3.8 mU/L; PTH 60 ng/L \227\206 Hand X-rays are shown in Fig. 44.1. 254 CASE HISTORIES IN RHEUMATOLOGY Fig. 44.1 X-ray of the patient \200\231s hands . 255 CASE 44 Questions 1. What metabolic diseases cause arthropathy? 2. What is the most likely diagnosis? 3. What do the hand X-rays show? What other imaging would be useful? 4. What is characteristic about this arthropathy and how should it be managed in the short and long term? 256 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What metabolic diseases cause arthropathy? Metabolic causes of arthropathy include: \227\206 hypothyroidism \227\206 hyperthyroidism \227\206 diabetes \227\206 diffuse idiopathic skeletal hyperostosis (DISH syndrome) \227\206 primary hyperlipidaemias \227\206 haemochromatosis \227\206 acromegaly. Hypothyroidism should be considered in all patients with carpal tunnel syndrome. It may occ ur in up to 10 % of cases and is due to peripheral tissue oedema in the wrist. It would als o account for the patient \200\231s weight gain, fatigue, and skin changes. Thyroid acropac hy is a skeletal abnormality specific to Graves \200\231 disease; it is a painless swelling of the fingers and toes which may be associated with clubbing and periostitis. Diabetics may develop a number of joint-related problems. Diabetic cheiroar- thropathy is m ost common in type 1 disease, but may occur in type 2 diabetes. Patients develop soft tissu e contractures that limit extension of the metacarpophalan- geal (MCP) and interphalangeal (IP) joints without evidence of intra-articular or muscle inflammation. Patients with diabe tic osteo-arthropathy develop destructive lytic joint lesions in association with periphera l neuropathy in type 2 diabetes. Hyperostotic spondylosis or DISH syndrome are more common in, although not confined to type 2 diabetics. DISH is caused by widespread new bone formation with general ossification of ligaments and tendons, especially the anterior longitudinal ligament of the spine. It is most characteris tic in the thoracic spine, but may cause stiffening and arthropa- thy in peripheral joints with reduced flexion of the fingers. Its association with the metabolic syndrome is thought to be related to hyperinsulinaemia and disturbances of GH. Primary hyperlipidaemias are rarely associated with arthritis. Tendinous xantho- mas are a recognized feature of some forms of familial hypercholesterolaemias. Haemochromatosis is an inherited disease where increased iron absorption results in iron lo ading of tissues. It presents with fatigue and a symmetrical arthrop- athy in middle-aged p atients. Liver abnormalities are demonstrated by chronic ALT elevation and type 2 diabetes may occur. It characteristically causes osteoar- thritis of the second and third MCP joints , but can affect other joints. 2. What is the most likely diagnosis? The most likely diagnosis is acromegaly. This patient had developed arthralgia with bilater al carpal tunnel syndrome, weight gain, diabetes, and hypertension. She had 257 CASE 44 normal TFTs. She was hypercalcaemic with a normal PTH. The diagnosis of acromegaly was conf irmed by a raised insulin-like growth factor 1 (IGF-1) of 78.4 nmol/L and failure of GH to suppress during a glucose tolerance test. Acromegaly is caused by the hypersecretion of GH from a pituitary adenoma resulting in elev ated IGF-I. Both hormones contribute to the features of the dis- ease. It is rare with a pr evalence of 50 \200\22370 cases per million and an incidence of 3 \200\2234 new cases per m illion per year. Characteristic changes caused by tissue over- growth include coarsened fac ial features, exaggerated growth of hands and feet, soft tissue hypertrophy, and macrogloss ia. Thickening of the skin is a manifesta- tion of the effect of GH on collagen tissue. The re is softening and thickening of the capsular and ligamentous structures, resulting in joi nt laxity. Metabolic conse- quences include increased insulin resistance and hypercalcaemia . Poor-quality sleep and snoring are commonly reported. Increased mortality is due to cardi ovascular, cerebrovascular, and respiratory disease. 3. What do the hand X-rays show? What other imaging would be useful? The X-rays of the patient \200\231s hands (Fig. 44.1 ) show soft tissue thickening, increas ed joint space, and enlargement and tufting of the terminal phalanges. An MRI of her pituit ary fossa demonstrated a pituitary adenoma. Heel-pad thickening, demon- strated on a latera l radiograph, is also a confirmatory sign. Joint-space widening is most frequently observed in the knees and in the MCP and IP joints. The epiphyses may undergo squaring and develop small osteophytes on the edges of the artic ular surfaces, especially in the MCP joints. Acromegaly is characterized by new bone format ion and by subcutaneous soft tissue and cartilage thickening. Axial arthropathy is a common finding and may affect the whole spine. Imaging of the spine demonstrates widened interver tebral spaces, vertebral enlarge- ment, and osteophyte formation with calcification of the intervertebral ligaments, resembling the changes observed in DISH. 4. What is characteristic about this arthropathy and how should it be managed in the short and long term? Arthropathy is a well-established feature of acromegaly and may be the first pres- entation of the disease. Joint symptoms or signs occur in 60 \200\22370 % patients. Acromegalic art hropathy has a characteristic biphasic presentation. In the first phase, soft tissue and ca rtilage hypertrophy result in joint widening and hypermo- bility. Chronic secretion of GH s timulates production of both circulating and local cartilage IGF-I. This induces chondrocyt e proliferation and cartilage matrix syn- thesis, with cartilage thickening which can be de monstrated by ultrasound. GH causes growth of fibroblasts and collagen formation with enlar gement of ligaments and joint laxity. Bilateral carpal tunnel syndrome frequently occurs an d is caused by both compression and hypertrophy of the median nerve. 258 CASE HISTORIES IN RHEUMATOLOGY With time the thickened poor-quality cartilage wears unevenly and fissures form, leading to exposure of subchondral bone. Joint stability is compromised by ligament laxity and synovi al hypertrophy with effusions. Secondary osteoarthritic changes affect both axial and perip heral joints, especially weight-bearing joints, and may be severe. The initial treatment of acromegaly is with trans-sphenoidal surgery to remove the pituitar y tumor. Radiotherapy and medical treatment with somatostatin ana- logues, such as octreoti de (a long-acting analog of somatostatin), or pegvisomant (a GH antagonist) may be required . Reversal of cartilage widening has been dem- onstrated with ultrasound. Surgical carpal t unnel decompression may be required. Although the first stage of acromegalic arthropathy ma y be reversible, secondary osteoarthritis changes may cause severe joint disease affecting both the axial and the appendicular skeleton. This should be managed with analgesia, physio therapy, occupational therapy, and orthotics before consideration of joint replacement. The use of NSAIDs is relatively contraindicated in view of the increased risk of cardiovascula r disease; 35 % patients with acromegaly develop hypertension. Borderline or raised serum calcium may occur in acromegaly and is attributed to vitamin D a ctivation by GH independent of PTH. However, the most common reason for hypercalcaemia in a cromegaly, occurring in 5 \200\22310 % of patients, is a parathyroid-secreting adenoma and is associated with multiple endocrine neoplasia I (MEN-I) syndrome. Further reading Colao A , Cannavo S , Marzullo P , et al . ( 2003 ). Twelve months of treatment with octreo tide-LAR reduces joint thickness in acromegaly . Eur J Endocrinol ; 148 : 31 \200\223 8 . Wassenaar MJE , Biermasz NR , van Duinen N , et al . ( 2009 ). High prevalence of arthropat hy, according to the definitions of radiological and clinical osteoarthritis in patients wi th long-term cure of acromegaly: a case \200\223control study . Eur J Endocrinol ; 160 : 35 7 \200\223 65. 259 CASE 45 Case 45 A 45-year-old woman with a 2-year history of increasing unsteadiness was referred from neur ology to the rheumatology department. She had a 10-year history of chronic fatigue, arthral gia, and myalgia. She had a history of photosensitive rash. She had stopped wearing contact lenses in her early twenties because of symptomatic dry eyes, carried a water bottle with her to work, and had a constant irritating dry cough. She had two healthy children. One bab y had had a transient neonatal rash. Her sister had autoimmune thyroid disease. On examination, she was obese and normotensive, with tender but not swollen wrist, finger, and knee joints. She had significant dental caries. She had a wide-based staggering gait an d was unable to heel \200\223toe walk. Neurological examination was other- wise normal. Investigations showed the following: \227\206 Hb 12.4 g/L; WCC 3.8 \227 109/L; lymphocyte 0.87 \227 109/L \227\206 Liver and renal function were normal \227\206 RF negative; ANA 1in 80 \227\206 Visual evoked responses were normal \227\206 Lumbar puncture for oligoclonal bands were matched in CSF and serum \227\206 MRI scan of brain showed extensive periventricular white matter changes in the frontal, parietal and occipital lobes (Fig. 45.1 ). 260 CASE HISTORIES IN RHEUMATOLOGY Fig. 45.1 MRI of brain showing extensive white matter changes. 261 CASE 45 Questions 1. This patient presents with a rare complication of a common connective tissue problem. What is the underlying diagnosis? 2. What bedside tests, blood tests, and laboratory tests will help to confirm the diagnosis of the connective tissue disease? 3. What are the common presentations of this condition and the treatment options? 4. What possible late complications occur? 262 CASE HISTORIES IN RHEUMATOLOGY Answers 1. This patient presents with a rare complication of a common connective tissue problem. What is the underlying diagnosis? The diagnosis is primary Sj gren \200\231s syndrome (pSS) with Sj gren \200\231s myelopat hy. Neurological Sj gren \200\231s syndrome occurs in 1 \200\2235 % of pSS patients. Clinical presentation is highly variable and can affect the peripheral and central nervous systems, cognitive function, and psychological state. Reported presentations include sensorimotor pe ripheral neuropathy, mononeuritis multiplex, optic neuropathy, cognitive dysfunction, and a cute and chronic transverse myelitis. Neurological symptoms precede diagnosis of pSS in 81 % of patients. 2. What bedside tests, blood tests, and laboratory tests will help to confirm the diagnosis of the connective tissue disease? \227\206 Schirmer \200\231s test for tear-flow: a simple bedside testing using blotting pa per strips to measure tear-flow over a 5 min period (positive test \211 5 mm in 5 min). \227\206 Immunology tests for anti-Ro or anti-La antibodies or both. In most published ser ies autoimmune serology for anti-Ro and anti-La antibodies is positive in 60 % of pSS patie nts. \227\206 Histopathology \200\224 minor salivary gland biopsy (Fig. 45.2 ). CNS lesions can be very difficult to distinguish from multiple sclerosis (MS) on MRI. MRI l esions of pSS resemble multiple-sclerosis-like deposits, but are more diffuse. Clinically, it can also be difficult to distinguish CSF in Sj gren \200\231s syndrome from that in mul tiple sclerosis, and the visual evoked potential responses can be Focal lymphocytic infiltrate Fig. 45.2 (See also Plate 17) Histology of the minor salivary gland. 263 CASE 45 positive in both. The main distinguishing feature is that matched oligoclonal bands are pre sent in both CSF and blood, whereas in multiple sclerosis they are present only in the CSF. The American \200\223European Consensus Group (AECG) classification criteria for pSS require four out of six positive, including either histopathology or serology. \227\206 Ocular symptoms \200\224 persistent troublesome dry eyes daily for more than 3 m onths, or current sensation of sand or gravel in the eyes or need for tear substitute more than three times daily. \227\206 Oral symptoms \200\224 daily feeling of dry mouth for > 3 months, or current per sistently swollen salivary glands in adults, or frequently drinking liquids to aid swallowi ng dry food. \227\206 Objective dry eyes \200\224 positive Schirmer \200\231s Test ( \211 5 mm in 5 min) or positive Rose Bengal score. \227\206 Histopathology \200\224 minor salivary gland biopsy showing focal lymphocytic si alad- enitis, ductal hyperplasia, and acinar atrophy. \227\206 A positive biopsy has, on focus, > 50 lymphocytes per 4 mm 2 tissue. The pre- dominant lymphocyte is type CD4 positive. \227\206 Objective dry mouth: unstimulated whole salivary flow <1.5 mL/15 min or parot- id sialography showing diffuse sialectasis without major duct involvement or sali- vary scint igraphy showing delayed uptake of tracer. \227\206 Serology: positive Ro or positive La antibodies or both. 3. What are the common presentations of this condition and the treatment options? Patients with Sj gren \200\231s syndrome often present late, in part because they adapt to the symptoms and also because there is significant salivary and tear reserve. The salivary flow rate may fall as low as 30 \200\22340 % of normal before patients complain of dry mou th. Although dry eyes and dry mouth are the most common presenting features, patients often present to general practice or other specialities. Common symptoms include fatigue, arthra lgia, intermittent non-erosive arthritis, and Raynaud \200\231s phenomenon. Dry eyes Symptoms include burning, itching, stinging, tired eyes, photophobia, and occa- si onally mucus discharge from the eyes. Tear substitutes escalate from watery drops (such as Hypromellose) to more viscous drops. Preservative-free drops are needed if they are used mo re than six times daily to prevent irritation. Paraffin- based gels help night-time dryness . Severe dry eyes can be helped by permanent or temporarily plugging of the tear duct punct ae. Dry mouth Symptoms are worsened by some medications such as tricyclic antidepressants, anti histamines, diuretics, and -blockers, which should be avoided if possible. 264 CASE HISTORIES IN RHEUMATOLOGY Tracheal and nasal dryness means that patients are hypersensitive to atmospheric irritants such as smoking and air-conditioning. Associated symptoms include difficulty in chewing or swallowing, hoarse voice, difficulty in speaking, and swollen salivary glands. Vigilance in checking for dental caries and oral candidiasis is important. Patients are advised to avoi d dehydration and seek regular dental care. Fluoride mouthwashes can improve oral hygiene. Salivary substitute sprays with replacement gels give limited symptomatic relief, and in se vere cases pilocarpine (muscarinic agonist) in doses increasing from 5mg daily up to 5mg fo ur times daily can help. Musculoskeletal and systemic features Musculoskeletal and systemic features are common. Pat ients may have positive rheumatoid factor and positive ANA. Joints are tender and painful r ather than swollen. Some patients present with true inflammatory arthritis, often misdiag- nosed as rheumatoid arthritis. Erosive arthritis is very rare. Non-specific systemic featur es of tiredness, lethargy, malaise, and exhaustion are common. Hydroxychlo- roquine has bee n used with anecdotal evidence of effect, particularly helping fatigue and arthralgia. Interstitial lung disease is seen on high-resolution CT scan in up to 30 % of pSS patients in some series. Some present with dry cough or exertion or dyspnoea. The majority are asymp tomatic. Skin rashes and skin dryness A variety of rashes may occur, including palpable purpura, sma ll-vessel vasculitis, urticaria, and flat purpura. These are often associated with hypergam maglobulinae- mia. More than 50 % of patients have dry skin resulting from lymphocytic-infi ltrated exocrine glands. Gynecological and obstetric problems Vaginal dryness is common and can be helped with over- the-counter vaginal lubri- cants. Hormone replacement therapy may be appropriated for menop ausal patients. pSS patients have normal fertility. Approximately 1 in 20 pregnancies in Ro -positive individuals are complicated by the development of the neonatal lupus rash. The ra sh generally appears at approximately 6 weeks of age and fades spontaneously over the subse quent 3 or 4 months. Approximately 30 % of mothers have no pSS symptoms at the time of birt h, but the majority eventually develop symptoms. A rarer life-threatening complication is congenital heart block which occurs in <2 % of pre gnancies with either Ro or La antibodies. Ultrasound scanning from approximately 16 weeks o f age can detect this. The risk is increased if a previous child has been born with congeni tal heart block. It is slightly more common in female children. Seventy-five per cent of af fected children survive, but nearly all require pacemakers in the first few months of life. Thrombocytopenia of the newborn is described, but is a much rarer complication and usually resolves spontaneously. 265 CASE 45 Neuropsychiatric involvement Neuropsychiatric involvement is well recognized, with atypical depression, anxiety, and psychosis. Psychological distress with fibromyalgic symptoms are present in > 20 % of pSS patients. It can be difficult to distinguish fibromyalgia spectrum patients with secondary sicca symptoms from pSS. 4. What are the late complications? A rare but important late complication of pSS is B-cell lymphoma. Patients often have raise d immunoglobulin levels which should be monitored at least annually. B-cell lymphoma affect s 1 \200\2235 % of patients with a relative risk of developing Hodgkin \200\231s lym- phoma of 44 compared with the normal population. The absolute risk is small and risk factors inc lude the presence of autoantibodies, monoclonal gammopathies, a sudden disappearance of ser um immunoglobulins, and disappearance of rheumatoid factor, lymphadenopathy, skin vasculiti s, peripheral nerve involvement, low-grade fever, anemia, major salivary gland swelling, an d lymphopenia. Other comorbidities Patients commonly have a family history of autoimmune disease. Thyroid disease occurs in \210 30 % of pSS patients, coeliac disease in up to 15 % , and primary biliary cirrhosis in \210 5 % , and there is an increased association with pernicious anemia. Other significan t comorbidities include depression, fibromyalgic symptoms, and distal renal tubular acidosi s. Further reading Delalande S , de Seze J , Fauchais A-L , et al . ( 2004 ). Neurologic manifestations in pri mary Sj gren syndrome: a study of 82 patients . Medicine ; 83 : 280 \200\223 91 . Fox RI , Dixon R , Guarrasi V , Krubel S ( 1996 ). Treatment of primary Sj gren \200\231s syndrome with hydroxychloroquine: a retrospective, open-label study . Lupus ; 5 : S31 \200\223 6 . Kruize AA , Hen RJ , Kallenberg CG , et al . ( 1993 ). Hydroxychloroquine treatment for p rimary Sj gren \200\231s syndrome: a two year double blind crossover trial . Ann Rheum Dis ; 52 : 360 \200\223 4 . Vincent TL , Richardson MP , Mackworth-Young CG , Hawke SH , Vena bles PJ ( 2003 ). Sj gren s syndrome-associated myelopathy: response to immunosuppressive treatment . Am J Med ; 114 : 145 \200\223 8 . Vitali C, Bombardieri S, Jonsson R , et al . ( 2002 ). Classification criteria for Sj gren \200\231s syndrome: a revised version of the European criteria proposed by the American \200\223European Consensus Group. Ann Rheum Dis ; 61 : 554 \200\223 8 . 266 CASE HISTORIES IN RHEUMATOLOGY Case 46 A 22-year-old female marathon runner was attending the sports clinic for manage- ment of bi lateral insufficiency fractures of the femoral head, confirmed on MRI. This had not occurre d in association with any increase in her usual training program and she was struggling to return to training. She did not have any past medical history of note and was not on any re gular medications. On further direct questioning she reported mild proximal weakness in the upper and lower limbs and on examination was noted to have a BMI of 17.2kg/m 2 with normal stature. Investigations showed the following: \227\206 Hb 10.8g/dL; MCV 72fL \227\206 ALP 320U/L \227\206 Calcium 2.2mmol/L \227\206 PTH 28pg/mL \227\206 1,25-dihydroxyvitamin D 3 7pg/mL \227\206 25-hydroxyvitamin D 3 36ng/mL. 267 CASE 46 Questions 1. Which underlying causes should be considered and what further information is required to come to a final diagnosis? 2. What is the most likely diagnosis and how should this be treated? 3. What rare diagnosis should be considered if the patient fails to respond to treat- ment as expected? 268 CASE HISTORIES IN RHEUMATOLOGY Answers 1. Which underlying causes should be considered and what further information is required to come to a final diagnosis? The low BMI in this female athlete raises the possibility of the female athlete triad. Furt her corroboration should be sought in the history including evidence of amen- orrhoea, poor dietary habits, and laxative and diuretic use. The presence of the female athlete triad in creases the risk of osteoporosis, which would be a possible explanation for the development of insufficiency fractures without any increased loading. Other risk factors for osteoporo sis should be identified and DEXA scan- ning should be considered. Fracture in the context of proximal muscle weakness raises the possibility of osteo- malaci a, which can be caused by vitamin D deficiency or a PTH-independent defect in renal handlin g of phosphate. Risk factors for vitamin D deficiency include reduced oral intake, decrease d sun exposure, malabsorption, severe liver disease, and renal insufficiency. Ageing is als o associated with significantly reduced 1- -hydroxylase activity in the kidney, and some antiepileptic medications such as phenytoin increase the deactivation of the active metabo lite 1,25-dihydroxyvitamin D in the liver. Characteristic features include bone pain and tenderness, proximal muscle weak- ness, and n on-fragility fracture. In children bone deformity occurs resulting in bowing of weight-bear ing bones and irregularity at the metaphyseal \200\223epiphyseal junction which is usually detected at the wrist and costochondral junctions. The latter results in the \200\230ricke tic rosary \200\231. Harrison \200\231s groove describes the indentation of the softened ri bs at the insertion of the diaphragm. Rapid growth of the softened skull results in frontal bossing and parietal bone flattening. Dentition may also be poor. Laboratory investigation s in vitamin D deficiency can show low serum calcium and phosphate, and elevated alkaline p hosphatase and PTH. Vitamin D 2 (ergocalciferol) is obtained from vegetable sources, whereas vitamin D 3 (chole calciferol) is mainly synthesized in the skin following exposure to UVB light and can also be derived from food sources such as oily fish and fortified foods including milk, juices, and cereals. Both forms of vitamin D are rapidly converted to 25-hydroxyvitamin D in the li ver but only a fraction is activated to 1,25-dihy- droxyvitamin D by the kidneys. Thus, the former is the best marker of body stores of vitamin D. In vitamin D deficiency 1,25-dihydr oxyvitamin D 3 levels may well be normal, whereas low 25-hydroxyvitamin D 3 levels are diag nostic. Osteomalacia due to altered phosphate homeostasis is rare but gives rise to the same bone histopathology. Causes include the following: \227\206 Excess antacid use, often over several years with phosphate-binding antacids. \227\206 Idiopathic hypophosphataemia. \227\206 X-linked hypophosphataemic rickets which is caused by vitamin D resistance and ma nifests with short stature and rickets in homozygous males, and variable growth and deformi ty in females. Early recognition is key in order to prevent long-term deformity. 269 CASE 46 \227\206 Fanconi syndrome is associated with a number of congenital and acquired con- diti ons where proximal renal tubular defects result in glycosuria, aminoaciduria, phosphaturia, and hypophosphataemia. Laboratory investigations show a very low phosphate and 1,25-dihydroxyvita- min D 3 level w ith normal or slightly low calcium and normal or slightly elevated PTH. 25-hydroxyvitamin D 3 levels are normal. The biochemical abnormalities detected so far in this case fit with a diagnosis of hypophosphataemic osteomalacia, and serum phosphate levels should be checked. The presence of a microcytic anemia also raises the possibility of gastrointesti- nal malab sorption, which could be associated with coeliac disease. This would account for the low BM I, leading to increased risk of osteoporosis. Malabsorption can also result in vitamin D de ficiency and osteomalacia, but the normal 25-hydrox- yvitamin D 3 levels make this unlikely unless vitamin D resistance is present. Further investigations showed: \227\206 serum phosphate 0.48mmol/L \227\206 creatinine 62 mol/L \227\206 urinanalysis normal \227\206 urinary phosphate increased (70mmol/day) \227\206 anti-endomyseal and anti-tissue transglutaminase antibodies normal. 2. What is the most likely diagnosis and how should this be treated? The most likely diagnosis in this case is idiopathic hypophosphataemic osteomalacia. The tr eatment depends on the exact underlying cause, but generally includes both phosphate and vi tamin D supplementation. 3. What rare diagnosis should be considered if the patient fails to respond to treatment as expected? If the patient does not respond from a biochemical or clinical perspective, a rare phenomen on to suspect is oncogenic associated osteomalacia. The tumor is usu- ally benign and of me senchymal origin. The mechanism is not completely eluci- dated, but it is thought to be med iated by the humoral factor fibroblastic growth factor 23 which deregulates proximal renal tubular phosphate handling. Some improvement can be seen with vitamin D and phosphate suppl ementation; how- ever, resection of the tumor usually results in cure. Further reading Hannan FM , Athanasou NA , Teh J , Gibbons CL , Shine B , Thakker RV ( 2008 ). Oncogenic hy pophosphataemic osteomalacia: biomarker roles of fibroblast growth factor 23, 1,25-dihydrox yvitamin D3 and lymphatic vessel endothelial hyaluronan receptor 1 . Eur J Endocrinol ; 158 : 265 \200\223 71 . Kennel KA , Drake MT , Hurley DL ( 2010 ). Vitamin D deficiency in adults: when to test and how to treat . Mayo Clin Proc ; 85 : 752 \200\223 8 . 270 CASE HISTORIES IN RHEUMATOLOGY List of cases by diagnosis Case 1: Paget \200\231s disease Case 2: Giant cell arteritis Cas e 3: Leprosy Case 4: Sarcoidosis Case 5: Gout Case 6: Enteropathic arthritis Case 7: Haemoc hromatosis Case 8: Hemophilia Case 9: Systemic lupus erythematosus Case 10: Hypothyroidism Case 11: Familial Mediterranean fever Case 12: Marfan \200\231s syndrome Case 13: Antiphosp holipid syndrome Case 14: Osteoporosis Case 15: Systemic-onset juvenile idiopathic arthriti s Case 16: Ankylosing spondylitis Case 17: Achilles tendinopathy Case 18: Adverse neural dy namics Case 19: HIV Case 20: Oligoarticular juvenile idiopathic arthritis and uveitis Case 21: Osteogenesis imperfecta Case 22: Stress fracture Case 23: Wegener \200\231s granulomato sis Case 24: Rheumatoid myocarditis Case 25: Paraneoplastic rheumatic disease Case 26: CNS vasculitis Case 27: Complex regional pain syndrome Case 28: Limited cutaneous systemic scle rosis Case 29: Antisynthetase syndrome Case 30: Whipple \200\231s disease Case 31: Female a thlete triad Case 32: Pars defect Case 33: Anterior knee pain Case 34: Relapsing polychondr itis Case 35: Eosinophilic fasciitis Case 36: Rheumatoid vasculitis Case 37: Septic arthrit is Case 38: Rheumatoid arthritis of the neck Case 39: Beh et \200\231s disease Case 40: Ta kayasu \200\231s arteritis Case 41: Raynaud \200\231s phenomenon Case 42: CRMO/SAPHO Case 4 3: Viral arthritis Case 44: Acromegaly Case 45: Sj gren \200\231s syndrome Case 46: Osteom alacia 271 LIST OF CASES BY AETIOLOGICAL MECHANISMS List of cases by aetiological mechanisms Inflammatory arthritis: 16, 24, 36, 37, 38 Inflamm atory autoimmune connective disease: 9, 13, 28, 29, 34, 41, 45 Other inflammatory condition s: 4, 6, 11, 35, 42 Pediatric inflammatory conditions: 15, 20 Vasculitis: 2, 23, 26, 39, 40 Inherited disorders: 7, 8, 12, 21 Metabolic: 1, 5, 7, 10, 14, 44 Soft tissue/sports \200 \231 injury: 17, 22, 27, 31, 32, 33 Mechanical dysfunction: 18 Infection: 3, 19, 37, 43, 30 Malignancy: 25 This page intentionally left blank Index Bold indicates the diagnosis of the case discussed within the page range. ankylosing spondylitis 97 \200\2238 Beh et \200\231s disease 226 enteropathic arthritis 36 eosinophilic fasciitis 201 in \202 ammatory spondyloarthropathy 102 juvenile idiopathic a rthritis 120 pregnancy 58 relapsing polychondritis 194 rheumatoid arthritis 142 , 143 rheum atoid vasculitis 207 septic arthritis risk 213 \200\22314 AA amyloidosis 66 , 67 abdominal pain 66 abdominal serositis 65 ACCP antibody 28 ACE inhibi tors 237 Achilles tendinopathy 99 \200\223102 acromegaly 42 , 253 \200\2238 acupuncture 159 acute febrile neutrophilic dermatosis 18 adalimumab 36 , 97 , 120 , 142 , 194 , 244 adenov irus 248 adhesive capsulitis 60 adverse neural dynamics 103 \200\2237 albumin 166 alcohol i ntake 30 , 44 aldolase 166 alendronate therapy 124 , 136 antibiotic therapy Lyme disease 252 prophylactic in Wegener \200\231s granulomatosis 136 , 137 reactive arthritis 252 septic arthritis 212 \200\22313 Whipple \200\231s disease 177 osteoporosis 85 Paget \200\231s disease 6 anticentromere antibody 162 anticitrullinated C-peptide (ACCP) antibody 28 anticoagulation therapy 237 anticonvulsants 159 antinuclear antibodies (ANA) 117 , 135 , 248 , 264 antiphos pholipid syndrome 56 , 75 \200\22382 antisynthetase syndrome 164 \200\22371 anxiety 265 aor tic dissection 72 aortic regurgitation 231 aortic root dilatation 72 appendectomy 64 , 65 , 66 arrhythmias 44 , 167 , 206 arterial thromboembolism 81 \200\2232 arterial ulcers 204 ar thralgia 18 , 60 , 110 , 138 , 225 , 230 , 259 , 264 arthritis 18 , 66 , 225 , 246 aspartat e transaminase (AST) 166 aspirin therapy 14 , 56 , 82 , 237 atlanto-axial subluxation 218 , 219 , 221 atorvastatin 30 , 199 auricular chondritis 193 autologous blood 101 avascular ne crosis 112 azathioprine therapy 14 , 36 , 120 , 155 , 170 , 194 , alkaline phosphatase (ALP) 4 , 7 allopurinol 29 -adrenergic receptor antagonists 237 ama urosis 231 amlodipine 30 , 136 , 236 amoxicillin 252 amyloidosis 66 , 67 anemia 230 iron-de \201 ciency 174 pernicious 265 anakinra 67 , 92 , 194 Andersson lesion 96 angiogra phy 231 \200\2232 angiotensin II receptor antagonists 163 , 237 ankle pain and swelling 20 , 46 ankylosing spondylitis 36 , 93 \200\2238 anorexia 172 anterior compartment syndrome, exercise-induced 128 anterior knee pain 186 \200\2239 anti-glomerular basement membrane antibodies 135 anti-La antibodies 56 , 262 anti-Mi- 2 169 anti-neutrophil cytoplasmic antibodies 206 , 207 , 231 Beh et \200\231s disease (BD) 226 , 227 pregnancy 56 , 58 Wegener \200\231s granulomatosis 136 (ANCA) 134 \200\2235 anti-Ro antibodies 56 , 168 , 262 anti-SRP 169 anti-synthetase 169 anti-thrombotics 237 ant i-TNF therapy B-cell lymphoma 265 back pain 6 , 93 , 96 , 182 274 INDEX band keratopathy 119 Beh et \200\231s disease 22 , 90 , 174 , 223 \200\2237 benzbromarone 30 bio \201 lms 212 bisphosphonate therapy CMRO/SAPHO 244 giant cell arteritis 14 hypocalc aemia risk 7 neuropathic pain 159 osteogenesis imperfecta 123 \200\2234 osteoporosis 85 Pag et \200\231s disease 6 \200\2237 side effects 7 blindness 6 , 13 blistering dactylitis 146 , 147 blood pressure differences in arms 228 , 231 blue sclera 123 boggy synovitis 48 , 52 bone biopsy 123 bone scan cerebrovascular disorders 225 cervical disc prolapse 104 cervical instability 219 , 222 cer vical sympathectomy 238 Charcot \200\231s joints 18 chemical sympathectomy 238 chest pain 6 2 , 231 chest wall 239 , 243 chest X-ray (CXR) chronic recurrent multifocal osteomyelitis (CRMO) 239 , 242 increased cardiac silhouette 138 , 141 myositis 166 sarcoidosis 20 , 23 childhood febrile episodes 62 , 64 , 65 choreiform movements 75 , 78 \200\2239 chronic auto immune thyroiditis 60 chronic non-bacterial osteomyelitis 242 chronic recurrent multifocal osteomyelitis (CRMO) 239 \200\22345 chronic recurrent multifocal osteomyelitis ciclosporin therapy 120 , 170 , 194 (CRMO) 242 Beh et \200\231s disease 226 , 227 HIV-associated psoriasis 111 macrophage activation synd rome 92 pregnancy 58 cirrhosis 44 , 265 CNS manifestations Paget \200\231s disease 5 SAPHO syndrome 243 stress fracture 129 bone tumors 242 Borrelia spp. 250 bosentan 163 , 237 botulinum toxin 237 brain biopsy 155 b reathing problems 131 , 138 , 141 brucellosis 250 \200\2231 , 252 bruises 75 bruits 231 Bud d \200\223Chiari syndrome 225 bursitis 100 , 112 Beh et \200\231s disease 225 relapsing polychondritis 194 CNS vasculitis 150 \200\2236 co-trimoxazole 136 , 137 , 177 coeliac disease 32 , 174 , 265 colchicine 24 , 29 , 66 , 67 complex regional pain syndrome 157 \200\22360 computed tomogra phy (CT) cervical spine 218 interstitial lung disease 264 myositis 167 , 170 Paget \200\231s disease 5 SAPHO syndrome 243 stress fracture 129 systemic-onset juvenile idiopathic arthritis 91 C-reactive protein (CRP) 9 , 91 , 166 , 190 , 198 , 201 calcitonin 7 calcium channel blockers 163 , 236 calcium pyrophosphate deposition 42 , 43 ca lcium supplementation 7 , 14 , 85 camping 246 , 248 canine distemper 8 CARD 15 gene 36 \200 \2237 cardiac/cardiovascular manifestations antiphospholipid syndrome 81 haemochromatosis 4 4 Marfan \200\231s syndrome 72 myositis 167 relapsing polychondritis 193 rheumatoid arthrit is 141 rheumatoid vasculitis 206 sarcoidosis 24 scleredema 198 computer use 104 congenital contractural arachnodactyly 70 congenital heart block 264 conne ctive tissue disease 198 , 224 , 251 contraceptive advice 82 coping styles 158 cornea band keratopathy 119 ulcerative keratitis 193 , 206 corneal melt syndrome 206 corticosteroids, see steroid therapy cough 131 , 193 , 231 , 259 , 264 Coxsackie virus 166, 248 creatine phosphokinase (CPK) 166 crescentic glomerulonephrit is 135 CREST syndrome 162 , 236 cricket injury 182 \200\2235 Crohn \200\231s disease 32 , 3 6 \200\2237 carpal tunnel syndrome 60 , 256 , 257 Castleman \200\231s disease 90 central cervical disc prolapse 104 cerebral angiography 155 275 INDEX eosinophilic granuloma 242 episcleritis 193 Epstein \200\223Barr virus (EBV) 18 , 248 eryth ema chronicum migrans 250 erythema marginatum 249 erythema nodosum 22 , 24 , 230 erythemato us nodules 15 , 18 erythrocyte sedimentation rate (ESR) 9 , 91 , 92 , crystal arthropathy 210 CT angiography 232 cyclophosphamide therapy 155 , 194 , 227 , 231 fertility 56 pregnancy 58 rheumatoid vasculitis 206 , 207 Wegener \200\231s granulomatosis 136 166 , 199 , 201 dactylitis 36 , 144 , 146 \200\2237 dapsone 194 deafness 6 , 123 , 193 deep cutaneous vascu litis 206 deep vein thrombosis 225 dental caries 259 , 264 dentinogenesis imperfecta 123 de pression 265 dermatomyositis 15 , 148 , 167 , 170 , 198 diabetes 44 , 199 , 256 diarrhea 17 2 diclofenac 119 dietary advice gout 30 haemochromatosis 44 etanercept 92 , 97 , 142 , 194 ethnicity 8 , 12 , 64 , 65 euthyroid autoimmune thyroid dise ase 61 Evan \200\231s syndrome 81 exercise link anterior compartment syndrome 128 eosinophilic fasciitis 199 exhaustion 264 extended juvenile idiopathic arthritis 117 extracorporeal shock wave therapy 101 eye manifestations Beh et \200\231s disease 225 , 226 juvenile idiopathic arthritis 119 , 120 Marfan \200\231 s syndrome 72 osteogenesis imperfecta 123 relapsing polychondritis 190 , 193 rheumatoid vas culitis 206 sarcoidosis 24 Sj gren \200\231s syndrome 263 diffuse cutaneous systemic sclerosis 162 diffuse idiopathic skeletal hyperostosis 256 diffu se in \201 ltrative lymphocytosis syndrome (DILS) 110 , 112