This patient responded well to a course of pulsed cyclophosphamide and oral corticosteroids , with resolution of symptoms and return to normal function. He started maintenance treatme nt with mycophenolate mofetil and has been carefully followed up as the relapse rate of the condition is estimated at 25 % . Early recognition of disease and prompt treatment is like ly to improve outcome. Further reading Birnbaum J , Hellmann DB ( 2009 ). Primary angiitis of the CNS . Arch Neurol ; 66 : 704 \200\223 9. Calabrese LH , Malleck JA ( 1988 ). Primary angiitis of the central nervous sys tem . Medicine ; 67 : 20 \200\223 39. Calabrese LH ( 2007 ). Narrative review: reversible cerebral vasoconstriction syndromes. Ann Int Med ; 146 : 34 \200\223 44. 156 CASE HISTORIES IN RHEUMATOLOGY Calabrese LH , Duna GF ( 2008 ). Vasculitis of the central nervous system . In: Ball E , Br idges SL (eds) Vasculitis ( 2 nd edn). Oxford : Oxford University Press . Hajj-Ali RA, Calabrese LH ( 2009 ). Central nervous system vasculitis . Curr Opin Rheumatol ; 21 : 10 \200\223 18. K ker W ( 2007 ). Cerebral vasculitis: imaging signs revisited . Neuroradiology ; 49 : 471 \200\223 9. 157 CASE 27 Case 27 A 26-year-old woman, who had been working part-time as a waitress and training to be a beau ty therapist, was referred to the rheumatology outpatient department with severe pain and w eakness in her legs. The patient stated that her leg symptoms occurred as a result of a fal l at her workplace 6 months previously when she slipped on wet tiles in the restaurant. The re was initial bruising of her left calf and thigh. Her employers were not sympathetic, den ying that the floor was wet. She was in the process of taking legal action against them. Sh e had not been able to work since because her legs were too painful; her mobility was sever ely affected and she was confined to her home. Her parents were present during the consulta tion and they provided the history. The patient was tearful and did not say very much, but complained of fatigue and pain. There was no past medical history apart from migraines and dysmenorrhea. On examination the patient was noted to be overweight. She could not walk without her fathe r assisting her. Both legs had normal tone; there was a global weakness of her legs related to pain. The skin was cool, especially below her knees, and she described marked hyperalge sia of the skin from the mid-thigh downwards. Reflexes were normal and the joints were norm al apart from exquisite pain on movement. Questions 1. What is the diagnosis? 2. Would the presence of more widespread trigger points and sleep disturbance change the diagnosis? 3. What is the approach to management? 4. What is the role of pharmacotherapy for neuropathic pain? 5. What are the risk factors for this patient having a poor outcome? 158 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the diagnosis? The working diagnosis is that of a complex regional pain syndrome (CRPS). This condition en compasses a diversity of painful conditions, often following trauma, coupled with abnormal regulation of blood flow and sweating, trophic changes, and oedema of the skin. The excruci ating pain and autonomic dysfunction is dis- proportionate to any inciting event. CRPS type I is formally identified as reflex sympathetic dystrophy. CRPS type II is the term that de scribes the condition when it coexists with documented nerve injury. CRPS I may follow trivial injury. Clinical features include allodynia, hyperalge- sia, oede ma, pseudo-motor and vasomotor abnormalities, and subsequent trophic changes. This results in a diminution in quality of life and overall reduction in health. There is an interplay w ith the organic features of the reflex sympathetic dystrophy and the non-organic pain modul ation disorder. A physical trauma is often the precipitating event and becomes a point of f ixation, particularly when there is a legal claim or compensation is sought. 2. Would the presence of more widespread trigger points and sleep disturbance change the diagnosis? The presence of widespread trigger points and sleep disturbance with fatigue would raise th e possibility that the patient had developed fibromyalgia. The definition encompasses pain and tenderness that affects muscles and tendons over the whole body and continues for more than 3 months. It is called a \200\230syndrome \200\231 because it is a collection of symp toms, rather than a disease. It is almost always present in association with non-restorativ e sleep. There is evidence that in these patients \200\231 psychological conditions, includ ing depression, panic disorders, anxiety, and post-traumatic stress, may play a part. Genet ic factors may also play a role in the pathogenesis of a fibromyalgia syndrome. Personality factors may also be involved. Buskila and col- leagues have analyzed coping styles of fibr omyalgia patients with specific emphasis on the differences between those patients with and without post-traumatic stress. The psychological concept of \200\230suppression \200\231 as a coping style is significantly more common in fibromyalgia patients with comorbid post- traumatic stress. 3. What is the approach to management? Management of CRPS I requires a clear therapeutic plan which needs the full par- ticipation and cooperation of the patient and family. Understanding the process and its presentation is paramount to the success of treatment. The physiotherapist often leads in the management . A graded exercise program, training the patient to use their legs fully, should be commen ced as soon as possible. Altering sensory stimuli such as hot, cold, light touch, and vibra tion are helpful in re-training nerves. Balance and proprioception are often lost early and need to be worked on. There is some evidence that mirror therapy may be helpful in CRPS I. 159 CASE 27 The primary tool of mirror therapy is a mirror from which the patient receives visual feedb ack in order to \200\230train \200\231 the brain to configure a new \200\230body map \200 \231. This so-called map is the mental representation that allows a person to be aware of w here each component of the body is at all times, even in complete darkness. The feedback th at is gained from the normal limb is used to train the painful limb. Clinical psychology and pain-management strategies need to proceed alongside the physical t herapies. The losses to self-esteem, work, and health need to be addressed, and their meani ng to the patient needs to be explored. Acupuncture and transcutaneous electrical nerve sti mulation (TENS) may have some value in the relief of pain, but the evidence base for these treatments is poor. 4. What is the role of pharmacotherapy for neuropathic pain? Pharmacotherapy has a role in the management of neuropathic pain. Drugs such as tricyclic a ntidepressants and serotonin reuptake inhibitors may be useful. Noradrenaline and serotonin are important mediators of descending inhibition of noxious signaling and are important in stress response pathways. Meta-analyzes have demonstrated the efficacy of tricyclic antide pressants in fibromyalgia. Selective serotonin reuptake inhibitors have limited efficacy. A nticonvulsants such as gabap- entin and pregabalin, which affect calcium flux and the relea se of excitatory amino acids, have been shown to be useful. The analgesic tramadol, which i s a -opioid receptor agonist inhibiting noradrenaline and serotonin reuptake, has been s hown to be useful. There has been some role for the use of bisphosphonates and also regional nerve blocks, in particular guanethidine. 5. What are the risk factors for this patient having a poor outcome? There are a number of predisposing factors for the development of a more wide- spread pain disorder in this patient. She had had a work-related injury, was taking legal action, was c urrently not working, had put on weight, and had lost self-esteem and independence. There i s a suggestion that there may be an unhealthy enmesh- ment with her family. The ongoing com pensation claim will, in itself, increase anxiety. She will need to undergo numerous assess ments by independent expert witnesses, and it is likely that she will be required to be ass essed by a psychiatrist. She may undergo covert video surveillance by legal teams, which ca n be very stressful. Furthermore, if she feels that she will achieve a significant financia l gain from the compensation, there may be a \200\230secondary gain \200\231 in her not re sponding to treatment. Her lack of self-esteem and weight gain may diminish her interest in her beauty therapy course and amplify her isolation and low mood. If she becomes secondari ly depressed and sedated by medication, her volition levels will be low. With prolonged red uction in physical activity, her aerobic fitness, proprioception, and muscle tone will all be reduced, making it more difficult to rehabilitate. 160 CASE HISTORIES IN RHEUMATOLOGY Further reading Ablin JN , Cohen H , Neumann L , Caplan Z , Buskila D ( 2008 ). Coping styles in fibromyalg ia: effective co-morbid posttraumatic stress disorder . Rheumatol Int ; 28 : 649 \200\223 56 . 161 CASE 28 Case 28 A 26-year-old woman was referred by her GP with an 8-year history of Raynaud \200\231s synd rome. She described several occasions where she had had infected ischaemic ulcers on her fe et. She smoked 15 cigarettes a day and was on the combined oral con- traceptive pill. She w as seen by the registrar, who noted spindled fingers with distal pulp atrophy. Her fingers and toes were cold and had a dusky blue discoloration. Investigations were arranged and she was advised to stop smoking. Her ENA was posi- tive for anticentromere antibody. Lung func tion tests showed a reduced TLCO of 72 % . The chest CT scan was normal, as was an echocard iogram. Questions 1. What is the diagnosis? 2. What does the positive anticentromere antibody mean? 3. Why is smoking cessation especially important in this patient? 4. Why was an echocardiogram arranged and how will this influence treatment? 5. What treatment approaches are there for Raynaud \200\231s syndrome? 162 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the diagnosis? The diagnosis is limited cutaneous systemic sclerosis. This is a subset of scleroderma whic h is characterized by the CREST syndrome: C alcinosis, R aynaud \200\231s syndrome, o E sph ageal involvement S clerodactyly, and T elangiectasia. The calcinosis most frequently occur s in areas of relative ischaemia such as the fingers and the tips of the ears. The cold dus ky fingers suggest Raynaud \200\231s syndrome, and distal pulp atrophy with spindled finger s is consistent with sclerodactyly. Oesophageal dysmotility may cause chronic reflux with d yspepsia; a barium swallow would help to elucidate this. Telangiectasia is often seen on th e fingers and face as well as on the upper chest. This form of scleroderma contrasts with t he diffuse cutaneous systemic sclerosis where there is more widespread skin thickening and major organ involvement such as parenchymal lung and renal disease. 2. What does positive anticentromere antibody mean? The presence of a positive anticentromere antibody (usually IgG) is associated with the CRE ST syndrome. In a study from the Mayo Clinic, serum samples from 539 subjects with scelerod erma were screened for the presence of the antibody and it was found in 11 % , most of whom had features of the CREST syndrome either independently or in association with primary bil iary cirrhosis. The antibody was rarely found in patients with rapidly advancing or diffuse scleroderma. The anti- centromere antibody is a useful indicator in patients with early sc leroderma as it may help to predict what pattern of scleroderma will evolve. Furthermore, i t is asso- ciated with the development of pulmonary hypertension. 3. Why is smoking cessation especially important in this patient? Smoking cessation is important as smoking exacerbates Raynaud \200\231s syndrome. There is evidence that smoking sensitizes the peripheral vasculature to the vaso- constricting effec ts. This is in part due to sensitization mediated by the inhibition of endothelial prostacy clin synthesis. The reduction in this patient \200\231s gas transfer suggests that she has already developed intrinsic lung disease secondary to smoking, and this would be further su pported by a reduction in the FEV 1 /FVC ratio. Smoking will also increase her risk of deve loping cardiovascular disease. 4. Why was an echocardiogram arranged and how will this influence treatment? The echocardiogram was arranged to assess pulmonary vessel hypertension. Patients with CRES T syndrome and anticentromere antibodies may have associated pulmonary artery hypertension, an important cause of mortality. These symptoms may initially be non-specific or silent, a nd consequently pulmonary hypertension is often under-recognized until the late stages. Ear ly treatment is associated with a better outcome. Echocardiography is a useful pointer, but right-heart catheterization 163 CASE 28 remains the gold standard. Conventional treatments for pulmonary hypertension are based on non-endothelial-specific drugs such as warfarin, oxygen, and diuretics. Calcium-channel blo ckers are often ineffective. Intravenous or aerosol-inhaled prostacyclin has been used and is the first-line treatment for the most severe cases. Phosphodiesterase-5 inhibitors (e.g. sildenafil) have been shown to be useful. Endothelin-1 is a potent vasoconstrictor and smo oth muscle mitogen. The orally administered dual endothelin-receptor antagonist bosentan ha s been shown to improve exercise capacity and cardiopulmonary haemodynamics in patients wit h pulmonary arterial hypertension. However, administration is limited by cost. 5. What treatment approaches are there for Raynaud \200\231s syndrome? Raynaud \200\231s syndrome is episodic vasospasm of peripheral arteries resulting in pallor followed by cyanosis and then redness due to hyperperfusion. There is associated pain and sometimes paraesthesia, and occasionally ulceration of the fingers, toes, pinnae of the ear s, and tip of the nose may occur. Treatment should initially be conservative and non-pharma cological. Patients should be advised to increase their core body temperature by dressing w armly and using thermal underwear and heated gloves. Avoiding the cold and smoking cessatio n are important. Calcium- channel antagonists such as nifedipine may be helpful, but are of ten limited in their use by side effects such as hypotension, peripheral oedema, and headac hes. Other drugs such as angiotenson II inhibitors, selective serotonin reuptake inhibitors , and the phosphodiesterase-5 inhibitors may be useful, but may also be limited by side eff ects. Topical nitrates can cause headaches and flushing. Intermittent prostacyclin infusion s may be useful and are often given at the start of the cold season. Their effect rarely la sts longer than 8 \200\22310 weeks. Further reading Carroll WD , Dhillon R ( 2003 ). Sildenafil as a treatment for pulmonary hypertension . Arch Dis Child ; 88 : 827 \200\223 8 . McHugh NJ , Csuka M , Watson H , et al . ( 1988 ). Infusion of iloprost, a prostacyclin ana log, for treatment of Raynaud \200\231s phenomenon in systemic sclerosis . Ann Rheum Dis ; 47 : 43 \200\223 7 . Powell FC , Winkelmann RK , Venencie-Lemarchand F ( 1984 ). The antic entromere antibody: disease specificity and clinical significance . Mayo Clin Proc ; 59 : 700 \200\223 6 . Rubin LJ , Badesch DB , Barst RJ , et al . ( 2002 ). Bosentan therapy for pulmonary arteria l hypertension. N Engl J Med ; 346 : 896 \200\223 903 . 164 CASE HISTORIES IN RHEUMATOLOGY Case 29 A 36-year-old previously fit green-keeper at a golf course was admitted to the infec- tious diseases unit with a 5-week history of puffy hands, weakness of the arms and legs, and fat igue. He was finding it difficult to stand from sitting and had episodes of night- time fev er. There was no travel history. He owned a dog. There was no history of tick bites, no con tact with other individuals with a similar history, no past medical history, and no relevan t family history. He had been a smoker of 15 cigarettes a day since age 19 years. Specific enquiry excluded Raynaud \200\231s syndrome, dryness of eyes or mouth, rashes, or difficult y in swallowing and there was no change in bowel habit. Examination revealed oedema of hands with scaly patches over the knuckles, pitting oedema o f the feet up to the knees, and purple scaling over the eyelids. His tempera- ture was 37 C, pulse 104 beats/min, and BP 120/65 mmHg. His chest was clinically clear and cardiac ex amination was normal. His muscle power was reduced to four- fifths in a proximal distributi on. Reflexes were normal. Tone was difficult to assess as there appeared to be oedema of th e muscles. There was a suggestion of synovitis at the wrists. 165 CASE 29 Questions 1. Which diseases will the infectious disease physicians want to exclude before referring the patient to rheumatology? 2. Which routine blood investigations would be helpful in the context of proximal muscle weakness and joint inflammation? 3. Which radiological investigations would be helpful in making a diagnosis? 4. How do the immunological blood tests help with the diagnosis and management? 5. What is the treatment for this patient with inflammatory muscle disease? 6. What are the other organ systems that may become involved and how does this relate to th e prognosis, compared with other inflammatory muscle diseases? 166 CASE HISTORIES IN RHEUMATOLOGY Answers 1. Which diseases will the infectious disease physicians want to exclude before referring t he patient to rheumatology? Viral infections such as adenovirus, Coxsackie virus (especially B4), influenza A and B, an d HIV may all present with systemic inflammation and features of a myositis. Bacterial infe ctions are less likely, but those that affect muscle include staphylococci and streptococci , Borrelia burgdorferi , Mycobacterium , and Mycoplasma . There may be elevated creatine ph osphokinase (CPK) levels and non-specific myopathic changes including fiber necrosis and in flammatory infiltrate on biopsy. Parasitic infections are usually associated with an eosino philia; these include Toxoplasma , Trichinella , microsporidia, Echinococcus , and Schistos oma . 2. Which routine blood investigations would be helpful in the context of proximal muscle we akness and joint inflammation? The FBC may show mild anemia of chronic disease and the platelet count may be elevated refl ecting inflammation. Renal function should be checked since it can be affected by muscle in flammation and myoglobinuria. The ESR will be elevated in 50 % of patients with inflammator y muscle disease, but commonly the CRP may not be increased to the same degree, as occurs i n SLE and scleroderma. The muscle enzymes are often elevated: CPK is released from damaged muscle and is a helpful indicator of disease severity. Elevated CPK occurs in 90 % when fir st seen. Increases occur with exacerbations and can precede the exacerbation by 5 \200\2236 weeks. LDH, predominantly LDH-5, may increase without necessarily correlating with cardiac involve ment. AST correlates with biopsy-proven muscle inflammation and is useful in combination wi th CPK. Aldolase may also be elevated. The albumin should be checked to exclude hypoalbuminaemia and nephrotic syndrome in view of the peripheral oedema. The results of the patient \200\231s blood tests were as follows: \227\206 Hb 10.9 g/L; WB C 14.8 \227 10 9 /L; neutrophils 11.5 \227 10 9 /L \227\206 Platelets 437 \227 10 9 /L \227\206 ESR 112 mm/h; CRP 53 mg/L \227\206 Creatinine 82 mol/L; ALT 535 IU/L; ALP 141 IU/L; albumin 29 g/L; CPK 12231 IU/L \227\206 Urine was a red \200\223brown color. 3. Which radiological investigations would be helpful in making a diagnosis? A CXR is required for assessment of the lung fields and cardiac size The lungs may be invol ved in myositis because of diaphragmatic and intercostal muscle weakness . 167 CASE 29 This can result in ventilatory failure or aspiration. Interstitial lung disease is a par- t icular feature of dermatomyositis associated with antisynthetase antibodies (such as the Jo -1 antibody). An acute interstitial pneumonitis leading to a fibrosing lung disease with po or prognosis occurs. A high-resolution CT (HRCT) scan of the lungs will be helpful in chara cterizing the lung disease. HRCT is also useful for assessing progression of pulmonary invo lvement and response to therapy. Pulmonary vasculitis and pulmonary hypertension may also o ccur. Cardiac involvement is commonly asymptomatic but can contribute to mortality. ECG and echoc ardiography may demonstrate the major cardiac complications including conduction disturbanc es, arrhythmias, and myocarditis. Heart block occa- sionally requires pacing. The most comm on arrhythmias are extrasystoles and tach- yarrhythmias. Pericardial effusions are seen in 5 \200\22325 % , but are usually asymptomatic. The muscles may be imaged using ultrasound o r MRI scanning. MRI is increas- ingly used to detect inflammation or muscle damage and may also reflect response to treatment. MRI may be helpful in determining the optimal muscle to biopsy. Fatty infiltration and atrophy are seen best with T 1 -weighted imaging and inflam - mation is seen best with T 2 -weighted or STIR imaging. Gadolinium can also be used to hi ghlight inflammation. The patient \200\231s CXR was normal. Echocardiography showed a minimal pericardial effusio n with normal systolic function. The muscle MRI showed widespread sym- metrical myositis an d significant subcutaneous oedema was also noted (Figs 29.1 and 29.2 ). Fig. 29.1 Widespread symmetrical myositis affecting predominantly the quadriceps, (thick ar rows) gracilis, and semitendinosis. There is also subcutaneous oedema (thin arrow). 168 CASE HISTORIES IN RHEUMATOLOGY Fig. 29.2 Myositis involving predominantly the rotator cuff muscles, triceps, and coracobra chialis with subcutaneous oedema. 4. How do the immunological blood tests help with the diagnosis and management? Inflammatory myopathies are considered to be autoimmune in nature. The antibodies in myosit is may be myositis-specific antibodies (MSA) (Table 29.1) or myositis-asso- ciated antibodi es (MAA). MAA are seen in patients with connective tissue diseases. The patient \200\231s results were as follows: \227\206 ANA negative \227\206 Jo-1 positive \227\206 ENA Ro positive \227\206 RhF negative \227\206 IgG 18.1 g/L; IgA 2.92 g/L; IgM 1.46 g/L. This indicates a polyclonal rise in the immunoglobulins consistent with the acute phase res ponse. The negative ANA is consistent with the absence of nuclear antibodies; both Jo-1 and Ro are cytosolic antibodies. The anti-synthetase syndrome is that associated with Jo-1 or other aminoacyl tRNA synthetas e antibodies. The clinical features are shown in Table 29.2. Twenty- five per cent of patie nts also have anti-Ro antibodies. 169 CASE 29 Table 29.1 Myositis-specific antibodies Anti-synthetase Anti-SRP Anti-Mi-2 Antigen Anti-cytoplasmic Anti-cytoplasmic Anti-nuclear Aminoacyl-tRNA synthetase Signal recognition particle Nuclear protein complex Jo-1 histidyl-tRNA PL-7 threonyl-tRNA PL-12 alanyl-tRNA Prevalence in PM/DM 20 \200\22350 % <5 % 5 \200\22310 % Clinical association Anti-synthetase syndrome Severe resistant PM Classic DM HLA association DRW52, DR3 DRW52, DR5 DRW53, DR7 Onset Acute, spring Very acute, winter Acute Clinical PM DM Severe PM Classic DM ILD (40 \200\22360 % ) Cardiac involvement Shawl sign rash Arthritis, deforming, but usually non-erosive Periungual erythema Cuticle overgrowth Mechanic \200\231s hands Raynaud \200\231s syndrome Steroid response Moderate Poor Good DM, dermatomyositis; PM, polymyositis; ILD, interstitial lung disease. Table 29.2 Features of the anti-synthetase syndrome Clinical feature Percentage ( n = 47) Myositis 100 Arthritis/arthralgia 94 Interstitial lung disease 89 Raynaud \200\231s syndrome 62 Fever 87 Mechanic \200\231s hands 71 DM rash 54 Anti-Ro antibody 25 Mortality 21 Female: male ratio 2.7 Adapted from Love LA et al (1991). Medicine ; 70 : 360 \200\22374. 170 CASE HISTORIES IN RHEUMATOLOGY Muscle biopsy remains the gold standard test for muscle inflammation, although MRI is a use ful non-invasive test and is helpful in monitoring the response to treat- ment. The biopsy in dermatomyositis shows perifascicular atrophy with shrinkage of muscle fibers at the edge of the fascicle. Inflammatory cells surround or invade the blood vessels. There is no inva sion of normal muscle fibers as seen in polymy- ositis and inclusion body myositis. 5. What is the treatment of this patient with inflammatory muscle disease? Treatment should be started without delay to avoid a poor outcome. Dermato- myositis and po lymyositis respond to steroids; however, there is a lack of good- quality evidence. Treatme nt is usually with 1mg/kg prednisolone initially which is continued until the CPK has retur ned to normal and strength has improved (usu- ally 4 \200\2236 weeks). Intravenous methylpr ednislone can be given for very ill patients. The response to treatment is often slower tha n is seen in SLE or rheumatoid arthri- tis, with a mean time to recovery of normal strength of around 3 months. The steroid dose is then gradually lowered. Steroid-sparing drugs such as methotrexate, azathioprine, mycophenolate mofetil, and leflunomide are increasingly bei ng used. There is some evidence that in the anti-synthetase syndrome, patients are more lik ely to respond to methotrexate than to azathioprine. Other drugs that have shown benefit is small studies include ciclosporin and intravenous immunoglobulin. The patient was commenced on prednislone 60 mg and methotrexate 15 mg/week. 6. What are the other organ systems that may become involved and how does this relate to th e prognosis compared with other inflammatory muscle diseases? Other organ involvement includes the lungs, heart, and skin. Lung function tests should be performed at base line and might show evidence of inflammatory lung disease. The patient \200\231s lung function tests were as follows: \227\206 PEFR 485 L/min 82 % predicted \227\206 VC \227\206 FEV 1 /VC \227\206 TLCO 4.8 L 91 % predicted 77 % 11.53 96 % predicted \227\206 KCO 1.58 116 % predicted The lung function tests are essentially within the normal range. The HRCT, which was arrang ed because of the association of pulmonary involvement with the Jo-1 antibody, showed minim al lymphadenopathy and no interstitial lung involvement (Fig. 29.3 ). It would be reasonabl e to repeat this in cases where the patient devel- oped symptoms, or if there is a change i n lung function tests which should be performed annually. 171 CASE 29 Fig. 29.3 HRCT of the chest \200\224 normal test. Further reading Joffe MM , Love LA , Leff RL , et al . ( 1993 ). Drug therapy of the idiopathic inflammator y myopathies:predictors of response to prednislone, azathioprine, and methotrexate and a comp arison of their efficacy . Am J Med ; 94 : 379 \200\223 87 . Love LA , Leff RL , Fraser DD , et al . ( 1991 ). A new approach to the classification of inflammatory myopathy: myositis-specific autoantibodies define useful homogeneous patient g roups . Medicine ; 70 : 360 \200\223 74. Oddis CV ( 2008 ). Idiopathic inflammatory myopathies: treatment and assessment . In: Klippel J , Stone J , Crofford L , White P (eds) Primer on the Rheumatic Diseases ( 13 th edn). New York : Springer ; pp. 375 \200\223 80 . Plotz PH , Dalakas M , Leff RL , Love LA , Miller FW , Cronin ME ( 1989 ). Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis and related disor ders . Ann Int Med ; 111 : 143 \200\223 57 . Tomasova Studynkova J , Charvat F , Jarosova K , Venkovsky J ( 2007 ). The role of MRI in t he assessment of polymyositis and dermatomyositis . Rheumatology ; 46 : 1174 \200\223 9. 172 CASE HISTORIES IN RHEUMATOLOGY Case 30 A 50-year-old Caucasian man presented with a 4-year history of fleeting large-joint arthrit is affecting the knees and ankles. In the 6 months prior to presentation, he had developed night sweats, anorexia, diarrhea, and associated weight loss. Examination revealed widespre ad lymphadenopathy, moderate hepatosplenomegaly, and a pyrexia of 38 C. Investigations showed the following: \227\206 Hb 8.4 g/L, MCV 72 fL \227\206 RF and ACPA negative \227\206 Anti-endomysial and tissue transglutaminase antibodies negative \227\206 Immunoglobulins normal \227\206 CRP 32 mg/L \227\206 Blood cultures negative \227\206 Upper and lower GI endoscopies were normal but there were numerous lymph nodes in the mesentery of the small bowel (Fig. 30.1 ). Fig. 30.1 (See also Plate 13) Mass of lymph nodes in the mesentery of the small bowel. 173 CASE 30 Questions \200\224Part 1 1. What is the differential diagnosis in this case? 174 CASE HISTORIES IN RHEUMATOLOGY Answer 1. What is the differential diagnosis for this case? The combination of constitutional upset, GI features, and arthritis raises a broad differen tial including infection, neoplasia, and IBD. The most important differential to exclude is malignancy. The combination of widespread lym phadenopathy with hepatosplenomegaly, fever, and weight loss is most suggestive of lymphoma . An excision lymph node biopsy is needed to explore this diagnosis further. The picture of iron-deficiency anemia also raises the pos- sibility of GI malignancy, but the normal colo noscopy makes this less likely. Metastatic disease should also be considered, in particular from a primary prostate source in this case. A detailed travel history is needed in order to focus screening for an underlying infectiou s cause. Common causes of lymphadenopathy include infectious mono- nucleosis, adenovirus, a nd CMV, but the prolonged history makes these somewhat unlikely. More chronic infectious ca uses to consider include giardiasis, amoebiasis, tuberculosis, brucellosis, histoplasmosis, and HIV. IBD is a possible explanation for the diarrhea and joint symptoms, but the nor- mal macrosc opic appearances on oesophagogastroduodenoscopy (OGD) and colonoscopy make this unlikely. B D can also give rise to diarrhea with arthritis (see Case 39), but the absence of the chara cteristic oral and genital ulceration would be highly atypical. Similarly, musculoskeletal involvement has been report- ed in up to 20 % of patients with coeliac disease, but the ne gative anti-endomysial and tissue transglutaminase antibody results go against this diagnos is. Other less likely possibilities include hyperthyroidism, malabsorption due to pancreatic disease, and other hematological diagnoses such as leukemia. Further investigations showed the following: \227\206 HIV, CMV, and toxoplasma serology negative \227\206 Tumor markers, including PSA, all negative \227\206 Serum ACE negative \227\206 CXR and TB ELISPOT negative \227\206 Lymph node biopsy showed reactive changes only \227\206 Bone marrow biopsy was normal apart from an increased number of eosinophils. 175 CASE 30 Questions \200\224Part 2 2. What rare diagnosis can explain all of the above findings and how is the diagnosis made? 3. How would you manage this condition? 176 CASE HISTORIES IN RHEUMATOLOGY Answers 2. What rare diagnosis can explain all of the above findings and how is the diagnosis made? Whipple \200\231s disease explains all of the above findings. Whipple \200\231s disease is due to an infection with Tropheryma whippelii and may cause diarrhea, malabsorption and ass ociated weight loss. Although the disease can occur worldwide, it commonly affects middle-a ged Caucasian males. It is characterized by two phases: the prodro- mal stage with intermit tent migratory arthralgia or arthritis, particularly affecting the knee, ankle, and wrist, and the steady state stage with typical manifestations including diarrhea and weight loss. Other less common features include hepat- osplenomegaly, ascites, myalgia, endocarditis, an d neurological involvement. Traditionally, periodic acid \200\223Schiff (PAS) staining of a duodenal biopsy speci- men has been the first-line diagnostic test (Fig. 30.2 ). The typical appearance is of foamy ma crophages containing numerous PAS-positive organisms within the lamina propria. PAS-positiv e cells can be found in any affected organ. However, PAS staining is non-specific and can a lso be seen with other infectious agents including Mycobacterium avium intracellulare , Cor ynebacterium , and Histoplasma . Immunohistochemistry using T.Whippelii -specific antibodie s improves histo- logical specificity and sensitivity. In addition, a polymerase chain reac tion (PCR)- based assay is now available in a few centers, but can be associated with false -positive detection in healthy individuals. Fig. 30.2 (See also Plate 14) Photomicrographs of the duodenal biopsy showing macrophages c ontaining PAS-positive granules. 177 CASE 30 3. How would you manage this condition? Whipple \200\231s disease is potentially fatal if left untreated but responds to antibiotic therapy. Current recommendations for the treatment of Whipple \200\231s disease com- prise induction therapy with intravenous antibiotics, commonly 14 days of ceftriax- one followed by continuation therapy with oral co-trimoxazole for 1 \200\2232 years. The response to tr eatment should be monitored closely as relapses are common, par- ticularly in CNS disease w hich is associated with a high rate of recurrence after apparently successful treatment. In view of the risk of relapsing CNS disease, cur- rent recommendations favor co-trimoxazole over penicillins as it has blood \200\223brain barrier penetration. Further reading Desnues B , Al Moussawi K , Fenollar F ( 2002 ). New insights into Whipple \200\231s diseas e and Tropheryma whipplei infections . Microbes Infect ; 12 : 1102 \200\223 10 . Pu chal X ( 20 02 ). Whipple \200\231s disease . Joint Bone Spine ; 69 : 133 \200\223 40 . 178 CASE HISTORIES IN RHEUMATOLOGY Case 31 A 28-year-old female runner presented with a 1-month history of right groin pain. She was a keen runner and ran competitively in marathons at a national level. Recently, she had incr eased her workload in preparation for a mountain challenge run. The pains were localized to her right groin and had come on insidiously but had gradually become worse over the preced ing month. At presentation, she was complaining of pain in the right groin on walking and o n any weight-bearing exercise. She denied any night pain. There was no history of an acute injury. She had sustained a right navicular stress fracture in the past which was treated conservat ively. She had been amenorrheic for 1 year and oligomenorrheic for 5 years prior to that. S he limited her intake of energy rich foods. She changed her running shoes every 300 \200 \223500 miles. On examination her BMI was 17 kg/m 2 . She had a limp due to pain on weight- bearing. There was no tenderness over the groin. Passive internal and external rotation of the hip exacer bated the pain only at the end range of movements. She had globaly good muscle strength aro und the hip joint. The DEXA scan showed T -scores of \200\2232.6 at the spine and \200\2232.8 at the hip. Th e MRI of the hip joint is shown in Fig. 31.1 . Fig. 31.1 MRI of the right hip. 179 CASE 31 Questions 1. What is the diagnosis? 2. What are the complications of this condition? 3. What other issues have been identified? 4. What other investigations would you request? 5. How would you treat this athlete? 180 CASE HISTORIES IN RHEUMATOLOGY Answers (a) (b) Fig. 31.2 (a) NOF stress fracture of the inferior surface on MRI (arrow). (b) NOF stress fr acture of superior surface on X-ray (arrowhead). 1. What is the diagnosis? The diagnosis is a stress fracture of the neck of the femur (NOF). Femoral neck stress frac tures can be classified as superior surface or inferior surface (Fig. 31.2 ). In this case the stress fracture is on the inferior surface (Fig. 31.2 ). NOF stress frac- tures are mor e commonly seen on the inferior surface (80 % ) than on the superior surface (20 % ). 2. What are the complications of this condition? NOF stress fractures are at high risk of progression to a complete displaced fracture with the possibility of avascular necrosis of the femoral head. Stress fractures of the superior surface are on the tension side of the femur; hence they are less stable and have a higher tendency to progress to a full fracture. Inferior surface fractures are on the compression side of the femur and are more stable. 3. What other issues have been identified? This athlete is noted to have a disordered eating pattern and amenorrhea, and she is also o steoporotic. This triad of conditions is termed the \200\230female athlete triad \200\231. The process is driven by an energy imbalance due to increased expenditure during exercise together with inadequate energy intake due to disordered eating patterns. This results in a low BMI and also shutting down of the hypothalamic \200\223pituitary axis, resulting in me nstrual disturbance. This in turn affects bone health and predisposes the athlete to stress fractures. 181 CASE 31 4. What other investigations would you request? Further investigations should be carried out to investigate the metabolic bone issues and t he amenorrhoea. Blood tests should include full blood count, bone profile, thyroid function , renal function, liver function, sex hormone profile, and vitamin D levels, and exclusion of malabsorption with endomysial or tissue transglutaminase antibodies. Prior to returning to sporting activities a formal biomechanical assessment should be considered, involving as sessment of the athlete \200\231s walking and running biomechanics. This would involve gait analysis using motion detectors and high-speed cameras in a gait laboratory. 5. How would you treat this athlete? There are two main issues that need to be addressed. Treatment of the stress fracture Treatment is either conservative or surgical. Conservative methods are favored for NOF stress fractures of the inferior surface. Conservative treatme nt includes immediate non-weight-bearing rest with the use of crutches. The non-weight bear ing period is usually guided by the patient \200\231s symptoms, but should last for at leas t 4 \200\2236 weeks. This is followed by a gradual introduction of activities, with a retur n to sport taking approx- imately 6 months. Surgical management is usually favored for the treatment of NOF stress fractures of the superior surface. Addressing the female athlete triad and associated issues This is paramount to prevent furt her stress fractures. A multidisciplinary team approach with input from a sport and exercis e medicine physician, a nutritionist, a psychologist and a coach is important. A considerab le amount of time should be spent educating the athlete on the issues surrounding the femal e athlete triad and developing strategies to address these. The key would be to address the energy imbalance by increasing energy intake, optimizing training sessions, and ensuring a dequate recovery time between training sessions. There could be some overlap with more seri ous eating disorders such as anorexia nervosa and bulimia. Hence, where appropriate, a psyc hiatrist may be added to the multidisciplinary team. Further reading