236 CASE HISTORIES IN RHEUMATOLOGY secondary Raynaud \200\231s. Endothelial cells regulate vascular tone by producing a number of vasodilatory mediators, and a deficiency of nitric oxide (NO), one such vasodilator, ha s been implicated in the pathogenesis of Raynaud \200\231s. The contribution of vasoconstri ctors such as endothelin-1 and angiotensin is also under investiga- tion. The association o f primary Raynaud \200\231s with migraine and Prinzmetal \200\231s angina suggests a system ic disorder rather than vasospasm isolated to the peripheries. Structural vascular changes seen in secondary Raynaud \200\231s include severe fibrotic proliferation of the intima wit h muscular hypertrophy. Such intimal pathology is often associated with intravascular throm bi, which can completely occlude the vessel lumen. Neurotransmitters from autonomic and sensory afferent nerves alter digital vascular tone an d are thought to be important in both primary and secondary dis- ease. Neurotransmitters im plicated include epinephrine, vasopressin, bradykinin, histamine, leukotrienes, and calcito nin gene-related peptide. Several circulating factors have been implicated in the pathogenesis of Raynaud \200\231s p henomenon, especially in the context of systemic sclerosis. Platelet activation, defective fibrinolysis, and oxidant stress have all been implicated. The mechanisms are not fully und erstood, but it is thought that these intravascular factors may reduce basal blood flow in the microvasculature, in turn exacerbating the effect of digital vasospasm. 4. What are the treatment options for this condition? The management of Raynaud \200\231s phenomenon depends on the severity of the disease, whic h can range from mild symptoms to digital ulceration and gangrene, and the presence of any underlying conditions. General treatment options are considered below. Lifestyle modification \227\206 Avoid exposure to sudden changes in ambient temperature \227\206 Smoking cessation \227\206 Avoid predisposing substances including caffeine. Drug treatment \227\206 Calcium-channel blockers have a vasodilatory effect with direct action on vascula r smooth muscle, alongside inhibition of platelet activation. The dihydropyridine group (ni fedipine, amlodipine, felodipine) is the least cardioselective and appears to be the most e fficacious for the treatment of Raynaud \200\231s phenomenon. Adverse effects such as heada ches and lower-extremity oedema result in discon- tinuation in many patients. Compliance ca n be enhanced by use of slow-release preparations and gradual dose escalation. Reflux sympt oms can be exacerbated in patients with CREST as lower oesophageal sphincter tone is lowere d. In patients with systemic sclerosis with moderate to severe pulmonary hyperten- sion, va sodilator therapy should be introduced with caution as it can result in hypotension and ass ociated vascular collapse. 237 CASE 41 \227\206 Topical glyceryl trinitrate has been shown to reduce the severity and number of a ttacks in both primary and secondary Raynaud \200\231s phenomenon. Frequent headaches often limit its use clinically. \227\206 Intravenous vasodila tory prostaglandins are particularly effective in secondary Raynaud \200\231s phenomenon, improving both the Raynaud \200\231s attacks and digital ulce ration. In addition to the affect on vascular tone, prostaglandins inhibit platelet aggrega tion. Iloprost, a prostaglandin analog, may have additional antifibrotic activity. Common s ide effects include headache, hypotension, nausea, and flushing. \227\206 Phosphodiesterase inhibitors such as sildenafil may be helpful in Raynaud \200 \231s phenomenon by enhancing the vasodilatory effect of both nitrous oxide and pros- tagla ndins. The evidence to date is inconclusive. \227\206 ACE inhibitors and angiotensin II receptor antagonists are often used in the trea tment of Raynaud \200\231s phenomenon, but the studies to date are inconclusive. \227\206 Endothelin receptor antagonists , such as bosentan, are effective in the treatmen t of pulmonary hypertension and have been shown to improve healing of existing ulcers or im prove Raynaud \200\231s attacks. Preliminary evidence suggests a role for the drug in the p revention of digital ulceration and amelioration of the symptoms from ulcers. \227\206 -adrenergic receptor antagonists , such as prazosin, show improvement in Rayna ud \200\231s attacks but frequent side effects limit use. Newer agents are better tolerated and currently under investigation. \227\206 Anticoagulation and anti-thrombotic therapy are often used in the context of seve re digital ischaemia. Although the use of anti-thrombotic therapy is not evi- dence based, the use of low-dose daily aspirin in patients with severe ischaemia or ulceration is genera lly accepted. Anticoagulation is most effective in the context of an embolic or vascular oc clusive process and is usually used as a short-term option. There is some pilot evidence fo r the use of longer-term heparin to reduce the severity of Raynaud \200\231s phenomenon, bu t the risk of adverse events necessi- tates more robust long-term evidence. \227\206 Ginkgo biloba has also been shown to be effective in patients with Raynaud \200 \231s disease. Surgical treatment Surgical treatment is usually reserved for patients with severe intracta ble digital ischaemia, which is most commonly seen in patients with underlying connective t issue disease. \227\206 Botulinum toxin can be injected into affected digits and acts by eliminating pres ynaptic cholinergic inhibition of neurogenic relaxation. The consequent paralysis of digita l artery muscle enhances digital blood flow. Botulinum toxin may also block stimulation of pain-transmitting C-fibers, ameliorating vasospasm- induced pain. 238 CASE HISTORIES IN RHEUMATOLOGY \227\206 Chemical sympathectomy is achieved by injecting anesthetic near the appropriate cervical or lumbar sympathetic ganglia with temporary effect. \227\206 Cervical sympathectomy is rarely recommended because of the associated compli- cations such as Horner \200\231s syndrome and persistent neuralgia. \227\206 Surgical debridement is the most common surgical technique employed in patients w ith Raynaud \200\231s phenomenon. Occasionally amputation is required for gangrene, intract able ulceration, or osteomyelitis. Further reading Bakst R , Merola JF , Franks AG Jr , Sanchez M ( 2008 ). Raynaud \200\231s phenomenon: path ogenesis and management . J Am Acad Dermatol ; 59 : 633 \200\223 53 . Lambova SN , Muller-Ladner U ( 2009 ). New lines in therapy of Raynaud \200\231s phenomenon . Rheumatol Int ; 29 : 355 \200\223 63 . Lambova SN , Muller-Ladner U ( 2009 ). The role of capillaroscopy in differentiation of pri mary and secondary Raynaud \200\231s phenomenon in rheumatic diseases: a review of the lite rature and two case reports . Rheumatol Int ; 29 : 1263 \200\223 71 . 239 CASE 42 Case 42 A 10-year-old boy presented to his GP with a 4-week history of anterior chest wall pain exa cerbated by deep inspiration that was severe enough to prevent him attending school. On exa mination he was systemically well, but had tenderness over the sternum and right second rib , which appeared prominent. A CXR showed a lytic lesion of the right second rib (Fig. 42.1 ). He was referred to the orthopedic team. Given the uncer- tain nature of the lesion it wa s thought prudent to commence treatment for osteomy- elitis with intravenous antibiotics. B lood cultures taken prior to treatment were subsequently found to be negative. Investigations showed the following: \227\206 Hb 10.4 g/dL; WCC 11.5 \227 10 9 /L; platelets 552 \227 10 9 /L; MCV 76.8 fL \227\206 ESR 62 mm/h; CRP 48.2 mg/L \227\206 CXR \200\224 see Fig. 42.1 for image of upper chest \227\206 MRI scan \200\224 see Figs 42.2 and 42.3 \227\206 Bone biopsy: mixed acute and chronic inflammatory cell infiltrate in the marrow s paces with numerous polymorphs extending into the surrounding soft tissue and muscle in kee ping with infection. No organisms seen on Gram staining. Osteomyelitis was considered the most likely initial diagnosis and he underwent a 6-week co urse of empirical intravenous ceftriaxone followed by a 6-month course of doxycycline and r ifampicin. At his annual review he was pain free and a follow-up MRI scan demonstrated part ial resolution of the rib and sternal lesions. However, he presented again at the age of 13 years with pain in the same rib and upper ches t wall, right hip, and lower back. During the subsequent year, he developed a pustular skin eruption on his finger and joint pain and swelling of his wrists, fingers, and knees. He u nderwent a technetium bone scan (Fig. 42.4 ). Fig. 42.1 X-ray of the upper chest. The arrow shows the site of the lytic lesion. 240 CASE HISTORIES IN RHEUMATOLOGY Fig. 42.2 MRI scan of the chest. Fig. 42.3 MRI scan of the chest. 241 CASE 42 Fig. 42.4 Technetium bone scan. Questions 1. What is demonstrated on the MRI and technetium bone scans? 2. What are the important differential diagnoses, and what was the most likely cause of his symptoms? 3. What is the rash likely to be? 4. How would you manage this case? 242 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is demonstrated on the MRI and technetium bone scans? The X-ray of the upper chest (Fig. 42.1 ) shows an osteolytic lesion of the right second ri b. The MRI scans (Figs 42.2 and 42.3 ) show expansion and destruction of the right second r ib with involvement of the sternum. An abnormal signal suggesting oedema can be seen to ext end into the surrounding soft tissues. The technetium bone scan (Fig. 42.4 ) demonstrates m ultiple areas of increased uptake, in particular right hip, left ankle, sternum, and upper two right ribs. 2. What are the important differential diagnoses, and what was the most likely cause of his symptoms? The two most important differentials at presentation were infection and malignancy. His ini tial presentation with pain, a lytic lesion on X-ray, and histological features of chronic inflammation was in keeping with infection although no organism was identified. Children with bone tumors may present with pain, which is often worse at night, localized t enderness, and swelling. Systemic features are absent in patients with benign lesions, but fever and weight loss may occur with malignancies. Benign tumors include osteoid osteoma an d osteoblastoma (an osteoid osteoma > 2 cm in diameter), which both occur more frequently i n boys. Eosinophilic granuloma is a localized Langerhans cell histiocytosis, characteristic ally occurring in children between 5 and 10 years of age and is seen as a lytic lesion on X -ray. Malignant mus- culoskeletal tumors of childhood include osteogenic sarcoma, rhabdomyo sarcoma, and Ewing \200\231s sarcoma. This child presented over 3 years with a number of inflammatory bone lesions but was system ically well. There was partial resolution of the initial lesion followed by the development of inflammatory bone lesions at other sites and new skin and joint disease. Although histo logical examination of the lesions demonstrated fea- tures typical of infection, no organis m was identified and the response to antibiotics was variable. The clinical picture evolved to include a pustular skin rash and joint inflammation. The bone lesions are typical of ch ronic relapsing multifocal osteomy- elitis (CRMO) with progression of the disease to the SA PHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). CRMO and SAPHO form part of the same syndrome and have identical bone pathology, with CRMO occurring more commonly in children. CRMO is at the more severe end of a spectrum of inflam matory bone lesions termed chronic non- bacterial osteomyelitis. Histologically the lesions are identical to bacterial osteomy- elitis but are not associated with infection. Lesions may occur at any skeletal site, but predominantly affect the metaphyses of long bones in ch ildren. It generally occurs at a median age of 10 years and is twice as frequent in females as in males. CRMO has been associated with the spondyloarthropathies and may form part of enthesitis-rel ated arthritis in children. However, the frequency of HLA B27 is 243 CASE 42 the same as in the general population. An association with IBD has also been reported. The SAPHO syndrome includes the same inflammatory bone lesions together with skin and joint manifestations. The clinical features of the SAPHO syndrome may not all be present at the outset; in particular, skin involvement may be absent. It may initially present in children and adults as CRMO alone, as in this case. A slight to moderate increase in inflammatory m arkers is common and there are no associated autoantibodies. Diagnosis is based on clinical , radiological, and histo- logical findings. A patient with SAPHO usually has multiple bony lesions affecting the anterior chest wall, r ib cage, spine, metaphyses of lamellar bone, pelvis, and mandible. There may be a soft tiss ue component, as in this patient. The anterior chest wall, involving the sternoclavicular j oint, is the most common site affected in 65 \200\22390 % of patients. The spine is affecte d in 33 % of patients and often involves the thoracic spine in the form of spondylodiscitis , osteosclerosis, and paravertebral ossifications. The sacroiliac joint may be involved. Lo ng bones are involved in 30 % of patients and flat bones, including the mandible and ilium, in 10 % of patients. Solitary bone lesions may occur and are most often present in the cla vicle or mandible. Peripheral arthritis has been reported in 92 % of cases of SAPHO. The most prominent feature on X-ray is the presence of hyperostosis and osteitis. CT and MR I are useful for localizing lesions. Appearances can be similar to that of chronic osteomye litis but there is no sequestrum or abscess formation. MRI is also useful in follow-up wher e T 2 -weighted sequences with fat suppression identify bone marrow oedema. Technetium bone scans can identify clinically silent lesions. Imaging does not exclude malignancy, particu larly in unifocal lesions where biopsy needs to be considered. The diagnostic criteria for SAPHO put forward by Kahn and colleagues in 1994 are as follows. \227\206 Chronic relapsing multifocal osteomyelitis involving the axial or peripheral skeleton: usually sterile or with the presence of Propionbacterium acnes spine may be involved with or without skin lesions. \227\206 Acute, subacute, or chronic arthritis with any of the following: palmoplantar pustulosis pustular psoriasis severe acne/hydradenitis. \227\206 Any severe osteitis with any of following: palmoplantar pustulosis pustular psoriasis severe acne or hydradenitis. Any one of the three presentations is sufficient for diagnosis. 244 CASE HISTORIES IN RHEUMATOLOGY 3. What is the rash likely to be? The pustular skin eruption on his finger is likely to be a palmoplantar pustulosis which is the most common skin manifestation associated with SAPHO and is thought to represent a var iation of psoriasis vulgaris. The prevalence of psoriasis in SAPHO is three times that in t he general population. Dermatological manifestations of SAPHO are generally neutrophilic pustular disorders: \227\206 psoriasis (pustular psoriasis, palmar-plantar pustulosis) \227\206 acne (acne conglobata, acne fulminans, or follicular occlusion triad). Other associated skin diseases include hydradenitis suppurativa, pyoderma gangrenosum, diss ecting scalp cellulitis, and Sweet \200\231s syndrome, all of which are pseudo-abscesses. 4. How would you manage this case? Initial management of inflammatory bone pain should be with an NSAID such as ibuprofen 30 m g/kg/day or naproxen 15 \200\22320 mg/kg/day and is effective in 80 % of cases. Bisphosphon ates are potent inhibitors of osteoclastic activity, and the nitrogen- containing bisphosph onate pamidronate has anti-inflammatory and pain-modifying activity. There are reports of successful treatment with corticosteroids and DMARDs, and these may be useful in controlling inflammatory joint disease. There are case reports of a partial resp onse to biological therapies such as infliximab and adalimu- mab in children with CRMO but not with anakinra. Severe skin lesions may respond to topical steroid creams. This boy was treated with NSAIDs, but continued to experience bone pain which responded wel l to a course of pamidronate infusions. His joint and skin disease was successfully treated with methotrexate 15 mg/m 2 . He had become deconditioned because of poor mobility during prolonged periods of pain, and required support from physiotherapy and occupational therapy in order to return to full activities. Further reading Catalano-Pons C , Comte A , Wipff J , et al. ( 2008 ). Clinical outcome in children with CR MO . Rheumatology 47 : 1397 \200\223 9. Eleftheriou D , Gerschman T , Sebire N , Woo P , Pilkington CA , Brogan PA ( 2010 ). Biolog ical therapy in refractory chronic non-bacterial osteomyelitis of childhood. Rheumatology ; 49 : 1505 \200\223 12 . Girschick HJ , Raab P , Surbaum S , et al . ( 2005 ). Chronic non-bacterial osteomyelitis i n children Ann Rheum Dis ; 64 : 279 \200\223 85 . Huber AM , Lam PY , Duffy CM , et al . ( 2002 ). C RMO: clinical outcomes after more than f ive years of follow-up. J Paediatr ; 141 : 198 \200\223 203 . Jansson A , Renner ED , Ramser J , et al . ( 2007 ). Classification of non-bacterial osteit is. Retrospective study of clinical immunological and genetic aspects in 89 patients . Rheu matology ; 46 ; 154 \200\223 60 . 245 CASE 42 Job-Deslandre C , Krebs S , Kahan A ( 2001 ). Chronic recurrent multifocal osteomyelitis: f ive- year outcomes in 14 pediatric cases. Joint Bone Spine ; 68 : 245 \200\223 51 . Kahn MF , Khan MA ( 1994 ), The SAPHO syndrome . Bailli re \200\231s Clin Rheumatol ; 8 : 333 \200\223 62 . Kahn MF ( 1993 ). Psoriatic arthritis and synovitis, acne, pustulosis, h yperostosis, and osteitis syndrome . Curr Opin Rheumatol ; 5 : 428 \200\223 35 . Kerrison C , Davidson JE , Cleary AG , Beresford MW ( 2004 ). Pamidronate in the treatment of childhood SAPHO syndrome. Rheumatology ; 43 : 1246 \200\223 51 . Vittecoq O , Said LA , Michot C , et al . ( 2000 ). Evolution of chronic recurrent multifoc al osteomyelitis toward spondylarthropathy over the long term. Arthritis Rheum ; 43 : 109 \200\223 19 . 246 CASE HISTORIES IN RHEUMATOLOGY Case 43 An 18-year-old nursery nurse presented with a 6-week history of a painful migratory arthrit is affecting her right ankle, left knee, and right wrist. She had a pale pink non- irritant rash on both forearms at the onset of illness which settled after a week. As a child she had missed schooling because of recurrent tonsillitis. At age 11 years she h ad been diagnosed with an irritable hip which had resolved spontaneously. She lived with he r parents and worked full time in a cr che looking after preschool children. She had retur ned from a camping holiday in Brittany 6 weeks before the onset of arthritis. She remembere d no insect bites and had no regular sexual partner. Her paternal grandmother had rheumatic fever in childhood. On examination she was afebrile, had normal skin and nails, blood pressure 90/60 mmHg, a re gular pulse of 80 beats/min, and a grade 2/6 basal systolic murmur. Her right wrist was swo llen and very tender but had a full range of passive movement. The overlying skin was warm and erythematous. Her other joints and spine were normal. Investigations showed the following: \227\206 Hb 12.3 g/dL; WCC 7.4 \227 10 9 /L; platelets 486 \227 10 9 /L \227\206 CRP 72 mg/L \227\206 CXR normal \227\206 ECG normal. 247 CASE 43 Questions 1. What is the differential diagnosis? 2. What further history and investigations will aid diagnosis? 3. What treatment options are available? 248 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis? \227\206 Viral related arthritis \227\206 Reactive arthritis \227\206 Post-streptococcal reactive arthritis \227\206 Acute rheumatic fever \227\206 Other infection-related arthritis (e.g. Lyme disease, Brucella , Gonococcus ) \227\206 Early inflammatory arthritis \227\206 Connective tissue disease. This patient is at risk of viral-related arthritis as her employment brings her into contac t with young children. The personal and family history of tonsillitis and rheumatic fever r aises the possibility of post-streptococcal-related arthritis or atypical rheumatic fever. The recent camping holiday in France raise the possibili- ties of reactive arthritis, gonoc occal arthritis, Lyme disease, and brucellosis. Early inflammatory arthritis and SLE can pr esent with migratory arthritis symptoms. The systolic murmur may be functional, long-standi ng, or part of the acute illness and needs investigation. 2. What further history and investigations will aid diagnosis? Viral-related arthritis Viral-related arthritis is common in children and young adults. The most common presentation is a symmetrical peripheral arthritis. Transient rashes are commo n and non-specific. Most are benign and resolve within 6 weeks, and patients only present i f the problem is severe or persistent. Rheumatoid factor and ANA may be transiently positiv e during the acute phase. Diagnostic signs and symptoms of spe- cific viral illnesses may d evelop after the arthritis and rash have resolved. \227\206 Parvovirus B19 is common, with presentations differing between children and adult s. Seventy per cent of children are asymptomatic, but some have mild flu- like symptoms and a bright red rash ( \200\230slapped cheek \200\231); joint symptoms are rare. In adults th e rash is rare and joint symptoms occur in up to 60 % with arthralgia or a symmetrical peri pheral small-joint arthritis resembling early rheumatoid arthritis. This resolves almost un iversally within 3 months. Some adults have a transient aplastic crisis, particularly those with hereditary spherocytosis. Maternal infection during pregnancy can lead to fetal hydra mnios and first- and second-trimester abortion. \227\206 EBV infection is common in older teenagers and can be associated with polyar- thralgia, polyarthritis, or a self-limiting monoarthritis. \227\206 Adenovirus and Coxsackie virus infections can be associated with rashes, polyar- thritis, pleurisy, pericarditis, or myocarditis. 249 CASE 43 \227\206 Mumps in adults can present with small- or large-joint arthritis which takes seve ral weeks to settle and can occur up to 4 weeks before the parotitis develops. \227\206 Adult rubella can present with peripheral polyarthritis and morning stiffness bef ore the rash appears. Arthritis associated with rubella and mumps is rare in the UK because of the successful vaccination program. \227\206 Hepatitis B presents with symmetrical large-joint and hand arthritis which may be migratory or persistent. Arthritis and an associated urticaria may precede the jaundice by weeks and persist after the acute hepatitis has settled. Transmission is by blood products or sexual contact. \227\206 HIV-related arthritis can be highly variable, ranging from mild arthralgia to debilitating arthritis which is usually monoarticular. Reactive arthritis It is important to exclude reactive arthritis. The arthritis is often mo no- or oligoar- ticular and persistent, but can be migratory. A careful history about risk of gas- trointestinal or genitourinary infections is needed. Genitourinary infections in pa rticular may be silent in females, or patients may not volunteer symptoms because of embarr assment or lack of understanding of any connection with arthri- tis symptoms. Associated sk in rashes include palmar pustulosis, keratoderma blen- horragica, and erythema nodosum. Rar ely, aortic valve disease and conduction abnormalities can occur. Streptococcal-related arthritis It is important to consider a diagnosis of acute rheumatic fever or post-streptococ- cal-related arthritis, as cardiac involvement occurs with recurre nt episodes and can be prevented by prophylactic penicillin. Rheumatic fever typically affe cts preschool children but can occur in older children and young adults, particularly in an insti- tutional setting. In rheumatic fever, the arthritis is migratory and the joints inv olved are often exquisitely tender, disproportionate to the physical signs. The arthritis a nd synovitis usually resolve spontaneously within a week. Post-streptococcal- related arthr itis is usually a more persistent large-joint oligoarticular arthritis. Cardiac involvement is less common but late cardiac complications have occurred in 10 % of patients. The diagnosis of acute rheumatic fever was modified in 1992 to include major criteria of ca rditis, polyarthritis, erythema marginatum, subcutaneous nodules, and chorea. Minor criteri a are a prolonged PR interval on ECG, arthralgia, fevers, and raised acute phase response. One major and two minor criteria are needed with evidence of antecedent streptococcal infec tion from throat swab culture or serial bloods for antistreptococcal antibodies. Skin involvement includes the characteristic evanescent erythema marginatum which is pink o r red, resolves from the center, and is associated with carditis. Painless firm subcutaneou s nodules may mimic rheumatoid arthritis. 250 CASE HISTORIES IN RHEUMATOLOGY Pericarditis can affect any part of the heart including conduction defects in heart block, valvular lesions affecting the aortic and mitral valve, pericarditis, and heart failure. Neurological sequelae include chorea (involuntary purposeless movements, grimaces of hands and face), muscular weakness, and emotional changes ranging from irritability to psychosis. Both post-streptococcal-reactive arthritis and acute rheumatic fever forms are non-suppurat ive sequelae of group A -haemolytic streptococcal infection. The other important conditi on is acute glomerulonephritis. Different M serotypes of the group A streptococci are assoc iated with these different sequelae (nephri- togenic, arthritogenic, and cardiogenic). Ther e has been a recent resurgence in post-streptococcal-related illness which may be related t o change in virulence and prevalence of different M serotypes. Host factors affecting susceptibility may include age, gender, associated viral infections, and genetic background. Acute rheumatic fever is more common in first-degree relatives of patients. Lyme disease Lyme disease is increasing in prevalence, particularly in southwest Britain du ring late spring and summer. The infective organism Borrelia is a Gram-negative spirochete transmitted via tick bites. Three species are found in Europe ( Borrelia burgdorferi , Borr elia garnii , and Borrelia afzelii ) and each presents with different clinical manifes- tat ions, although all three can cause arthritis. The pathognomonic rash of erythema chronicum migrans occurs within a few days to a month after the bite. It is classi- cally a purple-re d well-demarcated rash near the site of the tick bite which can take up to 4 weeks to settl e. Patients often do not recall a tick bite. Lymphadenopathy, conjunctivitis, and systemic malaise can follow. Joint pains are often migratory but a chronic arthritis, commonly affec ting the knee, can develop. Fifty-five per cent develop carditis with conduction problems. Acute neuroborreliosis occurs in 10 \200\22315 % of patients, presenting as meningitis, fac ial nerve palsy, which is often bilateral (or other cranial neuropathies), painful sensorim otor, or radiculopathy. Diagnosis of early Lyme disease is by detection of a rise in IgM an tibodies which peak 6 \200\2238 weeks after exposure. Gonococcal infection Gonococcal infection (see Case 37) can cause both septic and reactive arthritis and is often associated with tenosynovitis. Patients are usually febrile and may present with asymmetrical migratory polyarthralgia. The associated papular or vesicular non - itchy rash occurs on trunk and limbs, with facial sparing. Joint aspiration is needed to distinguish between septic arthritis and reactive arthritis. Pancarditis including conducti on disturbance can occur, as can osteomyelitis, hepatitis, and meningitis. Brucellosis Unpasteurized cheese is widely eaten in France and may be a source of brucellos is in the current case. Septic arthritis is a common complication of Brucella infection, 251 CASE 43 presenting as a large-joint monoarthritis or unilateral sacroiliitis or spondylitis. Transi ent reactive symmetrical peripheral polyarthritis can also occur. Endocarditis occurs infre quently, usually affects the aortic valve, and is a life-threatening complication. Blood tests show anemia, leucopenia, and sometimes thrombocytopenia with an inflammatory re sponse. Joint aspiration is usually sterile. Prolonged culture (6 weeks) of the organism fr om blood and bone marrow is the current gold standard for diagnosis. A new PCR assay has be en developed which can provide positive results in 10 days. Connective tissue disease and early inflammatory arthritis Connective tissue disease and ea rly inflammatory arthritis should be considered. SLE is more common in young women who may present with rash, arthritis, and carditis (see case 9). ANA is a useful screening test but may be transiently raised during any acute infection. Early rheumatoid arthritis can present as palindromic rheumatism with a migra- tory, often large-joint, arthritis. Joint symptoms flare to a peak and resolve com- pletely in hours or days. Patients are well between attacks. Up to one-third of patients subsequently go on to develop persistent rheumatoid arthritis. Psoriatic and enteropathic arthritis may present with a short-lived migratory arthritis. Ps oriatic rashes may be short-lived and a family history is important, particularly in the yo ung. Further investigations \227\206 Throat swabs for -haemolytic streptococcus are positive in a third of patients without prior antibiotics, and in a tenth with prior antibiotics. Serial blood samples for streptococcal serology such as ASOT and anti-DNAse B : single tests give 80 % sensitivity; two tests increase sensitivity to 90 % . \227\206 RF and ANA may both be transiently raised during acute infections and settle to normal. The test should be interpreted in the clinical context. \227\206 Viral serology to demonstrate a rise in serial IgM antibody titres during an acut e illness, or a slower rise in IgG titres after the acute illness. \227\206 Hepatitis B serology and HIV status if appropriate. \227\206 Stool sample: most commont organisms associated with reactive arthritis are Campylobacter , Salmonella , Shigella , and Yersinia . \227\206 Genitourinary investigation for Chlamydia , Gonococcus , and syphilis. \227\206 ECG to look for conduction abnormalities, PR interval, and tachycardia. \227\206 CXR. \227\206 Echocardiogram to look for structural valvular lesions or pericardial effusion. 3. What treatment options are available? \227\206 Most viral-related arthritis is self-limiting, as are most cases of reactive arth ritis. NSAIDs and analgesics are helpful in symptom relief. 252 CASE HISTORIES IN RHEUMATOLOGY \227\206 Intra-articular corticosteroid injections can help resolve the joint swelling of reactive arthritis. This may be important to help patients return to work. \227\206 Antibiotic treatment of the underlying infection in reactive arthritis is an independent consideration and does not speed arthritis resolution. \227\206 Reactive arthritis patients who are HLA B27 positive are at increased risk of dev eloping a persistent oligoarthritis or even spondylarthritis. These patients usually respon d to a prolonged course of DMARDs such as sulfasalazine, meth- otrexate, or leflunomide. \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