 \227\206 AAS \200\224 65 % (Fig 38.4 ) \227\206 ventral subluxation (VS) \200\224 20 % (Fig. 38.5 ) \227\206 subaxial subluxation \200\224 15 \200\22325 % . 220 CASE HISTORIES IN RHEUMATOLOGY Atlanto Axial Subluxation Fig. 38.4 Lateral radiograph of cervical spine demonstrating atlanto-axial subluxation. Ventral subluxation Fig. 38.5 Ventral subluxation. 221 CASE 38 The O \200\223C1 and atlanto-axial C1 \200\2232 joints have a higher risk of subluxation th an the lower cervical intervertebral joints as they are synovial joints. C1 anterior arch d efects, dens erosions, or dens fractures sometimes cause posterior AAS. Although posterior or lateral AAS has a higher risk of cord compression, anterior AAS predominates. VS occurs secondary to cartilage and bone destruction at the O \200\223C1 and C1 \200\2232 joints and is commonly preceded by AAS. This can present with a more severe neurological deficit and a poor prognosis. Patients with RA and cervical disease should have plain radiographs of the cervical spine ( in both flexion and extension) and a CT scan. MRI may also be useful to image the spinal co rd. Thoracolumbar vertebral abnormalities Although the cervical spine is most commonly affected in RA, any synovial joint in the vertebral column can be affected. Involvement of the apop hyseal joints and discovertebral junctions has been reported in the lumbar and thoracic spi ne. Intervertebral disc-space narrowing, irregularity of the subchondral margins of the ver tebral bodies, erosion, and sclerosis can be seen on imaging. Vertebral osteoporotic crush fracture RA patients, particularly those with significant expo sure to corticosteroids, are at risk of osteoporosis with subsequent wedge compression or f racture of the verte- bral bodies. In addition, the resulting kyphosis which can be seen in these patients may lead to significant pain, deformity, and instability, and increase the technical difficulties of spinal surgery. 4. What conservative measures may be useful for rheumatoid neck disease? The main aims in conservative treatment of rheumatoid neck disease are to relieve symptoms and prevent bone destruction. \227\206 Patients require optimal DMARD therapy to control disease activity. \227\206 Physiotherapy, in particular neck muscle strengthening exercises, and practical aids (e.g. a book rest when reading). \227\206 A stiff neck collar can improve neck symptoms by restricting atlanto-axial move- ment, and is particularly useful for car journeys. Prolonged or continuous use of stiff nec k collars can lead to weakness of neck muscles and is only recommended for patients with se vere instability. \227\206 Occipital nerve block may provide significant temporary relief for severe high cervical and occipital pain. 5. What are the indications for neck surgery and what complications may occur? Whilst neurological examination can be difficult to interpret in patients with severe defor ming RA of the feet, as in this patient, careful observation for evidence of neurological d eterioration is important to detect early signs of myelopathy, as this may require urgent s urgical intervention. 222 CASE HISTORIES IN RHEUMATOLOGY The main indications for cervical spinal surgery in RA are intractable pain, myelopathy, and AAS > 8 mm. Early prophylactic cervical spinal arthrodesis (fusion) with or without decom- pression can reduce the potential for paralysis. Surgical intervention in patients with significant cer vical instability or subluxation without neurological deficit and minimal pain is controver sial. Surgery in rheumatoid neck disease is complex and surgical site infection rates may b e increased due to concomitant corticosteroid use, osteoporotic bone, and rheumatoid diseas e activity. Perioperative complications include vertebral artery injury, transient and pers istent dysphagia or dyspnoea caused by pharyngeal obstruction, and neurological deteriorati on (e.g. paraparesis). Late postoperative complications include malunion and non-union. Further reading Calleja M ( 2009 ). Rheumatoid Arthritis Spine Imaging . http://emedicine.medscape.com/ article/398955-overview. Kauppi M ( 1996 ). Conservative treatment for rheumatoid cervical spine . Lancet ; 347 : 16 95 . Moncur C, Williams HJ ( 1988 ). Cervical spine management in patients with rheumatoid arthritis . Review of the literature. Phys Ther ; 68 ; 509 \200\223 15 . Neo M ( 2008 ). Treatment of upper cervical spine involvement in rheumatoid arthritis patie nts . Mod Rheumatol ; 18 : 327 \200\223 35 . Santavirta S, Kontinnen YT , Laasonen E , Honkanen V , Antti-Poika I , Kauppi M ( 1991 ). Ten year results of operations for rheumatoid cervical spine disorders . J Bone Joint Surg Br ; 73 : 116 \200\223 20 . Winfield J , Cooke D , Brook AS , Corbett M ( 1981 ). A prospective study of the radiologic al changes in the cervical spine in early rheumatoid disease . Ann Rheum Dis ; 40 : 109 \200\223 14 . Wollowick AL Casden AM , Kuflik PL , Neuwirth MJ ( 2007 ). Rheumatoid arthritis in the cervical spine: what you need to know . Am J Orthop ; 36 : 400 \200\223 6 . Zoma A , Sturrock RD , Fisher WD , Freman PA , Hamblen DL ( 1987 ). Surgical stabilization of the rheumatoid cervical spine. A review of indications and results . J Bone Joint Surg B r ; 69 : 8 \200\223 12 . 223 CASE 39 Case 39 A 35-year-old Caucasian male was referred to the rheumatology clinic with a 1-month history of knee and ankle pain, which had resolved by the time he was seen. He had previously been diagnosed with ulcerative colitis, requiring total colectomy in which a section of the sma ll bowel, including the terminal ileum, had been resected to form an ileo-anal pouch anasto mosis. He subsequently had recurrent episodes of pouchitis which were treated with steroids and antibiotics. Six years later he developed florid mouth ulceration. The past medical history included a DVT at the age of 25, which had been treated with stand ard anticoagulation, and recurrent superficial thrombophlebitis. He had no history of genit al ulcers. He had been treated for anterior uveitis with topical corticosteroids. On examination, he had large mouth ulcers and tender erythematous lesions on the shins. He had a normal spine and neck examination. Investigations showed the following: \227\206 Hb 12.0 g/dL; MCV 85 fL; MCH 30 pg; WCC 6.2 \227 10 9 /L; platelets 214 \227 10 9 /L \227\206 ESR 36 mm/h: CRP 50 mg/mL \227\206 Normal renal and liver function tests \227\206 Negative ANA, thrombophilia screen, and HLA B27. Questions 1. What are the causes of severe oral ulceration? 2. Give the differential diagnoses. What is the most likely cause of his illness? 3. What are the clinical features of this condition? 4. What is the disease pathogenesis? 5. How should this condition be managed? 224 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What are the causes of severe oral ulceration? \227\206 Idiopathic recurrent oral stomatitis \227\206 Nutritional (iron, vitamin B 12 , folate deficiencies) \227\206 Infection (HIV, herpes simplex virus 1, CMV in immunocompromised patients) \227\206 Drug reaction (nicorandil, bisphosphonates, NSAIDs) \227\206 Gastrointestinal (ulcerative colitis, coeliac disease, Crohn \200\231s disease) \227\206 Multisystem autoimmune disease (SLE, Reiter \200\231s disease, MAGIC) \227\206 Dermatological (Sweet \200\231s syndrome, erythema multiforme, bullous skin disea se) \227\206 Hematological (cyclical neutropenia, lymphoma) \227\206 Periodic fever syndromes: PFAPA (periodic fever, aphthous pharyngitis, and cervical adenopathy), familial Hibernian fever. 2. Give the differential diagnoses. What is the most likely cause of his illness? \227\206 IBD-related spondyloarthropathy \227\206 BD \227\206 Reactive arthritis \227\206 Sarcoidosis \227\206 Connective tissue disease. An IBD-related spondyloarthropathy may be considered in view of the develop- ment of joint pain in the lower limbs, inflammatory eye disease, and oral ulceration. However, it would n ot explain the history of thromboembolic disease, and is less likely given the negative HLA B27. A history of recent bowel or genitourinary infec- tion may give rise to consideration of a reactive arthritis, but does not explain features such as florid mouth ulceration or DVT. Sarcoidosis may present with arthritis or arthralgia and erythema nodosum, and in rare r cases may involve the eye, but is unlikely to cause thromboembolism or inflammatory bowel lesions. A connective tissue disease may present with oral ulceration and arthralgia of th e small joints, and be associated with thrombosis, but is unlikely in the presence of a neg ative ANA and thrombophilia screen. In view of the recurrent oral ulceration, arthralgia, e rythema-nodosum-like lesions, inflammatory eye disease, and history of throm- bosis, the mo st likely diagnosis is BD. 3. What are the clinical features of this condition? Beh et \200\231s (pronounced Betjet \200\231s) disease (BD) is a multisystem chronic relap sing inflammatory disorder characterized by vasculitis of arteries and veins of all sizes i n multiple organs. The International Study Group for Beh et \200\231s Disease diagnostic c riteria published in 1990 include recurrent oral ulceration (three times in 1 year) 225 CASE 39 and two of the following: recurrent genital ulcers, ocular inflammation, cutaneous lesions, and a positive pathergy test. There are no diagnostic laboratory tests but raised inflamma tory markers may be present . Oral ulceration is the most important diagnostic feature. Genital ulcers are the second mos t common manifestation and may be preceded by a papule or pustule and heal with scarring. B oth oral and genital ulcers are painful. Diagnostic cutaneous lesions are present in 80 % of patients as papulopustular or acneiform lesions and erythema nodosum. Extragenital ulceration, superficial thrombophlebitis, and c utaneous vasculitis may also occur. Pathergy, which is a cutaneous hypersensitivity to trauma, may be noted after venesection. It can be formally tested by the insertion of two large (20G) needles subcutaneously to 3 m m, a few centimeters apart, followed by examination by a physician after 48 hours. The test is positive if a papule or pustule develops at the site of insertion. Gastrointestinal disease occurs in up to 30 % of patients and can be difficult to different iate from IBD. In this case, the original diagnosis of ulcerative colitis was probably inco rrect and the patient was likely to have intestinal BD. This takes the form of mucosal ulce ration and may be severe with large penetrating ulcers affect- ing any part of the gut, but most commonly located in the ileocaecal region. Ocular inflammation is more frequent and severe in men, is bilateral in 85 % cases, and may lead to blindness. It can take the form of anterior, posterior, or pan- uveitis, retinal v asculitis, optic neuritis, retinal vein occlusion, or the formation of a hypopyon. Posterio r uveitis carries a particularly poor prognosis. This patient had a history of eye involvem ent and should be regularly screened by slit-lamp examination with aggressive management of eye disease. Approximately 5 % of patients with BD have neurological involvement. The CNS manifestations of BD may be parenchymal (80 % of cases) or vascular. Cerebrovascular disorders include du ral sinus thrombosis, arterial dissection, occlusions, and aneurysms. Peripheral neuropathy is uncommon. Major vessel involvement may be due to inflammation or thrombosis and can involve both vein s and arteries. Large vessel disease is predominantly venous, pre- senting as DVT or superf icial thrombophlebitis. It may involve the superior and inferior vena cava. Budd \200\223Ch iari syndrome is caused by hepatic venous outflow obstruction within the liver or inferior vena cava and should be suspected in patients with BD who develop ascities and hepatospleno megaly. Arterial or aortic rupture is the leading cause of sudden death in patients with BD . The presence of a pulmonary aneurysm in the setting of vasculitis is highly suggestive of BD. However, although major vessels may be involved, most manifestations are due to small- vessel disease. Renal disease is most commonly caused by amyloidosis, but may also be caused by glomerulonephritis or tubulointerstitial nephritis. Arthritis and arthralgia occur in 60 % of patients as non-deforming oligoartic- ular diseas e affecting knees, ankles, and wrists. This is usually transient, lasting <2 months. 226 CASE HISTORIES IN RHEUMATOLOGY 4. What is the disease pathogenesis? BD prevalence and disease manifestations show regional and ethnic differences. BD is most c ommon in Turkey, and its prevalence in the UK is much less at one in 100,000. It is a genet ic disorder in which an environmental trigger, such as infection, is thought to stimulate a utoinflammatory and autoimmune pathways, resulting in a systemic vasculitic and thrombotic disease. The presence of oral ulceration in 70 % of patients with BD has led to the suggest ion that oral microbial flora are implicated in the process. BD is associated with the major histocompatibility complex (MHC) class I anti- gen HLA B510 1 which is expressed in 60 % of patients and increases the susceptibil- ity to ocular disea se. This contrasts with most classical autoimmune disorders which have an MHC class II asso ciation. Mutation of factor V Leiden is a common hereditary abnormality causing hypercoagul ability and is associated with BD. Superficial thrombophlebitis is observed in combination with thrombosis in large veins, and clusters are observed with dural sinus thrombosis. BD shares characteristics with the inherited autoinflammatory disorders (e.g. FMF). These i nvolve the innate arm of the immune system in which recurrent inflammatory attacks occur wi th over-expression of proinflammatory cytokines. Symptoms include recurrent mucocutaneous l esions and non-deforming arthritis, but differ from BD by the presence of characteristic ep isodic fevers and serositis. Onset is usually in childhood. BD also resembles an autoimmune disorder, since it involves increased T- and B-cell respons es to heat-shock proteins, but it does not have the classical features of an autoimmune dis ease such as the presence of autoantibodies, a female prepon- derance, or association with other autoimmune diseases. 5. How should this condition be managed? There have been no large randomized controlled trials of the management of BD. It is charac terized by unpredictable exacerbations and remissions, but the exacer- bations often become less severe and frequent with the passage of time. Therapy is guided by the clinical pictu re, and aggressive immunosuppression is given, where necessary, to limit organ damage. Many patients can be managed symptomatically with mouthwashes and local steroids for oral u lceration and NSAIDs or colchicine for short episodes of arthritis. Corticosteroids, azathi oprine, ciclosporin, interferon, and thalidomide can be used for more severe symptoms. An aggressive approach is taken in treating inflammatory eye disease which may lead to blin dness. Acute episodes are controlled with corticosteroids and cyclo- phosphamide or ciclosp orin. Azathioprine has been shown to reduce or prevent recurrences of inflammatory eye dise ase and preserve visual acuity. Anti-TNF treatments, such as infliximab, have also been sho wn to be effective. Thrombophlebitis is due to active inflammation of the endothelium with result- ant thrombos is which does not embolize. Thus anticoagulation, which increases the risk of pulmonary hem orrhage in cases of pulmonary arteritis with aneurysm, 227 CASE 39 is not necessary in such cases. However, anticoagulation will be required for cases of DVT or cerebral venous sinus thrombosis. Azathioprine is used to treat severe thrombophlebitis. Acute arteritis is treated with pulsed cyclophosphamide and steroids according to standard protocols for vasculitis. Some patients go into complete remission, unlike in other autoimmune diseases. Patients wit h onset before 25 years of age have a poorer prognosis. Mortality and eye disease are incre ased among young males. This patient had intermittent courses of prednisolone and failed tr eatment with azathioprine and infliximab. He had a good response to ciclosporin 3 mg/kg/day but routine monitoring demonstrated a rise in creatinine from 50 to 70 mol/L. Ciclospori n nephrotoxicity is an impor- tant cause of renal failure in patients with BD. Thalidomide 300mg daily was even- tually successful in controlling his disease. Further reading Barnes CG ( 2006 ). Editorial. Treatment of Beh et \200\231s syndrome . Rheumatology ; 45 : 245 \200\223 7 . Direskeneli H ( 2006 ). Autoimmunity vs auto inflammation in Beh et \200\231s. Do we oversimplify a complex disorder? Rheumatology ; 45 : 1461 \200\223 5 . Keogan MT ( 2009 ). Clinical Immunology Review Series: an approach to the patient with recurrent orogenital ulceration, including Beh et \200\231s syndrome . Clin Exp Immunol ; 156 : 1 \200\223 11 . Sfikakis PP , Markomichelakis N , Alpsoy E , et al . ( 2007 ). Anti- TNF therapy in the management of Beh et \200\231s disease \200\224 review and basis for r ecommendations . Rheumatology ; 46 : 736 \200\223 41 . Yazici H , Fresko I , Yurdakul S ( 2007 ). Beh et \200\231s syndrome: disease manifestatio ns, management, and advances in treatment . Nat Clin Pract Rheumatol ; 3 : 148 \200\223 55 . 228 CASE HISTORIES IN RHEUMATOLOGY Case 40 A 21-year-old female Caucasian medical student presented to her GP with new-onset Raynaud \200\231s phenomenon affecting both hands. She described pain and color changes in her left arm when she raised her arms above her head. During her medical student training she had d iscovered that the blood pressure was different when taken in each arm. Otherwise, she was systemically well. On examination, her blood pressure was 180/94 mmHg on the left and 110/6 0 mmHg on the right. There were no palpable pulses at her left wrist. Investigations showed the following: \227\206 Hb 10.2 g/L, MCV 82 fL, platelets 312 \227 10 9 /L, WCC 6.3 \227 10 9 /L \227\206 ESR 18 mm/h, CRP <6 mg/L \227\206 Negative ANA and thrombophilia screen \227\206 MRA revealed occlusion of the left subclavian and proximal axillary arteries (Fig . 40.1 ) \227\206 Urine analysis was normal. A diagnosis of Takayasu \200\231s arteritis (TakA) was made and treatment was commenced. Fig. 40.1 Magnetic resonance arteriogram. 229 CASE 40 Questions 1. What are the similarities and differences between giant cell arteritis (GCA) and Takayasu \200\231s arteritis (TakA)? 2. Describe the course of TakA. 3. What are the treatment options for TakA? 4. Which imaging modalities may be useful in TakA? 230 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What are the similarities and differences between giant cell arteritis (GCA) and Takayasu \200\231s arteritis (TakA)? GCA and TakA are primary large-vessel vasculitides. Inflammation of the large arteries, suc h as the aorta and its major branches, occurs in a number of other disor- ders including Ka wasaki disease, BD, rheumatoid arthritis, syphilis, and tuberculo- sis. GCA almost exclusiv ely affects people over the age of 50 years and the incidence is highest in those who are a ged 75 \200\22385 years. TakA classically affects youing East Asian women, but occurs in bo th genders. The female-to-male ratio declines from East to West. Both GCA and TakA present with signs of systemic inflammation: fever, malaise, myalgia, wei ght loss, and anemia. GCA typically causes vasculitis of the extracra- nial branches of the aorta and spares intracranial vessels. Branches of the external and internal carotid arter ies are particularly susceptible, leading to the classic man- ifestations of headache, scal p tenderness, and jaw claudication. TakA involves the large elastic arteries. Dilation, ane urysms, and thrombosis occur more frequently in TakA than GCA. The histopathology of arterial lesions in both diseases may be indistinguishable, with a pa n-arteritis and mononuclear infiltrates within all layers of the arterial wall. Typically a ctivated T cells and macrophages are arranged in granulomata. The underlying etiology is un known for both diseases but evidence suggests T-cell- mediated autoimmunity. Circulating au toantibodies against aortic endothelial cells, which have been shown to induce aortic endot helial cell apoptosis, have been demonstrated. It is still unclear whether these antibodies are truly pathogenic and occur in a variety of other conditions where vascular inflammatio n is present. 2. Describe the course of TakA TakA has an initial acute inflammatory phase and a chronic healed fibrotic phase with the d evelopment of vascular insufficiency. Clinical features are similarly divided into an early pre-pulseless systemic phase and a late occlusive phase char- acterized by diminished or a bsent pulses. In the early inflammatory phase, patients may show non-specific features of m alaise, low-grade fever, night sweats, weight loss, arthralgia, fatigue, and rashes, includ ing erythema nodosum. Investigations may show a normocytic anemia and elevated inflammatory markers, but there are no specific disease markers. The presentation may overlap with thos e of infection or hematological malignancy, which should be excluded. However, clinical man i- festations may be undetectable, as in this patient who presented with evidence of vessel damage and no history of inflammatory symptoms. Other conditions which may then be conside red include coarctation of the aorta and Marfan \200\231s syndrome, ergotism, and neurofibr omatosis, which have specific features enabling them to be differentiated from TakA. The inflammatory phase may remit spontaneously, but usually progresses insidi- ously to the chronic phase. Vessel inflammation results in fibrosis, stenosis, and 231 CASE 40 thrombus formation, and subsequent symptoms reflect end-organ ischaemia. Patients may notic e easy fatiguability of the upper limbs, pain, and intermittent claudication. Many patients have diminished pulses or no pulses in the arm and blood pressure differences due to subcl avian stenosis. Diminished pulses in the left upper limb are more frequent than on the righ t because of the vascular anatomy. There may be vascular bruits, particularly affecting the carotids and the subclavian and abdominal vessels. Patients with upper-limb vascular invol vement may present as this woman did with Raynaud \200\231s phenomenon, ischaemic pain, and a difference in systolic blood pressure between arms. Patients with carotid artery involve ment may present with neurological disease such as stroke, postural dizziness, seizures, an d amaurosis. Aortic regurgitation results from dilatation of the ascending aorta. Hypertens ion most often reflects renal artery stenosis. Pulmonary vessel involve- ment may cause cou gh, dyspnoea, chest pain, and pulmonary hypertension. 3. What are the treatment options for TakA? Initial treatment of TakA is induction of remission with corticosteroids followed by mainte nance with a steroid-sparing agent to reduce arterial inflammation and prevent complication s of aneurysm and occlusion. High-dose prednisolone, at 1 mg/kg (maximum of 60 mg), is advi sed for the first month and should then be gradually tapered. This improves constitutional symptoms and halts disease pro- gression. Additional immunosuppressive agents should also b e considered, par- ticularly in those who fail to respond clinically initially or flare whe n the steroids are tapered. Preliminary small studies have shown benefit with the use of me th- otrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, and infliximab. Other important management issues include hypertension and the prevention and treatment of thromb osis. Since TakA generally affects women of child-bearing age, management of hypertension i n pregnancy is important. TakA may result in permanent stenosis and the definitive treatment for occlusive disease is surgical. The indications for surgical treatment include: \227\206 hypertension from coarctation of the aorta or renovascular disease \227\206 end-organ or peripheral limb ischaemia \227\206 arterial aneurysm or aortic regurgitation. Surgical techniques include surgical bypass grafting, percutaneous transluminal angioplasty , and vascular stenting, and should be delayed until the acute phase is over to minimize th e risk of procedural complications and re-occlusion. 4. Which imaging modalities may be useful in TakA? A number of imaging modalities are useful for the investigation of patients pre- senting wi th symptoms suggestive of large-vessel vasculitis. These include conven- tional or digital subtraction angiography, MRI and MRA, CT and CT angiography, PET, and high-resolution ultra sound. Imaging is used to assess active inflamma- tion in the vessel wall or structural cha nges. Conventional angiography has been the gold standard investigation of TakA, demonstrat ing vessel involvement such as 232 CASE HISTORIES IN RHEUMATOLOGY luminal irregularity, stenosis, occlusion, and aneurysm formation. However, it does not pro vide information on arterial wall changes and exposes the patient to contrast media and rad ioactivity. Imaging with MRI/MRA avoids these risks and may demonstrate early vessel-wall t hickening, typical of inflammatory lesions. It may be useful in disease monitoring. Ultraso und examination is also non-invasive and is increasingly used to assess large-vessel vascul itis. It is particularly useful for visualization of the common carotid and vertebral arter ies but assessment of deep- er vessels is limited. CT angiography with contrast enhancement demonstrates vessel wall oedema which may be associated with inflammation but has been sho wn to have poor correlation with progression of vascular lesions. It is also limited by the requirement of iodinated contrast and radiation exposure. FDG-PET demonstrates abnormal up take of radioactive glucose in the wall for large vessels ( > 4 mm) and can detect pre-sten otic disease in patients presenting with non-specific features. It results in a significant radiation exposure and is an expensive procedure. It may be very useful in diagnosis but n ot as yet in assessment of disease activity or monitoring. Further reading Andrews J , Mason JC ( 2007 ). Takayasu \200\231s arteritis \200\224 recent advances in im aging offer promise . Rheumatology ; 46 : 6 \200\223 15 . Brunner J , Feldman BM , Tyrrell PN et al . ( 2010 ). Takayasu arteritis in children and adolescents . Rheumatology ; 49 : 1806 \200\223 14 . Johnston SL , Lock RJ , Gompels MM ( 2002 ). Takayasu arteritis: a review . J Clin Pathol ; 55 : 481 \200\223 6 . Maksimowicz-McKinnon K , Clark TM , Hoffman GS (2009). Takayasu art eritis and giant cell arteritis: a spectrum within the same disease? Medicine ; 88 : 221 \200\223 6 . Mukhtyar C , Guillevin L , Cid MC , et al . ( 2009 ). EULAR recommendations for the management of large vessel vasculitis . Ann Rheum Dis ; 68 : 318 \200\223 23 . Weyand CM , Goronzy J ( 2003 ). Medium and large vessel vasculitis . N Eng J Med ; 349 : 16 0 \200\223 9 . 233 CASE 41 Case 41 A 27-year-old female with discoid lupus was referred to the rheumatology clinic with hand p ain. Her pain was associated with episodic attacks of well-demarcated color changes affecti ng both hands, usually on exposure to cold. She had not experienced any digital ulceration but was concerned that her lupus had become more systemic in nature. She smoked 20 cigarett es a day and drank eight cups of coffee a day. She had a past medical history of migraine a nd there was a family history of primary Raynaud \200\231s phenomenon in her aunt. She had recently been prescribed hydroxychloroquine and topical steroid therapy for a rash. Examination of the rash revealed circular erythematous scaly lesions over her chest and proximal arms. Musculoskeletal examination was normal. Investigations showed the following: \227\206 Negative ANA \227\206 Normal FBC, ESR, and complement levels \227\206 Normal urinalysis. Questions 1. What additional bedside test should be performed and what might it show? 2. Which conditions are associated with secondary Raynaud \200\231s phenomenon and how may the clinical presentation differ from primary Raynaud \200\231s? 3. What is known of the pathophysiology of Raynaud \200\231s phenomenon? 4. What are the treatment options for this condition? 234 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What additional bedside test should be performed and what might it show? Nailfold capilloroscopy enables the morphology of the capillaries to be examined in order t o help distinguish between primary and secondary Raynaud \200\231s phenomenon. A drop of im mersion oil is placed on the nailbed and the capillaries are examined using a magnifying le ns. A normal appearance would show uniform morphology and homogenous distribution of the sm all capillary loops beneath the cuticle. In contrast, abnormal capillaroscopy findings show discrete dilated capillary loops and loss of surrounding loop structures. These findings a re usually seen in the context of secondary Raynaud \200\231s phenomenon. 2. Which conditions are associated with a secondary Raynaud \200\231s phenomenon and how ma y the clinical presentation differ from primary Raynaud \200\231s? Ten per cent of healthy people have primary or idiopathic Raynaud \200\231s phenomenon- whi ch occurs in the absence of underlying disease. Secondary Raynaud \200\231s phenomenon (Ray naud \200\231s syndrome) is associated with an underlying disease. The distinguishing featu res are summarized in Table 41.1 . Table 41.1 Characteristics of primary and secondary Raynaud \200\231s phenomenon Characteristic Primary Secondary Age at onset <30 years > 30 years Associated autoimmune disease No Yes Pattern of involvement Symmetrical Asymmetrical Pain with attacks Infrequent Frequent Trophic changes (digital ulceration, fissuring, gangrene) Infrequent More common Nailfold capillaries Normal Abnormal ESR Normal Elevated Autoantibodies Negative or low titres Elevated titres 235 CASE 41 The conditions associated with secondary Raynaud \200\231s phenomenon include the following. \227\206 Rheumatological disorders: systemic sclerosis systemic lupus erythematosus dermatomyositis, polymyositis Sj gren \200\231s syndrome vasculitis. \227\206 Traumatic: vibration injury. Other conditions that may mimic Raynaud \200\231s phenomenon are as follows. \227\206 Vascular occlusive disease: thromboembolic disease arteriosclerosis thoracic outlet syndrome. \227\206 Drug-induced: -adrenergic blockers \227\217 cocaine ciclosporin vinblastine bleomycin cisplatin. \227\206 Hyperviscosity disease: polycythaemia cryoglobulinaemia paraproteinaemia. Overall the features of this case are most consistent with a diagnosis of primary Raynaud \200\231s phenomenon. Although she has a diagnosis of cutaneous lupus, there is no evidence of any systemic complications and the lack of any associated trophic changes makes Raynaud \200\231s disease more likely. Furthermore, the family history and the past history of mig raine and lifestyle habits put the patient at a higher risk of developing primary Raynaud \200\231s phenomenon. 3. What is known of the pathophysiology of Raynaud \200\231s phenomenon? The exact pathophysiology is not fully understood, but the three main mechanisms can be div ided into vascular, neural, and intravascular abnormalities. In primary Raynaud \200\231s phenomenon the vascular abnormalities are likely to be functio nal compared to a combination of defective function and structure in 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