A recent retrospective review found that clinical factors associated with persistent fibros is included the presence of morphea-like skin lesions, younger age at onset, truncal involv ement, and presence of dermal fibrosclerosis on histopathological specimens. The developmen t of aplastic anemia is a rare and serious complication. Further reading Lakhanpal S , Ginsburg WW , Michet CJ , Doyle JA , Moore SB ( 1988 ). Eosinophilic fasciiti s: clinical spectrum and therapeutic response in 52 cases . Semin Arthritis Rheum ; 17 : 221 \200\223 31 . Servy A , Cl rici T , Malines C , Le Parc JM , C t JF ( 2011 ). Eosinophilic fasciitis: a rare skin sclerosis . Patholog Res Int ; 716935. 202 CASE HISTORIES IN RHEUMATOLOGY Case 36 A 71-year-old woman presented to the rheumatology clinic with a painful ulcer of the right lower leg. She reported worsening fatigue over the previous 6 months and had lost about hal f a stone in weight over this time. She was known to have RF-positive rheumatoid arthritis, diagnosed 40 years previously. Her disease had been difficult to control and she had under gone multiple joint replacements and spinal stabilization. She had had leg ulcers in the pa st but was concerned that this ulcer was not healing, was intensely painful, and often bled . On examination, there was a large circumferential ulcer on the medial aspect of the right l ower leg, extending upwards from the ankle (Fig. 36.1 ). The ulcer was oozing blood. Fig. 36.1 (See also Plate 16) Circumferential leg ulcer. 203 CASE 36 Investigations showed the following: \227\206 Hb 9.5 g/L; WCC 6.59 \227 10 9 /L (neutrophils 4.81, lymphocytes 0.92); platelet s 231 \227 10 9 /L; MCV 83.8 fL \227\206 Sodium 139 mmol/L; potassium 4.1 mmol/L \227\206 Urea 9.3 mmol/L; creatinine 84 mol/L \227\206 CRP 54 g/L; ESR 46 mm/h . Questions \200\224Part 1 1. What are the possible causes of leg ulcers in patients with RA? 2. What is the approach to management of RA leg ulcers? 204 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What are the possible causes of leg ulcers in patients with RA? Patients with RA are predisposed to the development of chronic leg ulcers, the etiology of which is commonly multifactorial. Venous insufficiency, vasculitis, and impaired arterial c irculation are the most common precipitating factors. Pyoderma gangrenosum is a rarer cause ; local malignant change and infection are reasons why there might be a delay in healing. Systemic rheumatoid vasculitis often presents as a cutaneous vasculitis with enlarging leg ulcers. Vasculitic ulcers are characteristically deep and painful, and are typically found in the areas of the medial and lateral malleoli. They are caused by a necrotizing vasculiti s of medium-sized arteries which is histologically similar to that seen in PAN. Venous ulcers commonly occur on the medial side of the leg. They are often associated with varicose eczema and local oedema. The surrounding skin is thick- ened with hyperkeratosis a nd there may be progression to chronic lipodermato- sclerosis. In contrast to vasculitic ul cers, venous ulcers are relatively painless unless infected. Venous ulceration is due to ch ronic venous insufficiency and is largely a downstream effect of venous hypertension. Risk factors include varicose veins, deep vein thrombosis, previous trauma or surgery, advanced age, and immobility. In addition, chronic glucocorticoid use in RA patients further promote s ulceration by increasing skin fragility. Arterial ulcers are usually found on the feet, particularly at pressure points such as the heel and toes. The ulcers appear \200\230punched out \200\231 with a well-defined border, and are characteristically painful. The patient will usually have other features of arteria l insufficiency including pale cool feet and leg pain on exertion or elevation. Arterial ul cers occur as a result of arterial insufficiency caused by atherosclerosis of the lower-lim b arteries. Patients will have an impaired ankle \200\223brachial pressure index (ABPI) on clinical assessment. In pyoderma gangrenosum, lesions often progress quickly and may start at the site of a mino r tissue injury, often first appearing as a small red papule or nodule. Breakdown of the sk in then results in the formation of painful ulcers. Classically, they have a well-defined b order and are violet or blue in color. As the lesions enlarge, the edge may be undermined a nd the surrounding skin can become indu- rated. Several ulcers may occur at the same time. In the case history described, the painful non-healing ulcer in a patient with long-standin g seropositive RA raises the possibility of underlying rheumatoid vasculitis. The additiona l constitutional symptoms of fatigue and weight loss are typical. Rheumatoid vasculitis usu ally occurs in long-standing RA after the inflammatory arthritis has subsided and patients are left with widespread joint destruction. Patients are usually positive for rheumatoid fa ctor and have rheuma- toid nodules. The onset of vasculitis is usually associated with cons titutional symptoms. However, symptoms such as fatigue, myalgia, and weight loss are non- s pecific and may be difficult to interpret in these debilitated patients. 205 CASE 36 2. What is the approach to management of RA leg ulcers? If there is no clinical evidence for a systemic vasculitis, ulcers should be managed in the same way as for any other patient with a leg ulcer. This may include moist saline dressing s to help debride layers of slough from granulation tissue. In patients with exudative ulce rs, occlusive hydrocolloid dressings are helpful. If there is no arterial insufficiency, co mpression bandages or stockings can help alleviate swell- ing due to venous stasis. If an u lcer fails to respond to these conservative measures, underlying rheumatoid vasculitis shou ld be considered. Since treatment involves aggressive immunosuppression, the diagnosis is b est first confirmed by biopsy of the lesion. Questions \200\224Part 2 3. What different types of rheumatoid vasculitis occur? 4. What are the principles of treatment of rheumatoid vasculitis? 5. Discuss the role of cyclophosphamide therapy for rheumatoid vasculitis. 206 CASE HISTORIES IN RHEUMATOLOGY Answers 3. What different types of rheumatoid vasculitis occur? Rheumatoid vasculitis affects a range of blood vessel types. These include medium- sized mu scular arteries, arterioles, and venules. Like other forms of systemic vasculitis, there is destructive inflammation of the vessel wall, which leads to vessel occlusion, tissue ischa emia, and necrosis. Many of the serious clinical manifesta- tions are caused by a medium-si zed vasculitis. However, sequelae of small-vessel involvement (e.g. purpura and petechiae) also occur. Rheumatoid vasculitis can affect several organs, with skin, peripheral nerves, eyes, and he art most commonly involved. Deep cutaneous vasculitis is the most common and can also cause digital ischaemia and gangrene. Peripheral nerve involvement is the result of a vasculitic neuropathy character- ized by in flammation of the vasa nervorum which results in infarction of periph- eral nerve fibers. D epending on the distribution of the inflammatory process, both mononeuritis multiplex and d istal sensory or sensorimotor neuropathy can occur. Vasculitic neuropathy is typically rapi d in onset and usually manifests as anaesthe- sia. If treated promptly, most patients have a gradual, although partial, return of nerve function. Ocular manifestations of rheumatoid vasculitis include scleritis and peripheral ulcerative keratitis (PUK). While anterior scleritis is readily diagnosed on clinical examination, pos terior scleritis is more subtle, and the symptoms of visual blurring and ocular tenderness are important clues. Both forms of scleritis are intensely painful. PUK is characterized by the development of ulceration near the corneo- scleral junction. Patients with PUK may dev elop the \200\230corneal melt \200\231 syndrome, caused by corneal keratolysis and subsequ ent perforation of the globe. This is a devastating complication as patients often abruptly lose vision in the affected eye. Pericarditis is usually the earliest presentation of the cardiac manifestations of rheumatoid vasculitis. Arrhythmias can also occur, although it is often difficult to attribute these directly to vasculitis as patients often have other rel evant comor- bidities. Acute coronary syndromes resulting directly from coronary arteritis are unusual. 4. What are the principles of treatment of rheumatoid vasculitis? Treatment should be guided by the type and severity of the organ damage. Systemic rheumatoid vasculitis requires aggressive immunosuppressive therapy, and therefore it is important to consider comorbidity. Treatment regimens usually start with a combinati on of high-dose glucocorticoids and cyclophosphamide, and parallel those used in primary sy stemic vasculitis. Glucocorticoids are accepted as playing an important role in achieving e arly disease remission, despite a lack of robust trial data. Pulsed methylprednisolone is u sed initially and patients can be switched to oral prednisolone after a few days. Maintenan ce therapy includes azathioprine and/or methotrexate. 207 CASE 36 Treatment is guided by monitoring clinical response as well as inflammatory markers (CRP, E SR) and markers of organ function (e.g. urea, creatinine). Treatment is continued until dis ease remission is achieved. 5. Discuss the role of cyclophosphamide therapy for rheumatoid vasculitis Cyclophosphamide is an established treatment of primary systemic vasculitides such as WG (s ee Case 23). Although no controlled trials have directly assessed the role of cyclophospham ide in the treatment of rheumatoid vasculitis, it is accepted as a first-line treatment. Of note, a small case series of rheumatoid vasculitis patients reported disease remission in all patients following daily oral cyclophosphamide therapy. If cyclophosphamide cannot be used, azathioprine is an appropriate alternative with cortico steroids. Methotrexate has also been used, although there is limited evidence for its effic acy in rheumatoid vasculitis. The role of TNF inhibitors in rheumatoid vasculitis is not es tablished. Case reports suggest positive outcomes, although it should be noted that randomi zed trials have shown no evidence for TNF inhibitors in WG or GCA. Further reading Heurkens AH , Westedt ML , Breedveld FC ( 1991 ). Prednisolone plus azathioprine treatment in patients with rheumatoid arthritis complicated by vasculitis . Arch Intern Med ; 151 : 2 249 \200\22354. Oien RF , Hakansson A , Hansen BU ( 2001 ). Leg ulcers in patients with rheumatoid arthriti s \200\224 a prospective study of etiology, wound healing and pain reduction after pinch g rafting . Rheumatology ; 40 : 816 \200\223 20. 208 CASE HISTORIES IN RHEUMATOLOGY Case 37 A 55-year-old woman with a history of seropositive erosive RA for 7 years attended the \200\230flare \200\231 clinic with a 1-day history of an acutely swollen, red, and painful right wrist, associated with increased fatigue and fever. She had been on weekly etanercept 50 mg for the previous year. In clinic 2 weeks previously, her joints were not inflamed an d the DAS28 was 3.0. Her medical history included a recent diagnosis of hypertension, for which bend- roflumethiazide had been prescribed. In clinic her temperature was 37.5 C. Examination of the right wrist revealed a hot tend er swollen erythematous joint. Movement of the joint was restricted due to pain. Investigations showed the following: \227\206 Hb 11.5 g/dL; MCV 84 fL; WCC 11.1 \227 109/L; neutrophils 9.0 \227 109/L; plate lets 320 \227 109/L \227\206 Sodium 135 mmol/L; potassium 3.0 mmol/L \227\206 Urea 11 mmol/L; creatinine 120 mol/L \227\206 LFTs normal \227\206 CRP 54 mg/L. Three milliliters of turbid synovial fluid was aspirated from the joint and sent to the lab oratory for analysis. The initial microscopy showed the following: \227\206 WCC 60 000 L; 80 % polymorphonuclear leucocytes \227\206 No organisms seen \227\206 No crystals seen. 209 CASE 37 Questions 1. What is the differential diagnosis, based on history and examination? 2. Apart from joint aspiration, what other investigations might be useful? 3. What is the most common causative agent responsible for this patient \200\231s diagnosis ? 4. How would you manage this patient? 5. What are the management strategies for patients who are on biological therapy? 210 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the differential diagnosis, based on history and examination? Septic arthritis This is essential to consider in any patient presenting with an acute monoarthritis, but especially in patients with inflammatory joint disease on immun osuppressant treatment. The acuteness of the presentation with associated fever should sugg est this as the most likely diagnosis. A normal joint has several defense mechanisms which protect it from infection. Synovial flu id itself has bactericidal activity, and normal synovial cells have phago- cytic activity. The inflammatory process that occurs in RA decreases these protective factors. Furthermore, already damaged synovium of patients with RA exhibits neo- vascularization and increased a dhesion factors, which both increase susceptibility to bacteraemia. Patients with RA may have a blunted response to infection \200\224 for example, no fever a nd a more insidious onset. Also, they can commonly present with a polyar- ticular distribut ion which can easily be mistaken for a flare. Such patients would be gravely ill. RA flare The acuteness and monoarticular presentation, in the context of a recent recording of relatively quiescent disease, make this less likely. Crystal arthropathy Gout or pseudo-gout may be considered, given the history of the thiazid e diuretic and the mild degree of renal impairment. Her gender and the absence of a previou s history of crystal arthropathy make it a less likely diagnosis than septic arthritis. How ever, polarized light microscopy on joint fluid analysis should be requested even in cases of suspected septic joints. Other causes Other less likely causes of an acute monoarthrosis to consider include trauma and a reactive arthritis. 2. Apart from joint aspiration, what other investigations might be useful? Microbiology Blood cultures are positive in \210 50 \200\22370 % of patie nts with septic arthritis. Consider addition of synovial fluid AFB testing and mycobacteriu m culture in any patient with a chronically infected joint and with immunosuppressant risk factors, such as anti-TNF therapy and HIV. 211 CASE 37 Plain X-ray of wrist Plain X-rays are not useful in diagnosis of septic arthritis, but can be of benefit in recording baseline findings especially in a patient with RA. They also may show chondrocalcinosis or any evidence of trauma. Early plain radiograph findings of septic joints may demonstrate soft tissue swelling and w idened joint space due to a joint effusion. Progression of sepsis usually leads to articula r cartilage destruction, seen initially as the loss of visualization of the white cortical line of the joint surface, followed by poorly defined marginal erosions and joint-space nar rowing. In more chronic cases superimposed osteo- myelitis, seen as a periosteal reaction, and bone destruction may develop. Other imaging Ultrasound scanning is of limited value as a diagnostic tool in patients with sus- pected septic joints. However, it is a sensitive tool for detecting joint effusions a nd thereby facilitating guided-needle aspiration for synovial fluid. This is useful in smal ler joints where direct aspiration may be difficult. MRI is a sensitive tool which is increasingly used in the evaluation and manage- ment of se ptic joints. The presence of a joint effusion, synovial enhancement, and perisynovial soft tissue oedema is closely correlated with diagnosis of a septic joint. These findings are us ually evident within 24 hours of onset of infection. Bone mar- row signal changes can indic ate associated osteomyelitis, the presence of which may guide surgical intervention as well as duration of antibiotic therapy. Other investigations A serum urate level is usually of little value in a patient with acute gout. 3. What is the most common causative agent responsible for this patient \200\231s diagnosis? Staphyloccocus aureus , streptococci, and Neisseria gonorrhea are bacteria with a high affi nity for synovium because of their specific adherence factors and toxin- related mechanisms . Organisms most commonly invade the joint via haematoge- nous spread, as well as via direc t inoculation and contiguous spread from periarticular infected tissue. Staphylococcus aureus accounts for more than 80 % of cases of septic arthritis in patients with RA. It also causes the vast majority of cases of bacterial arthritis in non-RA adults and children above the age of 2 years. S.aureus has a variety of tissue adhesion receptors, termed microbial surface components recognizing adhesive matrix molecules (MSCRAMM). These mediate adherence to extracellular joint components, for example fibronectin, elastin, and hyaluronic acid. Invasion of the joint by S.aureus is followed by release of chondrocyte p roteases by the organism. This, combined with the cytokine synthesis from the host \200\231 s polymorphonuclear leucocytes, results in rapid cartilage degradation. Irreversible subcho ndral bone loss can occur within days. 212 CASE HISTORIES IN RHEUMATOLOGY S.aureus is also the most common organism implicated in prosthetic joint infec- tions. MSCR AMMS are implicated in the adherence of the bacteria to implanted medical devices such as p rosthetic joints. Prosthetic joint infections are associated with a high morbidity. The pathogenesis of prost hesis infections is related to the development of biofilms. Biofilm formation is particular ly associated with S.aureus , coagulase-negative staphylococci, and Pseudomonas aeruginosa. Having adhered to the surface of the prosthesis, the bacteria cluster together. Because of a lack of metabolic substances and an accumulation of waste products, the organisms enter a slow-growing state. This results in significant resistance to growth-dependent antimicrob ial agents. Furthermore, the synthesis of a polymeric matrix of saccharides, or glycocalyx, protects the bacteria from the host \200\231s defenses and antimicrobial therapy. This exp lains the indolent nature of prosthetic infections and the difficulties in eradicating the infection. Prosthetic joint infections can be classified according to the route of infection and accor ding to onset of symptoms after infection. Routes of infection include perioperative direct contamination, haematogenous seeding from a distant focus of infection, and contiguous see ding from an adjacent focus of infection. Early prosthetic infections (i.e. within 3 months ) are usually acquired during surgery and are associated with virulent organisms such as S. aureus . Delayed infections, occur- ring before 24 months, are also usually due to inoculat ion at the time of surgery but in association with less virulent organisms, such as coagula se-negative staphylococci. Late infection after 24 months is most frequently caused by haem atogenous seeding. The next most common organisms associated with septic arthritis are strepto- cocci, particu larly group A -haemolytic streptococci and Streptococcus pneumoniae . Septic arthritis c aused by Gram-negative bacteria is more common in the very young, the elderly, the immunosu ppressed, and intravenous drug abusers. Patients with HIV have a higher prevalence of joint infections than the normal population. Opportunistic organisms, such as mycobacteria and f ungi, are more commonly implicated in this subset of patients. Gonococcal arthritis needs to be in the differential diagnosis for younger sexually active individuals. The synovial fluid Gram stain and culture in gonococcal arthritis is less like ly to be positive. N.gonorrhea tends to cause less of a polymorphonuclear leucocyte respons e, thereby in part explaining the relatively smaller amount of joint destruction seen with this organism when compared with staphylococcal infection. 4. How would you manage this patient? Management is multidisciplinary, including microbiology and orthopedic advice. Empirical antibiotic therapy should be commenced before the results of synovial fluid Gram stain or culture are available if there is a high index of suspicion of septic arthritis. L ocal policy and guidelines will influence choice of antibiotic. The current BSR recommendat ions for empirical therapy are as follows. 213 CASE 37 \227\206 No risk factors for atypical organisms: intravenous flucloxacillin 2 g four times daily or intravenous clindamycin if penicillin allergic. \227\206 High risk of Gram negative sepsis: second- or third-generation cephalosporin (i.e. cefuroxime or ceftriaxone). \227\206 Suspected gonococcus: intravenous ceftriaxone. The choice of antibiotic should be adjusted depending on synovial fluid culture and organis m sensitivity. The microbiology team should be involved in decision- making. Antibiotics are usually given intravenously for up to 2 weeks, and then orally for 4 weeks. However, this may vary depending on the response to therapy. Local hospital services may a llow insertion of PICC lines and treatment on an outpatient basis via a home IV team or equ ivalent. The infected joint should ideally be drained to dryness, either via closed-needle approach or arthroscopically. The orthopedic team should be involved early on, especially f or hip or prosthetic joint sepsis. There has been much debate in previous years about the benefits versus the risks of intra-a rticular steroid injections in patients with septic arthritis. Evidence from animal models suggests that the use of corticosteroids in addition to antibiotics could improve outcomes. One study in humans has also shown some benefit. A double-blind randomized placebo-control led trial in 123 children compared intravenous dexamethasone and antibiotics with antibioti cs alone. The addition of steroid reduced the duration and extent of joint damage. The theory behind steroid use is based on the fact that bacterial antigens pro- mote cytoki ne proliferation and activate chondrocyte proteases. Despite antibiotic treatment, inflamma tion may persist and intra-articular corticosteroid may limit this inflammatory damage. How ever, there is concern that steroid, especially early on, may mask the signs of infection a nd delay diagnosis. 5. What are the management strategies for patients who are on biological therapy? Biological therapy should be stopped when there is infection. Unfortunately, there is curre ntly little guidance and evidence on when biological therapy should be restarted after such an event. BSR guidelines on anti-TNF prescribing state that joint sepsis within the previous 12 month s is a contraindication to commencing biological therapy. This may be indefinite for an inf ected prosthetic joint, especially if the prosthesis is to be left in situ . This is based on clinical opinion, rather than strong trial evidence. Data from the UK National Biologics register suggest that patients on anti-TNF are twice as likely to develop septic arthritis as those on DMARDS alone. The risk of septic arthritis is greatest in the first year of therapy, peaking at around 10 months. 214 CASE HISTORIES IN RHEUMATOLOGY Staphylococci are the most common organisms; Listeria and Salmonella were reported in the g roup treated with anti-TNF agents. Native and prosthetic joints were equally at risk in bio logically treated patients. In clinical practice the risks of anti-TNF therapy may need to be balanced with treating un controlled RA. In challenging situations the decision regarding restarting biological thera py earlier should involve discussing risks and benefits with the patient, as well as seekin g opinion from microbiology and other experts. Further reading Coakley G , Mathews C , Field M , et al . ( 2006 ). BSR & BHPR, BOA, RCGP and BSAC guidelin es for management of the hot swollen joint in adults . Rheumatology ; 45 : 1039 \200\223 41 . Galloway JB ( 2010 ). Risk of Septic Arthritis in Patients with Rheumatoid Arthritis Treate d with Anti-TNF therapy : Results from the BSR Biologics Register . Available online at: ht tps://www. rheumatology.org.uk/includes/documents/cm_docs/2010/o/op49_hall08a_thu_1400_ gal loway.pdf . Goldberg D ( 1998 ). Septic arthritis . Lancet ; 351 : 197 \200\223 202 . Lane S , Merry P ( 1999 ). Intra-articular corticosteroids in septic arthritis: beneficial or barmy ? Ann Rheum Dis ; 58 : 142 \200\223 7 . Ledingham J , Deighton C ( 2005 ). Update on the British Society for Rheumatology guideline s for prescribing TNF blockers in adults with rheumatoid arthritis . Rheumatology ; 45 : 15 7 \200\223 63 . Odio CM , Ramirez T , Arias G , et al . ( 2003 ). Double blind, randomized , placebo controlled study of dexamethasone therapy for haematogenous septic arthritis in c hildren . Pediatr Infect Dis J ; 22 : 883 \200\223 8 . Sakiniene E , Bremell T , Tarkowski A ( 1996 ). Addition of corticosteroids to antibiotic t reatment ameliorates the course of experimental Staphylococcus aureus arthritis . Arthritis Rheum ; 39 : 1596 \200\223 1605 . Shirtliff ME , Mader JT ( 2002 ). Acute septic arthritis . Clin Microbiol Rev ; 15 : 527 \200\223 44 . 215 CASE 38 Case 38 A 69-year-old woman with a 15-year history of seropositive rheumatoid arthritis (RA) presen ted with increasing neck pain and arm weakness. Over the preceding 9 months, she had experi enced bilateral numbness and paraesthesia in her hands, suggestive of bilateral carpal tunn el syndrome. She denied lower-limb weakness or bowel or bladder disturbance. Her RA was tre ated with methotrexate and certolizumab, a pegylated anti-TNF- monoclonal antibody. She had previously used many DMARDs, including hydroxychloroquine, sulfasalazine, gold, and cic losporin, which had been ineffective in controlling her disease. In the past, she had under gone arthroplasty of her left shoulder, left knee, right hip, and bilateral forefoot. Examination of her limbs revealed normal power and reflexes. Her plantar reflexes were not interpretable because of the previous forefoot surgery. Perineal sensation was intact. The CT cervical spine and MRI spine of her neck are shown in Figs 38.1 and 38.2 . Subluxed C1 Spinal canal Vertebral body (C3) Fig. 38.1 CT scan of cervical spine. 216 CASE HISTORIES IN RHEUMATOLOGY Fig. 38.2 MRI scan of neck. 217 CASE 38 Questions 1. Describe the radiographic findings. What abnormalities are indicated by the arrows? 2. What is the diagnosis? 3. What other spinal complications may occur in rheumatoid arthritis? 4. What conservative measures may be useful for rheumatoid neck disease? 5. What are the indications for neck surgery and what complications may occur? 218 CASE HISTORIES IN RHEUMATOLOGY Answers 1. Describe the radiographic findings. What abnormalities are indicated by the arrows? Figure 38.1 demonstrates almost complete erosion of the odontoid peg with bony fragments be hind the anterior arch of C1. There is severe posterolateral subluxation of C1 on C2 with n o significant spinal canal narrowing. There is marked degenerative change at C4/5 and C6/7. The MRI confirms the odontoid peg erosion and subluxation at C0/1 and C1/2. CT is the best modality to visualize bone and alignment abnormalities in the cervical spine as it can detect disc disease, fractures, tumors, infection, and stenosis. MRI is used for evaluation of the spinal cord and neural components. It can detect subtle c hanges in bone, and is superior to CT in the evaluation of herniated disks, spinal stenosis , abscesses, osteomyelitis, tumors, or other masses near the spinal cord. MRI can demonstra te the presence of pannus (hyperplastic rheuma- toid synovium) and its erosive effects on a rticular cartilage and local bone, as well as its resolution following immunosuppressant th erapy. The relationship of the odontoid peg to the brainstem and oedematous changes in the cord can be evalu- ated. Further advantages of MRI are the absence of ionizing radiation an d the infrequent need for intravenous contrast (gadolinium), the latter being much less all ergenic than the iodinated contrast medium used in CT scanning. The main indications for MRI imaging in rheumatoid cervical spine disease are: \227\206 abnormal measurements of C1 to C2 on plain radiographs \227\206 intractable suboccipital or cervical pain \227\206 progressive or severe subluxation \227\206 symptoms of cord compression \227\206 vertebral artery compression. 2. What is the diagnosis? The diagnosis is a cervical myelopathy secondary to erosion of the odontoid peg and transve rse band of the cruciform ligament causing atlanto-axial instability and subluxation. In rh eumatoid cervical spine disease, synovitis with pannus formation leads to erosion of ligame nts, bones, and synovial joints (Fig. 38.3 ). Posterior move- ment of the odontoid peg may impinge on the upper cervical cord, particularly during neck flexion, with neurological seq uelae. The rupture of the transverse ligament, and then the alar and apical ligaments, comb ined with erosion of the atlanto-axial (C1 \200\2232) joint leads to anterior atlanto-axial subluxation (AAS). The usual symptoms of odontoid peg erosion are severe neck pain, pain or par- aesthesia of the arms, limb weakness, sensory changes in the lower limbs, gait dif- ficulties (spastic g ait), and neck instability. In some patients, the first presentation is unexplained falls. The onset is often insidious and the symptoms are non-specific; therefore it is important t o maintain a high index of suspicion for cervical spine involvement in rheumatoid patients. 219 CASE 38 Atlanto-axial subluxation of 2.5 mm or more Vertical subluxation Disc space narrowing affecting upper cervical disks without osteophytosis Multiple subluxation of 1 mm or more Vertebral plate erosions and sclerosis Apophyseal joint erosions and sclerosis Osteoporosis Fig. 38.3 Radiographic criteria for rheumatoid arthritis of the cervical spine. Reproduced from Winfield J, Cooke D, Brook A.S, Corbett M (1981). A prospective study of the radiologi cal changes in the cervical spine in early rheumatoid disease. Ann Rheum Dis , 40 ; 109 \200\223114 with permission from BMJ Publishing Group Ltd. RA patients undergoing general anesthesia need careful pre-operative assess- ment and vigil ant perioperative care to avoid cervical hyperextension and cervical cord injury during int ubation. Patients with damage at the occipito-cervical (O \200\223C1) and C1 \200\2232 joints may pr esent with high neck pain or occipital neuralgia, myelopathy, hydrocephalus, and rarely sud den death. The neurological sequelae can develop from a direct com- pressive effect on the spinal cord or from ischaemia. Compression of the spinal cord and eventually the brainstem can result from subluxation of the spine or from direct pressure by a synovial pannus. 3. What other spinal complications may occur in rheumatoid arthritis? The spinal complications of RA can be subdivided as follows: \227\206 cervical instability \227\206 thoracolumbar vertebral abnormalities \227\206 vertebral osteoporotic crush fracture. Cervical instability The most common patterns of cervical instability are: \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.