182 CASE HISTORIES IN RHEUMATOLOGY Case 32 A 17-year-old male cricketer presented with a 2-month history of left-sided lower back pain . He was a right-arm fast bowler and had recently been selected to play for his county unde r-18 team. In addition, he played twice a week for his local club. Because of his county co mmitments, he had doubled the amount of overs he bowled per week. Bowling exacerbated the p ain and rest relieved it. The back pain had become more intense since an episode 2 weeks pr eviously when he had bowled at full speed and had developed excruciating lower back pain im mediately afterwards. On examination there was tenderness immediately to the left of the midline of the spine at the level of the L5 vertebrae. His gluteal and hamstring muscles had reduced flexibility. T here was poor muscular control in the lumbar, pelvic, and hip regions, resulting in inadequ ate core stability during activities. Flexion of the spine was full and pain free, but exte nsion exacerbated the pain. Passive rotation to the left while in lum- bar spine extension caused significant discomfort. The MRI scan of the lumbar spine is shown in Fig. 32.1 . Fig. 32.1 MRI scan of the lumbar spine. 183 CASE 32 Questions 1. What does the MRI scan show? 2. Which sports predispose to this condition? 3. What factors have contributed to the development of this condition? 4. How would you manage this patient? 5. How would you prevent a recurrence of his problem? 184 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What does the MRI scan show? The MRI scan shows a stress fracture of the left pars interarticularis of the L5 ver- tebra e (see Fig. 32.1). 2. Which sports predispose to this condition? Sports which involve repetitive extension and rotation of the spine predispose athletes to vertebral stress fracture. Examples include gymnastics, tennis, fast bowling in cricket, hi gh jumping, pole vaulting, and weight-lifting. 3. What factors have contributed to the development of this condition? There are intrinsic and extrinsic risk factors associated with a pars interarticularis stre ss fracture. Extrinsic factors include an increase in workload, for example in the current case an increase in the number of overs bowled per week. Changes in the playing surface or footwear may also contribute. Intrinsic factors include biome- chanical errors in the bowli ng action. Bowling actions can be classified as one of three techniques: front on, side on, or a mixed technique where the lower half of the body is front on and the upper half is si de on during delivery of the ball. It has been postulated that mixed bowling actions may in crease the risk of developing pars interarticularis stress fractures. Other proposed intrin sic factors include poor core stability, gluteal and hamstring muscle inflexibility, and co ngenital defects of the neural arch of the vertebrae. 4. How would you manage this patient? The patient should stop activities that exacerbate his pain. He should not resume extension activities, including bowling, until he can extend without any discom- fort. A core stabil ity strengthening program should be initiated. Furthermore, inflexibility of the gluteal an d hamstring muscles should be addressed via a stretching program. The patient should be adv ised that it could take approximately 4 months to return to sport. 5. How would you prevent a recurrence of his problem? The intrinsic and extrinsic factors that resulted in the injury must be addressed. A multid isciplinary team approach with good communication between the patient, his coach, and the p hysiotherapists is important. He may have to reduce either his club or his county commitmen ts to reduce the number of overs bowled. The England and Wales Cricket Board has strict reg ulations regarding the maximum number of overs that any youth under the age of 19 can bowl per bowling spell and per day. Both he and his club should be advised to adhere to these re gulations. His bowling action should be assessed with his coach and he should continue his core stabil ity strengthening program and the hamstring and gluteal muscle stretching exercises. 185 CASE 32 Further Reading Brukner P, Khan K ( 2006 ). Clinical Sports Medicine ( 3rd edn). Sydney : McGraw-Hill. Engl and and Wales Cricket Board (ECB) ( 2011 ). ECB Fast Bowling Directives . Available at: http://www.ecb.co.uk/ecb/publications/ecb-fast-bowling-directives ,100,BP.html (accessed 6 June 2011) . 186 CASE HISTORIES IN RHEUMATOLOGY Case 33 A 28-year-old female runner presented to the sport and exercise medicine clinic with left a nterior knee pain. She had started regular running 6 weeks previously as she was preparing for the London Marathon that was taking place in 4 months. At presentation, she was running three times a week, up to 5 km at a time. Prior to this she had not engaged in regular phy sical activity. The onset of the knee pain was insidious but had become gradually worse ove r the preceding 4 weeks. The pain was notably worsened on running and she had noted stiffne ss after driving. She had not suffered any injury to the left knee. On examination, she was noted to over-pronate at the subtalar joint of the left foot. She h ad weak hip abductors and reduced flexibility of her hip flexors which was more pronounced on the left side. She had little quadriceps muscle bulk. The inferior patellar facets were tender to palpation. The patellar tendon was non-tender. Joint range of motion was normal a nd pain free. Examination of the knee ligaments and menisci was normal. Hip joint examinati on was normal. 187 CASE 33 Questions 1. What are the main differential diagnoses of anterior knee pain associated with physical activity? 2. What is the diagnosis in this case? 3. What is the underlying pathophysiology of this condition? 4. What factors may contribute to development of this condition? 5. How would you manage this condition? 188 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What are the main differential diagnoses of anterior knee pain associated with physical activity? Anterior knee pain is a common complaint amongst inactive and physically active subjects. T he common causes of anterior knee pain in the physically active are: \227\206 patello-femoral pain syndrome (PFPS) \227\206 patellar tendinopathy \227\206 fat pad impingement \227\206 quadriceps tendinopathy \227\206 Osgood \200\223Schlatter disease and osteochondritis dissecans (young patients) \227\206 referred pain from the hip joint (especially slipped capital femoral epiphysis in younger subjects). 2. What is the diagnosis in this case? The likely diagnosis in this case is PFPS. This is a term used to describe all peripatellar and retropatellar pain in the absence of other pathology. Clinical examination should be s ufficient to exclude other potential causes of anterior knee pain and further investigation s are not necessary. 3. What is the underlying pathophysiology of this condition? The exact cause and origin of PFPS is currently unknown. It is thought that multiple struct ures in and around the knee joint can contribute to the pain. When the knee is at full exte nsion the patellar is lateral to the trochlea of the femur. During knee flexion, the patell a moves medially to lie in the intercondylar notch of the femur. This brings it into contac t with a larger surface area, offsetting the increased load within the patello-femoral join t (PFJ). Dysfunctional movement of the patella during flexion will result in alterations in intra-articular pressure. This may cause pain when combined with increased loading on the PFJ, for example when running or climbing stairs. 4. What factors may contribute to development of this condition? Any factor that increases PFJ load can contribute to the development of PFPS; there are int rinsic and extrinsic factors. Extrinsic factors include increases in training frequency, po or shock-absorbent footwear, and running on hard surfaces. Intrinsic factors relate to subo ptimal patellar movement which include the following: \227\206 Patellar position \227\206 Decreased gluteus medius strength and endurance \227\206 Weak hip flexors 189 CASE 33 \227\206 Inadequate muscle flexibility in the hip flexors, hamstrings, and soleus/gastroc- nemius complex \227\206 Increased subtalar pronation \227\206 Tight lateral structures of the knee \227\206 Delayed onset of vastus medialis obliterans (VMO) muscle contraction com- pared with the vastus lateralis muscle \227\206 Increased knee valgus. 5. How would you manage this condition? PFPS is best treated with an individually tailored program addressing intrinsic and extrins ic factors. Pain can be treated with ice, simple analgesics, and taping of the patella. Ext rinsic factors should be addressed and patients advised to have rela- tive rest from aggrav ating activities and to engage in non-exacerbating exercise such as swimming. Any training errors should be corrected and patients educated regarding footwear and running surfaces. S trength and stretching programs should be developed, guided by the intrinsic factors identi fied. In strengthening programs, particular attention should be paid to VMO muscle, hip abd uctors, and hip external rotator muscles. Hip flexors, hamstrings, and soleus/gastrocne- mi us complex muscle flexibility should be improved. Orthotics may be used in patients who ove r-pronate. The patient should be advised that it may take up to 12 weeks before they see th e benefits of the exercise program. Further reading Crossley K , Cook J , Cowan S , McConnell J ( 2006 ). Anterior knee pain . In: Brukner P, K han K (eds). Clinical Sports Medicine ( 3rd edn). Sydney : McGraw-Hill ; pp. 506 \200\223 37 . Fagan V , Delahunt E ( 2008 ). Patellofemoral pain syndrome: a review on the associated neu romuscular deficits and current treatment options . Br J Sports Med ; 42 : 789 \200\223 95 . 190 CASE HISTORIES IN RHEUMATOLOGY Case 34 A 72-year-old man had been under the care of the rheumatology department for 3 years with a polyarthritis involving his hands, knees, and ankles. The hands had been especially uncomf ortable across the wrists and MCPs. The blood tests had been normal apart from an elevated CRP of 25 \200\22330 mg/L . A diagnosis of RA had been made, although the RF and ACPA tests were negative, X-rays did not demonstrate erosions, and there was no family history of RA or autoimmunity. The past medical history included chronic bronchitis, probably smoking-related, although he had stopped smoking 18 years previously. Medications included simvas- tatin for elevated c holesterol and low-dose aspirin. His RA was treated with sulfasala- zine 2 g daily for 2.5 years . At his routine follow-up appointment he was noted to have a red left eye. He also described pain on the pinnae of both ears such that he had difficulty sleeping on his side. Examinat ion revealed that the pinnae were swollen, red, and tender. The ear lobes were normal. An o phthalmology assessment confirmed scleritis in the left eye. The rest of the ocular examina tion was normal. At this point, the ESR was 55 mm/h and the CRP was 48 mg/L. The diagnosis was revised, the sulfasalazine was discontinued, and he was com- menced on 40 mg of prednisolone, to which there was a prompt positive response in all the clinical and laboratory parameters. 191 CASE 34 Questions 1. What is the diagnosis and why? 2. What is the pathophysiology of this condition? 3. What clinical features might occur in patients with this diagnosis? 4. What is the treatment? 5. What is the prognosis? 192 CASE HISTORIES IN RHEUMATOLOGY Answers 1. What is the diagnosis and why? The diagnosis is chronic relapsing polychondritis (RP). This is a rare chronic disorder of cartilage characterized by recurrent episodes of inflammation involving carti- laginous str uctures, predominantly those of the ears, nose, and laryngotracheo- bronchial tree. Other a ffected structures include the eyes, cardiovascular system, peripheral joints, skin, middle and inner ear, and CNS. RP may occur at any age, however, the disease usually has an onset during the fifth decade of life. There is no gender difference, but it is probably more co mmon in Caucasians (few data exist). 2. What is the pathophysiology of this condition? The etiology is unknown. Evidence for an autoimmune pathogenesis includes the presence of i nfiltrating T cells, antigen \200\223antibody complexes in affected cartilage, cellular and humoral responses against collagen type II and other collagen anti- gens, and the observat ion that immunosuppressive regimens usually suppress the disease. The level of antibodies t o type II collagen present during the acute episodes correlates with the severity of the ep isode. Treatment with prednisolone is associ- ated with a decrease in antibody titre. An au toimmune etiology is further sup- ported by the high prevalence of other autoimmune disorde rs found in these patients: 25 \200\22335 % of patients have a concurrent autoimmune diseas e, and the asso- ciations include thyroid disease, vasculitis, RA, SLE, Sj gren \200\231s syndrome, and IBD. Familial clustering has not been observed. Susceptibility for developing RP is increased slightly by the HLA-DR4 haplotype. Several reports have linked relapsing RP with malignancy. It is thought to be paraneoplasti c in these cases, most often hematological, but solid tumors have been described. 3. What clinical features might occur in patients with this diagnosis? As in this case, the non-specific and episodic nature of RP may result in delay in diagnosi s. General signs and symptoms of constitutional upset with fever and weight loss are common . Diagnostic criteria for RP were first proposed by McAdam and colleagues and have been mod ified several times. The criteria are as follows (three of the six clinical features are necessary for diagnosis): \227\206 bilateral auricular chondritis \227\206 non-erosive seronegative inflammatory polyarthritis \227\206 nasal chondritis \227\206 ocular inflammation \227\206 respiratory tract chondritis \227\206 audiovestibular damage. 193 CASE 34 Auricular chondritis occurs in 85 \200\22395 % and maybe unilateral or bilateral, sparing t he lobules. \227\206 The ear cartilage softens and collapses forwards. The external auditory canal can collapse after one or more episodes. \227\206 Nodularity of the auricle may develop. \227\206 Calcification occurs in 40 % of patients. The arthritis is non-erosive and seronegative, and is a polyarthritis in 52 \200\22385 % of patients. The acute onset of an inflamed joint may mimic a crystal arthropathy. Nasal chondritis occurs in 48 \200\22372 % of patients and the classical saddle-nose deformity may develop in long-standing disease. Ocular sequelae occur in 50 \200\22365 % and are related to the episodic inflammation of the uveal tract, conjunctivae, sclerae, and/or corneas. \227\206 The most common conditions are episcleritis (39 % ) and scleritis (14 % ). \227\206 Eyelid oedema, iritis, and retinopathy are found in 9 % of patients, and 5 % have ocular muscle paresis or optic neuritis. \227\206 Ulcerative keratis is found in 4 % of patients and has been associated with perfo ra- tion and endophthalmitis. Respiratory tract involvement affects 40 \200\22356 % of patients. Tenderness to palpation may occur over the anterior trachea or thyroid cartilage. Chondritis weakens the tracheal c artilage rings, resulting in wheezing, dyspnoea, cough, and hoarseness. The upper airways c an become stenosed and replaced by collapsible fibrotic tissue. Airways superior to the tho racic inlet collapse upon inspiration, and airways below the thoracic inlet collapse upon e xpiration, therefore both inspiratory stridor and expiratory wheezing may be noted. Inflamm ation and swelling of the glottis, lar- ynx, and subglottic tissues may require tracheostom y. Acute inflammation of the distal airways can lead to obstruction and recurrent pneumonia . Audiovestibular derangements occur in 46 \200\22350 % of patients. Sudden loss of hear- ing is usually permanent, but tinnitus, nausea, vomiting, and vertigo may subside. In some pat ients, hearing loss is attributed to vasculitic damage to cranial nerve VIII. Other systems that may be involved include the following: \227\206 Cardiovascular Affects 24 % of patients. Aortic and mitral valve regurgitation, aortic aneurysm, aortitis, aortic throm- bosis, peri carditis, first- to third-degree heart block, and myocardial infarc- tion due to ostial ste nosis of a coronary artery or arteries have been reported. \227\206 Skin Skin lesions are found in 17 \200\22339 % of patients. Specific lesions are limited to erythema and oedema overlying the inflamed cartilaginous structures. Other non-specific skin lesions have been reported including Sweet \200\231s syndrome, aphthous ulcers, urticarial vasculitis, and panniculitis. 194 CASE HISTORIES IN RHEUMATOLOGY MAGIC syndrome \200\224 mouth and genital ulcers with inflamed cartilage. This is characterized by an overlap of RP with BD. \227\206 Central nervous system CNS manifestations are rare and related to a small- and/or medium-vessel vasculitis. \227\206 Renal 22 % of patients have evidence of glomerulonephritis based on renal biopsy or the presence of microhaematuria and proteinuria. Patients with renal damage are older and more likely to have extra-renal vas- culitis and arthritis. The biopsy findings include segmental necrotizing glomerulonephritis with or without cresce nts, interstitial lymphocytic infiltrates, interstitial fibrosis, active tubulitis, and glo merulosclerosis. 4. What is the treatment? No controlled trials of therapy for RP have been published. The aim of treatment is to reli eve symptoms and preserve the integrity of cartilaginous structures. Steroids are the mainstay of treatment. Prednisolone (20 \200\22360 mg/day) is admin- ister ed in the acute phase and is tapered for maintenance. Severe flares may require 80 \200\223 100 mg/day. Most patients require a low daily dose of steroid for maintenance. However, int ermittent administration of high doses only during flares of the con- dition can be success ful. Other medications reported to control symptoms and delay progression of the disease include dapsone (25 \200\223200 mg/day), azathioprine, methotrexate, cyclophos- phamide, and ciclo sporin. Leflunomide has also been used with some success. There are case reports describing successful treatment with the TNF- inhibitors infliximab, etanercept, and adalimumab. A nakinra, an interleukin 1 receptor antagonist, and rituximab have also shown benefit. NSAID s are not effective. Medical care must include assessment for and treatment of other autoimmune disorders. As RP is a complex multisystem condition it requires a team approach to manage- ment includ ing dermatologists, ophthalmologists, cardiologists, neurologists, and plastic surgeons. Su rgical care may include tracheostomy, permanent tracheostomy placement, tracheal stent plac ement, aortic aneurysm repair, cardiac valve replace- ment, and saddle-nose deformity repai r. 5. What is the prognosis? A survival rate of 94 % at 8 years has been reported, but this may be shorter if there is a ssociated systemic vasculitis. The most frequent causes of death are infection secondary to corticosteroid treatment or re spiratory compromise (10 \200\22350 % of deaths result from airway com- plications), system ic vasculitis, and malignancy unrelated to RP. 195 CASE 34 Although the life expectancy in all patients with RP is decreased compared with age- and se x-matched healthy individuals, patients with renal involvement have a significantly lower a ge-adjusted life expectancy. Complications of RP such as saddle nose, systemic vasculitis, laryngotracheo- bronchial str icture, arthritis, and anemia in patients younger than 51 years por- tend a poorer prognosi s than in age-matched patients with RP without complications. Among patients older than 50 years, only anemia is associated with a poorer prognosis. Renal involvement is a poor progn ostic factor at all ages. Further reading Letko E , Zafirakis P , Baltatzis S , Voudouri A , Livir-Rallatos C , Foster CS ( 2002 ). R elapsing polychondritis: a clinical review . Semin Arthritis Rheum ; 31 : 384 \200\223 95 . McAdam LP , O \200\231Hanlan MA , Bluestone R , Pearson CM ( 1976 ). Relapsing polychondrit is: prospective study of 23 patients and a review of the literature . Medicine (Baltimore) ; 55 : 193 \200\223 215. Priori R , Conti F , Pittoni V , Valesini G ( 1997 ). Relapsing polychondritis: a syndrome rather than a distinct clinical entity? Clin Exp Rheumatol ; 15 : 334 \200\223 5 . Trentham DE , Le CH ( 1998 ). Relapsing polychondritis . Ann Intern Med ; 129 : 114 \200 \223 22. 196 CASE HISTORIES IN RHEUMATOLOGY Case 35 A 29-year-old man was referred to the rheumatology outpatient department with a 2-month his tory of cramps and muscular aching in his arms and thighs. He was nor- mally healthy, apart from hay fever in the summer. He worked as a forklift-truck driver in a warehouse. He had no significant family history, apart from non-insulin-dependent diabetes in his father, and his only travel in the preceding 5 years had been to Europe. He exercised regularly and ha d run a marathon 3 months previously. Following the marathon, he recalled having an upper r espiratory infection and cough which had settled completely with a 7-day course of amoxicil lin. On direct questioning, he denied rash or Raynaud \200\231s phenomenon. Clinical examination revealed slight tenderness of the arms and thighs. The tissue felt tau t, tethered, and oedematous. His face, neck, and torso were normal. Nailfolds were normal. Respiratory examination, muscle power, and neurological examination were normal. Investigations showed the following: \227\206 Hb 14.6 g/L; WBC 5.8 \227 109/L; eosinophil count 1.2 \227 10 9 /L; platelets 3 35 \227 10 9 /L \227\206 ESR 45 mm/h; CRP 16.3 mg/L \227\206 Biochemistry normal \227\206 CPK 321 IU/mL \227\206 Thyroid function normal. 197 CASE 35 Questions 1. Give a differential diagnosis for this man \200\231s symptoms. 2. What radiological investigations may be helpful? 3. What single test would be required to secure the diagnosis? 4. What treatment modalities may be useful? 5. What is the prognosis? 198 CASE HISTORIES IN RHEUMATOLOGY Answers 1. Give a differential diagnosis for this man \200\231s symptoms Potential causes of skin tethering in this case include: \227\206 scleroderma \227\206 overlap connective tissue disease with features of scleroderma \227\206 scleredema \227\206 eosinophilic fasciitis (EF) \227\206 eosinophilia \200\223myalgia syndrome. The absence of Raynaud \200\231s phenomenon is an important negative finding and would be a gainst the diagnosis of scleroderma or a connective tissue disease. Furthermore, the normal nailfolds and a normal facial appearance without any skin tightening are against a diagnos is of scleroderma. An autoantibody profile may be helpful in diagnosing an autoimmune disea se, but if it were negative, it would not exclude the diagnosis . Occasionally there can be muscle pains and a brawny oedema of the soft tissues in the early stages of dermatomyositis. The normal muscle power and muscle enzymes would be against thi s diagnosis in this case. Viral or autoimmune polymy- ositis (see Case 29) may also present with muscle pains. The raised CRP suggests tissue injury, and therefore other mechanical o r non-specific causes of aching such as fibromyalgia (see Case 27) are unlikely. Scleredema is characterized by a woody non-pitting induration of the skin with mild erythem a. Although regarded as a benign self-limiting skin disease, sclerede- ma may be persistent and involve the viscera. A skin biopsy will demonstrate increased collagen in affected sit es. Involvement of the skin over the joints may cause limited range of motion. Scleredema o n the face can result in difficulty in opening the eyes and the mouth. Although rare, exten sive truncal involvement may cause restrictive lung disease. Unlike scleroderma, the tongue may be involved in scleredema, resulting in dysarthria and difficulty with mastication and tongue protrusion. The absence of oesophageal involvement distinguishes scleredema from sc leroderma. Cardiac involvement is rare in scleredema but may result in cardiomyopathy. Fift y per cent of scleredema cases occur in individuals younger than 20 years of age. Scleredem a can be categorized into three clinical subgroups. Each has a different history, course, a nd prognosis. \227\206 Group 1, scleredema adultorum, includes scleredema after acute respiratory infect ion. Patients have a history of a preceding febrile illness, particularly an upper respirat ory tract streptococcal infection. The onset of the skin lesions is rapid, and the conditio n usually clears spontaneously in 6 months to 2 years. The duration is not affected by the use of antibiotics. The term scleredema adul- torum is considered by some to be a misnomer because most pediatric patients fall into this group. The patient described in this case ma y fit this picture in view of his history of respiratory illness. However, he did not have the typical pattern 199 CASE 35 of skin involvement: there was no torso involvement and the skin induration was more distal than proximal. A skin and fascial biopsy would be helpful. \227\206 Group 2 includes scleredema patients whose disease occurs insidiously with no pre ceding illness. This group is associated with a monoclonal gammopathy and myeloma. \227\206 Group 3, scleredema diabeticorum, is scleredema associated with diabetes melli- t us and includes patients with pre-existing diabetes, which is typically adult in onset and insulin dependent. This disorder tends to occur more often in males, and this subgroup of p atients typically experience a more protracted course that is refractory to therapy. As in group 2, the onset of skin lesions is insidious. The upper back typically demonstrates eryt hema and induration, and a pebbled appearance may develop. EF is a rare localized fibrosing disorder of the fascia described by Shulman in 1974. The e tiology and pathophysiology are unclear. Current understanding of the dis- ease relies on a few case series and multiple case reports. Fascial thickening in the setting of eosinophil ia, elevated ESR, and hypergammaglobulinaemia are key ele- ments of the syndrome (Fig. 35.1 ). Visceral involvement is generally absent. However, an association with several hematolo gical diseases is recognized and it frequently carries a poor prognosis. A number of possib le triggers have been report- ed. There is a preceding history of vigorous exercise or trau ma in 30 \200\22350 % of patients. Multiple drugs have also been implicated, including simv astatin, atorvasta- tin, and phenytoin. Several cases have been associated with positive Bo rrelia serology. Fig. 35.1 (See also Plate 15) Fascial sclerosis with lymphocytic, plasma cell, and eosinoph ilic infiltration. (Reproduced from Servy A et al . (2010) Patholog Res Int ; 2011 Amand ine Servy et al .) 200 CASE HISTORIES IN RHEUMATOLOGY Eosinophilia \200\223myalgia syndrome and toxic oil syndrome are two disorders that share c ommon clinical and histopathological features with EF, including periph- eral eosinophilia. In contrast with EF, these two conditions present in epidemic form and appear to be almost universally toxin-associated, as in the case of the Spanish toxic oil syndrome in 1981. 2. What radiological investigations may be helpful? MRI is the imaging modality of choice and shows characteristic findings of fascial thickeni ng, abnormal signal intensity, and contrast enhancement. MRI may aid in diagnosis, locating a biopsy site, and monitoring the response to treatment. Although ultrasonography has not been used frequently or studied in EF, one case report has shown that it can aid early diag nosis. 3. What single test would be required to secure the diagnosis? The diagnosis is that of eosinphilic fasciitis. The definitive diagnosis requires a full- t hickness incisional skin biopsy. The specimen should include the skin, fat, fascia, and sup erficial muscle in continuity. Biopsy is especially important in an atypical presentation. The hallmarks of EF are inflammation, oedema, thickening, and sclerosis of the fascia. In t he acute phase, lymphocytes, plasma cells, histiocytes, and eosinophils infiltrate deep fas cia and an adjacent subcutis layer. Distribution of the eosinophils in the fascia may be fo cal, and a close relationship appears to exist between blood and tissue eosinophilia. In th e deeper portions of the panniculus, a similar infiltrate is found in the fibrous septa and at the periphery of the fat lobules. Deep in the fascia, the inflammatory infiltrate can e xtend into the epimysium, perimysium, and endomysium. In addition, vascular cuffing with ly mphocytes and plasma cells is often seen. As the disease progresses, the inflammatory changes are replaced by generalized sclerosis a nd thickening of the fascia and adjacent tissue layers. In situ hybridization with specific cDNA demonstrates that lesional fibroblasts produce excess collagen and display elevated T GF- . Therefore the pathogenesis appears to involve the concomitant increase in the expr ession of genes for TGF- and extracellular matrix proteins in fibroblasts in the affecte d tissues. 4. What treatment modalities may be useful? When considering medical therapies for EF, especially second-line agents, it should be born e in mind that up to a third of cases may resolve spontaneously. Systemic corticosteroids are the initial therapeutic agent of choice. Prednisolone is typic ally used in doses ranging from 20 to 100 mg/day. Response is considered satisfactory with reduction in oedema, improvement in skin thickening, resolution of carpal tunnel syndrome ( which may also be a feature), and a gradual decrease in joint contracture. Eosinophilia and inflammatory markers frequently resolve promptly after initiation of steroid therapy. 201 CASE 35 Disease-modifying or steroid-sparing agents may be useful in persistent or ster- oid-resist ant cases. Treatment numbers are small, and controlled trials are lacking. Case reports det ail the use of multiple additional agents including antihistamines, cimetidine, hydroxychlo roquine, azathioprine, ciclosporin, dapsone, tacrolimus, methotrexate, griseofulvin, ketoti fen, and interferon- , with varying rates of response. Recent data suggest that anti-TNF - agents may also be beneficial. Physical therapy should be initiated to improve joint mobility and to decrease contractures . Surgical release has been used in some cases to manage significant joint contractures. 5. What is the prognosis? The loss of oedema is usually the first clinical sign of improvement and can occur within 4 weeks of commencing treatment. The skin becomes softer, but it can take 3 \200\2236 months before maximum reduction in induration and contractures is achieved. A degree of induratio n can remain even after many months of corticosteroid therapy. There is not a good correlat ion between clinical disease activity and laboratory find- ings. The eosinophilia and CRP u sually return to reference ranges within 4 \200\2238 weeks, although the ESR and hypergamma globulinaemia may remain abnormal for up to 12 weeks. 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.