A heliotrope hue to upper eyelids evolves. A mild eruption on the face follows, typically e xtending down the nasolabial folds. An erythematous or violacious maculopapular eruption ap pears over the extensor surfaces of the PIP joints, elbows, and knees. The erythematous pla ques over the PIPJs (Gottren \200\231s papules) can atrophy. Nail cuticles become erythemat ous owing to periungual vasculitis (the nail-fold capillary vessels show thickening, tortuo sity, dropout, and thrombosis seen under the microscope). Muscles and joints \200 Epidemiology A survey in the UK in 1995 suggested an incidence of 1.9 per million children below the age of 16 years. In the USA, between 1995 and 1998, data suggested an incidence o f 3.2 per million children below 17 years. There does not seem to be an ethnic difference. Mean age of onset was 6.8 years in the UK survey with 5:1 girls to boys. One characteristic suggestive sign of muscle weakness is dif \201 culty with prolonged ele vation of the head whilst supine. An inability to do an unassisted sit up and Gower \200 \231s sign (an inability to rise from the \202 oor without using the hands to \200\230cl imb up \200\231 the legs) are reliable signs of truncal and proximal leg muscle weakness, r espectively. Dysphagia (palatal muscle weakness) is common with more severe presentations a nd a nasal speech pattern may develop. These children are at risk of aspiration pneumonia. Etiology and pathogenesis Genetic \200 HLA-DQA1*0501 is associated with JIIM in several ethnic groups. CHAPTER 8 Autoimmune connective tissue diseases 299 Weakness of respiratory muscles and impaired ability to increases the risk of aspiration pn eumonia. About 60% of JDM patients have in \202 ammatory arthritis, two-thirds having an o ligoarticular pattern of arthritis and a third, polyarticular. Many children have a \202 itting or migratory arthralgia. In insidious onset disease, joint contractures can develop and need to be discriminated from any limitation of joint movement owing to arthritis. Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), and both physic ian and patient global assessments of disease and skin activity. Most tools are available a t the NIH website (see Resources below). \200 Measurement of height, weight, and pubertal status should be done regularly. The CMAS asses ses function, as well as muscle strength, and is validated for use in children with JIIMs t o serially measure the child \200\231s proximal muscle power. Nail-fold capillaries should be examined for infarcts. Contractures, arthritis, and calcinosis assessed. Serial MR scans of proximal muscle may be helpful in assessing ongoing in \202 ammation in the absence of other markers of activity. \200 \200 \200 Other \200 Co-existent \201 brosing alveolitis may be under-diagnosed. Chest auscultation and simple spirometry should be undertaken. Visceral vasculitis occurs in a minority of children, wit h abdominal pain, GI bleeding, and perforation. Dystrophic calcification occurs in about 40 %, often within 6 months of onset of the disease. Calcinosis is seen as super \201 cial pl aques or nodules, or as deep tumorous deposits in muscle or in the inter-muscular fascial p lane. Subcutaneous calcinosis can erupt sometimes discharging in ulcerated skin lesions. It may occur during the healing phase of the disease. Lipodystrophy \200\223 generalized or partial loss of subcutaneous fat; occurs in a minority of children. Treatment Objectives of treatment Induction of remission of the inflammatory disease, preve ntion of loss of muscle bulk and strength, controlling skin disease, and minimizing the sid e effects of immunosup- pression long-term. Ensuring adequate growth and devel- opment, mai ntaining progress at school, and social development through the input of a multidisciplinar y care team is of obvious importance. Physical therapies Dedicated pediatric physiotherapy is a key component of retaining muscle strength once the in \202 ammatory muscle disease is controlled on medication. Investigations Laboratory \200 Immunosuppression \200 Creatine kinase (CK) may be raised, although this is not essential to make the diagnosis. I ts detection depends on at what stage of the disease it is measured. LDH, ALT, and AST are enzymes derived from both liver and muscle. GGT \200\223 a specific liver enzyme \200\223 is not elevated in myositis. ESR is not a good marker of muscle in \202 ammation and is of ten normal even in active disease. ANA is not always positive but anti-tRNA antibodies have been described (e.g. Jo-1). Von Willebrand factor, a marker of endothelial cell activa- ti on, may be useful for monitoring vasculitic complications. High dose glucocorticoids (GCs) are given (prednisolone 2 mg/kg/day in 3 divided doses) for about 6 weeks. Dose is tapered slowly depending on response. If there is a poor response t o oral GCs, or in the presence of dysphagia, dysphonia, pulmonary disease or gastrointestin al vasculitis, pulse intravenous methylpred- nisolone is given. Children need to remain rep lete in vitamin-D (de \201 ciency may evolve as children will be advised to avoid exposure of skin to the sun because of the photosensitive skin rash). Secondary hyperparathyroidism should be avoided by remaining vitamin-D replete and keeping dietary calcium intake adequa te. If DXA scanning suggests very low Z scores where fragility fractures have also occurred , then a bisphospho- nate needs to be considered to protect against GC- induced osteoporosi s. Immunosuppression, with methotrexate (MTX) 15 mg/ m2 by subcutaneous injection, is often introduced early as a \200\230steroid-sparing \200\231 strategy, despite limited publishe d evidence for its effect. Cyclophosphamide, IVIG, azathioprine and ciclosporin have been u sed for GC and MTX resistant disease, or where there is intolerance to MTX. There is notabl e trial activity in this area (see IMACS and PRINTO). Anti-TNFA is being used increasingly for persistent disease and in one notable series, infliximab has shown to be effective in r efractory JDM (see Riley et al., 2008). Rituximab (anti-CD20) trials in JDM are being under - taken under the auspices of the International Myositis Assessment and Clinical Studies (I MACS) group. Topical tacrolimus may be useful adjunctive treatment for the JDM rash. Imaging \200 Mild myositis as demonstrated by MR scanning (using fat-suppressed T2-weighted sequences) m ay be present without elevation of muscle enzymes. A CXR and pulmonary function testing wit h a check of transfer factor and then if necessary HRCT chest should be done if there is re spiratory compromise. Discriminating thoracic muscle weakness from intrinsic lung disease a s a cause of dyspnoea is key. Differential diagnoses \200 The presence of Raynaud \200\231s phenomenon should raise the suspicion of mixed connective tissue disease (MCTD) or SLE as alternative diagnoses. Post-infectious myositis (in \202 uenza A&B, cocksackie B) causes a raised CK, but usually lasts just 3 \200\2235 days. Metab olic myopathies and in \202 ammatory myositis accom- panying other autoimmune connective t issue diseases - such as Systemic Sclerosis (SSc) \200\223 need to be considered. Disease activity assessment Commonly used and validated tools for assessing disease activit y are the Childhood Health Assessment Questionnaire (CHAQ), Manual Muscle Testing (MMT), Ch ildhood Myositis JUVENILE DERMATOMYOSITIS 300 Patient advice The JDM rash is photosensitive. It is critical to advise children and their parents that the child needs to protect the skin from the sun: wear UVA/UVB sunblock on are as affected by the rash, but also other exposed surfaces, and wear a hat with a brim or at least a peaked cap. Physician information Pediatric Rheumatology International Trials Organization (PRINTO). In formation about current and previous studies in JDM. Available at: www.printo.it Internatio nal Myositis Assessment and Clinical Studies (IMACS) group studies (see, for example, www.e dc.gsph. pitt.edu/rimstudy/referphys.html) Natural history and prognosis The disease has a high mortality if left untreated (from hist orical accounts before glucocorticoid use). \200 Most children are ill for a number of ye ars. \200 A cohort of 65 patients were followed up over a median of 7.2 years (Huber, 200 0): 37% had a monocyclic course, going into permanent remission after about 2 years of acti vity and 63% had a continuous or polycyclic course. A signi \201 cant minority had signi \201 cant growth impairment. The duration of JDM and severity from calcinosis may associate with TNFA genotype allelic variation. ICD10 codes M33.0 Juvenile dermatomyositis References Compeyrot-lacassagne S, Feldman BM. In \202 ammatory Myopathies in Children. Rheum Dis Clin N Am 2007; 33: 525 \200\22353. Bohan A, Peter JB. Polymyositis and dermatomyositis (part 1 of 2). N Eng J Med 1975; 292: 34 \200\2237. Brown VE, Pilkington CA, Feldman BM, Davidson JE. An interna- tional consensus survey of th e diagnostic criteria for juvenile dermatomyositis (JDM). Rheumatology (Oxford) 2006; 45: 9 90 \200\2233. Huber AM, Lachenbruch PA, et al. Alternative scoring of the cutane- ous asses sment tool in juvenile dermatomyositis: results using abbreviated formats. Arthritis Care R es 2008; 59: 352 \200\2236. Resources Assessment tools Health assessment tool (CHAQ) score is found on the BSPAR websit e (www.bspar.org.uk;) or from www.niehs. nih.gov/research/resources/collab/imacs/ diseaseac tivity.cfm, where other assessment tools can be found. The (abbreviated) Cutaneous Assessme nt Tool. See Huber et al., 2008. Muscle strength testing: Manual Muscle Test (MMT). Avail- able at: www.niehs.nih.gov/research/resources/ collab/imacs/diseaseactivity.cfm; Myositis D isease Activity Assessment Tool; see also www. niehs.nih.gov/ Huber AM, Lang B, LeBlanc CMA, et al. Medium and long term func- tional outcomes in a multi center cohort of children with juvenile dermatomyositis. Arthritis Rheum 2000; 43: 541 \200 \2239. Riley P, McCann LJ, et al. Effectiveness of In \202 iximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Rheumatology 2008; 47: 877 \200\22380. See also Dermatomyositis (adults), see p. 290 Idiopathic juvenile osteoporosis; see p. 35 Patient information The Myositis Association. Available at: www.myositis.org Myositis Suppo rt Group (UK). Available at: www.myositis. org.uk/r Arthritis Research Campaign. Various re sources, but see www.arc.org.uk/news/arthritistoday/123_4.asp This page intentionally left blank INCLUSION BODY MYOSITIS 302 Inclusion body myositis De \201 nition Sporadic inclusion body myositis (IBM), \201 rst described in 1967, is ch aracterized by both in \202 ammation and abnormal accumulation of proteins within muscle f orming distinctive inclusions. It was originally considered a variant of polymyo- sitis but is now recognized as a clinically and pathologically distinct entity within the group of i diopathic in \202 ammatory myopathies. Debate is ongoing as to whether IBM arises as a pri mary immune-mediated disease or whether muscle in \202 ammation occurs secondary to degene rative processes. Etiology and pathophysiology Genetic factors \200 \200 HLA-DR3 is present in 75% of cases. Other alleles within the autoimmune 8.1 HLA ancestral h aplotype (HLA-A1, B8, DRB3*0101, DRB1*0301, DQB1*0201) are also associated. Familial forms of IBM are seen but are extremely rare. Environment It has been speculated that viruses may trigger in \202 ammation in IBM. IBM, like PM, may develop in the presence of HIV and HTLV-1 infection. It is noteworthy that the clonally activated CD8+ T cells in these patients are retrovirus speci \201 c. Diagnostic criteria The diagnostic criteria of Griggs (see Griggs et al., 1995, and Griggs et al., 2006) are widely accepted: Clinical features \200 \200 \200 Pathogenesis The etiology of IBM is unknown. It is likely that ageing and environmental fac tors play a contributory role in genetically predisposed individuals. \200 Duration of illness >6 months. Age at onset >30 years. Slowly progressive muscle weakness a ffecting arms and legs. May have a selective pattern and be asymmetrical. Patients must hav e at least one of: \200 \200 \200 IBM is characterized by both in \202 ammation and muscle degeneration; however, it is uncl ear which of these is the primary pathological process. An immune basis for IBM is favored by the substantial overlap of pathological features with polymyositis. Both involve ubiquit ous expression of HLA class I antigens on muscle \201 bres, which are surrounded and inva ded by CD8+ cytotoxic T cells. Subsets of these autoinvasive CD8+ T-cells are clonally expa nded, presumably in response to speci \201 c antigens expressed by myo \201 bres. However , a key-differentiating feature of IBM is the formation of vacuoles and abnormal accumulati on of amyloid-like proteins within muscle \201 bres. These degen- erative changes have si milarities to those seen in Alzheimer \200\231s disease and analogous disease mechanisms ha ve been suggested, with abnormal protein processing as a primary pathogenic event. This cou ld potentially mediate cell damage by triggering the endoplasmic stress response, which add itionally induces up-regulation of MHC-1 expression and thus may perpetuate muscle in \202 ammation (see PM for further explanation of these pathological processes). \201 nger \202 exor weakness; wrist \202 exor > wrist extensor weakness; quadriceps m uscle weakness. Laboratory features \200 Creatine kinase (CK) < \22712 the upper limit of the refer- ence interval. EMG \200\223 my opathic or mixed pattern. May be both short and long duration motor unit potentials. Muscle biopsy \200 In \202 ammatory myopathy characterized by: \200 endomysial mononuclear cell in \201 ltrate and invasion of non-necrotic muscle \201 bres (predominantly by CD8 positive [CD8+] T cells); myo \201 bre necrosis and regeneration; H LA class I expression in otherwise morphologically healthy muscle \201 bres. Vacuolated m uscle \201 bres. Either: \200 \200 \200 intracellular (within muscle \201 bres) ubiquitin-positive inclusions and amyloid deposit s; nuclear and/or cytoplasmic 15 \200\22320 nm tubulo \201 lamentous inclusions on electro n microscopy. Clinical features Key features in history \200 Presentation is usually after the age of 50 years, although symptoms may develop from the a ge of 30 years onwards. Insidious onset of muscle weakness over >6 months. Mean time from s ymptom onset to diagnosis is 6 years. Weakness involves both proximal and distal muscles, m ay be asymmetrical and is usually painless. Frequent falls are a common presenting feature as a result of the predilection for quadriceps involvement. Loss of manual dexterity. The \201 nger \202 exors are affected early, particularly \202 exor digitorum profundus an d \202 exor pollicis longus. Patients complain of dif \201 culty manipulating small item s, e.g. a pen or keys, and problems grasping and lifting. Dysphagia occurs in up to 60% of patients, but is rarely a presenting symptom. Dyspnoea \200\223 respiratory muscle weaknes s can develop. De \201 nite IBM: All diagnostic biopsy features present. No other clinical or laboratory features are mandatory. \200 \200 Probable IBM Characteristic clinical and laboratory features, but incomplete biopsy criteri a. Epidemiology IBM is the most common in \202 ammatory myopathy in people aged over 50 years old. It is more common in northern European, white North American and Australian popula- t ions. Prevalence estimates vary from 4.9 to 10.7 per million in these areas. However, the t rue frequency is probably higher as IBM has traditionally been under recognized and misdiag nosed as polymyositis or other diseases. In contrast to polymyositis (PM) and dermatomyosit is (DM), there is a male predominance in IBM. CHAPTER 8 Autoimmune connective tissue diseases 303 Other features include cytochrome oxidase negative \201 bres and ragged red \201 bres d ue to abnormal mitochon- dria. Muscle biopsy \201 ndings in early IBM are sometimes indis - tinguishable from those seen in PM. Key features on examination \200 Look for selective atrophy of quadriceps and forearm \202 exors \200\223 muscle wasting may be prominent. Neck \202 exors may be affected in more advanced disease. A weak grip m ay be detectable on shaking hands. Might be unable to stand from sitting unaided. Facial we akness is quite common (in contrast with PM). Extra-ocular muscles are spared. Re \202 exe s may be absent if muscle atrophy is severe. Muscle power in proximal and distal groups sho uld be graded against resistance using the MRC scale (see IMACS website for guidance on man ual muscle testing). \200 \200 \200 \200 \200 \200 Other Electromyography (EMG) Findings may be similar to the other in \202 ammatory myopa- thies and are therefore not diagnostic. EMG typically dem- onstrates increased spontaneous activity in conjunction with myopathic features manifest as low-amplitude, short duration p otentials on voluntary activation. However, long duration potentials may co-exist in some p atients with IBM, potentially leading to confusion with neurogenic disorders such as motor neuron disease. Co-morbidities IBM may occasionally associate with autoimmune connective tissue diseases, b ut less commonly than PM/DM. Treatment Objectives of treatment \200 \200 \200 Differential diagnosis The differential is wide (see PM pp. 285 \200\223286 or differential diagnosis of progressive muscle weakness). Conditions more likely to be confused with IBM include: \200 \200 \200 Improve muscle strength. Maintain swallowing, prevent aspiration pneumonia. Preserve mobili ty, function, and quality of life. Polymyositis (PM). Motor neuron disease: look for fasciculations. Hereditary vacuolar myopa thies, e.g. myo \201 brillar myopa- thies, hereditary inclusion body myopathy. Muscular dy strophies: ask about family history Physical therapies \200 Exercise programs have been shown to improve muscle strength and function. Creatine supplem ents may be helpful. Knee-locking braces and ankle-foot orthoses may help to prevent falls. Strategies to treat dysphagia include cricopharygngeal myotomy, bougie dilatation, and bot ulinum toxin. \200 Key points Features favoring a diagnosis of IBM over PM \200 More gradual onset of weakness, over months to years, rather than weeks to months. Age of o nset over 50 years and male sex. Early involvement of quadriceps, but also distal muscles, particularly \201 nger \202 exors. Asymmetrical muscle weakness. Normal or only mildly elevated CK. Absence of autoantibodies. Failure to respond to steroids and other immunosup- pressants. Immunosuppressive therapies There are no established effective treatments for IBM; therefor e, therapy is empirical and varies between centers. \200 Despite the evidence for an ongo ing in \202 ammatory process in IBM, trials of glucocorticoids, and other immunosup- press ants have been disappointing. In view of the limited therapeutic options, many advocate an initial trial of prednisolone plus another immunosup- pressive agent for 3 \200\2236 months . Methotrexate, azathioprine, mycophenolate, ciclosporin, cyclophosphamide, and others have been trialed but with limited success. \200 \200 \200 \200 Investigations Laboratory \200 Glucocorticoids (GCs) Most patients derive no bene \201 t from treatment with GCs. Stabili zation of symptoms has been reported in some cases, although this is seldom maintained and may simply re \202 ect the natural history of the disease. Interestingly, although GCs red uce muscle in \202 ammation, the degenerative changes and muscle weakness continue to prog ress. CK can be normal or moderately elevated, usually less than 10 times the upper limit of norm al. Autoantibodies, including myositis-speci \201 c autoantibodies, are found in IBM. Howe ver, they are not a characteristic feature, and are more commonly associated with PM or DM. Imaging MR imaging may demonstrate the characteristic selective involvement of quadriceps a nd forearm \202 exors. Early muscle in \202 ammation may be detectable before clinically signi \201 cant weakness develops. Intravenous immunoglobulin (IVIG) In 3 double-blind studies of IVIG, improvements in muscle strength overall were minimal and not sustained. However, IVIG may be considered on an ind ividual case basis as it may be helpful in some patients. IVIG has been used successfully t o treat dysphagia. Histology Muscle biopsy is essential for de \201 nitive diagnosis of IBM. \200 Antithymocyte globulin A 12-month randomized, open trial in 10 patients showed promising re sults. Quadriceps is the best site to sample unless atrophy is very severe. Characteristically the re is a triad of histological \201 ndings: in \202 ammatory in \201 ltrates, rimmed vac uoles, and abnormal protein accumulation, evident as amyloid deposits and \201 lamentous inclusions (see diagnostic criteria). Other Interferon-B and etanercept have proved relatively ineffec- tive in clinical trials. A trial of the T-cell depleting antibody alemtuzumab is ongoing. INCLUSION BODY MYOSITIS 304 Surgery Tendon transfers to maintain pincer grip are worth consid- ering, e.g. extensor car pi radialis to replace atrophied \202 exor tendons. ICD-10 codes M60.8 Other myositis See also Polymyositis Dermatomyositis Metabolic myopathies The nervous system p. 282 p. 290 p. 522 p. 90 Prognosis IBM typically follows a gradually progressive course with slow, inexorable declin e in muscle function. However, up to 50% of patients experience 3 \200\2236-month periods o f tempo- rary stabilization of symptoms making response to thera- peutic trials dif \201 c ult to interpret. The majority of patients require a wheelchair by 10 years from symptom on set. More rapid functional decline may be seen in older people. References Cherin P, Pelletier S, Teixeira A, Laforet P, Simon A, Herson S, et al. Intraven ous immunoglobulin for dysphagia of inclusion body myositis. Neurology 2002; 58: 326. Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K. Treatment of inclusion-b ody myositis with IVIg: a double-blind, placebo-controlled study. Neurology 1997; 48: 712 \200\22316. Resources Assessment tools MITAX myositis intention to treat index MYOACT myositis disease activity assessment myositis damage index MDI SF-36 short form 36 Studies to validate these tools in IBM are ongoing Dalakas MC. Sporadic inclusion body myositis diagnosis, pathogenesis and therapeutic strat egies. Nat Clin Pract Neurol 2006; 2(8): 437 \200\22347. Griggs RC, Askanas V, DiMauro S, Engel A, Karpati G, Mendell JR et al. Inclusion body myosi tis and myopathies. Ann Neurol 1995; 38: 705 \200\22313. Griggs RC. The current status of treatment for inclusion-body Guidelines There are no current therapeutic guidelines for sIBM. myositis. Neurology 2006; 66(2 Suppl 1): S30 \200\2232. Lindberg C, Trysberg E, Tarkowski A, Oldfors A. Anti-T-lymphocyte globulin treatment in inc lusion body myositis: a randomized pilot study. Neurology 2003; 61: 260 \200\2232. Patient organizations The Myositis Support Group (UK). Available at: www. myositis.org.uk T he Myositis Association (US). Available at: www. myositis.org Needham M, Mastaglia FL. Inclusion body myositis: current patho- genetic concepts and diagn ostic and therapeutic approaches. Lancet Neurol 2007; 6: 620 \200\22331. Tawil R, Griggs RC. Inclusion body myositis. Curr Opin Rheumatol 2002; 14: 653 \200\2237. Internet sites International Myositis Assessment and Clinical Studies Group (IMACS) for man ual muscle testing guidelines, grad- ing scheme and score chart and details of tools for as sess- ing disease activity, damage and patient reported outcomes in myositis. Available at: www.niehs.nih.gov/research/ resources/collab/imacs/main.cfm Walter MC, Lochmuller H, Toepfer M, Schlotter B, Reilich P, Schroder M, et al. High-dose im munoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlle d study. J Neurol 2000; 247: 22 \200\2238. This page intentionally left blank UNDIFFERENTIATED (AUTOIMMUNE) CONNECTIVE TISSUE DISEASE 306 Undifferentiated (autoimmune) connective tissue disease \200 \200 \200 \200 \200 \200 De \201 nition People with undifferentiated autoimmune connective tissue disease (UAICTD/U CTD) have features suggestive of autoimmune disease, but do not ful \201 l any individual classi \201 cation criteria. A minority of patients subsequently develop a more de \201 n ed condition [e.g. rheumatoid arthritis (RA), systemic lupus erythematous (SLE), Sj gren \200\231s syndrome]; however, stable UCTD should be considered a distinct clinical entity. RA. Systemic sclerosis. Primary biliary sclerosis. MCTD. Polymyositis (PM). Sarcoidosis. An tiphospholipid syndrome. Treatment The major clinical manifestations dictate therapy and management decisions should not be in \202 uenced by the predicted de \201 nite diagnosis. Symptomatic treatment is usually suf \201 cient and includes: \200 \200 \200 \200 Preliminary classi \201 cation criteria \200 Signs and symptoms suggestive of an AICTD, but not ful \201 lling the criteria for any de \201 ned AICTD. Positive ANA. Disease duration of at least 3 years. \200 Patients with shorter follow-up should be de \201 ned as having early UCTD, includi ng patients who will develop a speci \201 c AICTD and patients with transitory disease. NSAIDs. Low dose glucocorticoids (GCs). Antimalarials (e.g. hydroxychloroquine). DMARDs. Prognosis Overall, UCTD is a mild condition. Patients require careful monitoring for the ev olution of disease to a more speci \201 c AICTD (in up to 25%); however, clinicians should not be hasty in making a de \201 nitive diagnosis as the undifferenti- ated nature usuall y persists. \200 Clinical features No speci \201 c signs or symptoms exist for UCTD. Most commonly patients suffer from: \200 Arthritis/arthralgias (if small joints consider RA, SLE, and sarcoid; if ankles exclusively consider sarcoid). Raynaud \200\231s phenomenon. Sicca symptoms (xerostomia and xerophthal mia). Dyspepsia and heartburn. Low grade fevers. Myalgias. Serositis. Fatigue. Weight loss Photosensitive rash. \200 \200 \200 \200 \200 \200 \200 \200 Neurological and renal disease is v irtually absent. Overall resolution of disease is less common than evolution. Evolution to SLE is not uncomm on and occurs within 5 years of disease onset. Predictors for the development of SLE includ e: \200 \200 \200 \200 \200 young age at onset; ethnicity (African-American); alopecia; serositis; presence of speci \201 c autoantibodies (e.g. dsDNA, Sm, phospholipid); low C3 and C4; photosensitive and dis coid rash; cardiac complications. Investigations The most frequent abnormalities include: \200 \200 \200 \200 Interes tingly, up to 80% of patients with UCTD have a single autoantibody speci \201 city (most c ommonly anti-Ro or anti-RNP), which remains stable over time. New auto- antibody speci \201 city should prompt a review to consider evolution of the disease. \200 \200 Data are sparse on predictors for the development of other AICTDs. It \200 \231s important that where insidious evolu- tion of internal organ disease is a possibility that relevant monitoring is undertaken \200\223 even sometimes on minimal clinical eviden ce for symptoms. Examples of this include monitoring KCO and RVSP for asymptomatic pulmonar y hypertension if there is anti-centromere antibody (SSc-sine-scleroderma), and monitoring urinalysis and urine microscopy for nephritis if there are raised DNA antibodies (SLE). No obvious triggers have been identi \201 ed for disease progression. Anemia. Leukopaenia \200\223 particularly lymphopaenia. Thrombocytopaenia. ANA (positive i n up to 90%). Antibodies with greater diagnostic value include: Anti-CCP antibodies (RA). Anti-dsDNA and anti-Sm antibodies (SLE). Anti-centromere antibodies (lcSSc). Anti-topoisomerase 1 [Scl-70] (dcSSc). Anti-thyroid antibodies have been associated with rash \200 \200 \200 in UCTD. Differential diagnosis In early disease the well-characterized AICTDs may present incomplet ely; therefore, the differential diagnosis includes: \200 SLE. \200 Sj grens syndrome. CHAPTER 8 Autoimmune connective tissue diseases 307 Mixed connective tissue disease De \201 nition First described in 1971, MCTD has clinical features of SLE, SSc, PM, and RA, but clinical features occur in association with U1RNP aut oantibodies. Some debate has appeared periodically in the literature as whether a condition has speci \201 c clinical features and should be de \201 ned essentially on the basis of the presence of a single autoantibody. \200 \200 \200 Dysphagia and re \202 ux symptoms. Sicca symptoms. Alopecia. Rash (telangiectasia, erythem a nodosum, discoid lesions). Florid myositis. Acute arthritis. Dyspnoea. Pleuritic pain. As eptic meningitis. Digital gangrene. High fever. Acute abdomen. Trigeminal sensory neuropath y. Lymphadenopathy. Malar rash and dermatomyositic rash are more frequent in children. Sign i \201 cant renal and central nervous system disorders are uncommon. A propensity exists f or the development of pulmonary hypertension and an SSc type vasculopathy. \200 \200 \200 \200 \200 \200 \200 \200 \200 Classi \201 cation criteria Several exist, but that of Alarcon-Segovia is the most widely used. Serologic criteria Anti-RNP antibodies at a haemagglutination titre >1:1600. Clinical criteria \200 \200 \200 \200 \200 Swollen hands. Synovitis. Biologically or histologically proven myositis. Raynaud \200\231s phenomenon. Acrosclerosis (with or without proximal SSc). If the serological criterion and at least three of the \201 ve clinical criteria are present then a diagnosis of MCTD can be made. However, a patient with suf \201 ciently elevated anti- RNP titres in combinatio n with swollen hands, Raynaud \200\231s phenomenon, and acrosclerosis with or without proxi mal SSc, must also have either synovitis or myositis to meet the criteria for diagnosis. Investigations Laboratory \200 \200 High titre ANA in a speckled pattern. The presence of U1 RNP antibodies is the sine qua non of MCTD. FBC: anemia of chronic disease, thrombocytopaenia. Hypergammaglobulinaemia. Hypoc omplementaemia and cryoglobulinaemia (present in up to one-third, but not associated with r enal or other organ involvement). \200 \200 Epidemiology \200 \200 \200 \200 Incidence remains unknown. Disease of the 2nd-4th decades of life. Mean age of onset 35 yea rs (10 years in children). More common in women (80%). Other \200 Pathophysiology MCTD is associated with HLA-DR4 or HLA-DR2 geno- types. Vascular changes si milar to SSc are seen however less fibrosis is present (see individual chapters for a detai led description of the relevant immune mechanisms for each \200\230subcategory \200\231 of MCTD. Nail-fold capillaroscopy reveals capillary dilatation and capillary loss. Cardiac transthor acic ECHO and pulmonary function tests are necessary to monitor for pulmonary hypertension. Oesophageal manometry abnormalities (up to 85%). Treatment Depends on disease manifestation. Raynaud \200\231s phenomenon is treated along s tandard lines (see pp. 269 \200\223270). Clinical features Symptoms seldom occur simultaneously and years may elapse before one can be con \201 dent of the diagnosis. The commonest manifestations in early disease include: \200 \200 \200 Other medications utilized include: NSAIDS. Proton pump inhibitors. Low dose glucocorticoid s. DMARDS (e.g. hydroxychloroquine and MTX). \200 \200 \200 Raynaud \200\231s phenomenon (75 \200\223100%). Arthralgia/arthritis. Hand oedema/sclerodac tyly (extension proximally is not a feature). Other early symptoms include Fatigue; Myalgia s/mild myositis; Serositis; Low-grade fever. Less common manifestations include: Prognosis In the early phase of disease the features of a single condition (usually systemi c sclerosis or SLE) predominate over the \200\230overlap \200\231 features. Invariably, al l patients will ful \201 l criteria for another AICTD at some stage. Pulmonary hypertensio n is the major cause of death in MCTD. \200 \200 \200 OVERLAP SYNDROMES 308 Overlap syndromes De \201 nition An overlap autoimmune connective tissue disease occurs when 2 or more autoi mmune rheumatological or connective tissue diseases are present simultaneously in the same indi- vidual. The following are considered established overlap syndromes: \200 \200 \200 \200 Autoantibodies of both disorders are present, such as IgM-RF; ANA, Anti-DNA, Anti-Ro. Sclerodermatomyositis or scleromyositis \200 \200 Features of SSc with myositis skin manifestations. Dermatological change occurs over yea rs and is not severe (absence of digital ulceration, trunk or face involvement, only mild t elangiectasia). High titre ANA. PM-Scl antibodies. Anti-U1 RNA absent. \200\230Rhupus \200\231: SLE/RA. Sclerodermatomyositis. Scleromyositis. MCTD (considered s eparately). Other \200\230overlaps \200\231 may be classi \201 ed as subsets of de \201 ned \200 \200 Treatment of overlap syndromes \200 CTDs including: \200 SLE/myositis. \200 RA/myositis. \200 SLE/APS. \200 RA/vasculit is. \200 SLE/vasculitis. Treatment follows the symptoms and severity of disease. Therapeutic modalities are those us ed in the individual AICTDs (see Rheumatoid arthritis, Systemic lupus erythematosus, System ic sclerosis). Prognosis Prognosis is variable and depends upon the extent of organ involvement, the respo nsiveness to treatment and any intervening complications. Clinical features Disease presentation is varied and comprises features of individual AICTD s in an overlapping fashion (see appropri- ate sections of the book for full descriptions o f the speci \201 c AICTDs). The following gives a brief overview of the recognized overlap AICTDs. Rhupus \200 \200 Criteria met for a diagnosis of both RA and SLE. Rheumatoid factor sero-positive, erosive, symmetrical polyarthritis usually pre-dates the onset of the clinical features of SLE. CHAPTER 8 Autoimmune connective tissue diseases 309 Resources (for UCTD, MCTD, and Overlap syndromes) Speci \201 c assessment tools and guidel ines do not exist for UCTD, MCTD, and Overlap syndromes. The quality and breadth of informa tion on a crude search engine screen is of variable quality. Readers are referred to indivi dual scien- ti \201 c and clinical reports where greater detail is required. Bodolay E, Csiki Z, Szekanecz Z, Ben T, Kiss E, Zeher M, et al. Five-year follow-up of 665 Hungarian patients with undifferenti- ated connective tissue disease (UCTD). Clin Exp Rheum atol 2003; 21: 313 \200\22320. Mosca M, Neri R, Bombardieri S. Undifferentiated connective tissue diseases (UCTD): a revie w of the literature and a proposal for preliminary classi \201 cation criteria. Clin Exp R heumatol 1999; 17: 615 \200\22320. Mosca M, Tani C, Neri C, Baldini C, Bombardieri S. Undifferentiated connective tissue disea ses (UCTD) Autoimmun Rev 2006; 6: 1 \200\2234 ICD-10 codes M35.1 Other overlap syndromes M35.8 See also SSc (p. 264) SLE (p. 240) RA (p. 197) PM (p. 282) Other speci \201 ed systemic involvement of connec- tive tissue Systemic involvement of co nnective tissue, unspeci \201 ed M35.9 References Alarcon-Segovia, D, Cardiel, MH. Comparison between 3 diagnostic criteria for mi xed connective tissue disease. Study of 593 patients. J Rheumatol 1989; 16: 328. EOSINOPHILIC FASCIITIS 310 Eosinophilic fasciitis De \201 nition Eosinophilic fasciitis (Schulman syndrome) was first described in 1974 as a disorder characterized by peripheral eosinophilia and fasciitis (manifest clinically as sy mmetrical swelling, induration, and thickening of the skin and subcuta- neous tissue of the extremities). It differed from the related condition systemic sclerosis (SSc) in that fasc ia was involved, rather than dermis, the digits were spared and Raynaud \200\231s phenomeno n was absent. More recently, the syndrome has been broadened to include elevation of the er ythrocyte sedimentation rate (ESR) and hypergammaglobulinaemia. Co-morbidities Eosinophilic fasciitis is frequently associated with haemato- logical abnorm alities, including malignant lymphoprolifera- tive diseases and, rarely, as a paraneoplasti c phenomenon (e.g. colorectal adenocarcinoma). It has also rarely been associated with auto immune thyroiditis. Investigations It is worth noting that laboratory changes and the clinical manifestations d o not necessarily correlate well. Peripheral blood eosinophilia is not necessary for the di agnosis. Laboratory \200 Diagnostic criteria The diagnosis rests on the clinical, laboratory, and biopsy \201 ndin gs. Speci \201 c criteria have not been developed. Peripheral blood eosinophilia in 64% (variable over time even in the absence of speci \201 c therapy). Hypergammaglobulinaemia in 75% cases (polyclonal increase in IgG). FBC may rev eal thrombocytopaenia, haemolytic anemia, pernicious anemia, leukemia, and aplastic anemia. In doubtful cases, given the association with haemato- logical malignancy, bone marrow asp iration (and trephine if necessary) should be considered. The majority have a raised ESR. A NA positive in one-third. Creatinine kinase (CK) and aldolase normal. Epidemiology \200 Very rare. \200 Caucasian > Afro Caribbean. \200 Females > males (a lthough data vary). \200 Mean age of onset 40 \200\22350 years. \200 Can occur in child ren who are more likely to suffer from persistent disease. \200 \200 Etiology and pathophysiology The etiology of eosinophilic fasciitis is unknown. It has been shown that \201 broblasts from affected patients pro- duce excess collagen in vitro and up-regulation of TGF-B and type 1 collagen mRNA has been seen. A cytotoxic immune response to an environmental or infectious agent is possible as CD8 positive (CD8+) T lymphocytes an d macrophages have been found in the fascial in \202 ammatory in \201 ltrate. Borrelia bu rgdorferi has been implicated as an inciting agent. Imaging Gadolinium-enhanced MR may reveal fascial enhancement consistent with acute in \202 ammation and/or deep fascial thickening. Histology Deep fascial biopsy, which includes skin, fat, fascia, and super \201 cial muscl e is required for the de \201 nitive diagnosis. Biopsy features include thickening of coll agen bundles of the super \201 cial muscle fascia with in \201 ltration of lympho- cytes, eosinophils and plasma cells. Clinical features \200 A history of signi \201 cant physical activity precedes the onset in 50% of patients. Skin changes occur sub-acutely and progress through several phases in the following order: \200 \200 Other investigations \200 \200 EMG can show evidence of underlying myositis. Pulmonary function tests show restrictive pat tern in those with severe truncal tissue involvement. blotchy skin erythema initially; non-pitting oedema (most commonly of the lower extremities ); peau d \200\231orange with hyperpigmentation; skin tightness with woody induration.