Transient ischemia Low-dose aspirin 1st non-cerebral arterial event Warfarin (INR 2 \200\2233) and aspirin Recurrent arterial/ venous event ? warfarin (INR 3 \200\2234) or LMWH, or add aspirin Catastrophic APS IV heparin IV methylprednisolone pulse Plasmapheresis OR IVIG Pregnancy No previous history Observation and/or low-dose aspirin Recurrent \201 rst trimester or second/ third trimester fetal loss Low-dose aspirin and heparin prophylaxis Previous thrombosis Low-dose aspirin and therapeutic LMWH Repeat fetal loss despite heparin and aspirin Consider hydroxychloroquine and prednisone 10 mg, in addition to the above Thrombocytopenia Mild (100 \200\223150 count) Observe Moderate (50 \200\223100) Observe Severe (<50) Corticosteroids (as ITP), IVIG, immunosuppression (e.g., rituximab) LMWH = low molecular weight heparin CHAPTER 11 The antiphospholipid syndrome 358 Catastrophic APS (CAPS) Introduction \200 This rare variant of APS affects small vessels and visceral organs and was \201 rst described in 1992. It is an important and serious co ndition that can present to many medical specialties. It can present in previously asymptomatic patients. \200 CAPS is associated with other au toimmune conditions such as SLE (see Chapter 9), RA (see Chapter 5) and SScl (see Chapter 1 2). \200 The trigger is an infection in 20% cases. Other precipitating factors include tr auma/surgery, malignancy, warfarin withdrawal in a patient with APS, pregnancy, and oral co ntraceptives. Despite these risk factors it is estimated that 45% cases have no known trigger. Mortality is greater than at 50% and many patients will require critical care. Clinical features \200 Rapid onset, diffuse peripheral and central thrombosis occurs lead ing to: \200 arterial and venous occlusion in the extremities \200 intra-abdominal organ in farction including renal failure (i.e., antiphospholipid-associated nephropathy) pulmonary emboli and adult respiratory distress syndrome \200 small vessel cerebrovascula r disease \200 aortic and mitral valve defects and myocardial infarction \200 other thr ombotic complications such as ovarian, testicular, adrenal and retinal vessel occlusion. Livedo reticularis, gangrene, and purpura are visible markers of the disorder on the skin. Bone marrow infarction and ARDS have also been reported. \200 Classi \201 cation criteri a have recently been produced. 1 Laboratory features These include: \200 Moderate to severe thrombocytopenia \200 Hemoly sis with schistocytes \200 Disseminated intravascular coagulation \200 High levels of I gG aCL antibodies or presence of lupus anticoagulant The differential diagnosis The clinician should consider the following conditions \200 Th rombotic thrombocytopenic purpura (red cell fragments more numerous than in CAPS) Heparin induced thrombocytopenia \200 HELLP syndrome (hemolysis, elevated liver enzymes a nd low platelets) 1 Cervera R, Font J, Gomez-Puerta JA et al . Validation of the preliminary criteria for the classi \201 ca- tion of the catastrophic antiphospholipid syndrome. Ann Rheum Dis, 2005; 64: 1205 \200\2231209. CATASTROPHIC APS (CAPS) 359 Hemolytic \200\223uremic syndrome \200 Cryoglobulinemia \200 Vasculitis \200 Dissemin ated intravascular coagulation \200 Sepsis \200 Paroxysmal nocturnal hemoglobinuria Treatment and prognosis \200 Treatment should always include an attempt to identify and t o address the precipitating event, as well as supportive care. In addition, IV heparin and high-dose corticosteroids should be considered. Life threatening CAPS should also be treated with plasmaphersis versus intravenous immunoglobulin (for 5 days at a dose of 0.4 g/kg/day). Case reports exist in single patients describing the use of prostacyclin, cyclosporin A, de \201 brotide, \201 brinolytics, and rituximab. \200 25% of survivors will develop further APS-related events. \200 Recurrence of CAPS is very rare. This page intentionally left blank 361 Chapter 12 Sj gren \200\231s syndrome (SS) Epidemiology and pathology 362 Clinical manifestations of SS 364 Investigation of SS 368 Tr eatment of SS 370 CHAPTER 12 Sj gren \200\231s syndrome (SS) 362 Epidemiology and pathology \200 Sj gren \200\231s syndrome (SS) is a chronic autoimmun e disease of unknown etiology, characterized by lymphocyte in \201 ltration of exocrine gl ands resulting in xerostomia and keratoconjunctivitis sicca. The condition may be primary, associated with speci \201 c extraglandular (systemic) disea se, or secondary, in association with a number of other autoimmune rheumatic diseases, incl uding RA (see Chapter 5) and SLE (see Chapter 10). Sj gren \200\231s syndrome is also strongly associated with the development of lymphoma. The syndrome affects women more than men in a ratio of 9:1, and tends to occur at 40 \200\22350 years of age. It can, however, occur at any age. Population prevalence is estimated at 0.1 \200\2230.5%. \200 The triggering of autoimmuni ty and the development and continuation of an autoimmune response remain a great source of interest in SS. The links between environmental stimulus and immunogenetics, and the studie s of humoral and lymphocyte activity may help to untangle the mechanisms whereby immunologi cal dysregulation can lead to malignant transformation of B cells involved in the immune pr ocess. \200 Epstein \200\223Barr and retroviruses have been implicated in pathogenesis. \200 HLA DR3 is strongly associated with SS. \200 Antibodies to the ribonucleoprotein co mplexes Ro and La are found and are thought to be formed when these antigens are exposed on the surface of apoptotic ce lls. RF and antinuclear antibodies are also common and patients may be erroneously diagnosed with RA. Recently discovered autoantigens in SS include fodrin and muscarinic acetylcholine receptor M3. Two sets of classi \201 cation criteria for primary SS are listed in Tables 12.1 and 12.2. \200 To satisfy classi \201 cation criteria for primary SS using the American- European Consensus Group (AECG) criteria, focal lymphocytic sialoadenitis (with a focus score of 1 or greater), or antibodies to Ro and/or La must be present. The 2012 American College of Rheumatology criteria emphasize the use of objective, rather than subjective, \201 ndings. Patients with a history of head and neck radiation, hepatitis C infection, HIV/AIDS, sarcoidosis, amyloidosis, graft-versus-host disease, and IgG4-related diseases ar e excluded by ACR criteria from participating in studies of Sj gren \200\231s syndrome, due to the presence of overlapping clinical features that may interfere with objective meas ures. EPIDEMIOLOGY AND PATHOLOGY 363 Table 12.1 Classi \201 cation criteria for primary Sj gren \200\231s syndrome. For clas si \201 cation purposes, 4 of 6 criteria must be present. Criteria Comment Ocular symptoms Dry eyes > 3 months, sense of sand/gravel in eyes, or use of tear substitutes >3 times/day Oral symptoms Dry mouth > 3 months, recurrent swollen salivary glands, frequent use of liquid to swallow Ocular signs Schirmer \200\231s test Corneal and conjunctival staining Oral signs Parotid scintigraphy Sialography Salivary \202 ow Focus score (# lymphocyte aggregates per 4 mm 2 ) must be \211 1 Focal lymphocytic sialadenitis Antibodies to Ro/La One of these two criteria must be positive for this diagnosis. Vitali C, et al. Classi \201 cation criteria for Sj gren \200\231s syndrome; a revised version of the European c riteria proposed by the American-European consensus group. Ann Rheum Dis, 2002; 61: 554 \200\2238. Table 12.2 American College of Rheumatology 2012 Classi \201 cation Criteria for Sj gre n \200\231s Syndrome. For classi \201 cation purposes, two of the three must be present Criteria Comment Serology 1. Ro or La positive, or 2. RF-positive and ANA \211 1:320 Focus score (cid:2) 1/ 4mm 2 Focal lymphocytic sialadenitis Keratoconjunctivitis sicca Requires ocular staining score of (cid:2) 3 Shiboski SC, et al. American College of Rheumatology Classi \201 cation Criteria for Sj gren \200\231s Syndrome: a data-driven, expert-consensus approach in the Sj gren \200 \231s International Collaborative Clinical Alliance Cohort. Arthritis Care and Research 201 2; 64: 475 \200\223487. CHAPTER 12 Sj gren \200\231s syndrome (SS) 364 Clinical manifestations of SS Glandular disease \200 The initial manifestations can be no n-speci \201 c and 8 \200\22310 years can elapse before the diagnosis is established. Typical initial features of \200\234sicca \200\235 syndrome include subjective dry eyes (x erophthalmia) in >50% at presentation, dry mouth (xerostomia) in 40%, and parotid/salivary gland enlargement in 25%. The prevalence of these manifestations increase with the duration of disease. There may be concurrent corneal and conjunctival damage (keratoconjunctivitis sicca), and dental caries from poor tear and salivary \202 ow, respectively. A number of other conditions can lead to a dry mouth or parotid/ salivary gland swelling, a nd these should be borne in mind during assessment. Dry eyes may be aqueous-de \201 cient (lacrimal gland disease, drugs, tear duct obstructio n, re \202 ex hyposecretion) or evaporative (Meibomian gland dysfunction, lip aperture dis order, low blink rate, corneal surface in \202 ammation, vitamin A de \201 ciency). The most common causes of dry eye disease are blepharitis or meibomian gland dysfunction. P rior LASIK surgery may also contribute to dry eyes. \200 Dry mouth may be associated with diseases that affect the salivary gland, including Sj gren \200\231s, IgG4-related dise ases, head and neck radiation, hepatitis C, HIV/AIDS, sarcoidosis, and lymphoma. Multiple drugs may also cause dry mouth. \200 Some causes of parotid gland enlargement in clude: Lymphoma \200 Neoplasia (rare) \200 HIV/AIDS \200 Hepatitis C \200 Sarcoid \200 I gG4-related sialoadenitis \200 Sialoadenosis (due to alcoholism, diabetes, bulimia, malnu trition) Extraglandular (systemic) disease Extraglandular disease is seen in one-third of patients w ith primary SS. The main symptoms are fatigue, low-grade fever, myalgias, and arthralgias ( see Table 12.3). Joints Joint pain is common; radiographs rarely reveal erosive changes. In con- trast to SS cl (see Chapter 12), Raynaud \200\231s in SS is not associated with digital ulceration and infarcts. Skin \200 The skin may be involved with itchy annular erythema, alopecia, and hyper/hypopigmentation. A hypersensitivity vasculitis may also develop. Vascular involvement in SS affects small and medium-sized vessels. The most common manifest ations are purpura, urticaria, and skin ulceration. Skin vasculitis in SS is more benign an d treatment with corticosteroids is not always needed. CLINICAL MANIFESTATIONS OF SS 365 Table 12.3 The incidence of extraglandular manifestations of primary Sj gren \200\231s s yndrome Condition Frequency (%) Arthralgias/arthritis 37 Raynaud \200\231s phenomenon 16 Cutaneous vasculitis 12 Pulmonary disease 9 Lymphadenopathy 7 Peripheral neuropathy 7 Renal disease 6 Autoimmune hepatitis 2 Lymphoproliferative disease 2 Myositis 1 Note: The true frequency of extraglandular manifestations among subjects who meet 2012 ACR classi \201 cation criteria for Sj gren \200\231s syndrome may be higher Pulmonary disease Pulmonary function abnormalities are seen in 25% of patients, but they ar e not usually clinically signi \201 cant. Interstitial lung disease may occur in patients with Sj gren \200\231s syndrome, who may present with cough and dyspnea. Non-speci \201 c interstitial pneumonia (NSIP) is the pattern most commonly associated with Sj gren \200\231s syndrome, and is associated with a good prognosis. Lymphocytic interstitial pneum onia (LIP), bronchiolitis, and amyloidosis are relatively uncommon. Renal disease \200 Interstitial nephritis may occur in patients with Sj gren \200\231s syndrome, and may respond to treatment with glucocorticoids. Distal (Type I) renal tubular acidosis is seen in up to 25% of patients with Sj gren \200\231s syndrome. This is generally associated with a mild metabolic acidosis, but patien ts may present with hypokalemia due to potassium wasting. Glomerulonephritis is rare and seen mainly in those with SS/SLE overlap. Membranoproliferative glomerulonephritis and membranous nephropathy are the forms of glomerular disease most commonly associated with Sj gren \200\231s syndrome. Gastrointestinal and hepatobiliary disease \200 Dysphagia due to dryness of the pharynx a nd esophagus is common. Chronic atrophic gastritis may occur due to lymphocytic in \201 lt ration similar to that seen in the salivary glands. \200 Subclinical hyperamylasemia may be observed CHAPTER 12 Sj gren \200\231s syndrome (SS) 366 There may be a close link between \200\234autoimmune cholangitis \200\235 of SS and primar y biliary cirrhosis (PBC). Sicca syndrome is found in approximately 50% of cases of PBC. Transaminitis may be due to hepatitis C. Hepatitis C can cause a Sj gren \200\231s-like disease often in association with a \200\234mixed \200\235 (type II) cryoglobulinemia. Neuromuscular disease \200 Peripheral sensory neuropathy is the most common neuromuscular feature of SS, and may require measurement of epidermal nerve density by skin biopsy to co n \201 rm the diagnosis. Mononeuritis multiplex as a consequence of vasculitis is well recognized as is the isolated involvement of cranial nerves, particularly the trigeminal an d optic nerve. A peripheral sensory neuropathy is also seen. Speci \201 c involvement of t he central nervous system remains a controversy. Multiple sclerosis-like syndromes may be s een. Myalgias are common; myositis is rare, but responds to immunosuppression (see Chapter 13, P olymyositis). Lymphoproliferative disease 1 \200 Patients with SS have approximately a 16-fold increase d risk of developing a lymphoma, compared to age, sex, and race-matched normal controls. The lymphoma s are primarily B cell in origin, usually expressing the monoclonal IgM- , and of two majo r types, either highly undifferentiated, or well-differentiated immunocytomas. \200 The c linical picture is diverse. The approach to therapy should be determined by the stage and h istological grade of the disease. \200 The salivary glands are the main site of lymphomat ous change. The presence of lymphadenopathy, organomegaly, or persistent, painful, and cont inuously enlarged salivary glands, in the absence of infection, should raise suspicion and warrants biopsy. Other organs and systems may be affected, including the reticuloendothelia l system, lungs, kidneys, and GI tract. Risk factors include monoclonal gammopathy, cryoglobulins, hypocomplementemia and major sal ivary gland swelling. Cardiovascular system 1 Anti-Ro and La antibodies cross the placenta and can cause fetal co n- genital heart block. Babies of mothers with these antibodies have a 1 in 50 risk of hear t block. If there is a prior history of congenital heart block during a previous pregnancy, this risk increases to 20%. Fetal heart rate monitoring in specialist centers is needed. O ral dexamethasone given to mothers early following detection of heart block may reverse the condi- tion. Neonatal lupus is also seen, its most common manifestation being a \202 ori d rash. Other pathology in SS \200 Over 50% of patients have antithyroid antibodies and altered t hyroid biochemistry without necessarily overt clinical symptoms. CLINICAL MANIFESTATIONS OF SS 367 Nonbacterial interstitial cystitis due to an intense in \202 ammation of the mucosa can cause frequency, nocturia, and perineal pain. Mild normochromic, normocytic anemia is common. Leukopenia is seen in 15 \200\22320% of pat ients with SS. The ESR is often raised, but the CRP usually normal. Other autoimmune diseases In a recent retrospective case review of 114 patients with primar y SS, 33% had an additional autoimmune disease, 6% two diseases, and 2% three diseases. Hyp othyroidism was most common condition seen. CHAPTER 12 Sj gren \200\231s syndrome (SS) 368 Investigation of SS \200 Common laboratory \201 ndings in primary SS are detailed in Ta ble 12.4. \200 To evaluate the glandular component of the disease, various tests are used . Setting a cut-off point between the normal and abnormal individual is dif \201 cult. Salivary \202 ow rates (sialometry) can be measured for whole saliva or separate secretio ns from different salivary glands, with or without stimulation. Patients with overt SS have decreased \202 ow rates. This technique can be confounded by concomitant use of drugs wi th anticholinergic properties. Anatomical changes in the ductal system can be assessed by radio contrast sialography. This can, however, be painful and there is some controversy about its sensitivity and speci \201 city. Scintigraphy, with uptake of 99 Tc, may provide a functional evaluation of all the salivary glands by observing the discharge of radioactivity form the glands after administration of lemon juice or candy. Scanning has a high sensitivity but low speci \201 city. Neither si alography nor scintigraphy are suggested as routine investigations. Schirmer \200\231s test is used for the evaluation of tear secretion. Strips of \201 lter paper 30 mm in length are slipped beneath the inferior eye-lid by a fold at one end of the strip. After 5 min, the length of paper that has been made wet by the tears is measured; wetting of <5 mm is a strong indication of diminished tear secretion. Ocular surface staining may be used to evaluate the tear \201 lm and demonstrate areas of damage on the ocular surface, including devitalized tissue. Ocular surface staining may be used to monitor response to treatment of dry eye over time. A labial gland biopsy is often essential to the establishment of a diagnosis of SS, particularly when the patient lacks anti-Ro or anti-La antibodies. \200 Because there is a (small) risk of sensory nerve damage, the biopsy should be performed by a surgeon with experience in the technique. The surgical approach is critical: a shallow incision through the lamina propria of the inner lip is the preferred technique, since it allows direct visualiz ation of the glands. Elliptical wedge and punch biopsies may not provide enough glands, and are associated with a higher risk of nerve injury. At least 4 \200\2236 glands must be harvested, since the pathologic process is focal. Biopsies should not be performed if there is mucosal in \202 ammation overlying the biopsy site or there is a past history of therapeutic head and neck irradiation. Focal lymphocytic sialadenitis is scored in terms of the number of lymphocytic foci (i.e., aggregates of 50 or more lymphocytes), which surround ducts or bloo d vessels and are adjacent to histologically- normal acini. The pathologist must measure the total surface area of the gland in order to calculate a focus score. INVESTIGATION OF SS 369 A score of 1 or more foci per 4 mm 2 is compatible with SS. However, focal lymphocytic sialadenitis can also be seen in hepatitis C, HIV, graft versus host disease and patients with autoimmune disease in the absence of sicca. Other possible \201 ndings include non-speci \201 c chronic sialadenitis, sclerosing chronic sialadenitis, and MALT lymphoma, which are not speci \201 c for a diagn osis of Sj gren \200\231s syndrome. Sclerosing chronic sialadenitis is particularly comm on among the elderly. Detection of germinal center-like lesions is associated with a higher risk of progression to non-Hodgkin \200\231s lymphoma. Table 12.4 Common laboratory \201 ndings in primary SS Finding Frequency (%) General Anemia 20 Thrombocytopenia 13 Leukopenia 16 Raised ESR 22 Monoclonal gammopathy 22 Hypergammaglobulinemia 22 Cryoglobulinemia 9 Serology ANA 74 Rheumatoid factor 38 Ro/SS-A 40 La/SS-B 26 ANCA 6 Antimitochondrial 5 Garcia-Carrasco M, et al. Primary Sj gren syndrome: Clinical and immunologic disease pat terns in a cohort of 400 patients. Medicine 2002; 81: 270 \200\22380. Note that the frequency of Ro-positivity among subjects who meet the 2012 American College of Rheumatology Classi \201 cation Criteria for Sj gren \200\231s syndrome is closer to 80%. CHAPTER 12 Sj gren \200\231s syndrome (SS) 370 Treatment of SS Table 12.5 summarizes the treatment options for Sj gren \200\231s syndro me. Other treatments \200 There is no evidence that azathioprine, low dose steroids, cyclosporine, in \202 iximab or methotrexate are useful. Table 12.5 The treatment of Sj gren \200\231s syndrome Condition Treatment Dry eyes Arti \201 cial tears Topical cyclosporine drops Punctal occlusion (plugs) Treatment of Mei bomian gland dysfunction (with warm compresses) Dry mouth Frequent sips of water and good oral hygiene Sugar free lozenges/lemon drops Arti \201 cial saliva Chromic erythematous candidiasis Topical treatments should be sugar-free, to avoid worsening of dental carries Sicca manifestations May improve with the cholinergic agent pilocarpine (side effects include \202 ushing/swea ting) or cemiveline (fewer side effects) Vaginal dryness Patients may respond to propionic acid gels. Rigorous treatment of infection. Advice on lub ricants etc. if there is pain with intercourse Salivary gland Acute suppurative parotitis should initially be treated with intravenous antibiotics, which much cover broadly for S. aureus (including MRSA) and anaerobes. Patients who exhibit an a dequate response may be transitioned to oral antibiotics Arthralgia Hydroxychloroquine 200 \200\223400 mg/day (see Drugs in RA, for monitoring) Systemic vasculitis Necrotizing vasculitis and glomerulonephritis \200\224 prednisone and/or cyclophosphamide. Cryoglobulinemic vasculitis \200\224rituximab. Leukocytoclastic vasculitis \200\224may be r efractory to immunosuppressive therapy. Liver disease Cholestasis may respond to ursodeoxycholic acid 10 \200\22315 mg/kg/day Chronic erythematosus candidiasis Topical nystatin, miconazole, or ketoconazole Interstitial lung disease Prednisone TREATMENT OF SS 371 Hydroxychloroquine normalizes ESR and immunoglobulin levels, but has no effect on salivary \202 ow rates. Many clinicians use it to treat fatigue, myalgias, and arthralgias. Rituximab may improve salivary \202 ow rates and diminish fatigue in patients with Sj gren \200\231s syndrome. Oral interferon alpha improves salivary \202 ow but long-term use may be limited. This page intentionally left blank 373 Chapter 13 Systemic sclerosis and related disorders Epidemiology and diagnostic criteria 374 Cutaneous features of scleroderma and their treatm ent 380 Systemic features of the disease, investigation, and treatment 384 Anti \201 brotic and immunosuppressive therapies for systemic sclerosis 390 Summary \200\224the approach to systemic sclerosis 392 Scleroderma-like \201 brosing diso rders 394 CHAPTER 13 Systemic sclerosis and related disorders 374 Epidemiology and diagnostic criteria \200 Scleroderma is a spectrum of rare disorders ran ging from limited to generalized, nonsystemic to systemic, and environmental to autoimmune rheumatic disease. Systemic scleroderma (systemic sclerosis) predominantly affects women an d is associated with production of collagen, widespread microvascular damage, and in \202 ammation. The spectrum of scleroderma and scleroderma-like syndromes includes: \200 Raynaud \200\231s phenomenon \200\224primary, secondary \200 Scleroderma (localized) \200\224morphea, linear, en coup-de-saber \200 Scleroderma (systemic) \200 \224limited cutaneous, diffuse cutaneous, scleroderma sine scleroderma Chemical induced \200\224environmental, occupational, drugs \200 Scleroderma-like disease (see Table 13.1) \200\224metabolic, immunological, localized sclerosis, and visceral disea se. There is no single diagnostic test for systemic sclerosis (SSc) although there are speci \201 c autoantibodies. For the purpose of separating it from other autoimmune rheumatic dis eases and identifying case pro \201 les, preliminary criteria were developed in 1980 by th e American Rheumatism Association. These criteria have a 97% sensitivity and speci \201 ci ty for de \201 nite SSc, but are less sensitive for the largest subset of patients with li mited cutaneous disease, failing to identify 10% of such cases. At minimum, a patient must have Raynaud \200\231s, a scleroderma-speci \201 c autoantibody, and abnormal nailfold capillaries to consider a diagnosis of SSc. Currently the most widely used classi \201 cation of SSc (see Table 13.2) de \201 nes two subsets divided into limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc). Over 60% of cases are in the \200\230limited \200\231 subset, where visceral involvement is late, some 10 \200\22330 years after onset of Raynaud \200\231s. The term limited cutaneous is now preferred to CREST (calcinosis, Raynaud \200\231s, esopha geal dysphagia, sclerodactyly, telangiectasia), although this acronym is a useful reminder of the common characteristics of lcSSc. DcSSc is more serious, of rapid onset, and associated with organ failure often within the \201 rst 5 years of presentation. Clearly, these models will continue to change and develop as knowledge of pathogenesis advances and immunological \201 ndings are matched to clinical subsets. Several chemical agents have been implicated in the development of scleroderma, including: \200 silica \200 organic chemicals: aliphatic hydrocarbons \200\224vinyl chloride, naphtha \200 aromatic hydrocarbons \200 \224benzene, toluene drugs: hydroxytryptophan, carbidopa, fen \202 uramine, bleomycin. EPIDEMIOLOGY AND DIAGNOSTIC CRITERIA 375 Table 13.1 Scleroderma-like syndromes Metabolic/ inherited Carcinoid syndrome Scleroderma-like lesions can be found with malignant carcinoid; their presence is associate d with a poor prognosis Acromegaly Associated with skin puf \201 ness that can mimic early scleroderma. Acromegaly- skin also associated with increase in sebum and sweat absent in SSc. Phenylketonuria Phenylalanine-restricted diet may improve skin changes. Amyloidosis Plaques from direct dermal in \201 ltration can mimic SSc; more common are alopecia, ecchy moses, and nail dystrophy. Immunological/ in \202 ammatory Chronic graft versus host disease Skin changes favor the trunk, hips, and thighs, but can affect the entire body. Associated with pruritis and hypopigmentation. Eosinophilic fasciitis Associated with painful induration of the skin, hypereosinophilia, and hypergammaglobulinem ia. Early skin changes described as \200\234peau d \200\231orange \200\235 Overlap/ undifferentiated autoimmune rheumatic disease Mixed connective tissue disease (MCTD) is associated with RNP-positivity, and is sometimes classi \201 ed as a form of scleroderma. Polymyositis-scleroderma overlap syndromes are as sociated with antibodies to the PM/Scl complex Scleredema Occurs with diabetes, monoclonal gammopathies, and after certain infections (e.g., strep th roat). Unlike SSc, occurs without Raynaud \200\231s phenomenon and has predilection for the back (Continued) CHAPTER 13 Systemic sclerosis and related disorders 376 Table 13.1 Scleroderma-like syndromes Scleromyxedema Papular waxy induration of the skin along the forehead, neck, and behind the ears. Systemic involvement may mimic scleroderma; neurologic involvement may be fatal Nephrogenic \201 brosing dermopathy Rapid induration of the skin and other organs associated with exposure to gadolinium- based contrast used for MRI in patients with renal insuf \201 ciency/failure Idiopathic pulmonary \201 brosis Patients diagnosed with idiopathic pulmonary \201 brosis should be evaluated for the pres ence of Raynaud \200\231s, capillary loop dilatation, and other signs of SSc and other CTD POEMS Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes. Hyperpigmentatio n is most common but acrocyanosis/ skin thickening are seen. Acquired Lipodermato- sclerosis Hyperpigmentation and induration of the lower extremities associated with chronic venous in suf \201 ciency Eosinophilic myalgia syndrome and toxic oil syndrome Acute syndromes caused by exposure to L-tryptophan and aniline-denatured rapeseed oil, resp ectively. Largely of historical interest. Bleomycin exposure Used as a model to study scleroderma EPIDEMIOLOGY AND DIAGNOSTIC CRITERIA 377 Table 13.2 The classi \201 cation of systemic sclerosis 1. \200\234Prescleroderma \200\235 Raynaud \200\231s phenomenon, nail fold capillary changes Disease-speci \201 c antinuclear antibodies: centromere (ACA) nucleolar (antitopoisomerase-1 (Scl-70)) 2. Diffuse cutaneous SSc Skin changes within 1 year of Raynaud \200\231s. Proximal and acral (face, arms, hands, feet) skin involvement Tendon friction rubs Early, signi \201 cant organ disease: interstitial lung disease oliguric renal failure ( \200\234scleroderma renal crisis \200\235) myocardial disease gastrointestinal disease Nailfold capillary dilatation and/or \200\234dropout \200\235 Scl-70 antibodies in up to 60% of patients RNA polymerase III antibodies in 25% of patients 3. Limited cutaneous SSc Raynaud \200\231s phenomenon for many years Acral skin involvement Late incidence of pulmonary hypertension with or without interstitial lung disease Skin calci \201 cation and telangiectasia Nailfold capillary dilatation and/or \200\234dropout \200\235 ACA antibodies in 70 \200\22380% of patients 4. Scleroderma sine Raynaud \200\231s scleroderma No skin involvement Presentation with lung \201 brosis, renal crisis, cardiac or gastrointestinal disease Antinuclear antibodies may be present CHAPTER 13 Systemic sclerosis and related disorders 378 These exposures likely explain only a very small fraction of patients who develop scleroderma or similar conditions. \200 There are three main abnormalities in scleroderma. Raynaud \200\231s phenomenon: A vasculopathy is found that manifests clinically as Raynaud \200\231s phenomenon, and pathologically as endothelial cell injury. Vascular injury may be the primary event either by vasomotor instability or microvascular intimal proliferation a nd vessel obliteration. Intravascular pathology in the form of increased platelet activity, red cell rigidity, and thrombosis may also be a factor. In \202 ammation occurs early in scleroderma, and may no longer be present at the time of diagnosis. Clinically, this active phase of scleroderma is associated with doughy, edematou s (not indurated) skin and the presence of tendon friction rubs (which can be felt by placi ng the hand over the tendon during active or passive range of motion). Fibrosis is the hallmark of several diseases, and in SSc it is widespread and nonorgan-speci \201 c. Excess deposition of collagen and extracellular matr ix protein is found in the skin and internal organs of patients with SSc. Current research focuses on the role of several proteins including endothelin-1 and transforming growth fact or- B . This page intentionally left blank CHAPTER 13 Systemic sclerosis and related disorders 380 Cutaneous features of scleroderma and their treatment Scleroderma \200\224localized skin ch anges (morphea; linear) \200 This is distinguished from SSc by: \200 the absence of Ray naud \200\231s, \200 the absence of vascular or organ damage \200 the distribution of s kin lesions. Morphea may be \200\234circumscribed \200\235 with just one or two lesions or \200\234generalized. \200\235 The rash is often itchy, violaceous or erythematous, and pro gresses to \201 rm \200\234hide-bound \200\235 skin with hypo- or hyperpigmentation and subsequent atrophy. \200 The \200\234circumscribed \200\235 condition tends to resolve w ithin three to \201 ve years and treatment is often unnecessary. The acral parts are spared, the trunk a nd legs being most often involved. The \200\234generalized \200\235 form can be dis \201 guring, leading to contractures, ul ceration, and occasionally malignancy. Generalized morphea may respond to PUVA. Methotrexat e may also be effective. \200 Guttate morphea is a variant with small 10 mm diameter papu les and minimal sclerosis, resembling lichen sclerosus et atrophicus. The lesions usually local ize to the neck, shoulders, and anterior chest wall. Linear morphea describes a band-like pattern of sclerosis, often in a dermatomal distributi on. The sclerotic areas often cross over joints and are associated with soft tissue and bon e atrophy, and growth defects. Treatment is similar to generalized morphea as above. Physic al therapy and appropriate exercises may help to minimize growth defects in the childhood f orm. En coup-de-saber is linear sclerosis involving the face or scalp and associated with hemiatrophy of the face on the same side. The lesion assumes a depressed ap pearance reminiscent of a scar from a saber. Scleroderma/systemic sclerosis (SSc) \200\224diffuse skin changes \200 The changes in the skin usually proceed through three phases: early, classic, and late. In the early stage, t here may be nonpitting edema of the hands and feet, most marked in the mornings and often a ssociated with Raynaud \200\231s. The skin then becomes taut, the epidermis thins, hair gro wth ceases, and skin creases disappear and the classic changes of scleroderma become more p ronounced. The classic changes remain static for many years. The late phase may evolve at any time. Truncal and limb skin softens such that it can be di f \201 cult to know that a person ever had sclerosis. However, the hand changes rarely res olve and continue to show the ravages of \201 brosis and contractures. During this phase of the disease digital pitting scars, loss of \201 nger pad tissue, ulcers, telangiectasi a, and calcinosis can occur. CUTANEOUS FEATURES OF SCLERODERMA & THEIR TREATMENT 381 All patients with SSc will have some involvement of the face and the digits (although this involvement may be mild). SSc never involves the mid-back. Skin thickening limited to the \201 ngers is called sclerodactyly . Limited scleroderma (lcSSc) is associated with skin involvement limited to the hands and face. This form of SSc, previously known as CREST, can lead to pul monary arterial hypertension in the absence of pulmonary \201 brosis. Diffuse scleroderma (dcSSc) is associated with taut hypo- or hyperpigmented skin involvement proximal to the elbow, knee, or clavicle. In this group the re is a preponderance of visceral involvement (such as pulmonary \201 brosis and renal cr isis) in the \201 rst \201 ve years of symptoms. A practical scheme for assessing dcSSc and lcSSc by dividing the disease into early and late stages is shown in Table 13.3. Raynaud \200\231s phenomenon (Table 13.4) \200 The overall prevalence of this phenomenon is between 3 \200\22310% of the population worldwide, variation depending on climate, skin color, and racial background in particular. In SSc, Raynaud \200\231s is present in approxi mately 95% of cases. Raynaud \200\231s is more than just cold \201 ngers, which is a common complaint, and often has nothing to do with autoimmunity or vasospasm. \200 A patient with Raynaud \200\231s experiences episodic vasospasm, with the following symptoms: \200 pallor of the digits (due to ischemia), followed by \200 cyano sis (due to deoxygenation), and then \200 redness with pain and tingling (due to hyperemi a following the return of blood). All three phases do not need to be observed to make a diagnosis of Raynaud \200\231s. Conti nuous blueness/cyanosis with pain, however, is not characteristic of Raynaud \200\231s. Symptoms that might suggest secondary Raynaud \200\231s include an onset in men, patients o lder than 35 years, symptoms all year round, digital ulceration, and asymmetry. The antinuclear antibodies discussed earlier (Table 13.2) should be sought, and nailfold capillaroscopy should be performed. Pathological changes seen on capil laroscopy include nailfold capillary dilatation, hemorrhage, and dropout. Both have a high predictive power for detecting those patients likely to develop SSc. Nailfold capillaroscopy can be performed by placing a drop of immersion oil on the nailfold, and then examining the area with an ophthalmoscope set at +4 0 diopters. If immersion oil is not available, clear surgical lubricant may suf \201 ce. Conservative measures should be directed at keeping the core body temperature warm, which e ncourages vasodilatation throughout the extremities. CHAPTER 13 Systemic sclerosis and related disorders 382 Table 13.3 Characterisitc \201 ndings in early and late systemic sclerosis Diffuse cutaneous features Early (<3 years from onset of disease) Late (>3 years from onset of disease) Constitutional Fatigue, weight loss Minimal Vascular Raynaud \200\231s (often mild) Severe Raynaud \200\231s. Telangiectasia Cutaneous Rapid progression involving arms, face, and trunk Stable or some regression Musculoskeletal Arthralgia, myalgia, stiffness Flexion contractures Gastrointestinal Dysphagia and \200\230heart burn \200\231 More severe dysphagia. Midgut and anorectal disease Cardiopulmonary Myocarditis, pericarditis, lung \201 brosis Progression of established disease/Pulm. Hypertension Renal Maximum risk of scleroderma renal crisis Crisis uncommon after 4 years Limited cutaneous features Early (<10 years from onset of disease) Late (>10 years from onset of disease) Constitutional None Digital ulceration or gangrene Vascular Severe Raynaud \200\231s. Telangiectasia Stable, calcinosis Cutaneous Mild sclerosis on face Flexion contractures Musculoskeletal Occasional joint stiffness More severe symptoms common. Midgut and anorectal disease Gastrointestinal Dysphagia and heartburn Slow progressive lung \201 brosis. Pulmonary hypertension. Cardiopulmonary Rarely involved Right-sided heart failure Renal Rarely involved Rarely involved CUTANEOUS FEATURES OF SCLERODERMA & THEIR TREATMENT 383 Table 13.4 The treatment of Raynaud \200\231s phenomenon Treatment Examples Comments Nonphar- macological Hand warmers. Protective clothing Universally helpful Evening primrose oil Effective in clinical trials Fish-oil capsules Parenteral vasodilator Nifedipine or Amlodipine Hypotension is possible with all of these agents. Sildena \201 l Losartan Topical nitroglycerin High rate of discontinuation due to side effects Prostacyclin For severe attacks, digital gangrene, and prior to hand surgery Surgery Digital sympathectomy. Debridement. Amputation CHAPTER 13 Systemic sclerosis and related disorders 384 Systemic features of the disease, investigation, and treatment The gastrointestinal tract ( Table 13.5) \200 The gastrointestinal tract is probably the most commonly involved system in SSc. Over 90% of all patients with lcSSc and dcSSc develop esophageal hypomotilit y, with >50% of patients with lcSSc having serious disease. The cause of gastrointestinal dysfunction in SSc is not entirely clear. Possible contributing factors include neural dysfunction, tissue \201 brosis, and muscle atrophy. In the earliest stages of neural dysfunction most patients are asymptomatic. Prokinetic drugs such as metoclopramide (5 \200\22310 mg po BID-TID) may help some patients with esophageal hypomotility.