 \200 \200 \200 Limited cutaneous systemic sclerosis (lcSSc) 60% (previously CREST: Calcinosis, Raynaud \200\231s Esophageal dysmotility, Sclerodacytly and Telangectasias) \200 \200 Raynaud \200\231s precedes other features. Skin involvement restricted \200\223 hands, fac e, forearms and feet. Pulmonary arterial hypertension. Telangiectasiae. Calcinosis. Severe gut disease. Interstitial lung disease (association with anti-SScl-70). Disease progressive in \201 rst few years then often stabilizes. Associated with anti-centromere antibodies (ACA). \200 \200 \200 \200 \200 Epidemiology SSc occurs more frequently in women, with a female: male ratio of 3:1. Peak ag e of onset is between 30 and 50 years. The UK prevalence is 120 per million with an annual inci- dence 4 per million per year. Although there is no racial predilection, the disease may occur more often and most severely in young black women. \200 Limited systemic sclerosis \200 \200 \200 Many environmental agents have been associated with the occurrence of SSc including silica, organic chemicals, e.g. paraf \201 n, vinyl chloride, resin, and toxic oils and drugs, in cluding appetite suppressants, bleomycin, hydroxytryp- tophan, carbidopa, bleomycin, and co caine. It has been suggested that silicone breast implants may contribute to the developmen t of SSc, but a recent large case-control study and meta-analyzes do not support an associa tion. Familial clustering may occur and a positive family history is the strongest risk fac tor identi \201 ed for SSc and the recurrence rate for \201 rst-degree relatives ( r) i s 54. However, the absolute risk for each \201 rst degree relative is less than 1%. High titres of ANA were present in \201 rst- degree relatives of patients with SSc. The highes t prevalence of SSc has been demonstrated in a genetically isolated population of Choctaw A merican Indians. In this population, SSc is strongly associated with a polymorphism in the 5 \200\231-untranslated region of the FBN1 gene. Association studies in other populations h ave indicated that polymorphism in the genes encoding type I collagen A2 chain (COL1A2) and transforming growth factor (TGF)-B may predispose to SSc. Emerging genetic associations wi th interstitial lung disease (e.g. \201 bronectin) and with microvascular disease (e.g. b one morphogenetic protein receptor II with pri- mary pulmonary hypertension and activin-rec eptor-like kinase with hereditary haemorrhagic telangiectasiae) warrant further exploration in SSc. Raynaud \200\231s phenomenon (RP). Abnormal nail-fold capillaroscopy. SSc-selective antibod ies (ACA, anti-Scl-70, anti-RNA polymerase I/III). Diagnosis based on objective documentation of Raynaud \200\231s and one other criterion OR subjective documentation of Raynaud \200\231s and BOTH other criteria. Systemic sclerosis sine scleroderma <2% \200 \200 \200 Raynaud \200\231s phenomenon visceral manifestations. SSc-selective antibodies. No skin inv olvement. Etiology and pathophysiology SSc is a chronic auto-in \202 ammatory syndrome, in which abe rrant behavior of both innate and adaptive elements of the immune system is evident. Endoth elial cell dysfunc- tion and damage is prominent. Microvascular damage with vasospasm and v essel dropout, and excessive deposition of extracellular matrix tissue lead to the main cli nical manifes- tations of disease. Aberrant innate and adaptive immune responses An aberrant immune response in SSc is most ob vious in the \202 orid cutaneous in \202 ammatory in \201 ltrate, which often accompani es early dcSSc. \200 The mononuclear in \201 ltrate consists of T cells (mainly CD4+), macrophages, natural kil ler cells, mast cells and, rarely, B cells. CHAPTER 8 Autoimmune connective tissue diseases 265 Oligoclonal expansion of CD4+ T cells in SSc skin lesions has been shown, suggesting local antigen-dependent T cell activation. Activated CD4+ T cells produce IL-4, IL-17 and TGF-B, which stimulate endothelial cells to express HLA and adhesion molecules, promotes PDGF rele ase, \201 broblast proliferation, and CTGF secretion, which promotes synthesis of collage n. In \202 ammatory cells (neutrophils, eosinophils, and lym- phocytes) are also present i n the bronchoalveolar lavage \202 uid of SSc patients with interstitial lung disease. As cutaneous fibrosis progresses, the inflammatory in \201 ltrate recedes, and a similar tran sition may occur in other tissues. It has been noted that graft-versus-host disease often r esembles SSc and it has been hypothesized that microchimerism \200\223 persistence of allo reactive cells either from maternal blood at birth or from fetal blood at parturition \200 \223 may drive the chronic (allo)immune response which manifests as SSc. Although B cells a re scarce in skin in \201 ltrates, an abnormal humoural response is well recognized by vir tue of the characteristic autoantibodies associated with SSc (e.g. anti- centromere, anti-S cl70, and anti RNA polymerase I/III). The role of autoantibodies in pathophysiology is unce r- tain, but anti-endothelial antibodies may mediate endothelial damage and anti- \201 bro blast antibodies may contribute to synthesis of matrix constituents. vascular smooth muscle cells of the tunica media (Figure 8.5). Endocrine, paracrine, autocr ine, and neuronal stimuli enable the resistance vessels to respond both to local (ischaemia /in \202 ammation) and systemic (e.g. maintenance of blood pressure) needs. \200 Dysregulation of vasomotor tone in SSc may re \202 ect intrinsic abnormalities of endothel ial cells or vascular smooth muscle cells, aberrant production of local soluble mediators ( e.g. from endothelial cells, platelets, or leucocytes), or neuroendocrine abnormalities. Ab normalities suggested in SSc-associated RP include: \200 endothelial cell damage, e.g. by infection, anti-endothelial antibodies, cytotoxic T cells, free radicals; increased contractile response to sudden cooling and to A2-adrenergic agoni sts; this appears to be mediated by the A2c-adrenoceptors and is associated with increased activity of protein tyrosine kinase; increased levels of endothelin and/or increased densit y of endothelin receptors; reduction of calcitonin gene-related peptide (CGRP) release from sensory afferent nerve endings (possibly related to ischaemic tissue damage); aberrant act ivation of platelets and/or coagulation cascade; oxidative stress probably contributes to e ndothelial cell damage; release of vasomotor mediators from mononuclear cells (e.g. mast ce lls) in underlying tissue. Endothelial dysfunction and microvascular disease Vascular tone is determined by the balanc e between vasoconstrictive and vasodilatory stimuli received by the Abnormal vasomotor responses are evident early in the pathophysiology of SSc. Hypotension (sensed by juxtaglomerular) VSMCs in kidney) Inflammation Adrenal medulla Shear stress to endothelium Platelets Bradykinin Norepinephrine Angiotensin II Thromboxane A2 Blood Endothelin Serotonin Depletion of ATP in tissues Endothelium Endothelial damage or exposure to toxins eNOS Adenosine Prostacyclin Nitric Oxide Vascular Smooth Muscle Cell VASOCONSTRICTION VASODILATION Calcitonin Gene-Related Peptide Histamine Adenosine Acetylcholine Norepinephrine Mast Cells Parasympathetic nerves Sympathetic nerves Sensory Afferent Nerves Figure 8.5 Factors in \202 uencing vasomotor tone. SYSTEMIC SCLEROSIS 266 Clinical features Raynaud \200\231s phenomenon RP is the initial symptom in more than 90% o f SSc cases. Transient vasospasm leads to classic color changes in the digits: white (ischa emia), blue (cyanosis), and red (reperfu- sion). This is usually triggered by the cold, smo king, or emotional stress. RP usually affects digits, but it can also affect other areas in cluding the tip of the nose, ear lobes, tongue and patellae (see Plate 5). \200 As disease progresses, structural changes in the walls of small and medium sized arteries l ead to \201 xed narrowing and ultimately occlusion of vessel lumens. Intimal proliferatio n and \201 brosis is mediated by migration of vascular smooth muscle cells into the intim a, their differentiation into myo \201 broblasts and the deposition of extracellular matri x proteins. The combination of this microvascular remodeling with vasomotor disturbance res ults in ischaemia-reperfusion cycles, which results in tissue damage by free radical format ion, endothelial activation (increased adhesion molecules, procoagulant surface) and platel et activation (release of more vasoconstrictive and procoagulant factors). Narrowing and ev entual occlusion of small arteries leads to digital ischaemia, pulmonary arterial hypertens ion, renal ischaemia and damage, and probably also dysfunction and damage in the gut and ot her organs. Primary RP \200\223 affects 10 \200\22315% of the general population and is commoner in wo men. RP occurring in the context of an AICTD is secondary and this may be distinguished fro m primary RP by: \200 \200 \200 \200 \200 onset after age 30 years; severe ischaemic pain; presence of elevated ANA titres; abnormal nail-fold capillary architecture; digital ulceration. Animal models \200 Skin and cutaneous features Scleroderma typically involves skin tightening and induration, with subsequent thickening and tethering to underlying tissues. \200 Demonstrate that certain genetic and environmental factors can reproduce aspects of the SSc phenotype. The tight skin (tsk1) mouse, a model for scleroderma, has duplication within th e \201 brillin 1 (FBN1) gene, which encodes a major constituent of extracellular matrix. Scleroderma can also be induced by bleomycin in a genetically susceptible mouse strain. The University of California Davis line 200 (UCD 200) chickens mimic the vascular damage since they develop early endothelial cell apoptosis followed by excessive perivascular collagen deposition. Scleroderma skin becomes shiny and smooth with loss of hair, sweat glands, and skin creases . Sclerodactyly is scleroderma in digits, which results in contractures and loss of functio n. Microstomia results from sclerodermatous changes around the mouth, and can impede access for dental work and, in severe cases, impair eating. Sicca syndrome \200\223 dry eyes, dr y mouth contributing to dysphagia, dyspareunia. Telangiectasiae \200\223 dilated blood ves sels, mainly capillaries and arterioles; these occur commonly on the face and upper trunk a nd blanch when pressure is applied. Calcinosis \200\223 calcium deposits in skin and subcu taneous tissue commonly in the hands, legs, and around joints. Calcinotic plaques may becom e inflamed and often ulcerate, releasing a white chalky material. Musculoskeletal Joint pains, stiffness, and reduced range of movement due to the overlying skin tightness are common features. \200 Synovitis and muscle weakness may indicate overlap with other autoimmune connective tissue diseases. Symmetrical non-erosive arthritis may occur, particularly early on in the disease course. Skin and joint capsule \201 brosis cause contractures, which restrict joint move ment. A mild chronic myopathy is common and may be associ- ated with slight elevation of mu scle enzymes. Myositis occasionally occurs in SSc. Figure 8.6 Cross-section of a digital artery from a patient with lcSSc showing intimal prol iferation and luminal narrowing (with permission from Professor A. Freemont). Risk factors \200 \200 Gastrointestinal Gut involvement occurs in about 90% of patients with SSc and is serious in about 50%. \200 SSc in \201 rst degree relative \200\223 54-fold increased risk. Males, African-American s, older age group \200\223 generally more severe disease. Exposure to environmental agent s (see above). Anti-centromere antibody is a risk factor for recurrent digital ulceration. Anti-Scl-70 antibody is a risk for interstitial lung disease. Anti-RNA polymerase III \200 \223 is a risk for severe skin involvement and scleroderma renal crisis. Glucocorticoids in the preceding month are associated with a 24-fold risk of scleroderma renal crisis. Initially, this appears to re \202 ect dysfunction of the mye- nteric nerves, but subseque ntly atrophy of normal tissue and replacement with \201 brous tissue underlie the reduced motility and exocrine insuf \201 ciency, which characterizes SSc-bowel disease. Oesophage al dysmotility gives rise to dysphagia and heartburn. Oesophageal stricture and Barrett \200\231s metaplasia occur rarely. Gastroparesis leads to loss of appetite and nausea. \200 \200 CHAPTER 8 Autoimmune connective tissue diseases 267 Small bowel dysmotility is associated with post- prandial bloating, pseudo-obstruction, and pneumatosis intestinalis. Primary biliary cirrhosis occurs in 3% of lcSSc patients. Stasi s favors bacterial overgrowth. Any exocrine insuf \201 ciency can contribute to malabsorp- tion. Large bowel dysmotility causes alternating constipation and diarrhea, pseudo-obstruc tion, and, occasionally, perforation. Anal sphincter dysfunction is common (although rarely discussed) and may lead to fecal incontinence. Telangiectasiae occurring in the gastrointe stinal tract may lead to bleeding and iron deficiency anemia. Watermelon stomach (gastric a ntral vascular ectasia) occurs in 5% SSc and may be the presenting feature. Respiratory Interstitial lung disease (ILD) occurs in about 80% of patients with SSc, but i s clinically signi \201 cant in about 40%. Pulmonary arterial hypertension (PAH) probably occurs in 12% patients with lcSSc (estimates vary widely). In dcSScl, the hidebound chest results in a ventilatory defect. Patients with oesophageal dysmotility are at risk from asp iration pneumonia. Pleurisy and pleural effusion may occur, but much less commonly than in SLE. \200 \200 Cardiac Pericardial effusions occur, although less commonly than in SLE. Myocardial \201 brosis may lead to arrhythmias and/or conduction disturbances. Atrial \201 brillation occ urs in 25% and ventricular ectopics/arrhythmias in up to 50%. Coronary artery disease does not appear to be increased compared with the general population. Right heart failure may o ccur secondary to interstitial lung disease or PAH. Renal involvement Scleroderma renal crisis is a serious and potentially fatal complication, which occurs mainly in dcSSc (incidence 10 \200\22320%), but can also occur in lcSSc and s cleroderma sine scleroderma. Typical features are summarized below. The incidence and outco me of renal crisis has been improved by the use of angiotensin converting enzyme (ACE) inhi bi- tors, but approximately 50% of patients still require dialysis. Differential diagnosis of RP AICTD or vasculitis \200 \200 \200 \200 \200 \200 \200 \200 \200 Systemic sclerosis. Systemic lupus erythematosus. Rheumatoid arthritis. Cryoglobulinaemia. Primary Sj gren \200\231s. Dermatomyositis/polymyositis. Mixed connective tissue disease. Giant cell arteritis/Takayasu disease. Thromboangiitis obliterans. Classical features of scleroderma renal crisis \200 \200 \200 \200 \200 \200 \200 \200 dcSSc within 5 years of diagnosis. Abrupt onset of BP >160/90 mmHg. Hypertensive retinopath y grade III/IV. Rapid rise in serum creatinine. Elevated plasma renin. Microangiopathic hae molytic anemia. Hypertensive encephalopathy; often seizures. Pulmonary oedema. Mechanical \200 Frost bite. \200 Trauma. \200 Vibration. Reduced macrovascular supply \200 \200 Atherosclerosis. Thoracic outlet obstruction. Other \200 \200 Drugs \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Hypothyroidism occurs in up to 40%. Carpal tunnel syndrome is often associated with the oed ematous/in \202 ammatory early stage of sclerodactyly. Trigeminal or glossopharyngeal neur algia are the most common cranial neuropathies. Peripheral and autonomic neuropathies also occur. Erectile dysfunction is under-recognized since patients tend not to discuss. Amphitamines. Bleomycin. Cisplatin. Vinblastin. B \200\223blockers. Cocaine. Nicotine. Ergo t preparation. Clonidine. Interferon. Methysegide. Sympathomemetics. \200 Key features in the history Raynaud \200\231s phenomenon Classic triphasic (red/white/blue) color changes, but all colors not required for diagnosis of RP. Historical features sugges tive of secondary RP include age >30 years at onset and severe ischaemic pain. Miscellaneous \200 \200 \200 \200 \200 Polycythemia vera. Hypothyroidism. Carpal tunnel syndrome. Paraneoplastic. Polyvinyl chlori de. Skin and cutaneous features Scerloderma skin (e.g. hands, face) feel tight and swollen. The re may be noticeable dif \201 culty opening mouth wide or chalky extrusions from skin. \200 Sicca symptoms: dry gritty eyes, dry mouth, vaginal soreness particularly on intercourse. D igital ulcers: location, past and present. SYSTEMIC SCLEROSIS 268 Investigations Laboratory investigations for annual review Hematology \200 Gastrointestinal symptoms: heartburn, bloating, abdominal pain, nausea, vomiting, constipat ion, diarrhea, unintended weight loss, fecal incontinence. Cardiorespiratory: dyspnoea, cou gh, chest pains. Musculoskeletal: joint pains, swelling, stiffness; muscle pain/weakness. N europathy: paraesthesiae, numbness, erectile dysfunction. Lifestyle: smoking, occupational/ recreational history (exposure to unusual solvents?). Drugs: include history of possible tr iggering agents for SSc and use of drugs associated with common co- morbidity, e.g. NSAIDs. \200 FBC and ESR may show evidence of anemia of chronic disease. An iron de \201 ciency anemia may be present in associa- tion with peptic ulcers (NSAID use?) or bleeding gut telangiecta siae. High platelet count and ESR are features of acute phase response and indicate ongoing in \202 ammation. Low white blood cells (WBCs), neutropenia, and/or lym- phopaenia and th rombocytopaenia may indicate the presence of an overlap autoimmune connective tissue diseas e. Key features on examination Skin involvement Sclerodacytly, distribution of scleroderma (li mbs, trunk, and face?), telangectasiae, calcinosis; microstomia can be assessed by incisor to incisor distance. Biochemistry \200 Renal function tests including estimated creatinine clearance from Cockcroft \200\223Gault formula: Estimated CrCl = {[140 \200\223 age (years)] \227 weight (kg)}/serum creat ( mol/l) (mul tiply by 0.85 in women). Microvascular Objective demonstration of vasomotor (red/white/blue) disturbance in digits, nose, patellae. Abnormal nail-fold capillary architecture in a patient with RP indicates th e presence of an AICTD and, in some centers, is used as a staging examination. Nailfold cap illaroscopy can be per- formed with an ophthalmoscope, using a drop of oil or gel (e.g. KY gel) as a magnifying lens. Digital ulceration, resorp- tion of \201 nger pulps and slow c apillary re \201 ll indicate digital ischaemia. \200 Liver function tests: screen for PBC or drug toxicity. Creatine kinase: marked elevation in dicates the presence of myositis. Thyroid function tests: hypothyroidism common. Bone bioch emistry including PTH and vitamin D, since malabsorption is common. Vitamin B12, folate, an d ferritin. Fasting lipid profile: SSc can be associated with increased risk of cardiovascu lar disease. \200 \200 Immunology \200 \200 ANA \200\223 positive in about 95% of patients with SSc. ENAs \200\223 will be performed when ANA is positive. See above for associations with anti-centromere, anti-Scl-70 and anti -RNA polymerase III. Anti- \201 brillarin antibodies (UN3RNP) are measured in some special ist centers and associated with pulmonary arterial hypertension. Other autoantibodies may b e positive in overlap AICTD syndromes, e.g. rheumatoid factor (RF), anti-dsDNA (SLE), lupus anticoagulant and antiphospholipid antibodies (APLS), anti-mitochondrial antibodies (PBC). Coeliac disease antibodies (IgA anti-tissue transglutami- nase or anti-endomysial antibodi es, but also check Igs to rule out IgA deficiency). Consider in patients with malabsorption (CD and SSc may co-exist). Complement C3 and C4, ANCA, cryoglobulins \200\223 consider if clinical picture suggests small vessel vasculitis. Immunoglobulins and protein electrophor esis, Bence- Jones protein estimation \200\223 request at diagnosis as part of a screen fo r neoplasia. (a) (b) Figure 8.7 Nail-fold capillaries from (a) healthy control subject and (b) patient with SSc showing abnormal widened capillary loops. (with permission from Dr A. Herrick) (see also Pl ate 9). Macrovascular Normal peripheral pulses exclude macrovascular causes of peripheral ischaemia . Check blood pressure to screen for renal involvement. Other \200 Imaging Radiographs \200 Check pulse rhythm and look for signs of right heart strain or failure. Chest expansion may be reduced in dcSSc (hidebound chest). Bibasal crepitations suggest ILD. Joints \200\223 assess range of movement and for synovitis. Muscles \200\223 look for wasting and reduced power. Urinalysis \200\223 screen for proteinuria in renal disease. CXR \200\223 useful at diagnosis as part of a screen for neopla- sia, if the diagnosis is unclear. Useful post-diagnosis if new cough or dyspnoea, although unnecessary if a high res olution CT chest is planned. In cases of suspected pneumoperitoneum, look for air under the diaphragm on CXR. \200 \200 CHAPTER 8 Autoimmune connective tissue diseases 269 High resolution CT (HRCT), US, and MR \200 Treatment High resolution CT of the chest may reveal honeycombing and ground glass opacities typical of nonspeci \201 c interstitial (NSIP) associated with AICTDs; may also show patulous esop hagus. In cases of aspiration pneumonia, changes will predomi- nantly affect right middle l obe. CT abdomen/pelvis may be included with the HRCT chest at diagnosis, as part of a scree n for underlying neoplasm. US or CT abdomen may be performed to investigate liver disease, or as investigation for abdominal pain/distension; dilated loops of bowel may be evident in dysmotility. Barium swallow may be performed to demonstrate oesophageal dysmotility. Objectives of management \200 \200 Con \201 rm diagnosis and identify any co-morbidity. Initial and annual screening program for complications or associated co-morbidity. Modi \201 cation of microvascular disease. M odi \201 cation of in \202 ammatory disease. Management of associated co-morbidity. \200 \200 Modi \201 cation of microvascular disease Several agents have been shown to have effects o n endo- thelial function, proliferative changes in the vessel wall, and/or to be anti-in \202 ammatory or anti-coagulant. These are listed below, since it is likely that they modif y the processes underlying the proliferative vasculopathy char- acteristic of SSc. The best data for clinical ef \201 cacy of many of these drugs has emerged from clinical trials of treatment of PAH and, more recently, of digital ulceration. However, further study is requ ired to subject all these agents to appropriate clinical trial, to delineate the ef \201 c acy for differ- ent microvascular beds and to understand whether drugs synergize in combina tion. Endoscopy \200 Upper GI endoscopy is required as investigation of possible peptic ulcer disease, and to mo nitor Barrett \200\231s esophagus and watermelon stomach. Colonoscopy may be required if a colonic neoplasm is suspected. AVOID glucocorticoids \200\223 prednisolone >15 mg per day (and possibly also lower doses) is associated with increased risk of scleroderma renal crisis. Other investigations \200 Pulmonary function tests \200\223 spirometry and transfer factor \200\223 are useful to s creen for and monitor ILD and pulmonary arterial hypertension (PAH). Lung volumes and trans fer factor decrease proportionately in ILD, but isolated or disproportionate drop in transf er factor should prompt further investigations for PAH (see \200\230The Chest \200\231, p. 54). The six-minute walk test is useful for monitoring patients with PAH. Echocardiogram \200\223 to detect pericardial effusion and as a screening test for PAH. In the presence of tricuspid regurgitation an estimated mean pulmonary artery pressure can be obtained. If th is value is > 35 mmHg, right heart catheterization is recommended to measure pulmonary arte ry pressure accurately. ECG \200\223 useful screen for arrhythmia, ischaemia, LVH; may sug gest right heart strain in PAH. Bone densitometry should be considered especially in post-m enopausal women or if fragility fractures have occurred. ACE inhibitors and angiotensin receptor blockers \200 ACE inhibitors have improved outcome in scleroderma renal crisis (1-year survival 76% in AC E inhibitor treated group instead of 18% in group without ACE inhibitors). It is likely tha t ACE inhibitors decrease the incidence of renal crisis, but this remains unproven. Unfortu nately, the recent QUINS study indicates that ACE inhibitors have no effect on the occurren ce of dig- ital ulcers or other vascular manifestations of lcSSc over 2 \200\2233-year trea tment period. Angiotensin receptor antagonists may be effective for digital microvascular d isease. In an RCT, losartan 50 mg od was superior to nifedipine in reducing frequency and s everity of RP attacks. Endothelin receptor blockers \200 Endothelin receptor antagonists (ERA) have demon- strated ef \201 cacy for both PAH and di gital ulceration in DBRCTs. The non-selective ERA bosentan (125 mg bd) improved 6-min walk and pulmonary haemodynamics in SSc-PAH patients included in two placebo-controlled trials. The open-label extension phase of these studies indicates survival in bosentan group of 86 % at 1 year and 73% at 2 years. The selective endothelin receptor A antagonist, sitaxsen- t an has also been shown to be effective in AICTD- associated PAH. The RAPIDS trials in SSc p atients with digital ulceration have shown that bosentan does not improve healing of existi ng ulcers, but that it decreases the incidence of new ulcers by approximately 50%. Bosentan and sitaxsentan are licensed to treat PAH and bosentan for SSc with ongoing digital ulcer disease. Differential diagnosis \200 Eosinophilia \200\223myalgia syndrome: myalgia, oedema, thickening and induration of the sk in, marked blood eosi- nophilia; associated with L-tryptophan ingestion. Eosinophilic fasci itis: tenderness and swelling of the extremities (orange-peel con \201 guration); associat ed with peripheral eosinophilia (see, p. 310). Primary biliary cirrhosis: ANA positive, oft en with rashes and telangectasiae. Primary pulmonary hypertension: distinguish from sclerod erma sine scleroderma. Toxic oil syndrome (adulterated rape seed oil). Porphyria cutanea ta rda. Radiation exposure: causes \201 brosis. Amyloidosis: waxy cutaneous in \201 ltratio n and involve- ment of viscera (see, p. 496). \200 \200 \200 Prostanoids. Continuous intravenous epoprostenol is the gold standard of treatment for prim ary PAH, since it improves exercise capacity and survival and is used in SSc-PAH patients w ho SYSTEMIC SCLEROSIS 270 deteriorate despite treatment with an ERA. Courses of intravenous iloprost are used cyclica lly to reduce frequency and severity of RP attacks and as salvage therapy for digital ulcer ation. Further study is required to de \201 ne the optimal duration and periodicity of the se courses. Oral and inhaled preparations of prostanoids are being studied, but current evi dence suggests limited ef \201 cacy at best. Constipation: stool softeners and bulking agents, e.g. lactulose and fybogel. Diarrhea: lop eramide. Malabsorption: refer to dietician; oral vitamin D3, and calcium and iron sulfate s upplementation and parenteral administration of vitamin B12. Occasionally, parenteral iron and ergocalciferol may be necessary. Total parenteral nutrition is required in a minority. Pruritis: moisturizers, anti-histamines; tricyclic antide- pressants may be helpful. Calcin osis: surgical removal often successful; assess local blood \202 ow since ischaemic tissu e may not heal. Various drugs have been tried, with positive case reports [diltiazem, bisph osphonates, low-dose (1 mg) warfarin, minocycline], but no RCT data are available. Chronic renal failure: liaise with renal team \200\223 phosphate binders, alfacalcidol, erythropoi etin, BP control and, ultimately, dialysis may be required. Arthritis may be treated with N SAIDs and intra-articular glucocorticoids. Aggressive inflammatory disease: e.g. myositis i n overlap syndromes may necessitate systemic glucocorti- coids, but ensure the patient is t aking an ACE inhibitor and monitor BP and renal function. Hypothyroidsism: replacement ther apy. Osteoporosis: ensure adequate vitamin D levels, no secondary hyperparathyroidism, and treat with bisphos- phonate if T-scores \211 \200\2232.5 if alendronate is not tolerated due to dysphagia/dyspepsia, use monthly oral ibandronate 150 mg or parenteral ibandronate 3 mg every 3 months. Sicca symptoms: see chapter on Sj gren \200\231s syndrome. ILD: vaccin ate against influenza, Pneumococcus and Haemophilus in \202 uenzae; prompt treatment of in tercur- rent infection; see \200\230The Chest \200\231 in Chapter 3, \200\230Organ involv ement in rheumatological disease \200\231. \200 Other therapies \200 Phosphodiesterase V inhibitors: Sildena \201 l 20 mg tds improved 6-min walk distance and pulmonary haemody- namics in a DBPRCT of AICTD-associated PAH. Case reports suggest that it may be also be effective for RP. Sildena \201 l is licensed as Revatio for use in PAH. Ca lcium channel blockers: e.g. nifedipine, are used for RP, but probably provide symptomatic relief only. They should be avoided in patients with SSc PAH. Nitrates: GTN patches placed on the forearm are sometimes used in severe digital ischaemia. Selective serotonin receptor antagonists (SSRIs): e.g. \202 uoxetine have vasodilator activity and have been shown to reduce RP attack severity. Alpha-1 antagonists: prazosin has been shown to improve RP, but the effect is modest. Anticoagulants are generally used in patients with PAH. However, ris ks may outweigh bene \201 t in patients with gastrointestinal telangectasiae due to risk o f GI bleed. Antiplatelet agents: prostacyclin inhibits platelet activation. Aspirin is rare ly used due to increased risk of dyspepsia and GI bleeding. Clopidogrel is an alternative b ut ef \201 cacy in SSc/RP is unknown. Statins improve endothelial function in a variety of contexts are currently being studied in SSc microvascular disease. \200 \200 Immunosuppression \200 Mycophenolate mofetil: retrospective analysis of patients with SSc-ILD suggest improvement; further investigation required. D-penicillamine: RCT demonstrated lack of ef \201 cacy fo r skin disease. Methotrexate: Three RCTs together show, at best a minimal effect on skin an d ILD. Azathioprine: appears to be of no/limited ef \201 cacy in skin and lung disease. Ci closporin A: trial data lacking, but known to cause hypertension and vasculopathy \200\223 avoid. Cyclophosphamide: An RCT in SSc with ILD compared placebo with IV cyclophosphamide (6 pulses) and low-dose prednisolone, followed by azathioprine; there were no signi \201 c ant differences in lung volume or transfer factor between placebo and active groups. Anti-T NFA biologics, rituximab, alemtuzumab: anecdotal reports only. Imatnib (tyrosine kinase inh ibitor, which inhibits PDGF signaling): case report of ef \201 cacy in severe dcSSc. Haema topoietic stem cell transplantation is being studied in two controlled trials (ASTIS in Eur ope and SCOT in USA). Treatment-related mortality has fallen to 2.5% from 12.5% reported in 2002, and preliminary reports indicate skin and microvascular disease may be improved. Multidisciplinary approach \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Chest physician. Specialist PAH unit. Gastroenterologist. Dentist. Renal physician. Dermato logist. Radiologists. Dietician. Orthopedic surgeon. Vascular surgeon. Physiotherapist \200\223 exercises to retain mobility and to optimize chest function. Occupational therapis t \200\223 hand exercises and aids/ strategies for overcoming disabilities. Speech therapi sts \200\223 for assessing and advising on severe oesophageal dysmotility. Patient advice \200 \200 Avoid smoking. Keep core and extremities warm, e.g. put coat on several minutes before leav ing house; use thermal gloves and socks in cold temperatures. Protect \201 ngers with glo ves whenever possible, e.g. dish washing and gardening. Seek medical advice with new digita l ulcers. Maintain careful oral hygiene and arrange regular dental checks. Management of associated morbidity See \200\230Patient Advice \200\231 for lifestyle measu res. \200 \200 \200 Dyspepsia: proton pump inhibitors and anti-acids. Dysmotility: metaclopramide to aid gastri c emptying. CHAPTER 8 Autoimmune connective tissue diseases 271 \200 For patients with dysphagia \200\223 avoid dry abrasive foods. For patients with gastroint estinal re \202 ux \200\223 avoid eating late in the evening, raise head of bed on blocks . For patients with delayed gastric emptying or small bowel dymotility \200\223 eat little and often. Gentle regular aerobic exercise to maintain cardiovascular/ respiratory \201 tness. Hand exercises to maintain range of movement. \201 ngers (L and R), thigh (L and R), leg (L and R), foot (L and R), score each of 20 sk in regions as follows: 0 = normal 1 = possible thickening 2 = de \201 nite thickening but mobile 3 = thickened and tethered Note: neck and back are sometimes omitted. Patient organizations Raynaud \200\231s & Scleroderma Association, 112 Crewe Road, Alsager, Cheshire, ST7 2JA, UK. Tel: 01270 872776. Freephone: 0800 9172494 (for UK enquiries only). www. raynauds.org.uk The Scleroderma Society, 3 Caple Road, London NW10 8AB, UK. Tel: 020 8961 4912. www.sclerodermasociety.co.uk Follow-up \200 Patients with rapidly-progressive disease, and/or com- mencing new therapies may need 2 \200\2233-monthly review. 6-monthly follow-up is appropriate for patients within the \201 rst 5 years of disease. Annual follow-up may be appropriate for patients with- out severe organ involvement >5 years post-diagnosis. Urinalysis, blood pressure monitoring should be routinely performed in the follow-up visits. ICD-10 codes M34 M34.1 M34.2 J99.1* G73.7* SSc CREST syndrome SSc induced by drugs and chemicals SSc with lung involvement SSc with my opathy Prognosis and natural history lcSSc \200 \200 5-year survival rate reported to be up to 86%. PAH is the most frequent cause of death. References Badesch DB, Hill, NS, et al. Sildena \201 l for pulmonary arterial hyper- tensi on associated with connective tissue disease. J Rheumatol 2007; 34: 2417 \200\22322. dcSSc \200 5-year survival of patients with severe ILD, renal crisis, or cardiac disease each around 5 0%. 5-year survival of dcSSc patients with renal crisis treated with ACE inhibitors approxi mately 70% (compared with less than 10% in the era before ACE-inhibitors were available). R isk of developing severe organ involvement is greatest during the \201 rst 5 years of dcS Sc. 10-year survival of dcSSc who do not develop severe organ involvement within the \201 rst 5 years is approxi- mately 80%. Charles C, Clements P, Furst DE. Systemic sclerosis: hypothesis- driven treatment strategies. Lancet 2006; 367: 1683 \200\22391. DeMarco PJ, Weisman MH, et al. Predictors and outcomes of scleroderma renal crisis. Arthritis Rheum 2002; 46: 2983 \200\2239. Denton CP, Humbert M, et al. Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a sub- group analysis of the pivotal clinical trials and the ir open-label extensions. Ann Rheum Dis 2006; 65: 1336 \200\22340. Dziadzio M, Denton CP, et al. Losartan therapy for Raynaud \200\231s phenomenon and sclerod erma: clinical and biochemical \201 ndings in a \201 fteen-week, randomized, parallel-g roup, controlled trial. Arthritis Rheum 1999; 42: 2646 \200\22355. Resources Assessment Tools \200\223 general measures \200 \200 \200 \200 Girgis RE, Frost AE, et al. Selective endothelin A receptor antago- nism with sitaxsentan f or pulmonary arterial hypertension associated with connective tissue disease. Ann Rheum Dis 2007; 66: 1467 \200\22372. Scleroderma-modi \201 ed health assessment questionnaire. Creatinine and creatinine cleara nce. Blood pressure and urinalysis for proteinuria. Raynaud \200\231s Condition Score \200 \223 daily self-assessment of RP activity using a 0-10 ordinal scale. Rodnan Skin Score. Or al aperture. Pulmonary function tests: vital capacity to monitor restrictive lung disease; transfer factor to monitor pulmonary vascular disease; 6-min walk distance. Echocardiograph y \200\223 estimated mean pulmonary arterial pressure and right heart catheterization. Hyd rogen breath tests. BMI. FBC \200\223 monitoring for anemia. Gliddon AE, Dore CJ, et al. Prevention of vascular damage in sclero- derma and autoimmune R aynaud \200\231s phenomenon: a multicenter, randomized, double-blind, placebo-controlled tr ial of the angiotensin-converting enzyme inhibitor quinapril. Arthritis Rheum 2007; 56: 383 7 \200\22346. \200 \200 Henness S, Wigley FM. Current drug therapy for scleroderma and secondary Raynaud \200\231s phenomenon: evidence-based review. Curr Opin Rheumatol 19: 611 \200\22318. Herrick AL. Pathogenesis of Raynaud \200\231s phenomenon Rheumatol 2005; 44: 587 \200\22396. Herrick AL, Worthington J. Genetic epidemiology of systemic sclerosis. Arthritis Res 2002; 4: 165 \200\2238. \200 \200 Hoyles RK, Ellis RW, et al. A multicenter, prospective, randomized, double-blind, placebo-c ontrolled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathi oprine for the treatment of pulmonary \201 brosis in scleroderma. Arthritis Rheum 2006; 5 4: 3962 \200\22370. Assessing Raynaud \200\231s (condition score) Circle below the number that best indicates t he dif \201 - culty you had today with your Raynaud \200\231s condition: Extreme No 0 1 2 3 4 5 6 7 8 9 10 dif \201 culty dif \201 culty LeRoy EC, Black C, et al. Scleroderma (systemic sclerosis) classi \201 - cation, subsets a nd pathogenesis. J Rheumatol 1988 15: 202 \200\2235. Korn JH, Mayes M, et al. Digital ulcer s in systemic sclerosis: preven- tion by treatment with bosentan, an oral endothelin recept or antagonist. Arthritis Rheum 2004; 50: 3985 \200\22393. Kuwana M. Potential bene \201 t of statins for vascular disease in systemic Rodnan skin score For face, neck, anterior chest, abdomen, upper back, lower back, upper ar m (L and R), forearm (L and R), hand (L and R), sclerosis. Curr Opin Rheumatol 2006; 18: 594 \200\223600. LeRoy EC, Medsger TA, Criteria for the classi \201 cation of early systemic sclerosis. J Rheumatol 2001; 28: 1573 \200\2236. SYSTEMIC SCLEROSIS 272 Sunderk tter C and Riemekasten G. Pathophysiology and clinical consequences of Raynaud \200\231s phenomenon related to systemic sclerosis. Rheumatol 2006; 45: iii33 \200\2235. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impac t of epoprostenol therapy. Circulation 2002; 106: 1477 \200\22382. Teixeira L, Mouthon L, et al. Mortality and risk factors of sclero- derma renal crisis: a F rench retrospective study of 50 patients. Ann Rheum Dis 2008; 67: 110 \200\22316.