Monitoring \200 Patients with any form of TIN should have their renal function monitored closely. Urine cal cium is thought to be a sensitive measure of sarcoidosis activity due to increased vitamin D activity in active granulomata. Patients on prolonged courses of GCs require monitoring f or the development of diabetes mellitus and glaucoma. Adequate calcium and vitamin D3 suppl ements and, if necessary speci \201 c osteoporosis therapy needs to be given as per guidel ines [e.g. American College of Rheumatology Guidelines or Royal College of Physicians (RCP) (UK)]. Risk factors \200 Diffuse skin involvement, GC use, ciclosporin, and joint contractures are associated with a n increased risk of SSc renal crisis. SSc renal crisis is associated with autoantibodies to RNA polymerase III and is less frequent in the presence of anti-centromere antibodies. In APLS, presence of coagulation factor mutations such as factor V Leiden, are associated with an increased risk of clinical activity including renal disease. There is an association be tween APLS and HLA-DR7 in several ethnic groups and HLA-DQ7 in some groups. Acute renal failure Acute renal failure, renal dysfunction developing and/or worsening over a period of days, can complicate several rheumatological disorders in the absence of abnor malities of the urinalysis. This presentation occurs in systemic scle- rosis (SSc; see also p. 264 \200\223272, the antiphospholipid syndrome (APLS; see also p. 274 \200\223280 and v ascular disease, and also, following diagnoses, commonly considered to have a nephritic, ne phrotic or TIN presentation when they have a benign or non-diagnostic urine sediment. Key clinical features \200 Thrombotic microangiopathies are characterized by haemolytic anemia and thrombocytopaenia. Both SSc renal crisis and APLS may result in dramatic elevations in blood pressure and acut e retinal changes, proteinuria and haematuria and pulmonary oedema. Not all patients with S Sc renal crisis will have typical skin manifestations of SSc. Other causes of microangiopat hy must be excluded: haemolytic-uraemic syndrome/thrombotic thrombocy- topaenic purpura and malignant hypertension. Use of medications known to increase the risk of SSc renal crisis, such as GCs or ciclosporin. Ciclosporin and other calcineurin inhibitors may induce thromb otic thrombocytopaenic purpura independent of SSc. Epidemiology \200 Autopsy studies indicate up to 80% of patients with diffuse cutaneous SSc have renal damage , although only 50% will have a clinical manifestation. Severe renal crisis can develop in a substantial minority of patients with SSc (mainly diffuse cutaneous disease). THE KIDNEY 80 renal dysfunction is associated with hyperparathyroidism that can cause bone pain and arthr algia or haemodialysis may be associated with the accumulation of B2 microglobulin leading to a secondary amyloidosis. Investigations \200 Clinical details are of primary importance in the rapid and accurate diagnosis of these con ditions. The underlying medical condition must be established. Renal biopsy con \201 rms a microscopic angiopathy, but will not distinguish between causes. The vast majority of patients with CKD do not progress to end stage renal failure but die o f cardiovascular disease. The management of cardiovascular risk is a important in managing these patients. Epidemiology and etiology \200 Treatment \200 Angiotensin conver ting enzyme inhibitor-based anti-hypertensive treatments are the mainsta y of treat- ing SSc renal crisis. Serum creatinine may rise initially, but the relaxation o f the efferent arteriole will reduce intra- glomerular pressure and reduce scarring, as wel l as increase interstitial blood \202 ow. Control of blood pressure with other agents may also be required. Intravenous prostacyclin can help improve microvascular lesions in SSc r enal crisis, but experience remains largely anecdotal. Rapidly progressive renal failure in APLS may respond to plasma exchange. Chronic anticoagulation in patients with APLS with a significant thrombotic complication, such as renal involvement, should be considered. Chronic glomerulopathy is an uncommon complication of RA. The most common pathologic lesion in this disorder is a mesangial proliferative lesion. Chronic urate nephropathy is now unc ommon. The decrease in urate nephropathy may be partially attributed to the decline in chro nic lead exposure, an important aetiological agent in saturnine gout in which lead was a ma jor contributor to renal dysfunction. Urate nephropathy is characterized by an elevation in serum urate out of keeping with the degree of renal dys- function (urate >535 mol/l in p atients with mild renal disease and >700 mol/l in patients with a creatinine >176 mol/l ). Up to 80% of patients with diffuse cutaneous SSc will have renal damage and up to 50% wi ll have chronic hypertension, mild proteinuria, or CKD. Although hyperparathyroidism is com mon in advanced CKD, clinically apparent bone disease is rare outside the dialysis populati on. Within the dialysis population, disor- ders of parathyroid hormone (PTH) that can resul t in fractures and bone pain include osteitis \201 brosa (due to excess PTH), osteomalaci a (due to inadequate mineralization), and adynamic bone disease (due to over suppression of PTH). See Chapter 14, p. 426. Haemodialysis related amyloidosis is a rare complication tha t is more common with increasing years on dialysis. This disorder is related to the increas ed generation of B2 microglobulin due to increased levels of in \202 ammation (perhaps due to contact of blood with the dialysis appa- ratus) and decreased clearance due to poor tra nsportation across the dialysis membrane. Atherosclerotic renal disease may affect any size blood vessels, but is most common in small vessels. The excess of atherosclerotic disease may be due to chronic in \202 am- mation causing endothelial dysfunction and/or the effect s of commonly used medications, such as non-NSAIDs, which cause hypertension, or GCs, which cause hyper- tension and hyperglycaemia. Prognosis Left untreated, SSc renal crisis may result in rapid loss of renal function and e nd-stage renal disease in <8 weeks. Monitoring \200 \200 Regular blood pressure monitoring is essential. Full blood count, \201 brin degradation p roducts, and blood smear are useful in monitoring microangiopathy. Antiphospholipid antibod y binding levels are of uncer- tain signi \201 cance. Chronic kidney disease (CKD) Some patients will present with a chronic elevation in serum c reatinine re \202 ecting a reduced glomerular \201 ltration rate (GFR). This reduction i n kidney function may be stable or slowly progressive, and is usually associated with a bla nd urine sediment. In patients with rheumatological diseases, the chronic glomerulopathy of RA, SSc, amyloidosis, chronic urate nephropathy/saturine gout results from chronic in \202 ammation, and is associated with micro-vascu- lar arteriopathy and interstitial \201 brosis in the kidney. Chronic NSAID use may exacerbate this chronic injury by promoting hy pertension and hyperglycaemia. The severity of chronic kidney disease is classi \201 ed on the basis of the patient \200\231s GFR (or estimate of glomerular \201 ltration rate on the basis of a stable serum creatinine). Key clinical features The duration and evolution of renal dysfunction is the most important component of the evaluation of renal disease. Patients with CKD that is not progressive ca n be investigated less aggressively than patients with new onset dysfunction or rapidly det eriorating renal function. In pa- tients with advanced CKD (stage V) enquiry about uraemic symptoms is mandatory, as they will determine the need for initiating renal replacement the rapy. Such symptoms include worsening fatigue, anorexia, generalized pruritis, a metallic t aste to food, and worsening oedema. Monitoring of \202 uid, electrolyte, particularly ser um potassium, and acid-base balance is important. Table 3.7 Chronic kidney disease (CKD) staging. Stage Glomerular \201 ltration rate (ml/min) >90, but some sign of kidney damage on another test (e.g. proteinuria) I II 60 \200\22390 III 30 \200\22359 IV 15 \200\22329 <15 or requires dialysis V Investigations \200 Renal biopsies are infrequently required in CKD, but patients with chronic in \202 ammator y diseases, are more likely to require a biopsy. Advanced chronic kidney disease (CKD) can be a cause of rheumatologic diseases. For example , severe chronic CHAPTER 3 Organ involvement in rheumatological disease 81 NICE (UK) chronic kidney disease guidance. Available at: http://www.nice.org.uk/guidance/ Urinalysis and the quanti \201 cation of proteinuria should be checked in all patients. Bl ood pressure should be monitored closely. Patients with stage V disease should have periodi c monitoring of serum electrolytes and bicarbonate. Patients with stage III-V disease shoul d have periodic monitoring of serum PTH (see p. 426). Dialysis related amyloidosis has a pr edilection for the cervical spine, scapulohumeral region and the carpal tunnels. Cystic bon e disease is also common. Urinary lead levels in patients with lead exposure. Serum urate t o guide allopurinol or other anti- hyperuricaemic therapy. \200 ICD10 codes N00-08 Glomerular diseases M32.1+ N08*5 M31.3 Wegener \200\231s Granulomatosis N04 SLE with organ involvement Glomerular disorders in systemic AICTDs Nephrotic syndrome Further reading Austin HA, III, Klippel JH, et al. Therapy of lupus nephritis. Controlled t rial of prednisone and cytotoxic drugs. N Engl J Med 1986; 314: 614 \200\22319. \200 Balow JE, Austin HA, III. Therapy of membranous nephropathy in systemic lupus erythematosus . Semin Nephrol 2003; 23: 386 \200\22391. Boumpas DT, Austin HA III, et al. Controlled tria l of pulse methyl- prednisolone versus two regimens of pulse cyclophosphamide in severe lup us nephritis. Lancet 1992; 340: 741 \200\2235. Treatment \200 Early referral to a nephrologist is indicated in patients with renal disease and a concomit ant rheumatological disease. In CKD referral may expedite a diagnostic biopsy or, when nece ssary, preparation for renal replace- ment therapy or renal transplantation. The cornerston es of management are adequately man- aging any underlying chronic disease, renal protection and the management of cardiovascular risk. This includes careful management of blood press ure, hyperlipidemia, diabetes mellitus, and smoking cessation. Aspirin use is warranted on the basis of trials in patients without CKD. There is some evidence for the preferential us e of angiotensin blockading drugs in patients with hyperten- sion and proteinuria, but this continues to be debated, particularly in the non-diabetic patient. Contreras G, Pardo V, et al. Sequential therapies for proliferative lupus nephritis. N Engl J Med 2004; 350: 971 \200\22380. Fauci AS, Haynes BF, Katz P, Wolff SM. Wegener \200\231s granulomatosis: prospective clinic al and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98: 76 \200\22385. Helin HJ, Korpela MM, Mustonen JT, Pasternack AI. Renal biopsy \201 ndings and clinicopat hologic correlations in rheumatoid arthritis. Arthritis Rheum 1995; 38: 242 \200\2237. Houssiau FA, Vasconcelos C, et al. Immunosuppressive therapy in lupus nephritis: the Euro-L upus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophos phamide. Arthritis Rheum 2002; 46: 2121 \200\22331. Jayne D, Rasmussen N, et al. A randomized trial of maintenance therapy for vasculitis assoc iated with ANCA autoantibodies. N Engl J Med 2003; 349: 36 \200\22344. Lachmann HJ, Goodman HJ, et al. Natural history and outcome in See also: CKD metabolic bone disease (p. 426). systemic AA amyloidosis. N Engl J Med 2007; 356: 2361 \200\22371. Resources Information and internet sites European Vasculitis Study Group. Available at: htt p:// www.vasculitis.org Vasculitis Foundation. Available at: http://www. vasculitisfoundati on.org UK Renal association. Available at: http://www.renal. org Walsh M, James M, et al. Mycophenolate mofetil for induction therapy of lupus nephritis: a systematic review and meta-analysis. Clin J Am Soc Nephrol 2007; 2: 968 \200\22375. Weening JJ, D \200\231Agati VD, et al. The classi \201 cation of glomerulonephritis in sys temic lupus erythematosus revisited. J Am Soc Nephrol 2004; 15: 241 \200\22350. THE GUT AND HEPATOBILIARY DISEASE 82 The gut and hepatobiliary disease The gut is frequently involved in autoimmune and heredi- tary connective tissue diseases (C TDs), and in both large and small vessel vasculitides. Clinical features re \202 ect the d efective connective tissue components in hereditary CTD, or the processes of chronic in \202 ammation, aberrant repair, vascular damage, and adverse drug reactions in the autoimmune CTDs (AICTDs)/vasculi tic syndromes. In addition, rheumatological disease often complicates infec- tive or in \202 ammatory disorders, which are predominantly gastroenterological. Table 3.8 Anatomical classi \201 cation of gastrointestinal involvement in rheumatological disease Mouth/pharynx Esophagus Stomach Small Intestine Large intestine Liver/pancreas/ gallbladder + + ++ + + + Rheumatoid arthritis (RA) +++ + + + + + SLE ++ +++ + ++ ++ +/ \200\223 Systemic sclerosis (SSc) ++ ++ + + + Dermato- & polymyositis +++ ++ + ++ Sj gren \200\231s syndrome (SS) + + + Wegener \200\231s granulomatosis (WG) + + + Churg \200\223Strauss syndrome (CSS) + + ++ + + Polyarteritis nodosa (PAN) + ++ + + Henoch \200\223Sch nlein purpura (HSP) +++ + ++ Beh et \200\231s disease + + Kawasaki disease Giant Cell + + Arteritis (GCA) + + + Cryoglobulinaemia + ++ Reiter \200\231s Syndrome + ++ ++ Marfan \200\231s/Ehlers \200\223Danlos ++ ++ Whipple \200\231s disease Classi \201 cation Megaesophagus occurs in Marfan Syndrome and some forms of Ehlers \200\223Danlos syndrome (E DS). Oesophageal perforation can occur in Beh ets. Aspiration can result from oesophageal dysmotility in SSc, DM or PM. Mega-esophagus occurs in Marfan Syndrome and EDS. Barrett \200\231s metaplasia occurs in >33% of SSc patients. Oesophageal candidiasis may occur in i mmunosuppressed patients, especially if neutropaenic; glucocorticoids increase the risk O esophageal varices (and upper GI hemorrhage) occur as a result of portal hypertension in pr imary biliary cirrhosis (PBC), which is particularly associated with SSc and SS. Hepatic \201 brosis and portal hypertension may also follow autoimmune hepatitis (see below) and dr ug-related hepatitis and \201 brosis. Portal vein thrombosis occurs in Beh ets and SLE. It results in portal hypertension. Nodular regenerative hyperplasia (RA, SLE) can cause por tal hypertension. Epidemiology Mouth \200 \200 Ulcers occur in SLE, Beh et \200\231s disease, RA, DM, and PM, PAN, and occasionally other vasculitides. Oral \201 ssures occur in Sj gren \200\231s syndrome (SS) and in cases of iron de \201 ciency (angular cheilosis). Xerostomia is common in SS and sarcoidosis. Temp oromandibular arthritis may cause pain and limita- tion of mastication in RA and JIA. Drugs used in in \202 ammatory rheumatological disorders may be associated with oral ulceration , candidiasis or (rarely) taste disturbance (dysgeusia). \200 \200 Esophagus \200 Oesophageal dysmotility occurs in 90% of SSc and is symptomatic in 80%. It is also freque ntly problematic in SS (associated with impaired lubrication of bolus) and in DM and PM. Oe sophageal dysmotility also occurs in RA and SLE, but may not correlate with manometric abno r- malities. Swallowing may be impaired by cervical spine and laryngeal involvement in RA. CHAPTER 3 Organ involvement in rheumatological disease 83 Stomach \200 Mucosal telangectasiae in SSc may be a cause of chronic blood loss and iron-de \201 ciency anemia. Gastritis is common across the range of autoin \202 ammatory conditions and in response to many disease-modifying or anti-in \202 ammatory drugs Gastric ulcers are particularly ass ociated with RA, PAN, Beh et \200\231s disease, CSS, HSP. Gastric antral vascular ectasia (GAVE) can occur in portal hypertension, or primarily in SS or SSc. Delayed gastric emptyin g is common in SSc ( 75%) and occurs in DM/PM, or from secondary amyloidosis. Eosinophilic in \201 ltration of the stomach can result in discrete masses in Churg \200\223Strauss syn drome (CSS). Liver/pancreas/gallbladder \200 Hepatitis and transaminitis occurs in RA, Adult Still \200\231s disease, SLE, and SS. Hepat itis is generally mild in these conditions, although in Adult Still \200\231s disease can f ollow a fulminant course. Hepatotoxicity is a common adverse effect of drugs used in Rheuma tological patients. Secondary amyloidosis can result in hepatosplenome- galy in RA. Non-spe cific hepatosplenomegaly occurs in RA (Felty \200\231s syndrome), SLE, and SS. Primary bili ary cirrhosis is associated with SS and SSc. Acalculous cholecystitis occurs in RA, PAN, WG , and HSP. Exocrine pancreatic insuf \201 ciency occurs in 25% patients with SS. Pancreat itis may complicate SS, SLE, PAN, and pancre- atic necrosis has been reported in SSc. Drugs may also cause pancreatitis. \200 Small intestine \200 Malabsorption is characteristic of Whipple \200\231s disease, and complicates RA, SLE, SS, Marfan syndrome, and EDS. Coeliac disease (CD) frequency is increased in SS. CD may be asso ciation with Spondylarthropathies (SpAs). Whipple \200\231s disease classically presents wi th weight loss, diarrhea, abdominal pain, and arthralgia or arthritis; neurological and con stitutional features may also occur. Whipple \200\231s disease may manifest as arthritis wi thout GI symptoms. Obstruction may rarely occur as a result of strictures following mucosal ulceration (RA, SLE, PM, DM, SS, PAN, CSS, Beh et \200\231s disease). Pseudo-obstruction may arise in dysmotility syndromes (SSc, Marfan syndrome, EDS, and also RA. Intussusception may occur in SSc, SLE, and HSP. Mucosal ulceration may complicate RA, SLE, PM, DM, CSS, HS P, Beh et \200\231s disease. Small bowel ischaemia or infarction may complicate PAN, CSS, WG, cryoglobulinaemia, Beh et \200\231s disease, and Giant Cell Arteritis (GCA). Vasculiti s of the small intestine may manifest as fever, abdominal pain, acute malabsorption, and ne phrotic syndrome (with hypogammaglobulinaemia and hypocom- plementaemia) owing to protein-l osing enteropathy or peritonitis. Mesenteric arterial rupture (leading to an acute abdo- me n and shock) may occur in Marfan Syndrome, EDS. Perforation has been associated with RA, SL E, SSc, DM, PM, PAN, CSS, HSP, WG, Beh et \200\231s disease, Marfan syndrome, and EDS, and this rarely may be accompanied by pneumatosis intestinalis. Amyloid, with resultant protei n-losing enteropathy is a rare complication of RA and SpAs. Table 3.9 Rheumatological manifestations of gastroenterological and hepatic diseases GI disease Rheumatological manifestation Crohn \200\231s disease SI 25%; AS 10%. Peripheral arthritis 20% Ulcerative colitis SI 15%; AS 7%. Peripheral arthritis 20% Migratory arthritis >60% \200 Whipple \200\231s disease Enteric infection Reactive arthritis, septic arthritis, osteomyelitis Intestinal bypass surgery Symmetrical polyarthralgia or polyarthritis >50% Lipid crystal polyarthritis. Bone infarcti on by fat embolism. Pancreatic arthritis syndrome Haemochromatosis Chrondrocalcinosis and CPPDD disease Wilson \200\231s disease Chrondrocalcinosis and CPPDD disease Primary biliary cirrhosis Polyarthritis 20%; SSc 20%. Sj gren \200\231s syndrome 50% Hepatitis A Prodromal polyarthralgia. Arthritis/ vasculiits rarely Hepatitis B Prodromal polyarthralgia. Arthritis 10%; PAN (rare) Hepatitis C Polyarthralgia 10%. Polyarthritis 5%. Mixed cryoglobulinaemia 10 \200\22350%; SLE-like s yndrome Large intestine \200 Colitis is associated particularly with Beh et \200\231s disease and SpA (often clinically silent), but may also complicate RA, SLE, WG, and other vasculitides. Colitis may be com- plicated by perforation. Appendicitis is common in the general population, but may present more frequently in PAN and HSP. Constipation and diarrhea are prominent problems in dysmoti lity syndromes (SSc, Marfan Syndrome, EDS), but also complicate SLE, PM, DM, and vasculitid es. Fecal incontinence is a common, but under-reported symptom in SSc. Megacolon and giant diverticulae may occur in Marfan Syndrome EDS and joint hypermobility syndrome (JHS); these carry an increased risk of perforation. Etiology/pathophysiology Mouth/pharynx Oral ulcers may re \202 ect the generalized aberran t interac- tion of leucocytes and endothelium, and an over-reactive local in \202 ammatory response to minor mucosal trauma. \200 In RA, mouth ulcers are often associated with anti- proliferative DMARDs, which are toxic t o rapidly-dividing cells, including mucosal epithelium. Oral ulcers in SLE may reflect depo sition of local immune complexes and ensuing in \202 ammatory response with mucosal breakd own. De \201 ciency of vitamin B12, folic acid, and iron can also result in oral ulceratio n. THE GUT AND HEPATOBILIARY DISEASE 84 Esophagus \200 Liver/pancreas/gallbladder Small vessel vasculitis resulting in patchy hypoperfusion leads to nodular regenerative hyperplasia of the liver in RA and SLE, and can cause portal hypert ension. Manometric abnormalities include low amplitude peri- staltic waves and reduced lower oesoph ageal (LOS) pressure in RA. Atrophy and \201 brosis of the oesophageal wall and damage to intrinsic nerves result in dysmotility ranging from incoordination to complete paralysis i n SSc. Loss of LOS pressure results in gastro-oesophageal re \202 ux disease (GORD) and pe ptic stricture in 8% of RA and SLE patients Inflammatory myopathy predominantly results in impaired deglutition in PM and DM, but also affects smooth muscle of the esophagus. Table 3.10 Gastrointestinal effects associated with drugs used in rheumatological patients Drug Effect NSAIDs Dyspepsia, nausea, peptic ulcer, abnormal liver function tests, protein-losing enteropathy. NSAIDs reduce the risk of colonic carcinoma. Glucocorticoids Peptic ulcer (in conjunction with NSAIDs). Stomach \200 Methotrexate Nausea, stomatitis, mouth ulcers, abnormal liver function tests, hepatic \201 brosis. Delayed gastric emptying can occur due to in \201 ltration with secondary amyloid (RA), eo sinophilia, and \201 brosis (CSS), atrophy, and scarring of the muscle layers (SSc), or i n \202 ammatory myopathy in PM or DM. Ulceration in RA is secondary to medication use (wit h- out, which it is no more common than in OA). Local mass-like lesions can occur in CSS. Azathioprine Nausea, diarrhea, abnormal liver function tests, hepatitis. Mycophenolate mofetil Nausea, vomiting, diarrhea, constipation, gastrointestinal ulceration, abnormal liver funct ion tests, hepatitis. Small intestine In \202 ammatory bowel disease (IBD) IBD and spondylarthritis (SpA) probab ly arise as a result of aberrant responses to gut bacteria and the development of an excess ive pro-in \202 ammatory T cell response, in particular mediated by the Th17 subset. \200 Le \202 unomide Stomatitis, diarrhea, vomiting, abnormal liver function tests. Sulfasalazine Nausea, vomiting, diarrhea (bloody), dyspepsia, abnormal liver function tests, hepatic necr osis, pancreatitis, cholestasis. Gold Mouth ulcers, diarrhea, cholestasis, hepatic necrosis, gold enterocolitis (fever, diarrhea, megacolon, eosinophilia). This model can be integrated with known genetic associations with IBD/SpA since variants of pattern rec- ognition receptors (NOD2/CARD15 polymorphism associated with Crohn \200\231s disease) and/or cytokine recep- tors (e.g. IL-23R polymorphism associate with Crohn \200 \231s disease and AS) could alter the dendritic cell response to micro-organisms and to the in \202 ammatory mileu itself. The well-recognized association of these diseases with HLA -B27 could re \202 ect the ability of this HLA molecule to in \202 uence the innate respo nse of dendritic cells to micro-organisms. Ciclosporin Nausea, gum hyperplasia, vomiting, diarrhea, abnormal liver function tests. Cyclophosphamide Nausea, vomiting, stomatitis, diarrhea, abnormal liver function tests. Hydroxychloroquine Nausea, vomiting, diarrhea. Colchicine Nausea, vomiting, diarrhea, gastrointestinal hemorrhage. Allopurinol Nausea, abnormal liver function tests. Bacterial over-growth Occurs as a result of impaired motility of the intestine in amyloidos is, SSc, DM, and PM; and can be due to diverticular disease in SSc, Marfan syndrome, and ED S. \200 In \202 iximab Dyspepsia, diarrhea, constipation, gastrointestinal hemorrhage, hepatitis, cholecystitis. Adalimumab Dyspepsia, diarrhea, constipation, taste disturbance, and oral ulcers. It may be exacerbated by the use of PPI in RA and SSc for gastro-protection from NSAIDs or GORD. Focal bowel wall thickening or intramucosal haemor- rhage can lead to intussuception in HSP, CSS, and SLE. Etanercept Dyspepsia, gastrointestinal hemorrhage, pancreatitis, cholecystitis. Rituximab Nausea and vomiting during infusion. Whipple \200\231s disease Caused by a bacterium Tropheryma whipplei. Affected tissues are i n \201 ltrated with foamy macrophages. It appears that aberrant activation of dendritic ce lls and macrophages, following ingestion of T. whipplei may result in a defective Th1 respo nse with persistence of both the bacterium and the aberrant in \202 ammatory response. Primary biliary cirrhosis (PBC) PBC is caused by an autoimmune response that destroys small intralobular bile ducts, resulting in cholestasis. The retained bile acids themselves caus e damage to hepato- cytes and increase expression of HLA antigens on these cells, which enh ances the autoimmune response. Anti- mitochondrial antibodies (AMA) are characteristic of P BC and occur in 95% patients; they are speci \201 c for pyruvate dehydrogenase epitopes lo cated on the inner mitochon- drial membrane. It is unclear what role AMA plays in the patho genesis of PBC. Large intestine \200 Colitis resembling Crohn \200\231s disease can occur in Beh et \200\231s with mucosal apht hae. Vasculitis resulting in mucosal or full-thickness ischaemia can occur in RA, SLE, WG, PAN, HSP, and other vasculitides. Scarring and atrophy of the ano-rectal musculature can re sult in fecal incontinence in SSc. Autoimmune pancreatitis Can be associated with salivary gland in \202 ammation that can mi mic SS and accompany other autoimmune conditions. CHAPTER 3 Organ involvement in rheumatological disease 85 Cough, wheezing, and dyspnoea results from aspiration from oesophageal dysfunction, especia lly in SSc. GORD can result in dysphagia due to oesophageal strictures or dysmotility (oeso phageal spasm). It can result in stricturing of the biliary or pancreatic ducts, and lead to features of sc lerosing cholangitis or pancreatic atrophy and exocrine dysfunction. The pancreas is in \201 l- trated with IgG4 secreting plasma cells and IgG4 levels are increased to >135 mg/l in serum. Stomach \200 Risk factors \200 \200 Epigastric or left hypochondrial pain may indicate gastritis or gastric ulceration (RA, SLE , CSS). Melaena indicates frank blood loss from stomach or small bowel. Nausea reflects gas tric atrophy (e.g. Sj gren \200\231s) or dysfunction, or may be an adverse reaction to dru gs. A gastric mass may occur in Sj gren \200\231s syndrome (lymphoma should be excluded) a nd CSS. Bloating, halitosis, and regurgitation can all reflect delayed gastric emptying, e. g. SSc. RA \200\223 associated with 5-fold risk of GI bleeding. DM is associated with pancreatic, stomach and colorectal carcinoma. SS is associated with lymphomas, including MALT lymphoma . Drug-induced GI disease. Clinical features General assessment Assess nutritional state (e.g. BMI, lean body mass), l ymph- adenopathy pallor, jaundice (look at sclerae) and nails for clubbing, koilonychia (ir on de \201 ciency). Small intestine \200 \200 Weight loss may indicate malabsorption. Melaena indicates frank blood loss from stomach or small bowel. Abdominal distension or bloating may indicate malabsorption, and/or dysmotilit y, bacterial over- growth (especially, SSc, EDS, Marfan syndrome) or ascites (SLE). Central abdominal pain, worse 30 \200\22360 min after eating, may suggest mesenteric ischaemia. Pe ripheral oedema may occur in a protein-losing enteropathy. Colicky abdominal pain may indic ate obstruction, pseudo-obstruction (RA, SSc, Kawasaki disease) or intussusception (RA, SSc , SLE). Absolute constipation (no \202 atus) and faeculent vomiting indicates obstruction . Severe abdominal pain with referred pain to shoulder (diaphragmatic irritation) may sugge st perforation and/ or GI hemorrhage. Unrelenting abdominal pain occurs in bowel infarction . Steatorrhoea (pale, oily, \202 oating stools) results from fat malabsorption. Examine skin Dermatitis herpetiformis indicates coeliac disease; erythema nodosum occurs in in \202 ammatory bowel disease, Beh et \200\231s disease, PAN, sarcoid, and sometimes in other vasculitides; pyoderma gangrenosum may signify co-existing in \202 ammatory bowel d isease or vasculitis. Red papules with surrounding atrophy, which evolve to porcelain-white scars, occur in Kohlmeier \200\223Degos syndrome (a cutaneo- intestinal arterio-occlusive syndrome). Mouth \200 Xerostomia (dry mouth) occurs in primary or secondary Sj gren \200\231s and typically in s arcoid. Look also for swollen salivary glands and lymphadenopathy. Xerostomia is associated with dental caries. Sicca symptoms can be caused by drugs (e.g. diuretics, tricyclic antid epressants). Oral ulcers on tongue, buccal mucosa and pharynx can occur in SLE, Beh et \200\231s disease (often with genital ulcers), DM, PM, PAN or in association with drugs (e. g. meth- otrexate, gold, and cyclophosphamide). Reduced oral aperture occurs in SSc sometim es making eating (and dental work) dif \201 cult. Dysphagia may be caused by weakness or i ncoordination of the skeletal (voluntary) muscle of the pharynx; this may occur in DM/PM an d (rarely) as a result of cranial neuropathy in small vessel vasculitis. Cervical spine def ormity and crico-arytenoid arthritis may affect deglutition in RA. Oral \201 ssures (angu lar cheilosis) and glossitis can re \202 ect iron de \201 ciency or malabsorption, (e.g. SSc). Mastication is impaired by temporomandibular joint arthritis in RA and JIA. Fissuring of the tongue due to vitamin B12 de \201 ciency. Mucositis and white colonies suggestive of candidiasis. \200 Large intestine \200 Diarrhea and/or constipation may both result from dysmotility (SSc, DM, PM, EDS, and Marfan syndromes). Pain, which starts in the midline and moves to the right iliac fossa may sugge st appendicitis. Bloody diarrhea occurs in the presence of mucosal ulceration or infarction . Rectal prolapse occurs with diarrhea or constipation. Liver/pancreas/gallbladder \200 Pruritis and, in more severe cases, jaundice, occurs in the presence of biliary obstruction . Upper abdominal pain, sometimes radiating to the inter- scapular region, occurs in pancre atitis. Malaise, nausea, and vomiting may accompany pain. Haematemesis may be severe and li fe-threatening in patients with portal hypertension and varices. \200 Esophagus \200 Dysphagia may be caused by dysmotility of the smooth (involuntary) muscle of the esophagus in SSc and by oesophageal strictures or webs (Sj gren \200\231s). Heartburn or central che st pain, often worse after eating or on bending/lying may occur in GORD. This is common in SSc and SLE (up to 10%), and may also arise from meg- aoesphagus in Marfan syndrome or EDS. Ischaemic heart disease must be excluded in patients with chest pain. Examination of the abdomen \200 \200 Distension/asymmetry suggests organomegaly or mass. Visible peristalsis with small intestin al dilatation is common in small bowel over-growth or obstruction. Telangectasiae (spider n aevi) on the chest and upper body (in a non-SSc patient) or caput medusae (rare) indicate c irrhosis. THE GUT AND HEPATOBILIARY DISEASE 86 Tenderness \200\223 guarding, rigidity and rebound tenderness \200\223 suggests a \200 \230surgical abdomen \200\231. Local tenderness suggests gastritis/peptic ulcer (LUQ), hepa titis or hepatic congestion or cholecystitis (RUQ), ileocolitis, or appendicitis (RLQ). PR examination in suspected appendicitis. Perineal ulcers in Beh et \200\231s or Crohn \200 \231s disease. Palpate liver, spleen and kidneys, and check for ascites (shifting dullness) in distended abdomen. Auscultate for tinkling bowel sounds that may suggest obstruction or pseudo-obstruction sounds in an ileus. Small bowel follow-through for characteristic \200\230hide- bound \200\231 appearance of s mall intestine in SSc or presence of diverticulae. CT chest, abdomen and pelvis \200\223 u sed to seek solid organ malignancy, lymphadenopathy in risk patients (e.g Sj gren \200\231 s syndrome, DM), and for pneumatosis cystoides intestinalis. CT, conventional angiography o f mesenteric arteries in suspected PAN or mesenteric ischaemia. MR enteroclysis ( \201 lli ng with contrast medium of small bowel) for suspected intussuception. MR angiography or 18F DG-PET for suspected large vessel vasculitides. Video capsule enteroscopy for mucosal abnor malities of the small intestine (telangiectasias, aphthae, ischaemic ulcers, lymphoma). Sma ll intestinal manometry for SSc or suspected intestinal dysmotility. \200 \200 Investigations Mouth \200 \200 \200 Iron studies in patients with angular cheilosis. Vitamin B12 and red cell folate in oral ul ceration WBC (especially neutrophil count) in patients with candidiasis. Orthopantomogram t o assess TMJ arthritis (usually requested by oral/maxillofacial surgeons). Minor salivary g land biopsy may enable a diagnosis of SS or MALT lymphoma associated with SS. Parotid biops y occasionally necessary to distinguish diabetic sialadenosis, sarcoid and SS. Large intestine \200 \200 FBC and iron studies if chronic GI bleed suspected. Colonoscopy for bleeding per rectum, wh ere ulceration or ischaemia suspected. CT colonography can be used to exclude signi \201 c ant lesions, where colonoscopy is hindered by stricture or high risk. Mesenteric angiograph y (invasive/CT/MR) in suspected ischaemia. Anorectal manometry for fecal incontinence. Rect al biopsy \200\223 for amyloid. Esophagus \200 \200 Oesophageal manometry in SSc, SLE, RA, DM, and PM. Video- \202 uoroscopy or \201 bre-opt ic endoscopic examination of swallow (FEES) in proximal impaired swallow. Barium swallow (S Sc, EDS) \200\223 use water soluble contrast if at risk of aspiration. OGD may reveal re \202 ux oesophagitis, peptic stricture, or Barrett \200\231s metaplasia associated with GOR D. 24-h pH studies with pH catheter or mucosal adherent capsule to assess acid re \202 ux. Nuclear scintigraphy can assess volume of re \202 ux in achlorhydric patients (other meth ods rely on pH drop). CXR \200\223 air under the diaphragm occurs following perforation of stomach, small or large bowel. \200 Liver/pancreas/gallbladder \200 LFTs \200\223 ALT/AST elevated in hepatocellular damage, whereas elevated bilirubin, alkal ine phosphatase and gamma GT indicated biliary obstruction. ALT/AST may be elevated in pati ents with myositis; alkaline phos- phatase and gamma GT are acute phase reactants, and an i soform of ALP is also released from bone. Elevated amylase re \202 ects acute pancreatitis (SS, PAN, and WG). Can be elevated with salivary disease (SS) or vomiting. Infectious hepa titis serology \200\223 for hepatitis A, B, C, EBV, CMV. Autoimmune hepatitis serology \200\223 anti-smooth muscle antibodies and anti-liver-kidney microsomal antibodies accompan y autoimmune hepatitis; anti-mitochondrial antibodies (and more speci \201 cally anti-pyru vate dehydro- genase antibodies) are associated with PBC. Serum IgG4 levels may be helpful in suspected autoimmune pancreatitis. HFE genotyping should be performed in individuals wit h elevated ferritin (without other elevated acute phase reactants) and transferrin saturati on >45%. USS abdomen \200\223 used to visualize liver, including biliary tree, gallbladder , and spleen; and Doppler ultrasound to interrogate portal and hepatic vein blood \202 ow . The view of pancreas is generally inadequate. Liver biopsy \200\223 generally performed under ultrasound guidance. Biopsy in suspected autoimmune hepatitis and to establish presen ce of cirrhosis. In haemochromatosis, biopsy liver if ferritin >1000 g/l. Note: Liver bio psy is not essential to con \201 rm the diagno- sis of PBC. Do NOT biopsy liver in suspect ed cases of amyloid. Stomach \200 \200 FBC and iron studies if chronic GI bleed suspected. Upper GI endoscopy in suspected gastric ulcer/cancer, biopsies for eosinophilic infiltration (CSS) and Helicobacter pylori (rapid urease test). Nuclear scintigraphic gastric emptying studies (solid and/ or liquid phase). Small intestine \200 Malabsorption screen (PTH, iron studies, vitamin B12, red cell folate, vitamins A and E, ma gnesium, phosphate, and calcium). Anti tissue-transglutaminase antibodies (85-95% sensitivi ty for celiac disease). Fecal pancreatic elastase is a measure of exocrine pancreatic dysfu nction. Albumin and immunoglobulins in suspected protein- losing enteropathy. Upper GI endo scopy for: suspected duodenal ulcer, coeliac disease, IBD affecting small bowel, with aspir ate and colony count for suspected bacterial over-growth and biopsies for coeliac disease, Giardia lamblia, and Whipple \200\231s bacillus. Glucose-hydrogen breath test for proximal small intestinal over-growth. CHAPTER 3 Organ involvement in rheumatological disease 87 Triple phase CT of the abdomen to examine pancreas and portal vasculature. Endoscopic ultra sound (EU) for visualization of upper GI mucosa where thickening is present on cross sectio nal modalities. EU gives good visualization of the pancreas (and for needle cytology of pan creatic masses). ERCP for suspected biliary and pancreatic ductal abnormalities. selective NSAIDs are associated with 50% risk of severe GI complications compared with non -selective NSAIDs. Risk of GI hemorrhage can be reduced by use of a proton pump inhibitor. Gastric antral vascular ectasia (GAVE): treat with argon beam ablation at endoscopy; look f or portal hypertension. Delayed gastric emptying can be improved with dom- peridone or eryt hromycin. Botulinum toxin injection into the pylorus can improve emptying in marginal cases . Treatment Mouth \200 Patients with any of the following risks for NSAID-associated GI disease should be prescrib ed a proton pump inhibitor: \200 \200 \200 \200 \200 