Postrenal azotemia \200 Nephrolithiasis is not a common cause of postrenal azotemia, but should be considered in a patient with gout. 5 \200\22310% of renal calculi in the United S tates are caused by uric acid; this is particularly common among patients with gout who hav e been treated with uricosuric agents (e.g., probenecid). RENAL MANIFESTATIONS 217 Sarcoidosis can cause hypercalcemia and hypercalcuria, which in turn can lead to nephrolith iasis and nephrocalcinosis, both of which can rarely cause postrenal azotemia. Methotrexate and trimethoprim/sulfamethoxazole can cause crystalluria and renal obstruction. Ultrasound is a useful modality to evaluate both for the presence of obstruction leading to hydronephrosis and renal calculi. Intrinsic renal failure \200\224 \200\234active sediment \200\235 \200 The nephritic synd romes are an important cause of rapidly progressive renal failure among patients with rheum atic diseases, particularly small vessel vasculitis and SLE. The presence of hematuria, proteinuria, and red blood cell casts strongly suggests the pres ence of glomerulonephritis, but a renal biopsy is crucial to determining the underlying dia gnosis and the severity/chronicity of the disease. Nephritic syndromes can be divided into \200\234focal proliferative \200\235 and \200\234diffuse proliferative \200\235 based on histology. Causes of focal proliferative glomerulonephritis include SLE, Henoch- Sch nlein purpura, and other forms of small vessel vasculitis. Diffuse proliferative glomerulonephritis is caused by cryoglobulinemia, SLE, anti-glomerular basement membrane (GBM) disease (Goodpasture \200\231s syndrome), and ANCA-associated vasculitis. Direct immuno \202 uorescence can also provide valuable information regarding the correct diagnosis. SLE is associated with multiple immunoreactants ( \200\234full house \200\235 st aining pattern). IgA deposition implies Henoch-Sch nlein purpura. Cryoglobulinemic vascu litis leads to IgG and C3 deposition. Sparse or absent immunoreactants on biopsy is sometim es called \200\234pauci-immune, \200\235 and implies an ANCA-associated vasculitis. Intrinsic renal failure \200\224 \200\234bland sediment \200\235 \200 A bland sediment re fers to a urine sample that is acellular; transparent hyaline casts may be seen. Remember t hat a bland sediment is also seen in prerenal and postrenal azotemia. Acute tubular necrosis (ATN) is used to describe causes of acute, intrinsic renal failure associated with a urine sediment that has muddy brown casts and tub ular epithelial cells. Nephrotoxic tubular injury from drugs is a common cause of ATN in patients with rheumatic disease. Prolonged prerenal azotemia can lead to permanent kidney damage; therefore, diseases of the renal artery (including polyarteritis nodosa and renal artery thrombosis from antiphosphol ipid antibody syndrome) should be considered. Interstitial nephritis is most commonly seen as a drug reaction (e.g., NSAIDs, azathioprine, allopurinol) Interstitial nephritis can also be seen as a manifestation of several rheumatic diseases, i ncluding Sj gren \200\231s, SLE, sarcoidosis, and eosinophilic granulomatosis with polya ngiitis (the Churg-Strauss syndrome). CHAPTER 4 The spectrum of presentation 218 NSAIDs cause renal vasoconstriction and interstitial nephritis, both of which can eventually lead to a chronic analgesic nephropathy. Unlike the other forms of ANCA-associated vasculitis, the mechanism of renal failure among patients with eosinophilic granulomatosis with polyangiitis (Churg-S trauss syndrome) is an interstitial nephritis; glomerulonephritis is relatively rare with t his diagnosis. The most common causes of secondary renal amyloidosis are rheumatoid arthritis and familial Mediterranean fever. Glomerular deposits of amyloid lead to proteinuria (which can be nephrotic range) and progressive renal failure. Scleroderma renal crisis \200 Scleroderma renal crisis is a rheumatologic emergency chara cterized by acute renal failure and malignant hypertension. Patients with diffuse cutaneous scleroderma are at greatest risk; scleroderma renal crisis generally occurs within the \201 rst 4 years after diagnosis, bu t it can occur at any time. Patients who are treated with corticosteroids may be at the hig hest risk. Urinalysis generally demonstrates a bland sediment. Kidney biopsy demonstrates evidence of a thrombotic microangiopathy that histologically cannot be distinguished from malignant hyp ertensive nephrosclerosis, hemolytic-uremic syndrome, SLE, or the antiphospholipid antibody syndrome. The cornerstone of therapy is gradually escalating doses of ACE- inhibitors, followed by an giotensin II receptor blockers (ARB) and calcium channel blockers if adequate blood pressur e control is not achieved. Renal tubular acidosis \200 Renal tubular acidosis (RTA) causes a nonanion gap metabolic acidosis caused by a failure of the renal tubules to maintain acid-base status. Type I RTA, caused by an inability to excrete acid, is found with Sj gren \200\231s syndrome and SLE. Type IV RTA is most commonly caused by hyporeninemic hypoaldosteronism, can occur as a result of treatment with NSAIDs, ACE-inhibitors, and ARBs . This is commonly associated with hyperkalemia. This page intentionally left blank CHAPTER 4 The spectrum of presentation 220 Endocrine manifestations Well-characterized musculoskeletal conditions occur in many endocr ine disorders. Some are speci \201 c for certain disorders; others are nonspeci \201 c, b ut occur with greater frequency among patients with endocrine disease. Musculoskeletal mani festations occur either as a result of metabolic dis- turbances or are in \202 uenced by a common link through their autoimmune pathophysiology. Diabetes \200 Dupuytren \200\231s contracture, trigger \201 nger, carpal tunnel syndrom e, diffuse idiopathic skeletal hyperostosis (DISH), and adhesive capsulitis all occur with greater fre quency among patients with diabetes. Some form of tissue or joint hypomobility/stiffness is common among patients with diabetes (see Table 4.5); in some cases, this can appear similar to scleroderma. These scleroderma-l ike skin changes are more prevalent among patients with type I diabetes. Table 4.5 Patterns of joint and tissue hypomobility or stiffness in diabetes by reported se ries. Tissue changes are thought to occur from excessive hydration (a consequence of an exc essive local production of sugar alcohols) Patient series Major abnormalities Associations Occasional lung \201 brosis. Microvascular diabetic complications Diabetics overall In about 30 \200\22340% mainly in long-standing disease: slow decrease in hand mobility; wa xy skin thickening ( \200\230scleroderma-like \200\231) Adults 55 \200\22376% prevalence of joint hypomobility in type 1/type 2 diabetes, respectively Not associated with diabetic complications Mature onset diabetes (mean 61 years) Stiffening of connective tissue (assessed in hands) Diabetic nephropathy Children with type 1 diabetes 31% have limited joint mobility None with glycemic control, retinopathy, or proteinuria Juvenile and young adult onset (age 1 \200\22324 years) diabetes 34% had skin thickening. Changes rarely proximal to MCPs and never proximal to wrists. Join t contractures in >50%, often third or fourth \201 ngers No \202 exor tendon rubs (as seen in scleroderma) ENDOCRINE MANIFESTATIONS 221 Hand weakness may be due to diabetic neuropathy and may be mistaken for carpal tunnel syndrome. Nerve conduction studies help discriminate between the se two diagnoses. Calci \201 cation of soft tissues around the shoulder occurs in approximately 20% of diabetics, and is associated with variable symptoms and disability. Diabetic amyotrophy (diabetic lumbosacral plexopathy) is uncommon. It presents acutely with pain, weakness, and wasting of the proximal lower limb muscles. It may be unilateral. Diff erential diagnosis includes myositis (see Chapter 14) and polymyalgia rheumatica (PMR \200 \224see Chapter 15). It is associated with uncontrolled hyperglycemia. The etiology is unkn own, but it is probably a neuromyopathy. Though rare (1:500 diabetics), neuropathic arthritis (Charcot joint) can occur in advanced disease. Most patients are aged 40 \200\22360 years and have poor glycemic control. Tarsal and metatarsal joints are most frequently affected (60%). The usual presentation is of swel ling of the foot with no or little pain. Trauma may have occurred. Early radiographic chang es can resemble OA (see Chapter 6). Asymptomatic osteolysis can occur at the distal metatarsals and proximal phalanges with rel ative joint sparing. The etiology is unknown. Osteomyelitis is not uncommon and needs to be discriminated from cellulitis and neuropathic arthritis (Charcot \200\231s joint). MRI or a triple- phase bone scan is helpful to establ ish the diagnosis. Osteomyelitis is usually disclosed by prominent blood \202 ow in the d ynamic ( \201 rst) phase and increased uptake of tracer by soft tissue and bone in later s tages. Cellulitis is associated with minimal uptake of tracer in bone in the delayed (third ) phase. Neuropathic joints display minimal \201 rst-phase abnormalities but prominent tr acer uptake in the third phase. Diabetic muscle infarction can present as a painful muscle mass and is a result of arterial narrowing. Often mistaken for thrombophlebitis, myositis or vasculi tis, this is a late complication of diabetes. Biopsy may be needed to con \201 rm this dia gnosis. Hypothyroidism \200 Over 25% of patients with hypothyroidism have an arthropathy. Because this arthropathy can lead to an erosive arthritis, it can be mistaken for RA (see C hapter 5). This arthropathy commonly involves the knees and hands; in children, the hips are most like ly to be affected. It is characterized by pain, stiffness, effusions, and synovial thickeni ng due to glycosaminoglycan deposition. Calcium pyrophosphate deposition may contribute to this arthropathy. Radiographically de \201 ned chondrocalcinosis is only marginally increased compared with controls (17% vs. 10%). About 1/10 patients with pseudogout are hypothyroid. Carpal tunnel syndrome is frequent (7%). Up to 10% of patients with carpal tunnel syndrome may have hypothyroidism. Hyperuricemia is common among patients with hypothyroidism but gout attacks are rare. Howev er, screening for hypothyroidism in CHAPTER 4 The spectrum of presentation 222 patients with gout is recommended. Treated hypothyroidism then requires review of the need for uric acid-lowering therapy. \200 Musculoskeletal symptoms are common, and may improve with treatment of hypothyroidism. Consequences of hypothyroidism in children included retarded bone age, short stature, and epiphyseal dysgenesis with premature epiphyseal plate closure and increased probability of slipped femoral epiphyses. Myopathy is relatively common. About 1 in 20 cases of acquired myopathy are due to hypothyroidism. The presentation can mimic polymyositis with elevation of muscle enzymes, but muscle biopsy typically shows no in \202 ammatory cell in \201 ltr ate. Improvement with thyroxine replacement is sometimes complicated by muscle cramps, but these should resolve in a few weeks. The combination of weakness, muscular stiffness, and an increase in muscle mass in an adult with myxedema is termed Hoffman \200\231s syndrome. Muscle mass increase is sometimes stri king and can take many months to resolve on treatment. The same condition occurs in childre n (Kocher \200\223Debre \200\223Semelaigne syndrome). Lymphocytic thyroiditis (Hashimoto \200\231s) is an autoimmune condition characterized by hypothyroidism and autoantibodies to thyroglobulin and thyroid microsomes. These antibodies are found in 40% of patients with primary Sj gren \200\231s disease bu t only about 10% are or have been overtly hypothyroid. Hyperparathyroidism (see also Chapter 16) Unless stated, points refer to both primary and s econdary disease: \200 Musculoskeletal symptoms are the initial manifestation in up to 16 % of patients with primary hyperparathyroidism. Hyperparathyroidism, chondrocalcinosis, and pseudogout frequently coexist. Pseudogout (CPPD ) can be triggered by parathyroidectomy. \200 A polyarthropathy can occur that can mimic RA. Unlike RA, synovial proliferation is absent. Radiographically, erosions have a predilec tion for the ulna side of distal upper limb joints, the joint space is preserved, pericapsu lar calci \201 cation is often present, and reactive bone formation may be observed An erosive polyarthritis favoring the large joints can occur with renal osteodystrophy in patients with chronic renal failure on dialysis. It does not appear to be related to CPPD. Hyperparathyroidism is associated with a speci \201 c shoulder arthropathy characterized b y intra/periarticular erosions of the humeral head. This may be subclincial. Subjective muscle weakness and fatigability are common complaints. Typically, muscle enzyme s are normal and biopsy shows type II \201 ber atrophy; the features of an in \202 ammat ory myopathy are generally absent. \200 The hallmark of radiographic changes is bone reso rption: subperiosteal (typically on the radial side of second and third phalanges), intracortical, subchondral, t rabecular, subligamentous, and localized (Brown \200\231s tumors) resorption patterns are s een. Bone sclerosis, periostitis, and chondrocalcinosis also occur. ENDOCRINE MANIFESTATIONS 223 Fragility fracture is common and often precedes a diagnosis of primary hyperparathyroidism. Although signi \201 cant and fast accretion of bone occurs after surgery, bone mass often remains low long term. Thyrotoxicosis \200 Hyperthyroidism can cause a proximal myopathy (70%), shoulder periart hritis (7%), acropachy (thickening of extremities), and osteoporosis. Acropachy is rare (<2% of patients with thyrotoxicosis) and most often occurs in treated patients who are hypo/euthyroid. It consists of clubbing, painful s oft tissue swelling of hands and feet, and periosteal new bone on the radial aspect of the second and third metacarpals. Clinically, this occurs most frequently in patients who have the ophthalmopathy or dermopathy associated with autoimmune thyroid disease. Graves \200\231 disease is frequently associated with fatigability and muscular weakness. I t is associated with autoimmune rheumatic and connective tissue diseases. Acromegaly \200 Overstimulation of bone and connective tissue cells from excessive growth hormone can result in several features: bursal and cartilage hyperplasia, synovial and bon y proliferation, an OA-like picture, backache, and hypermobility. Joint complaints usually manifest about 10 years after the onset of clinical acromegaly. Knees are frequently affected. Joint symptoms are not typical of an in \202 ammatory arthritis \200\224morning stiffness is not prominent and joint swelling is present in <50% of patients. Carpal tunnel syndrome (see Chapter 2) affects >50% of patients and is frequently bilateral. Back and neck pain and radicular symptoms from nerve root compression or spinal stenosis are not uncommon and are related to axial bony proliferation . A painless proximal myopathy occurs infrequently. \200 Radiographs characteristically sho w widened joint spaces (e.g., >2.5 mm in adult MCPs) and a thickened heel pad (>23 mm in men and >21.5 mm in women ). Diagnosis relies on demonstration of a failure of growth hormone to be suppressed by a gluc ose tolerance test, but a lateral skull radiograph is a good screening test as 90% have enl argement of the pituitary fossa. CHAPTER 4 The spectrum of presentation 224 Gut and hepatobiliary manifestations \200 Musculoskeletal features frequently occur in pa tients with gut or hepatobiliary disease (see Table 4.6) Data on the frequency of rheumatologic features are largely based on studies of hospital pa tients with clinically overt gut or biliary disease. This may lead to an underestimate of t he frequency of association. \200 The most frequent associations are: sacroiliitis, arthr itis, and enthesitis in patients with in \202 ammatory bowel disease; in \202 ammatory ar thritis in celiac disease and viral hepatitis; and degenerative arthritis in hemochromatosi s and Wilson \200\231s disease. The frequency of enthesitis in patients with in \202 ammatory bowel disease may be underes timated. Enthesitis may be detected at the medial/lateral humeral epicondyles, Achilles \200\231 tendon insertion, calcaneal plantar fascia origin and insertion, and the patellar tendon origin and its insertion at the tibial tubercle. Radiology studies in patients with in \202 ammatory bowel disease suggest that sacroiliitis is under-recognized by clinicians. Severity of rheumatologic manifestations \200 Optimal surveillance strategies for the mus culoskeletal manifestations of gut or biliary disease are not known in many instances. Life-threatening vasculitis may occur from chronic viral infection. Hepatitis B is associated with polyarteritis nodosa, and hepatitis C may lead to cryoglobul inemic vasculitis. In most patients who develop joint in \202 ammation or enthesitis after bacterial dysenter y, the condition is self-limiting. Chronicity and severity may be linked to HLA B27. Progre ssive spondylitis is rare. Gut and hepatobiliary conditions in patients with rheumatic diseases (see Tables 4.7 and 4. 8) \200 The most common problem among patients with RA is dyspepsia associated with gastr oduodenal erosions or ulcers due to NSAIDs. Peptic lesions may be clinically silent and may present with dropping hemoglobin levels or an acute bleed. Rheumatoid arthritis may be the most common cause of AA amyloidosis. Biopsies of the upper gastrointestinal tract will demonstrate amyloid deposits in 13% of patients. There are nume rous gastrointestinal manifestations of amyloidosis, including gastrointestinal hemorrhage, malabsorption, obstruction, and hepatomegaly. Scleroderma has numerous gastrointestinal manifestations including refractory gastroesophag eal re \202 ux disease, gastric antral vascular ectasia ( \200\234watermelon stomach \200 \235), esophageal dysmotility, bacterial overgrowth syndrome, and fecal incontinence. The r e \202 ux associated with scleroderma often requires treatment with high dose proton pump inhibitors. \200\234Watermelon stomach \200\235 can lead to signi \201 cant acute and chr onic hemorrhage. The bloating and abdominal distension caused by bacterial overgrowth may r espond to cyclic courses of antibiotics. Table 4.6 Rheumatological features in patients with gut or hepatic disease Gastrointestinal disorder Rheumatic manifestation Association Enteric infection Reactive arthritis: self-limiting in most Arthritis in 2% who get shigella, salmonella, yersinia, campylobacter or C . dif \201 cile overall but in 20% of infected who are HLA B27+ Crohn \200\231s disease Arthritis 20%. as 10%. Sacroiliitis in 26% 60% of spondyloarthropathy patients have histological evidence of bowel in \202 ammation. See also below G U T Ulcerative colitis Arthritis 20%. AS 7%. Sacroiliitis 15% See also above. Severity of gut and joint in \202 ammation varies in its association but S I joint/pine in \202 ammation does not A N D Whipple \200\231s disease Migratory arthritis in >60% T. whippelii identi \201 ed in small bowel. Diarrhea occurs in >75% ultimately H E P A T O B Intestinal by-pass surgery(blind loop syndrome) Polyarticular symptoms 50%in scleroderma Intestinal bacterial overgrowth in small bowel. ?Associated with joint symptoms I L Celiac disease Arthritis is rare ?Increased intestinal permeability I A R Y M A N I F E S T A T O N S Viral enteritis Rare (<0.5%) Most common: coxsackie or echo Hepatitis A Arthralgia 15%. Vasculitis rare Causal association Hepatitis B Arthralgia 10 \200\22325%. PAN Etiological. Hepatitis C Sialadenitis in >50%. Vasculitis (cryoglobulinemic) ?Etiological in Sj gren \200\231s. Hepatitis C identi \201 ed in 27 \200\22396% of pati ents with cryoglobulinemia I (Continued) 2 2 5 2 2 6 C H A P T E R Table 4.6 (Contd.) Gastrointestinal disorder Rheumatic manifestation Association 4 Primary biliary cirrhosis Polyarthritis 19%. Scleroderma 18%. Sj gren \200\231s 50% Autoimmune \200\234overlap. \200\235 Features may be subclinical T h e Chronic active hepatitis Polyarthralgia or arthritis in 25 \200\22350% Autoimmunity s p e c t r u m o f Hemochromatosis OA 50% Iron storage disease Wilson \200\231s disease OA in 50% adults. Chondrocalcinosis Copper storage disease p r e s e n t a t i o n GUT AND HEPATOBILIARY MANIFESTATIONS 227 Table 4.7 Gut and hepatobiliary manifestations in rheumatological diseases (I: General) Disease Abnormalities Presentation with Rheumatoid arthritis (Chapter 5) TMJ arthritis Esophageal dysmotility GI vasculitis (0.1%) Portal hypertension Liver involve ment (Felty \200\231s) Hepatosplenomegaly Esophageal dysmotility GI vasculitis Protein-losi ng enteropathy Peritonitis Hepatosplenomegaly (30%) Esophageal dysmotility Delayed gastric emptying Intestinal dysmotility and \201 brosis (80%) Pseudo and wide mouth diverticula M uscle weakness Disordered motility Vasculitis (rare) Hypomotility Impaired mastication Dysphagia, re \202 ux Ulcers, pain, infarction Splenomegaly (Felty \200\231s) Enzyme abnormalities Palpable viscera Dysphagia, re \202 ux Ulcers, pain, perforation Hypoalbuminemia Systemic lupus erythematosus (Chapter 10) Ascites (10%), serositis Palpable viscera Scleroderma (Chapter 13) Heartburn/dysphagia Aggravated re \202 ux Malabsorption, pseudo- obstruction (<1%) Hemorrh age, stasis, bacterial overgrowth Aspiration, dysphagia Dysphagia, constipation Ulcers, per foration Dysphagia, re \202 ux, pseudo-obstruction Xerostomia, dysphagia Dysphagia (>60%) Masses, dyspepsia Polymyositis and dermatomyositis (Chapter 14) MCTD Sj gren \200\231s syndrome (Chapter 12) Membrane desiccation Esophageal webs (10%) Gastric in \201 ltrates/ atrophy Pancreatitis H epatic dysfunction Hepatic cirrhosis Ileocolonic in \202 ammation Pain, amylasemia Hepatomegaly ( (cid:2) 25%) Primary biliary cirrhosis May be asymptomatic Spondyloarthritis (Chapter 8) Adult onset Still \200\231s Systemic JIA (Chapter 9) Hepatitis, peritonitis, hepatosplenomegaly Serositis Hepatomegaly Pain or abnormal enzymes ( (cid:2) 75%) Abdominal pain Abnormal enzymes Marfan, Ehlers- Danlos (Chapter 16) Defective collagen Hypomotility, malabsorption, visceral rupture/laxity CHAPTER 4 The spectrum of presentation 228 Table 4.8 Gut and hepatobiliary manifestations in rheumatic diseases (II: Vasculitis [see a lso Chapter 15]) Disease Frequency of GI vasculitis and features Polyarteritis nodosa 80% (mesenteric). Buccal ulcers, cholecystitis (15%), bowel infarction, perforation, append icitis, pancreatitis, strictures, chronic wasting syndrome Henoch \200\223Sch nlein purpura 44 \200\22368%. Abdominal pain, melena, hematemesis, ulcers, intussusception, cholecystitis , infarction, perforation, appendicitis (cid:2) 40%. Hemorrhage, ulceration, infarction, pe rforation Eosinophilic granulomatosis with polyangiitis Beh et \200\231s syndrome Buccal and intestinal ulcers, hemorrhage, perforation, pyloric stenosis, rectal ulcers Systemic lupus erythematosus 2%. Buccal ulcers, ileocolitis, gastritis, ulceration, perforation, intussusception, volvul us (1%), pneumatosis Kawasaki disease Abdominal pain, intestinal obstruction, noninfective diarrhea Granulomatosis with polyangiitis <5%. Cholecystitis, appendicitis, ileocolitis, infarction Juvenile dermatomyositis Well recognized. Perforation, pneumatosis MCTD Rare. Ulceration, perforation, pancreatitis RA (including RF + JIA) 0.1%. Buccal ulcers, abdominal pain, peptic ulcers, acalculous cholecystitis, gut infarctio n, and perforation Polymyositis and dermatomyositis Very rare. Mucosal ulcers, perforation and pneumatosis Cryoglobulinemia Rare. Ischemia and infarction In SLE, serious gut and hepatobiliary manifestations are relatively uncommon (5%), but naus ea, anorexia, vomiting, and diarrhea are quite frequent. Mesenteric vasculitis is classically caused by polyarteritis nodosa, but can be seen with a variety of rheumatic illnesses, including Takayasu \200\231s arteritis, ANCA-associated va sculitis, and (rarely) with SLE. Although mesenteric angina is the symptom most strongly as sociated with mesenteric vasculitis, the earliest sign of intestinal ischemia is diarrhea. Henoch-Sch nlein purpura is an IgA-mediated small vessel vasculitis that presents with c olicky abdominal pain and purpura. Although generally mild and self-limited in children, it can occasionally cause intussusception and bowel necrosis. GUT AND HEPATOBILIARY MANIFESTATIONS 229 Gut and hepatobiliary side effects from drugs used in treating rheumatic and bone diseases \200 Such side effects are common: \200 NSAIDs are a common cause of gastrointestinal d istress. COX-2 inhibitors were developed to decrease the risk of peptic ulcer disease; most have been with drawn from the market due to concerns regarding increased risk of cardiovascular events. On ly celecoxib remains on the market in the United States, but it may be no more effective th an taking a conventional NSAID with a proton pump inhibitor. Glucocorticoids are also associated with gastritis, peptic ulcer disease, and gastrointesti nal hemorrhage. Although the absolute increase in events is small, the combination of stero ids and NSAIDs results in a synergistic increase in the risk of gastrointestinal sequelae. \200 Methotrexate may cause stomatitis, which may respond to supplemental folate. Nausea, emesis, and altered taste may also occur, which may respond to dose reduction. Methotrexate can cause a transaminitis; therefore, we generally recommend that patients treated with methotrexate abstain from alcohol. Sulfasalazine: Gut and hepatobiliary side-effects are common and may occur in up to 20% of patients. The most frequent are mostly mild: indigestion, nausea, vomiting, anorexia, and a bdominal pain. Gut ulceration, bloody diarrhea, and serious liver problems are rare. In abo ut 65% of side-effects occur in the \201 rst 3 months of treatment. \200 Azathioprine c an cause nausea (15%), vomiting (10%), and abdominal pain (8%). Diarrhea is rare (5%). Live r enzyme abnormalities are often mild and may remit on lowering the dose. The GI side effec ts can occur in patients with normal levels of thiopurine methyltransferase. D-penicillamine causes altered taste (25% within the \201 rst 3 \200\2236 months), nausea or vomiting (18%), and stomatitis/mouth ulcers (5%). Hepatotoxicity and hem orrhagic colitis are rare. Chloroquine and hydroxychloroquine, used in mild SLE particularly, can cause nonspeci \201 c GI intolerance (10%). The onset is often insidious. Cyclosporine causes gingival hyperplasia, nausea, diarrhea, and elevation in hepatic enzymes. Effects of cyclophosphamide on the gut are frequent and include nausea, vomiting, diarrhea, and stomatitis. Serious hepatotoxicity is rare. Chlorambucil has a low incidence of GI side effects. \200 Le \202 unomide can cause naus ea (8 \200\22313%), diarrhea (up to 25%), and abnormal liver enzymes. In studies to date, most rises in transaminases have been mild (< t wo-fold) and are reversible on drug withdrawal. \200 Oral bisphosphonates (such as alendr onate and risedronate) can cause nausea, dyspepsia, and diarrhea. Esophageal ulceration has occasionally been noted with alendronate though it is thought this occurs only in people w ho do not follow the instructions for taking them. Myalgias and arthralgias can also occur. Calcitonin either given as subcutaneous injection or as nasal spray can give abdominal pains and diarrhea. CHAPTER 4 The spectrum of presentation 230 Malignancy Rheumatic features may be clues to the existence of cancer; these may be caused directly (through tissue invasion) or indirectly (as a paraneoplastic phenomenon). Primary and secondary neoplastic diseases of bone and joints \200 Synovial tumors are rar e. Sarcoma (synovioma) is more common in men than women and unusual in those over 60. It us ually occurs in the legs (70%) and can occur around tendon sheaths and bursa. At diagnosis, pulmonary metastases are common. Para-articular involvement by bone tumors may give a monoarticular effusion. Invasion of sy novium may occur and malignant cells can be detected in joint \202 uid. Breast, bronchoge nic carcinoma, GI tumors, and melanoma can all metastasize to joints. Lymphomas and leukemias may simulate various conditions and cause synovitis in a single or in multiple joints. Arthritis complicating the presentation of myeloma or an acute leukemia is most likely to b e polyarticular and asymmetric. \200 In adults, arthritis complicating leukemia is rare ( 5% of cases). \200 Leukemia is the most common cause of neoplastic skeletal symptoms in childhood and adolescence (15% of leukemia cases). Neuroblastomas are the most frequent cause of a solid tumor metastasizing to the skeleton in children. Clues that may lead to a suspicion of malignancy directly causing musculoskeletal symptoms \200 Constitutional symptoms. \200 The coexistence of bone pain (also consider metaboli c bone diseases, sarcoid, and enthesitis-related conditions). Hemorrhagic joint \202 uid (also consider trauma, pigmented villonodular synovitis (PVNS), chondrocalcinosis). Radiographs that show adjacent bone destruction, perhaps with loss of cortex (also consider infection). Radiographic calci \201 cation in soft-tissue mass (consider synovioma). Paraneoplastic myopathies Paraneoplastic myopathies may occur before, during, or after the diagnosis of malignancy: \200 Myopathy is usually due to carcinomatous neuromyopathy. \200 Polymyositis, dermatomyositis, Eaton \200\223Lambert myasthenic syndrome (ELMS) and h ypophosphatemic (oncogenic) osteomalacia are all found in association with malignancy (see Table 4.9). Carcinomatous neuromyopathy is a condition characterized by symmetric muscle weakness and wasting. The myopathy can pre-date malignancy. Table 4.9 Myopathy and links with malignancy Condition Typical pattern of weakness Common cancer associations Other features Carcinomatous neuromyopathy Pelvic girdle \200\224symmetric Lung: 15% men, 12% women. Ovary: 16%. Stomach: 7% men, 13% women Wasting, EMG abnormality, and increase in muscle enzymes are notinvariable Dermatomyositis (+?PM) Proximal limb. Truncal Re \202 ects underlying cancer frequency in local population Response to steroids is usual Myasthenia gravis (MG) Frequently ocular and bulbar Thymus. Any Muscle strength \202 uctuates (fatigability). Responds to anticholinesterases muscles involved Eaton \200\223Lambert myasthenicsyndrome (ELMS) Pelvic girdle muscles. Altered gait. Ocular muscles not affected Small cell lung. Can occur up to 2 \200\2233 years after ELMS Autonomic disturbances. EMG + poor response to anticholinesterasedistinguish from MG Oncogenic osteomalacia Generalized. Develops insidiously Small, discrete mesenchymal tumors in bone, soft tissues, and sinuses. Neuro \201 bromatos is Bone pain and bone demineralization. Hypophosphatemia and lowcirculating 1,25 OH vitamin D M A L G N A N C Y I 2 3 1 CHAPTER 4 The spectrum of presentation 232 Nonmyopathic paraneoplastic syndromes The nonmyopathic paraneoplastic syndromes are rare: \200 Hypertrophic pulmonary osteoarthropathy (HPOA) consists of clubbing, periostitis of tubular bones, and an arthropathy (may range from arthralgias to d iffuse polyarthritis). Suspicion of this should prompt a request for an isotope bone scan, which typically shows abnormally increased bone turnover in the long bones. Radiographs oft en show periosteal elevation. HPOA complicates 20% of primary lung tumors, but it is associ ated with other malignancies. Polyarthritis may be the presenting feature of cancer. Most cases occur in those over 60 ye ars old. Unlike RA, the arthritis associated with malignancy tends to be asymmetric, and do es not cause erosions. \200 Eosinophilic fasciitis, severe bilateral palmar fasciitis (of ten mistaken for scleroderma), and fasciitis associated with panniculitis have been associa ted with malignancy. Cases of \200\234shoulder \200\223hand \200\235 syndrome (a form of r e \202 ex sympathetic dystrophy) that have been reported in association with malignancy pr obably re \202 ect similar pathological processes. Rheumatic diseases associated with an increased incidence of malignancy There are a number of rheumatic diseases that are associated with an increased incidence of malignancy compare d with healthy populations. These are dealed with brie \202 y here and in more detail in P art 2 of this book. \200 Non-Hodgkin \200\231s lymphoma is most strongly associated with RA. Myeloma and paraproteinemias are also found in RA patients. The relative risk of colon cancer among RA patients is 0.77; this may be due to the use of chronic NSAIDs in this patient population, which may be protective. Use of cyclophosphamide is associated with an increased risk of lymphoma and bladder cancer. Methotrexate may also be associated with an increased risk of lymphoma. Chronic azathioprine use is associated with an increased risk of skin cancer; patients taki ng azathioprine long term should be counseled about sun protection and monitoring for skin cancer. Non-Hodgkin \200\231s lymphoma develops in a subset of patients with Sj gren \200\231s s yndrome (4%). Its onset may be indicated by rapid enlargement of salivary glands, the appea rance of a paraprotein, or decrease in circulating immunoglobulins or RF titer. Scleroderma has been associated with an increased risk of both lung cancer and non-Hodgkin \200\231s lymphoma. Dermatomyositis is probably associated with malignancy in adults, though convincing evidenc e for an association of polymyositis with malignancy is lacking. Neither is associated with malignancy in children. Part II The clinical features and management of rheumatic diseases 5 Rheumatoid arthritis (RA) 6 Osteoarthritis (OA) 7 The crystal arthropathies 8 The spondyl oarthropathies 9 Juvenile idiopathic arthiritis (JIA) 10 Systemic lupus erythematosus (SLE) 11 The antiphospholipid (antibody) syndrome (APS) 12 Sj gren \200\231s syndrome (SS) 13 S ystemic sclerosis and related disorders 14 Idiopathic in \202 ammatory myopathies \200\224 polymyositis 235 261 271 283 309 329 351 361 373 (PM) and dermatomyositis (DM) 397 417 443 481 499 15 Primary vasculitides 16 Metabolic bone diseases and disorders of collagen 17 Infection a nd rheumatic disease 18 Miscellaneous conditions 19 Common upper limb musculoskeletal lesions 20 Back pain 21 Complementary and alternative medicine in 529 537 rheumatology 553 561 22 Rheumatologic emergencies 235 Chapter 5 Rheumatoid arthritis (RA) Disease criteria and epidemiology 236 Incidence, prevalence, and morbidity 238 The clinical features of rheumatoid arthritis 239 Organ disease in rheumatoid arthritis 240 The evaluat ion and treatment of rheumatoid arthritis 244 Rheumatoid factor positive polyarthritis in c hildhood 259 CHAPTER 5 Rheumatoid arthritis (RA) 236 Disease criteria and epidemiology There is no perfect test for rheumatoid arthritis (RA). T he diagnosis rests on a composite of clinical and laboratory observations. It is a common s ys- temic in \202 ammatory disease characterized by the presence of a destructive polyarth ritis with a predisposition for affecting the small joints of the hands and feet and the wr ists (although it can affect any synovial joint). Disease criteria are often developed for epidemiological work and for classi \201 cation i n the context of clinical trials. Classi \201 cation criteria for RA in particular are dom inated by signs and symptoms from the musculoskeletal system. It is important to remember, however, that there are a number of \200\234extra-articular \200\235 manifestations to the disease, with involvement of, for example, the eyes, lungs, skin, heart, and nervous syste m. The criteria for the diagnosis of RA ranges from the original American Rheumatism Associati on (ARA) scheme of 1958, through the develop- ment of the simpler New York criteria, to the 1987 ARA criteria (see Table 5.1) which replaced the 1958 ARA criteria. These criteria wer e not designed to diagnose patients with RA; in particular, it is often dif \201 cult to a pply these criteria to the diagnosis of \200\234possible, \200\235 \200\234early, \200 \235 or atypical RA. It is most straightforward to apply these criteria in clinical trials aimed at patients with well-established disease. Signi \201 cant evidence, however, indicates that early treatment of rheu- matoid arthriti s greatly improves the long-term outcomes associated with this disease, highlighting the im portance of early diagnosis and therapy. For this reason, in 2010, the American College of Rheumatology (ACR) and the European Leagu e Against Rheumatism (EULAR) developed a revised set of classi \201 cation criteria (see T able 5.2), designed to identify patients with early RA, at the time of initial presentation . Therefore, the new criteria are not interchangeable with the old criteria; using the new criteria, for example, a patient who presents with 6 weeks of bilateral knee swelling or te nderness, in the setting of a high-positive rheumatoid factor and abnormal ESR, would be cl assi \201 ed as having rheumatoid arthritis by the 2010 criteria, but not the 1987 criteri a. DISEASE CRITERIA AND EPIDEMIOLOGY 237 Table 5.1 The 1987 American College of Rheumatology criteria for the diagnosis of rheumatoi d arthritis Criterion Comments 1 Morning stiffness Duration >1 hour lasting >6 weeks 2 Arthritis of at least three joints* Soft tissue swelling/exudation lasting >6 weeks 3 Arthritis of hand joints Wrists, MCPs, or PIPs lasting >6 weeks 4 Symmetrical arthritis At least one area, lasting >6 weeks 5 Rheumatoid nodules 6 Positive rheumatoid factor 7 Radiographic changes Erosions, particularly wrists, hands,and feet At least four criteria must be ful \201 lled and there are no exclusion criteria. * Possib le areas: metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), wrist, e lbow, knee, ankle, metatarsophalangeal joints (MTP). Table 5.2 The 2010 American College of Rheumatology/European League Against Rheumatism crit eria for rheumatoid arthritis Criterion Score 2 \200\22310 large joints 1 Joint Involvement* 1 \200\2233 small joints 2 4 \200\22310 small joints 3 >10 joints 5 Serology \200 Low-positive RF or ACPA 2 High-positive RF or ACPA 3 Acute phase reactants Abnormal CRP or ESR 1 Symptom duration (cid:2) 6 weeks 1