InternalMed_Harrison

InternalMed_Harrison. Eosinophilic fasciitis is a rare idiopathic disorder associated with induration of the skin that generally develops rapidly. Adults are primarily affected. The skin has a coarse cobblestone “peau d’orange” appearance. In contrast to SSc, internal organ involvement is rare, and Raynaud’s phenomenon and SSc-associated autoantibodies are absent. Furthermore, skin involvement spares the fingers. Full-thickness excisionalbiopsyofthelesionalskinrevealsfibrosisofthesubcutaneousfasciaandisgenerallyrequiredfordiagnosis.Inflammationandeosinophil infiltration in the fascia are variably present. In the acute phase of the illness, peripheral blood eosinophilia may be prominent. MRI appears to be a sensitive tool for the diagnosis of eosinophilic fasciitis. In some patients, eosinophilic fasciitis occurs in association with, or preceding, myelodysplastic syndromes or multiple myeloma. Treatment with glucocorticoids leads to prompt resolution of the eosinophilia. In contrast, skinchanges generally


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InternalMed_Harrison. in association with, or preceding, myelodysplastic syndromes or multiple myeloma. Treatment with glucocorticoids leads to prompt resolution of the eosinophilia. In contrast, skinchanges generally show slow and variable improvement. Theprognosis of patients with eosinophilic fasciitis is good.


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InternalMed_Harrison. 2166 DEFINITION, INCIDENCE, aND PrEVaLENCE Haralampos M. Moutsopoulos, Athanasios G. Tzioufas Sjögren’s syndrome is a chronic, slowly progressive autoimmune disease characterized by lymphocytic infiltration of the exocrine glands result ing in xerostomia and dry eyes. Approximately one-third of patients present with systemic manifestations; a small but significant number of patients develop malignant lymphoma. The disease presents alone (primary Sjögren’s syndrome) or in association with other autoimmune rheumatic diseases (secondary Sjögren’s syndrome) (Table 383-1). Middle-aged women (female-to-male ratio, 9:1) are primarily affected, although Sjögren’s syndrome may occur at any age, including childhood. The prevalence of primary Sjögren’s syndrome is ~0.5–1%, while30% of patients with autoimmune rheumatic diseases suffer from secondary Sjögren’s syndrome.


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InternalMed_Harrison. Sjögren’s syndrome is characterized by both lymphocytic infiltration of the exocrine glands and B lymphocyte hyperreactivity. An oligomonoclonal B cell process, which is characterized by cryoprecipitable monoclonal immunoglobulins (IgMκ) with rheumatoid factor activity, is evident in up to 25% of patients. Sera from patients with Sjögren’s syndrome often contain auto-antibodies to non-organ-specific antigens such as immunoglobulins (rheumatoid factors) and extractable nuclear and cytoplasmic antigens (Ro/SS-A, La/SS-B). Ro/SS-A autoantigen consists of two polypeptides (52 and 60 kDa, respectively) in conjunction with cytoplasmic RNAs, whereas the 48-kDa La/SS-B protein is bound to RNA III polymerase transcripts. Autoantibodies to Ro/SS-A and La/SS-B antigens are usually detected at the time of diagnosis and are associated with earlier diseaseonset,longerdiseaseduration,salivaryglandenlargement, and more intense lymphocytic infiltration of minor salivary glands.


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InternalMed_Harrison. The major infiltrating cells in the affected exocrine glands are activated T and B lymphocytes. T cells predominate in mild lesions, whereas B cells are dominant in more severe lesions. Macrophages and dendritic cells also are found. The number of macrophages positive for interleukin (IL) 18 has been shown to correlate with parotid gland enlargement and low levels of the C4 component of complement, both of which are adverse predictors for lymphoma development.


InternalMed_Harrison

InternalMed_Harrison. Ductal andacinarepithelial cells appeartoplay a significant rolein the initiation and perpetuation of autoimmune injury. These cells (1) express classIImajorhistocompatibilitycomplex(MHC)molecules,costimulatory molecules, and abberant expression of intracellular autoantigens on cell membranes and thus are able to provide signals essential for lymphocytic activation; (2) inappropriately produce proinflammatory cytokines and lymphoattractant chemokines necessary for sustaining the autoimmune lesion and allowing progression to more sophisticated ectopic germinal center formation, which occurs in one-fifth of patients; and (3) express functional receptors of innate immunity, particularly Toll-like receptors (TLRs) 3, 7, and 9, that may account for the perpetuation of the autoimmuneresponse.


InternalMed_Harrison

InternalMed_Harrison. Both infiltrating T and B cells have a tendency to be resistant to apoptosis. Levels of B cell–activating factor (BAFF) have been found to be elevated in patients with Sjögren’s syndrome, especially those with hypergammaglobulinemia,andprobably accounts for thisantiapoptotic effect. Glandular epithelial cells seem to have an active role in the productionofBAFF, whichmaybe expressedandsecretedafterstimulation with type I interferon as well as with viral or synthetic double-stranded RNA. The triggering factor for epithelial activation appears to be a persistent enteroviral infection (possibly with coxsackievirus strains). Type I and type II interferon signatures have been described in ductal epithelial cells and T cells,respectively;their detection impliesthat interferons exert direct and cross-regulating effects on the pathogenic process.


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InternalMed_Harrison. A defect in cholinergic activity mediated through the M3 receptor and redistribution of the water-channel protein aquaporin 5, both leadingtoneuroepithelialdysfunctionanddiminishedglandularsecretions, have been proposed. Molecularanalysisofhumanleukocyteantigen(HLA)classIIgenes has revealed that Sjögren’s syndrome, regardless of the patient’s ethnic origin, is highly associated with the HLA DQA1*0501 allele. Genome-wide association studies have disclosed an increased prevalence of single-nucleotidepolymorphismsin genes of IRF-5 and STAT-4, which participate in the activation of the type I interferon pathway. The majority of patients with Sjögren’s syndrome have symptoms related to diminished lacrimal and salivary gland function. In most patients, the primary syndrome runs a slow and benign course. The initial manifestations can be mucosal or nonspecific dryness, and 8–10 years may elapse from the initial symptoms to full-blown development of the disease.


InternalMed_Harrison

InternalMed_Harrison. The principal oral symptom of Sjögren’s syndrome is dryness (xerostomia). Patients report difficulty in swallowing dry food, an inabilitytospeakcontinuously,aburningsensation,anincreaseindental caries, and problems in wearing complete dentures. Physical examination shows a dry, erythematous, sticky oral mucosa. There is atrophy of the filiform papillae on the dorsum of the tongue, and saliva from the major glands is either not expressible or cloudy. Enlargement of the parotid or other major salivary glands occurs in two-thirds of patients with primary Sjögren’s syndrome but is uncommon in those with the secondary syndrome. Diagnostic tests include sialometry, sialography, and scintigraphy. Newer imaging techniques, including ultrasound, MRI, and magnetic resonance sialography of the major salivary glands, are also being used. Biopsy of the labial minor salivary gland permits histopathologic confirmation of focal lymphocytic infiltrates.


InternalMed_Harrison

InternalMed_Harrison. Ocular involvement is the other major manifestation of Sjögren’s syndrome. Patients usually describe a sandy or gritty feeling under the eyelids. Other symptoms include burning, accumulation of secretions in thick strands at the inner canthi, decreased tearing, redness, itching, eye fatigue, and increased photosensitivity. These symptoms, which define keratoconjunctivitis sicca, are attributed to the destruction of corneal and bulbar conjunctival epithelium. Diagnostic evaluation of keratoconjunctivitis sicca includes measurement of tear flow by SchirmerItestanddeterminationoftearcomposition,withassessment of tear breakup time or tear lysozyme content. Slit-lamp examination ofthecorneaandconjunctivaafterrosebengalstainingrevealspunctuate corneal ulcerations and attached filaments of corneal epithelium.


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InternalMed_Harrison. Involvement of other exocrine glands, which occurs less frequently, includes a decrease in mucous gland secretions of the upper and lower respiratorytree,resultingin drynose,throat, andtrachea(xerotrachea). In addition, diminished secretion of the exocrine glands of the gastrointestinal tract leads to esophageal mucosal atrophy, atrophic gastritis, andsubclinicalpancreatitis.Dyspareuniaduetodrynessoftheexternal genitalia and dry skin also may occur. Extraglandular (systemic) manifestations are seen in one-third of patients with Sjögren’s syndrome (Table 383-2) but are very rare in patients whose Sjögren’s syndrome is associated with rheumatoid aMucosa-associated lymphoid tissue.


InternalMed_Harrison

InternalMed_Harrison. arthritis. Patients with primary Sjögren’s syndrome more often report easy fatigability, low-grade fever, Raynaud’s phenomenon, myalgias, and arthralgias.Mostpatientswithprimary Sjögren’ssyndromeexperience at least one episode of non-erosive arthritis during the course of their disease. Manifestations of pulmonary involvement are frequently evident histologically but are rarely important clinically. Dry cough is themajormanifestationthatisattributedtosmallairwaydisease. Renal involvement includes interstitial nephritis, clinically manifested by hyposthenuria and renal tubular dysfunction with or without acidosis. Untreated acidosis may lead to nephrocalcinosis. Glomerulonephritis is a rare finding that occurs in patients with mixed cryoglobulinemia or with systemic lupus erythematosus overlapping with Sjögren’s syndrome. Vasculitis affects small and medium-sized vessels. The most common clinical features are purpura, recurrent urticaria, skin ulcerations, glomerulonephritis, and


InternalMed_Harrison

InternalMed_Harrison. overlapping with Sjögren’s syndrome. Vasculitis affects small and medium-sized vessels. The most common clinical features are purpura, recurrent urticaria, skin ulcerations, glomerulonephritis, and mononeuritis multiplex.


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InternalMed_Harrison. Different autoantibodies may determine the clinical expression of the disease. Patients positive for anticentromere autoantibody present with a clinical picture similar to that of limited scleroderma (Chap. 382). Antimitochondrial antibodies may connote liver involvement in the form of primary biliary cirrhosis (Chap. 369). Autoantibodies to 21-hydroxylate have recently been described in almost 20% of patients; their presence is associated with a blunted adrenal response. Centralnervoussysteminvolvementisrarelyrecognized.Afewcases ofmyelitisassociatedwithantibodytoaquaporin4havebeendescribed.


InternalMed_Harrison

InternalMed_Harrison. Centralnervoussysteminvolvementisrarelyrecognized.Afewcases ofmyelitisassociatedwithantibodytoaquaporin4havebeendescribed. Lymphoma is a well-known manifestation of Sjögren’s syndrome that usually presents later in the illness. Persistent parotid gland enlargement, purpura, leukopenia, cryoglobulinemia, low C4 complement levels, and ectopic germinal centers in minor salivary gland biopsy samples are manifestationssuggestingthedevelopmentoflymphoma.Itisinteresting thatthesameriskfactorsaccountforglomerulonephritisandlymphoma and that these risk factors are the ones that confer increased mortality risk. Most lymphomas are extranodal, low-grade marginal-zone B cell lymphomas and are usually detected incidentally during evaluation of the labial biopsy. The affected lymph nodes are usually peripheral. Survival rates are decreased in patients with B symptoms, lymph node mass >7 cm in diameter, and high or intermediate histologic grade.


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InternalMed_Harrison. Routine laboratory tests in Sjögren’s syndrome reveal mild normochromic, normocytic anemia. An elevated erythrocyte sedimentation rate is found in ~70% of patients.


InternalMed_Harrison

InternalMed_Harrison. Primary Sjögren’s syndrome is diagnosed if (1) the patient presents with eye and/or mouth dryness, (2) eye tests disclose keratoconjunctivitis sicca, (3) mouth evaluation reveals the classic manifestations of the syndrome, and/or(4) the patient’s serum reacts with Ro/SS-A and/or La/SS-B auto-antigens. Labial biopsy is needed when the diagnosis is uncertain or to rule out other conditions that may cause dry mouth or eyes or parotid glandenlargement (Tables 383-3 and 383-4). Validated diagnosticcriteriahavebeenestablishedbyaEuropeanstudyandhavenowbeenfurther improvedbyaEuropean-Americanstudygroup(Table 383-5).Hepatitis C virus infection should be ruled out since, apart from serologic tests, the clinicopathologic picture is almost identical to that of Sjögren’s syndrome. Enlargement of major salivary glands, particularly in seronegative patients, should raise the suspicion of IgG4-related syndrome, which may present also as chronic pancreatitis, interstitial nephritis, retroperitoneal


InternalMed_Harrison

InternalMed_Harrison. salivary glands, particularly in seronegative patients, should raise the suspicion of IgG4-related syndrome, which may present also as chronic pancreatitis, interstitial nephritis, retroperitoneal fibrosis, and aortitis.


InternalMed_Harrison

InternalMed_Harrison. Treatment of Sjögren’s syndrome is aimed at symptom relief and limitation of the damaging local effects of chronic xerostomia and keratoconjunctivitis sicca through substitution for or stimulation of the missing secretions (Fig. 383-1). Lack of autoantibodies to Ro/SS-A and/or La/SS-B Lymphoid infiltrates of salivary glands by CD8+ T lymphocytes Association with Presence of autoantibodies Lymphoid infiltrates of salivary glands by CD4+ T lymphocytes Association with Lack of autoantibodies to Ro/SS-A and/or La/SS-B 2168 taBle 383-5 reVISeD InternatIOnal ClaSSIfICatIOn CrIterIa fOr Sjögren’S SynDrOMea,b,c I. Ocular symptoms: a positive response to at least one of three validated questions. 1. Have you had daily, persistent, troublesome dry eyes for more than 3 months? 2. Do you have a recurrent sensation of sand or gravel in the eyes? 3. Do you use tear substitutes more than three times a day?


InternalMed_Harrison

InternalMed_Harrison. II. Oral symptoms: a positive response to at least one of three validated questions. 1. Have you had a daily feeling of dry mouth for more than 3 months? 2. Have you had recurrent or persistently swollen salivary glands as an adult? 3. Do you frequently drink liquids to aid in swallowing dry foods? III. Ocular signs: objective evidence of ocular involvement defined as a positive result to at least one of the following two tests: 1. Shirmer’s I test, performed without anesthesia (≤5 mm in 5 min) 2. Rose Bengal score or other ocular dye score (≥4 according to van Bijsterveld’s scoring system) IV. Histopathology: In minor salivary glands focal lymphocytic sialoadenitis, with a focus score ≥1. V. Salivary gland involvement: objective evidence of salivary gland involvement defined by a positive result to at least one of the following diagnostic tests: 1. Unstimulated whole salivary flow (≤1.5 mL in 15 min) 2. Parotid sialography 3. Salivary scintigraphy


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InternalMed_Harrison. VI. Antibodies in the serum to Ro/SS-A or La/SS-B antigens, or both. aExclusion criteria: past head and neck radiation treatment, hepatitis C infection, AIDS, preexisting lymphoma, sarcoidosis, graft-versus-host disease, use of anticholinergic drugs. bPrimary Sjögren’s syndrome: any four of the six items, as long as item IV (histopathology) or VI (serology) is positive; or any three of the four objective-criteria items (III, IV, V, VI). cIn patients with a potentially associated disease (e.g., another well-defined connective tissue disease), the presence of item I or item II plus any two from among items III, IV, and V may be considered indicative of secondary Sjögren’s syndrome. Source: From C Vitali et al: Ann Rheum Dis 61:554, 2002. ©2002 with permission from BMJ Publishing Group Ltd.


InternalMed_Harrison

InternalMed_Harrison. Avoid Smoking areas, windy, low humidity environment, drugs with anticholinergic action, diuretics Lubrication Artificial tears without preservatives, bicarbonate-buffered electrolyte solutions Oral hygiene after each meal Topical application of fluoride Lubrication Water Local stimulation Sugar-free, flavored lozenges or gum Systemic stimulation As for dry eyes Oral candidiasis Topical nystatin or clotrimazole lozenges Apply Local wet heat Treat superinfection Antibiotics, analgesics Persistent, hard Rule out lymphoma Local stimulation Cyclic adenosine mono-phosphate, cyclosporine 2% olive solution Systemic stimulation Pilocarpine (5 mg thrice daily orally); cevimeline (30 mg thrice daily orally) Severe dry eyes Nasolacrimal duct occlusion (temporary or permanent); soft contact lenses; corneal transplantation Glandular manifestations Extraglandular manifestations Parotid gland enlargement Dry mouth Dry eyes Arthritis Cold protection: gloves Raynaud’s phenomenon Bicarbonate


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InternalMed_Harrison. lenses; corneal transplantation Glandular manifestations Extraglandular manifestations Parotid gland enlargement Dry mouth Dry eyes Arthritis Cold protection: gloves Raynaud’s phenomenon Bicarbonate replacement Renal tubular acidosis CHOP + anti-CD20 Vasculitis Standard treatment Lymphoma Hydroxychloroquine (200–400 mg/d) or Methotrexate (0.2–0.3 mg/kg body weight weekly) plus Prednisolone (<10 mg daily orally)


InternalMed_Harrison

InternalMed_Harrison. FIGUrE 383-1 Treatment algorithm for Sjögren’s syndrome. CHOP, cyclophosphamide, adriamycin (hydroxydaunorubicin), vincristine (oncovin), and prednisone. To replace deficient tears, several ophthalmic preparations are readily available (hydroxypropyl methylcellulose; polyvinyl alcohol; 0.5% methylcellulose; Hypo Tears). If corneal ulcerations are present, eye patching and boric acid ointments are recommended. Certain drugs that may decrease lacrimal and salivary secretions, such as diuretics, antihypertensive drugs, anticholinergics, and antidepressants, should be avoided. For xerostomia, the best replacement is water. Propionic acid gels may be used to treat vaginal dryness. To stimulate secretions, orally administered pilocarpine (5 mg thrice daily) or cevimeline (30 mg thrice daily) appears to improve sicca manifestations, and both are well tolerated. Hydroxychloroquine (200 mg) is helpful for arthralgias and mild arthritis.


InternalMed_Harrison

InternalMed_Harrison. Patients with renal tubular acidosis should receive sodium bicarbonate by mouth (0.5–2 mmol/kg in four divided doses). Glucocorticoids (1 mg/kg per day) and/or immunosuppressive agents (e.g., cyclophosphamide) are indicated only for the treatment of systemic vasculitis. Anti–tumor necrosis factor agents are ineffective. Monoclonal antibody to CD20 appears to be effective in patients with systemic disease, particularly in those with vasculitis, arthritis, and fatigability. Combination of anti-CD-20 with a classic CHOP regimen (cyclosporine, adriamycin [hydroxydaunorubicin], vincristine [oncovin], and prednisone) leads to increased survival rates among patients with high-grade lymphomas. the Spondyloarthritides Joel D. Taurog, John D. Carter


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InternalMed_Harrison. the Spondyloarthritides Joel D. Taurog, John D. Carter The spondyloarthritides are a group of overlapping disorders that share certain clinical features and genetic associations. These disorders include ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis and spondylitis, enteropathic arthritis and spondylitis, juvenile-onset spondyloarthritis (SpA), and undifferentiated SpA. The similarities in clinical manifestations and genetic predisposition suggest that these disorders share pathogenic mechanisms.


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InternalMed_Harrison. AS is an inflammatory disorder of unknown cause that primarily affectstheaxial skeleton;peripheral jointsandextraarticular structures are also frequently involved. The disease usually begins in the second or third decade; male-to-female prevalence is between 2:1 and 3:1. The term axial spondyloarthritis is coming into common use, supported by criteria formulated in 2009 (Table 384-1). This classification includes both definite AS and early stages that do not yet meet classical criteria for AS, but it probably also includes other conditions with a different natural history. AS shows a striking correlation with the histocompatibility antigen HLA-B27 and occurs worldwide roughly in proportion to the prevalence of B27 (Chap. 373e). In North American whites, the prevalence of B27 is 7%, whereas it is 90% in patients with AS, independent of disease severity.


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InternalMed_Harrison. In population surveys, AS is present in 1–6% of adults inheriting B27, whereas the prevalence is 10–30% among B27+ adult first-degree relatives of AS probands. Concordance rate in identical twins is about 65%. Susceptibility to AS is determined largely by genetic factors, with B27 comprising less than one-half of the genetic component. Genome-wide single-nucleotide polymorphism (SNP) analysis has identified over 30 additional susceptibility alleles. Inflammatory back paind on MRI highly suggestive of itis according to modified New York criteriac Good response to NSAIDsh


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InternalMed_Harrison. Inflammatory back paind on MRI highly suggestive of itis according to modified New York criteriac Good response to NSAIDsh Family history of SpAi aSensitivity 83%, specificity 84%. The imaging arm (sacroiliitis) alone has a sensitivity of 66% and a specificity of 97%. bBone marrow edema and/or osteitis on short tau inversion recovery (STIR) or gadolinium-enhanced T1 image. cBilateral grade ≥2 or unilateral grade 3 or 4. dSee text for criteria. ePast or present, diagnosed by a physician. fPast or present pain or tenderness on examination at calcaneus insertion of Achilles tendon or plantar fascia. gPast or present, confirmed by an ophthalmologist. hSubstantial relief of back pain at 24–48 h after a full dose of NSAID. iFirst-or second-degree relatives with ankylosing spondylitis (AS), psoriasis, uveitis, reactive arthritis (ReA), or inflammatory bowel disease (IBD). jAfter exclusion of other causes of elevated CRP.


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InternalMed_Harrison. Abbreviations: ASAS, Assessment of Spondyloarthritis International Society; CRP, C-reactive protein; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti- inflammatory drugs; SpA, spondyloarthritis. Source: From M Rudwaleit et al: Ann Rheum Dis 68:777, 2009. Copyright 2009, with permission from BMJ Publishing Group Ltd. Sacroiliitis is often the earliest manifestation of AS. Knowledge of its pathology comes from both biopsy and autopsy studies that cover a range of disease durations. Synovitis and myxoid marrow represent the earliest changes, followed by pannus and subchondral granulation tissue. Marrow edema, enthesitis, and chondroid differentiation are also found. Macrophages, T cells, plasma cells, and osteoclasts are prevalent. Eventually the eroded joint margins are gradually replaced by fibrocartilage regeneration and then by ossification. The joint may become totally obliterated.


InternalMed_Harrison

InternalMed_Harrison. In the spine, the specimens studied have either been surgically resected in advanced disease or taken from autopsies. There is inflammatory granulation tissue in the paravertebral connective tissue at the junction of annulus fibrosus and vertebral bone, and in some cases along the entire outer annulus. The outer annular fibers are eroded and eventually replaced by bone, forming the beginning of a syndesmophyte, which then grows by continued endochondral ossification, ultimately bridging the adjacent vertebral bodies. Ascending progression of this process leads to the “bamboo spine.” Other lesions in the spine include diffuse osteoporosis (loss of trabecular bone despite accretion of periosteal bone), erosion of vertebral bodies at the disk margin, “squaring” or “barreling” of vertebrae, and inflammation and destruction of the disk-bone border. Inflammatory arthritis of the apophyseal (facet) joints is common, with synovitis, inflammation at the bony attachment of the joint capsule,


InternalMed_Harrison

InternalMed_Harrison. and inflammation and destruction of the disk-bone border. Inflammatory arthritis of the apophyseal (facet) joints is common, with synovitis, inflammation at the bony attachment of the joint capsule, and subchondral bone marrow granulation tissue. Erosion of joint cartilage by pannus is often followed by bony ankylosis. This may precede formation of syndesmophytes bridging the adjacent disks. Bone mineral density is diminished in the spine and proximal femur early in the course of the disease.


InternalMed_Harrison

InternalMed_Harrison. Peripheral synovitis in AS shows marked vascularity, which is also evident as tortuous macrovascularity seen during arthroscopy. Lining layer hyperplasia, lymphoid infiltration, and pannus formation are also found. Central cartilaginous erosions caused by proliferation of subchondral granulation tissue are common. It should be


InternalMed_Harrison

InternalMed_Harrison. The Spondyloarthritides 2170 emphasized that the characteristics of peripheral arthritis in AS and other forms of SpA are similar, and distinct from those of rheumatoid arthritis. Inflammation in the fibrocartilaginous enthesis, the region where a tendon, ligament, or joint capsule attaches to bone, is a characteristic lesion in AS and other SpAs, both at axial and peripheral sites. Enthesitis is associated with prominent edema of the adjacent bone marrow and is often characterized by erosive lesions that eventually undergo ossification. Subclinical intestinal inflammation has been found in the colon or distal ileum in a majority of patients with SpA. The histology is described below under “Enteropathic Arthritis.”


InternalMed_Harrison

InternalMed_Harrison. The pathogenesis of AS is immune-mediated, but there is little direct evidence for antigen-specific autoimmunity, and there is evidence to suggest more of an autoinflammatory pathogenesis. Uncertainty remains regarding the primary site of disease initiation. The dramatic responseofthediseasetotherapeuticblockadeoftumornecrosisfactor α (TNF-α) indicates that this cytokine plays a central role in the immunopathogenesis of AS. Other genes related to TNF pathways show association with AS, including TNFRSF1A, LTBR, and TBKBP1. More recent evidence strongly implicates the interleukin (IL) 23/IL-17 cytokine pathway in AS pathogenesis. At least five genes in this pathway show association with AS, including IL23R, PTER4, IL12B, CARD9, and TYK2. All of these genes are also associated with inflammatory bowel disease (IBD), and three of them are associated with psoriasis. Serum levels of IL-23 and IL-17 are elevated in AS patients. Mice expressing high levels of IL-23 show spontaneous


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InternalMed_Harrison. inflammatory bowel disease (IBD), and three of them are associated with psoriasis. Serum levels of IL-23 and IL-17 are elevated in AS patients. Mice expressing high levels of IL-23 show spontaneous infiltration in the entheses of CD3+CD4–CD8– cells bearing IL-23 receptors and producing IL-17 and IL-22. This finding suggests the possibility that site-specific innate immune cells may play a critical role in the anatomic specificity of the lesions. Mast cells and, to a lesser extent, neutrophils appear to be the major IL-17-producing cells in peripheral arthritis, whereas neutrophils producing IL-17 are prominent in apophyseal joints. High levels of circulating γδ T cells expressing IL-23 receptors and producing IL-17 have been found in AS patients.


InternalMed_Harrison

InternalMed_Harrison. Other associated genes encode other cytokines or cytokine receptors (IL6R, IL1R1, IL1R2, IL7R, IL27), transcription factors involved in the differentiation of immune cells (RUNX3, EOMES, BACH2, NKX2-3, TBX21), or other molecules involved in activation or regulation of immuneorinflammatoryresponses(FCGR2A,ZMIZ1,NOS2,ICOSLG).


InternalMed_Harrison

InternalMed_Harrison. The inflamed sacroiliac joint is infiltrated with CD4+ and CD8+ T cells and macrophages and shows high levels of TNF-α, particularly early in the disease. Abundant transforming growth factor β (TGFβ) has been found in more advanced lesions. Peripheral synovitis in AS and the other spondyloarthritides is characterized by neutrophils, macrophages expressing CD68 and CD163, CD4+ and CD8+ T cells, and B cells. There is prominent staining for intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), matrix metalloproteinase 3 (MMP-3), and myeloid-related proteins 8 and 14 (MRP-8 and MRP-14). Unlike rheumatoid arthritis (RA) synovium, citrullinatedproteinsandcartilagegp39peptide–majorhistocompatibility complexes (MHCs) are absent. However, citrullinated proteins can be seen in the circulation.


InternalMed_Harrison

InternalMed_Harrison. No specific event or exogenous agent that triggers the onset of disease has been identified, although overlapping features with reactive arthritis and IBD and the involvement of the IL-23/IL-17 pathway suggest that enteric bacteria may play a role, and microdamage from mechanical stress at enthesial sites has also been implicated.


InternalMed_Harrison

InternalMed_Harrison. It is firmly established that HLA-B27 plays a direct role in AS pathogenesis,butitspreciseroleatthemolecularlevelremainsunresolved.Rats transgenic for HLA-B27 develop arthritis and spondylitis, and this is unaffectedbytheabsenceofCD8.Itthusappearsthatclassicalpeptideantigen presentation to CD8+ T cells may not be the primary disease mechanism. However,theassociationofASwithERAP1,whichstronglyinfluencesthe MHC class I peptide repertoire, is only found in B27+ patients, and this suggests that peptide binding to B27 is nonetheless important. The pairs of ERAP1 alleles found in AS patients show diminished peptidase activity, compared with those found in healthy controls. The B27 heavy chain has an unusual tendency to misfold, a process that may be proinflammatory. Geneticandfunctionalstudiesinhumanshavesuggestedarolefornatural killer (NK) cells in AS, possibly through interaction with B27 heavy chain homodimers. SpA-prone B27 rats show defective dendritic cell function and share with AS


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InternalMed_Harrison. killer (NK) cells in AS, possibly through interaction with B27 heavy chain homodimers. SpA-prone B27 rats show defective dendritic cell function and share with AS patients a characteristic “reverse interferon” gene expression signature in antigen-presenting cells.


InternalMed_Harrison

InternalMed_Harrison. New bone formation in AS appears to be largely based on enchondral bone formation and occurs only in the periosteal compartment. It correlates with lack of regulation of the Wnt signaling pathway, which controls the differentiation of mesenchymal cells into osteophytes, by the inhibitors DKK-1 and sclerostin. Indirect evidence and data from animal models also implicate bone morphogenic proteins, hedgehog proteins, and prostaglandin E2. There is sharp controversy as to whether vertebral new bone formation in AS is a sequela of inflammation or whether it arises independently of inflammation. The second hypothesis is based on the observation that syndesmophyte formation is not suppressed by anti-TNF-α therapy that potently suppresses inflammation. TNF-α is also a known inducer of DKK-1, which inhibits bone formation. Recent magnetic resonance imaging (MRI) studies suggest that it is vertebral inflammatory lesions that undergo metaplasia to fat (increased T1-weighted signal) that are the


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InternalMed_Harrison. inhibits bone formation. Recent magnetic resonance imaging (MRI) studies suggest that it is vertebral inflammatory lesions that undergo metaplasia to fat (increased T1-weighted signal) that are the predominant site of subsequent syndesmophytes despite anti-TNF-α therapy, whereas early acute inflammatory lesions resolve. A recent study suggested that the rate of syndesmophyte formation decreases after >4 years of anti-TNF-α therapy.


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InternalMed_Harrison. The symptoms of the disease are usually first noticed in late adolescence or early adulthood; the median age in Western countries is approximately 23 years. In 5% of patients, symptoms begin after age 40. The initial symptom is usually dull pain, insidious in onset, felt deep in the lower lumbar or gluteal region, accompanied by low-back morning stiffness of up to a few hours’ duration that improves with activityandreturnsfollowinginactivity.Withinafewmonths,thepain has usually become persistent and bilateral. Nocturnal exacerbation of pain often forces the patient to rise and move around.


InternalMed_Harrison

InternalMed_Harrison. In some patients, bony tenderness (presumably reflecting enthesitis or osteitis) may accompany back pain or stiffness, whereas in others it may be the predominant complaint. Common sites include the costosternal junctions, spinous processes, iliac crests, greater trochanters, ischial tuberosities, tibial tubercles, and heels. Hip and shoulder (“root” joint) arthritis is considered part of the axial disease. Hip arthritis occurs in 25–35% of patients. Shoulder arthritis is much less common. Severe isolated hip arthritis or bony chest pain may be the presenting complaint, and symptomatic hip disease can dominate the clinical picture. Arthritis of peripheral joints other than the hips and shoulders, usually asymmetric, occurs in up to 30% of patients. Neck pain and stiffness from involvement of the cervical spine are usually relatively late manifestations but are occasionally dominant symptoms. Rare patients, particularly in the older age group, present with predominantly constitutional


InternalMed_Harrison

InternalMed_Harrison. of the cervical spine are usually relatively late manifestations but are occasionally dominant symptoms. Rare patients, particularly in the older age group, present with predominantly constitutional symptoms.


InternalMed_Harrison

InternalMed_Harrison. AS often has a juvenile onset in developing countries. Peripheral arthritis and enthesitis usually predominate, with axial symptoms supervening in late adolescence. Initially, physical findings mirror the inflammatory process. The most specific findings involve loss of spinal mobility, with limitation of anterior and lateral flexion and extension of the lumbar spine and of chest expansion. Limitation of motion is usually out of proportion to the degree of bony ankylosis and is thought to possibly reflect muscle spasm secondary to pain and inflammation. Pain in the sacroiliac joints maybeelicitedeitherwithdirectpressureorwithstressonthejoints.In addition,there is commonlytenderness uponpalpationofthe posterior spinous processes and other sites of symptomatic bony tenderness.


InternalMed_Harrison

InternalMed_Harrison. ThemodifiedSchobertestisausefulmeasureoflumbarspineflexion. The patient stands erect, with heels together, and marks are made on the spineat the lumbosacral junction(identified by ahorizontalline between theposterosuperioriliacspines)and10cmabove.Thepatientthenbends forward maximally with knees fully extended, and the distance between the two marks is measured. This distance increases by ≥5 cm in the case ofnormalmobilityandby<4cminthecaseofdecreasedmobility.Chest expansion is measured as the difference between maximal inspiration andmaximalforcedexpirationinthefourthintercostalspaceinmalesor just below the breasts in females, with the patient’s hands resting on or just behind the head. Normal chest expansion is ≥5 cm. Lateral bending measures the distance the patient’s middle finger travels down the leg with maximal lateral bending. Normal is >10 cm.


InternalMed_Harrison

InternalMed_Harrison. Limitation or pain with motion of the hips or shoulders is usually present if these joints are involved. It should be emphasized that early in the course of mild cases, symptoms may be subtle and nonspecific, and the physical examination may be unrevealing.


InternalMed_Harrison

InternalMed_Harrison. The course of the disease is extremely variable, ranging from the individual with mild stiffness and normal radiographs to the patient with a totally fused spine and severe bilateral hip arthritis, accompanied by severe peripheral arthritis and extraarticular manifestations. Pain tends to be persistent early in the disease and intermittent later, with alternating exacerbations and quiescent periods. In a typical severe untreated case with progression of the spondylitis to syndesmophyte formation, the patient’s posture undergoes characteristic changes, with obliterated lumbar lordosis, buttock atrophy, and accentuated thoracic kyphosis. There may be a forward stoop of the neck or flexion contractures at the hips, compensated by flexion at the knees. Disease progression can be estimated clinically from loss of height, limitation of chest expansion and spinal flexion, and occiput-to-wall distance.Occasionalindividualsareencounteredwithadvanced deformities who report having never had


InternalMed_Harrison

InternalMed_Harrison. clinically from loss of height, limitation of chest expansion and spinal flexion, and occiput-to-wall distance.Occasionalindividualsareencounteredwithadvanced deformities who report having never had significant symptoms.


InternalMed_Harrison

InternalMed_Harrison. The factors most predictive of radiographic progression (see below) are the presence of existing syndesmophytes, high inflammatory makers, and smoking. In some but not all studies, onset of AS in adolescence and early hip involvement correlate with a worse prognosis. In women, AS tends to progress less frequently to total spinal ankylosis, although there may be an increased prevalence of isolated cervical ankylosis and peripheral arthritis. In industrialized countries, peripheral arthritis (distal to hips and shoulders) occurs in less than one-half ofpatientswithAS,usuallyasalatemanifestation,whereasindeveloping countries, the prevalence is much higher, with onset typically early in the disease course. Pregnancy has no consistent effect on AS, with symptoms improving, remaining the same, or deteriorating in one-third of pregnant patients, respectively.


InternalMed_Harrison

InternalMed_Harrison. The most serious complication of the spinal disease is spinal fracture, which can occur with even minor trauma to the rigid, osteoporotic spine. The lower cervical spine is most commonly involved. These fractures are often displaced and cause spinal cord injury. A recent survey suggested a >10% lifetime risk of fracture. Occasionally, fracture through a diskovertebral junction and adjacent neural arch, termed pseudoarthrosis, most common in the thoracolumbar spine, can be an unrecognized source of persistent localized pain and/or neurologicdysfunction.Wedgingofthoracicvertebraeiscommonand correlates with accentuated kyphosis.


InternalMed_Harrison

InternalMed_Harrison. The most common extraarticular manifestation is acute anterior uveitis, which occurs in up to 40% of patients and can antedate the spondylitis.Attacksaretypicallyunilateral,causingpain,photophobia, and increased lacrimation. These tend to recur, often in the opposite eye. Cataracts and secondary glaucoma are not uncommon sequelae. Up to 60% of patients with AS have inflammation in the colon or ileum. This is usually asymptomatic, but frank IBD occurs in 5–10% of patients with AS (see “Enteropathic Arthritis,” below). About 10% of patients meeting criteria for AS have psoriasis (see “Psoriatic Arthritis,” below). Aortic insufficiency, sometimes leading to congestive heart failure, occurs in a small percentage of patients, occasionally early.Third-degreeheartblockmayoccuraloneortogetherwithaortic insufficiency. Subclinical pulmonary lesions and cardiac dysfunction mayberelativelycommon.Caudaequinasyndromeandupperpulmonary lobe fibrosis are rare late complications. Retroperitoneal


InternalMed_Harrison

InternalMed_Harrison. insufficiency. Subclinical pulmonary lesions and cardiac dysfunction mayberelativelycommon.Caudaequinasyndromeandupperpulmonary lobe fibrosis are rare late complications. Retroperitoneal fibrosis is a rare associated condition. Prostatitis has been reported to have an increased prevalence. Amyloidosis is rare (Chap. 137).


InternalMed_Harrison

InternalMed_Harrison. Several validated measures of disease activity and functional outcome are in widespread use in the study and management of AS, particularly the Bath Ankylosing Spondylitis Disease Activity Index 2171 (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS), both measures of disease activity; the Bath Ankylosing SpondylitisFunctionalIndex(BASFI),ameasureoflimitationinactivities of daily living; and several measures of radiographic changes. The Harris hip score, although not specific for AS, can be helpful. Despite persistence of the disease, most patients remain gainfully employed. Some but not all studies of survival in AS have suggested that AS shortens life span, compared with the general population. Mortality attributable to AS is largely the result of spinal trauma, aortic insufficiency, respiratory failure, amyloid nephropathy, or complications of therapy such as upper gastrointestinal hemorrhage. The impact of anti-TNF therapy on outcome and mortality is not yet


InternalMed_Harrison

InternalMed_Harrison. insufficiency, respiratory failure, amyloid nephropathy, or complications of therapy such as upper gastrointestinal hemorrhage. The impact of anti-TNF therapy on outcome and mortality is not yet known, except for significantly improved work productivity.


InternalMed_Harrison

InternalMed_Harrison. No laboratory test is diagnostic of AS. In most ethnic groups, HLAB27 is present in 80–90% of patients. Erythrocyte sedimentation rate (ESR)andC-reactiveprotein (CRP) are often,but notalways, elevated. Mildanemia maybe present. Patients with severe disease may show an elevatedalkalinephosphataselevel.ElevatedserumIgAlevelsarecommon. Rheumatoid factor, anti-cyclic citrullinated peptide (CCP), and antinuclear antibodies (ANAs) are largely absent unless caused by a coexistentdisease, although ANAs may appear with anti-TNF therapy. Circulating levels of CD8+ T cells tend to be low, and serum matrix metalloproteinase 3 levels correlate with disease activity. Synovial fluid from peripheral joints in AS is nonspecifically inflammatory. In cases with restriction of chest wall motion, decreased vital capacity and increased functional residual capacity are common, but airflow is normal and ventilatory function is usually well maintained.


InternalMed_Harrison

InternalMed_Harrison. Radiographically demonstrable sacroiliitis, usually symmetric, is eventually present in AS. The earliest changes by standard radiography are blurring of the cortical margins of the subchondral bone, followed by erosions and sclerosis. Progression of the erosions leads to “pseudowidening” of the joint space; as fibrous and then bony ankylosis supervene, the joints may become obliterated. In the lumbar spine, progression of the disease leads to straightening, caused by loss of lordosis, and reactive sclerosis, caused by osteitis ofthe anterior cornersof the vertebral bodies with subsequent erosion, leadingto“squaring”oreven“barreling”ofoneormorevertebralbodies. Progressive ossification leads to eventual formation of marginal syndesmophytes, visible on plain films as bony bridges connecting successive vertebral bodies anteriorly and laterally.


InternalMed_Harrison

InternalMed_Harrison. Years may elapse before unequivocal sacroiliac abnormalities are evident on plain radiographs, and consequently, MRI is being increasingly used in diagnosing AS. Active sacroiliitis is best visualized by dynamic MRI with fat saturation, either T2-weighed turbo spin-echo sequence or short tau inversion recovery (STIR) with high resolution, or T1-weighted images with contrast enhancement. These techniques sensitively identify early intraarticular inflammation, cartilage changes, and underlying bone marrow edema in sacroiliitis (Fig. 384-1). They are also highly sensitive for evaluation of acute and chronic spinal changes (Fig. 384-2). Reduced bone mineral density can be detected by dual-energy x-ray absorptiometry of the femoral neck and the lumbar spine. Use of a lateral projection of the L3 vertebral body can prevent falsely elevated readings related to spinal ossification.


InternalMed_Harrison

InternalMed_Harrison. It is important to establish the diagnosis of early AS before the development of irreversible deformity. This goal presents a challenge for several reasons: (1) Back pain is very common, but AS is much less common; (2) an early presumptive diagnosis often relies on clinical grounds requiring considerable expertise; and (3) young individuals with symptoms of AS often do not seek medical care. The widely used modified New York criteria (1984) are based on the presence of definite radiographic sacroiliitis and are too insensitive in early The Spondyloarthritides


InternalMed_Harrison

InternalMed_Harrison. The Spondyloarthritides FIGUrE 384-1 Early sacroiliitis in a patient with ankylosing spondylitis, indicatedbyprominentedemainthejuxtaarticularbonemarrow(asterisks),synoviumandjointcapsule(thin arrow),andinterosseousligaments(thick arrow)onashorttauinversionrecovery(STIR)magneticresonanceimage.(From M Bollow et al: Zeitschrift f Rheumatologie 58:61, 1999. Reproduced with permission.) or mild cases. In 2009, new criteria for axial SpA were proposed by the Assessment of Spondyloarthritis International Society (ASAS) (Table 384-1). They are applicable to individuals with ≥3 months of back pain with age of onset <45 years old. Active inflammation of the sacroiliac joints as determined by dynamic MRI is considered equivalent to definite radiographic sacroiliitis (see below).


InternalMed_Harrison

InternalMed_Harrison. AS must be differentiated from numerous other causes of low-back pain, some far more common than AS. To qualify as the criterion for inflammatory back pain of axial SpA (Table 384-1), the chronic (≥3 months) back pain should have four or more of the following characteristic features: (1) age of onset <40 years old; (2) insidious onset; (3) improvement with exercise; (4) no improvement with rest; and (5)painatnightwithimprovementupongettingup.Othercommon features of inflammatory back pain include morning stiffness >30 min, awakening from back pain during only the second half of the night, and alternating buttock pain. In clinical decision-making, all of these features are additive. The most common causes of back pain other than AS are primarily mechanical or degenerative rather than primarily inflammatory and tend not to show clustering of these features.


InternalMed_Harrison

InternalMed_Harrison. Less-common metabolic, infectious, and malignant causes of back pain must also be differentiated from AS, including infectious spondylitis, spondylodiskitis, and sacroiliitis, and primary or metastatic tumor. Ochronosis can produce a phenotype that is clinically and radiographically similar to AS. Calcification and ossification of paraspinous ligaments occur in diffuse idiopathic skeletal hyperostosis (DISH), which occurs in the middle-aged and elderly and is usually not symptomatic. Ligamentous calcification gives the appearance of “flowing wax” on the anterior bodies of the vertebrae. Intervertebral disk spaces are preserved, and sacroiliac and apophyseal joints appear normal, helping to differentiate DISH from spondylosis and from AS, respectively.


InternalMed_Harrison

InternalMed_Harrison. All management of AS should include an exercise program designed to maintain posture and range of motion. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first line of pharmacologic therapy for AS. These agents reduce pain and tenderness and increase mobility in many patients with AS. There is mounting evidence that continuous high-dose NSAID therapy slows radiographic progression, particularly in patients who are at higher risk for progression. However, many patients with AS have continued symptoms despite NSAID therapy and are likely to benefit from anti-TNF-α therapy. Patients with AS treated with infliximab (chimeric human/mouse anti-TNF-α monoclonal antibody), etanercept (soluble p75 TNF-α receptor–IgG fusion protein), adalimumab, or golimumab (human anti-TNF-α monoclonal antibodies, or certolizumab pegol [humanized mouse anti-TNF-α monoclonal antibody]) have shown rapid, profound, and sustained reductions in all clinical and laboratory measures of disease activity. In a


InternalMed_Harrison

InternalMed_Harrison. or certolizumab pegol [humanized mouse anti-TNF-α monoclonal antibody]) have shown rapid, profound, and sustained reductions in all clinical and laboratory measures of disease activity. In a good response, there is significant improvement in both objective and subjective indicators of disease activity and function, including morning stiffness, pain, spinal mobility, peripheral joint swelling, CRP, and ESR. MRI studies indicate substantial resolution of bone marrow edema, enthesitis, and joint effusions in the sacroiliac joints, spine, and peripheral joints (Fig. 384-2). Similar results have been obtained in large randomized controlled trials of all four agents and many open-label studies. About one-half of the patients achieve a ≥50% reduction in the BASDAI. The response tends to be stable over time, and partial or full remissions are common. Predictors of the best responses include younger age, shorter disease duration, higher baseline inflammatory markers, and lower baseline


InternalMed_Harrison

InternalMed_Harrison. stable over time, and partial or full remissions are common. Predictors of the best responses include younger age, shorter disease duration, higher baseline inflammatory markers, and lower baseline functional disability. Nonetheless, some patients with long-standing disease and even spinal ankylosis can obtain significant benefit. Increased bone mineral density is found as early as 24 weeks after onset of therapy. There is evidence that anti-TNF therapy does not prevent syndesmophyte formation, although this may apply mainly during the early years of therapy. A mechanism for this has been proposed based on the observation that TNF-α inhibits new bone formation by upregulating DKK-1, a negative regulator of the wingless (Wnt) signaling pathway that promotes osteoblast activity. Serum DKK-1 levels are inappropriately low in AS patients and are also suppressed by anti-TNF therapy.


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InternalMed_Harrison. FIGUrE 384-2 Spinal inflammation (spondylodiskitis) in a patient with ankylosing spondylitis and its dramatic response to treatment with infliximab. Gadolinium-enhanced T1-weighted magnetic resonance images, with fat saturation, at baseline and after 24 weeks of infliximab therapy. (From J Braun et al: Arthritis Rheum 54:1646, 2006.) Infliximab is given intravenously, 3–5 mg/kg body weight, and then repeated 2 weeks later, again 6 weeks later, and then at 8-week intervals. Etanercept is given by subcutaneous injection, 50 mg once weekly. Adalimumab is given by subcutaneous injection, 40 mg biweekly. Golimumab is given by subcutaneous injection, 50 or 100 mg every 4 weeks. Certolizumab pegol is given by subcutaneous injection, 400 mg every 4 weeks.


InternalMed_Harrison

InternalMed_Harrison. Although these potent immunosuppressive agents have thus far been relatively safe, patients are at increased risk for serious infections, including disseminated tuberculosis. Hypersensitivity infusion or injection site reactions are not uncommon. Cases of anti-TNF-induced psoriasis have been increasingly recognized. Rare cases of systemic lupus erythematosus–related disease have been reported, as have hematologic disorders such as pancytopenia, demyelinating disorders, exacerbation of congestive heart failure, and severe liver disease. The overall incidence of malignancy does not appear to be increased in AS patients treated with anti-TNF therapy, but isolated cases of hematologic malignancy have occurred shortly after the start of treatment.


InternalMed_Harrison

InternalMed_Harrison. Because of the expense, potentially serious side effects, and unknown long-term effects of these agents, their use should be restricted to patients with a definite diagnosis and active disease (BASDAI ≥4 out of 10 and expert opinion) that is inadequately responsive to therapy with at least two different NSAIDs. Before initiation of anti-TNF therapy, all patients should be tested for tuberculin (TB) reactivity, and reactors (≥5 mm on PPD testing or a positive quantiferon test) should be treated with anti-TB agents. Contraindications include active infection or high risk of infection; malignancy or premalignancy; and history of systemic lupus erythematosus, multiple sclerosis, or related autoimmunity. Pregnancy and breast-feeding are relative contraindications. Continuation beyond 12 weeks of therapy requires either a 50% reduction in BASDAI or absolute reduction of ≥2 out of 10, and favorable expert opinion. Switching to a second anti-TNF agent may be effective, especially if there was


InternalMed_Harrison

InternalMed_Harrison. therapy requires either a 50% reduction in BASDAI or absolute reduction of ≥2 out of 10, and favorable expert opinion. Switching to a second anti-TNF agent may be effective, especially if there was a response to the first that was lost rather than primary failure. Sulfasalazine, in doses of 2–3 g/d, has been shown to be of modest benefit, primarily for peripheral arthritis. A therapeutic trial of this agent should precede any use of anti-TNF agents in patients with predominantly peripheral arthritis. Methotrexate, although widely used, has not been shown to be of benefit in AS, nor has any therapeutic role for gold or oral glucocorticoids been documented. Potential benefit in AS has been reported for thalidomide, 200 mg/d, perhaps acting through inhibition of TNF-α.


InternalMed_Harrison

InternalMed_Harrison. Ustekinumab (anti-IL-12/23) and secukinumab (anti-IL-17) monoclonal antibodies have shown promising efficacy in clinical trials, but have not yet been approved for use in AS. The most common indication for surgery in patients with AS is severe hip joint arthritis, the pain and stiffness of which are usually dramatically relieved by total hip arthroplasty. Rare patients may benefit from surgical correction of extreme flexion deformities of the spine or of atlantoaxial subluxation. Attacks of uveitis are usually managed effectively with local glucocorticoid administration in conjunction with mydriatic agents, although systemic glucocorticoids, immunosuppressive drugs, or anti-TNF therapy may be required. TNF inhibitors reduce the 2173 frequency of attacks of uveitis in patients with AS, although cases of new or recurrent uveitis after use of a TNF inhibitor have been observed, especially with etanercept.


InternalMed_Harrison

InternalMed_Harrison. Coexistent cardiac disease may require pacemaker implantation and/or aortic valve replacement. Management of axial osteoporosis is at present similar to that used for primary osteoporosis, since data specific for AS are not available. Reactive arthritis (ReA) refers to acute nonpurulent arthritis complicating an infection elsewhere in the body. In recent years, the term has been used primarily to refer to SpA following enteric or urogenital infections. Other forms of reactive and infection-related arthritis not associated with B27 and showing a spectrum of clinical features different from SpA, such as Lyme disease and rheumatic fever, are discussed in Chaps. 210 and 381.


InternalMed_Harrison

InternalMed_Harrison. The association of acute arthritis with episodes of diarrhea or urethritis hasbeenrecognizedforcenturies.AlargenumberofcasesduringWorld Wars I and II focused attention on the triad of arthritis, urethritis, and conjunctivitis, often with additional mucocutaneous lesions, which becamewidely knownby eponyms that are now ofhistoric interestonly.


InternalMed_Harrison

InternalMed_Harrison. The identification of bacterial species capable of triggering the clinical syndrome and the finding that many patients possess the B27 antigen led to the unifying concept of ReA as a clinical syndrome triggered by specific etiologic agents in a genetically susceptible host. A similar spectrumofclinicalmanifestations can betriggeredby enteric infection with any of several Shigella, Salmonella, Yersinia, and Campylobacter species; by genital infection with Chlamydia trachomatis; and by other agents as well. The triad of arthritis, urethritis, and conjunctivitis represents a small part of the spectrum of the clinical manifestations of ReA and only a minority of patients present with this “classic triad” of symptoms. Although emerging data suggest that asymptomatic Chlamydia trachomatis infections might trigger ReA, for the purposes of this chapter, the use of the term ReA will be restricted to those cases of SpA in which there is at least presumptive evidence for a related symptomatic


InternalMed_Harrison

InternalMed_Harrison. might trigger ReA, for the purposes of this chapter, the use of the term ReA will be restricted to those cases of SpA in which there is at least presumptive evidence for a related symptomatic antecedent infection. Patients with clinical features of ReA who lack evidence of an antecedent infection will be considered to have undifferentiated spondyloarthritis, discussed below.


InternalMed_Harrison

InternalMed_Harrison. InitialreportsmayhaveoverestimatedtheassociationofReAwithHLAB27, since 60–85% of patients who developed ReA triggered by Shigella, Yersinia, or Chlamydia were B27-positive. However, other studies demonstratedalowerprevalenceofB27inReAtriggeredbySalmonella,with one study suggesting no association in Campylobacter-induced ReA. Several more recent community-based or common-source epidemic studies demonstrated that the prevalence of B27 in ReA was below 50%. The most common age range is 18–40 years, but ReA can occur rarely in children and occasionally in older adults.


InternalMed_Harrison

InternalMed_Harrison. TheattackrateofpostentericReAgenerallyrangesfrom1%toabout 30%dependingonthestudyandcausativeorganism,whereastheattack rate of postchlamydial ReA is about 4–8%. The gender ratio in ReA following enteric infection is nearly 1:1, whereas venereally acquired ReA occurs mainly in men. The overall prevalence and incidence of ReA are difficult to assess because of the lack of validated diagnostic criteria, variable prevalence and arthritogenic potential of the triggering infectious agents, and inconstant genetic susceptibility factors in different populations. In Scandinavia, an annual incidence of 10–28:100,000 has been reported. Thespondyloarthritides were formerly almostunknown in sub-Saharan Africa. However, ReA and other peripheral SpAs have now become the most common rheumatic diseases in Africans in the wake of the AIDS epidemic, without association to B27, which is very rare in these populations. ReA is often the first manifestation of HIV infection and often remits with disease


InternalMed_Harrison

InternalMed_Harrison. in Africans in the wake of the AIDS epidemic, without association to B27, which is very rare in these populations. ReA is often the first manifestation of HIV infection and often remits with disease progression. In contrast,


InternalMed_Harrison

InternalMed_Harrison. The Spondyloarthritides 2174 WesternwhitepatientswithHIVandSpAareusuallyB27-positive,and the arthritis flares as AIDS advances. Synovial histology is similar to that of other SpAs. Enthesitis shows increased vascularity and macrophage infiltration of fibrocartilage. Microscopic histopathologic evidence of inflammation mimicking IBD has routinely been demonstrated in the colon and ileum of patients withpostentericReAand lesscommonly inpostvenereal ReA. The skin lesions of keratoderma blennorrhagica, associated mainly withvenereallyacquired ReA,arehistologically indistinguishable from pustular psoriatic lesions.


InternalMed_Harrison

InternalMed_Harrison. The bacteria identified as definitive triggers of ReA include several Salmonella spp., Shigella spp., Yersinia enterocolitica, Yersinia pseudo-tuberculosis, Campylobacter jejuni, and Chlamydia trachomatis. These triggering microbes are gram-negative bacteria with a lipopolysaccharide component to their cell walls. All four Shigella species (Shigella sonnei, Shigella boydii, Shigella flexneri, and Shigella dysenteriae) have been implicated in cases of ReA, with S. flexneri and S. sonnei being the most common. After Salmonella infection, individuals of Caucasian descent may bemore likely than thoseof Asian descent todevelop ReA.Children may be less susceptible to ReA caused by Salmonella and Campylobacter. Yersinia species in Europe and Scandinavia may have greater arthritogenic potential than in other parts of the world, and C. trachomatis appears to be a common cause worldwide. The ocular serovars of C. trachomatis appear to be particularly, perhaps uniquely, arthritogenic.


InternalMed_Harrison

InternalMed_Harrison. There is also evidence implicating Clostridium difficile, Campylobacter coli, certain toxigenic Escherichia coli, and possibly Ureaplasma urealyticum and Mycoplasma genitalium as potential triggers of ReA. Chlamydia pneumoniae is another trigger of ReA, albeit far less common than C. trachomatis. There have also been numerous isolated reports of acute arthritis preceded by other bacterial, viral, or parasitic infections, and even following intravesicular bacillus Calmette-Guérin (BCG) treatment for bladder cancer.


InternalMed_Harrison

InternalMed_Harrison. It has not been determined whether ReA occurs by the same pathogenic mechanism following infection with each of these microorganisms, nor has the mechanism been elucidated in the case of any one of the known bacterial triggers. Most, if not all, of the organisms well established to be triggers share a capacity to attack mucosal surfaces, to invade host cells, and to survive intracellularly. Antigens from Chlamydia, Yersinia, Salmonella, and Shigella have been shown to be present in the synovium and/or synovial fluid leukocytes of patients with ReA for long periods following the acute attack. In ReA triggered by Y. enterocolitica, bacterial lipopolysaccharide (LPS) and heat-shock protein antigens have been found in peripheral blood cells years after the triggering infection. Yersinia DNA and C. trachomatis DNA and RNA have been detected in synovial tissue from ReA patients, suggesting the presence of viable organisms despite uniform failure to culture the organism from these specimens.


InternalMed_Harrison

InternalMed_Harrison. C. trachomatis DNA and RNA have been detected in synovial tissue from ReA patients, suggesting the presence of viable organisms despite uniform failure to culture the organism from these specimens. In C. trachomatis–induced ReA specifically, the bacterial load in synovial tissue of patients with remitting disease is lower than that of active disease, but mRNAs encoding proinflammatory proteins are equal to or higher than those of active disease. The specificity of these findings is unclear, however, since chromosomal bacterial DNA and 16S rRNA from a very wide variety of bacteria have also been found in synovium in other rheumatic diseases, albeit less frequently. In several older studies, synovial T cells that specifically responded to antigens of the inciting organism were reported and characterized as predominantly CD4+ with a TH2 or T regulatory phenotype. More recent work has documented high levels of IL-17 in ReA synovial fluid, but the source has not been identified. HLA-B27


InternalMed_Harrison

InternalMed_Harrison. characterized as predominantly CD4+ with a TH2 or T regulatory phenotype. More recent work has documented high levels of IL-17 in ReA synovial fluid, but the source has not been identified. HLA-B27 seems to be associated with more severe and chronic forms of the “classic triad” of ReA, but its pathogenic role remains to bedetermined. HLA-B27 significantly prolongs the intracellular survival of Y. enterocolitica and Salmonella enteritidis in human and mouse cell lines. Prolonged intracellular bacterial survival, promoted by B27, other factors, or both, maypermit traffickingof infectedleukocytes fromthe site ofprimaryinfection tojoints,whereaninnate and/oradaptiveimmune response to persistent bacterial antigens may then promote arthritis.


InternalMed_Harrison

InternalMed_Harrison. The clinical manifestations of ReA constitute a spectrum that ranges from an isolated, transient monoarthritis or enthesitis to severe multisystem disease. A careful history will usually elicit evidence of an antecedent infection 1–4 weeks before onset of symptoms of the reactive disease, particularly in postenteric ReA. However, in a sizable minority, no clinical or laboratory evidence of an antecedent infection can be found, particularly in the case of postchlamydial ReA. In cases of presumed venereally acquired reactive disease, there is often a history of a recent new sexual partner, even without laboratory evidence of infection.


InternalMed_Harrison

InternalMed_Harrison. Constitutional symptoms are common, including fatigue, malaise, fever, and weight loss. The musculoskeletal symptoms are usually acute in onset. Arthritis is usually asymmetric and additive, with involvement of new joints occurring over a few days to 1–2 weeks. The joints of the lower extremities, especially the knee, ankle, and subtalar, metatarsophalangeal, and toe interphalangeal joints, are most commonly involved, but the wrist and fingers can be involved as well. The arthritis is usually quite painful, and tense joint effusions are not uncommon, especially in the knee. Dactylitis, or “sausage digit,” a diffuse swelling of a solitary finger or toe, is a distinctive feature of ReA andotherperipheralspondyloarthritidesbutcanbeseeninpolyarticular gout and sarcoidosis. Tendinitis and fasciitis are particularly characteristic lesions, producing pain at multiple insertion sites (entheses), especially the Achilles insertion, the plantar fascia, and sites along the axial skeleton. Spinal,


InternalMed_Harrison

InternalMed_Harrison. are particularly characteristic lesions, producing pain at multiple insertion sites (entheses), especially the Achilles insertion, the plantar fascia, and sites along the axial skeleton. Spinal, low-back, and buttock pain are quite common and may be caused by insertional inflammation, muscle spasm, acute sacroiliitis, or, presumably, arthritis in intervertebral joints.


InternalMed_Harrison

InternalMed_Harrison. Urogenital lesions may occur throughout the course of the disease. In males, urethritis may be marked or relatively asymptomatic and may be either an accompaniment of the triggering infection or a result ofthereactivephaseofthedisease;interestingly,itoccursinbothpostvenereal and postenteric ReA. Prostatitis is also common. Similarly, in females, cervicitis or salpingitis may be caused either by the infectious trigger or by the sterile reactive process. Ocular disease is common, ranging from transient, asymptomatic conjunctivitis to an aggressive anterior uveitis that occasionally proves refractory to treatment and may result in blindness.


InternalMed_Harrison

InternalMed_Harrison. Mucocutaneous lesions are frequent. Oral ulcers tend to be superficial,transient, andoftenasymptomatic. The characteristicskin lesions, keratoderma blennorrhagica, consist of vesicles and/or pustules that become hyperkeratotic, ultimately forming a crust before disappearing. They are most common on the palms and soles but may occur elsewhere as well. In patients with HIV infection, these lesions are often extremely severe and extensive, sometimes dominating the clinical picture (Chap. 226). Lesions may occur on the glans penis, termed circinate balanitis; these consist of vesicles that quickly rupture to form painless superficial erosions, which in circumcised individuals can form crusts similar to those of keratoderma blennorrhagica. Nail changes are common and consist of onycholysis, distal yellowish discoloration, and/or heaped-up hyperkeratosis.


InternalMed_Harrison

InternalMed_Harrison. Less-frequent or rare manifestations of ReA include cardiac conduction defects, aortic insufficiency, central or peripheral nervous system lesions, and pleuropulmonary infiltrates. Arthritis typically persists for 3–5 months, but more chronic courses do occur. Chronic joint symptoms persist in about 15% of patients and in up to 60% of patients in hospital-based series, but these tend to be less severe than in the acute stage. Recurrences of the acute syndrome are also common. Work disability or forced change in occupation is common in those with persistent joint symptoms. Chronic heel pain is often particularly distressing. Low-back pain, sacroiliitis, and frank AS are also common sequelae. In most studies, HLA-B27–positive patients have shown a worse outcome than B27-negative patients. Patients with Yersinia-or Salmonella-induced arthritis have less chronic disease than those whose initial episode follows epidemic shigellosis.


InternalMed_Harrison

InternalMed_Harrison. The ESR and acute-phase reactants are usually elevated during the acute phase of the disease, often markedly so. Mild anemia may be present. Synovial fluid is nonspecifically inflammatory. In most ethnic groups, 30–50% of the patients are B27-positive. The triggering infection usually does not persist at the site of primary mucosal infection through the time of onset of the reactive disease, but it may be possible to culture the organism, e.g., in the case of Yersinia-or Chlamydia-induced disease. Serologic evidence of exposure to one of the causative organisms with elevation of antibodies is nonspecific and is of questionable utility. Polymerase chain reaction (PCR) for chlamydial DNA in first-voided urine specimens may have high sensitivity in the acute stage but is less useful with chronic disease.


InternalMed_Harrison

InternalMed_Harrison. In early or mild disease, radiographic changes may be absent or confined to juxtaarticular osteoporosis. With long-standing persistent disease, radiographic features share those of psoriatic arthritis; marginal erosions and loss of joint space can be seen in affected joints. Periostitis with reactive new bone formation is characteristic, as in all the SpAs. Spurs at the insertion of the plantar fascia are common. Sacroiliitis and spondylitis may be seen as late sequelae. Sacroiliitis ismorecommonlyasymmetricthaninAS,andspondylitis,ratherthan ascending symmetrically, can begin anywhere along the lumbar spine. The syndesmophytes are described as nonmarginal; they are coarse, asymmetric, and “comma”-shaped, arising from the middle of a vertebral body, a pattern less commonly seen in primary AS. Progression to spinal fusion is uncommon.


InternalMed_Harrison

InternalMed_Harrison. ReA is a clinical diagnosis with no definitively diagnostic laboratory test or radiographic finding. The diagnosis should be entertained in any patient with an acute inflammatory, asymmetric, additive arthritis or tendinitis. The evaluation should include questioning regarding possible triggering events such as an episode of diarrhea or dysuria. On physical examination, attention must be paid to the distribution of the joint and tendon involvement and to possible sitesof extraarticular involvement, such as the eyes, mucous membranes, skin, nails, and genitalia. Synovial fluid analysis may be helpful in excluding septic or crystal-induced arthritis. Culture, serology, or molecularmethods may help to identify a triggering infection, but they cannot be relied upon.


InternalMed_Harrison

InternalMed_Harrison. Although typingfor B27 has low negative predictive value in ReA, it may have prognostic significance in terms of severity, chronicity, and the propensity for spondylitis and uveitis. Furthermore, if positive, it can be helpful diagnostically in atypical cases. HIV testing is often indicated and may be necessary in order to select appropriate therapy.


InternalMed_Harrison

InternalMed_Harrison. It is important to differentiate ReA from disseminated gonococcal disease (Chap. 181), both of which can be venereally acquired and associated with urethritis. Unlike ReA, gonococcal arthritis and tenosynovitis tend to involve both upper and lower extremities equally, spare the axial skeleton, and be associated with characteristic vesicular skin lesions. A positive gonococcal culture from the urethra or cervix does not exclude a diagnosis of ReA; however, culturing gonococci from blood, skin lesion, or synovium establishes the diagnosis of disseminated gonococcal disease. PCR assay for Neisseria gonorrhoeae and C. trachomatis may be helpful. Occasionally, only a therapeutic trial of antibiotics can distinguish the two.


InternalMed_Harrison

InternalMed_Harrison. ReA shares many features in common with psoriatic arthropathy. However, psoriatic arthritis is usually gradual in onset; the arthritis tends to affect primarily the upper extremities; there is less associated periarthritis; and there are usually noassociated mouth ulcers,urethritis, or bowel symptoms. Most patients with ReA benefit to some degree from high-dose NSAIDs, although acute symptoms are rarely completely ameliorated, and some patients fail to respond at all. Indomethacin, 75–150 mg/d in divided doses, is the initial treatment of choice, but other NSAIDs may be tried.


InternalMed_Harrison

InternalMed_Harrison. Prompt, appropriate antibiotic treatment of acute chlamydial 2175 urethritis or enteric infection may prevent the emergence of ReA, but is not universally successful. Data regarding the potential benefit of antibiotic therapy that is initiated after onset of arthritis are conflicting, but several trials suggest no benefit. One long-term follow-up study suggested that although antibiotic therapy had no effect on the acute episode of ReA, it helped prevent subsequent chronic SpA. Another such study failed to demonstrate any longterm benefit. A promising recent double-blind placebo-controlled study assessing combination antibiotics showed that a majority of patients with chronic ReA due to Chlamydia benefited significantly from a 6-month course of rifampin 300 mg daily plus azithromycin 500 mg daily for 5 days, then twice weekly, or 6 months of rifampin 300 mg daily plus doxycycline 100 mg twice daily. The possibility remains that acute Chlamydia-induced ReA might respond more favorably


InternalMed_Harrison

InternalMed_Harrison. mg daily for 5 days, then twice weekly, or 6 months of rifampin 300 mg daily plus doxycycline 100 mg twice daily. The possibility remains that acute Chlamydia-induced ReA might respond more favorably to antibiotic therapy than the postenteric variety.


InternalMed_Harrison

InternalMed_Harrison. Multicenter trials have suggested that sulfasalazine, up to 3 g/d in divided doses, may be beneficial to patients with persistent ReA.1 Patients with persistent disease may respond to azathioprine, 1–2 mg/ kg per day, or to methotrexate, up to 20 mg per week; however, these therapeutic regimens have never formally been studied. Although no controlled trials of anti-TNF-α in ReA have been reported, anecdotal evidence supports the use of these agents in severe chronic cases, although lack of response has also been observed.1


InternalMed_Harrison

InternalMed_Harrison. Tendinitis and other enthesitic lesions may benefit from intralesional glucocorticoids. Uveitis may require aggressive treatment to prevent serious sequelae (see above). Skin lesions ordinarily require only symptomatic topical treatment. In patients with HIV infection and ReA, many of whom have severe skin lesions, the skin lesions in particular respond to antiretroviral therapy. Cardiac complications are managed conventionally; management of neurologic complications is symptomatic. Comprehensive management includes counseling of patients in the avoidance of sexually transmitted disease and exposure to enteropathogens, as well as appropriate use of physical therapy, vocational counseling, and continued surveillance for long-term complications such as AS. Patients with a history of ReA are at increased risk for recurrent attacks following repeated exposures.


InternalMed_Harrison

InternalMed_Harrison. Psoriatic arthritis (PsA) refers to an inflammatory musculoskeletal disease that has both autoimmune and autoinflammatory features characteristically occurring in individuals with psoriasis. The association between arthritis and psoriasis was noted in the nineteenth century. In the 1960s, on the basis of epidemiologic and clinical studies, it became clear that unlike RA, the arthritis associated with psoriasis was usually seronegative, often involved the distal interphalangeal (DIP) joints of the fingers and the spine and sacroiliac joints, had distinctive radiographic features, and showed considerable familial aggregation. In the 1970s, PsA was included in the broader category of the spondyloarthritides because of features similar to those of AS and ReA.


InternalMed_Harrison

InternalMed_Harrison. Estimates of the prevalence of PsA among individuals with psoriasis range from 5 to 42%. The prevalence of PsA appears to be increasing in parallelwithdisease awareness;recent datausingscreeningtools suggest that 20% or more of patients with psoriasis have undiagnosed PsA. The durationandseverityofpsoriasis increaseone’s likelihood ofdeveloping PsA. In white populations, psoriasis is estimated to have a prevalence of 1Azathioprine, methotrexate, sulfasalazine, pamidronate, and thalidomide have not been approved for this purpose by the U.S. Food and Drug Administration at the time of publication.


InternalMed_Harrison

InternalMed_Harrison. The Spondyloarthritides 2176 1–3%. Psoriasis and PsA are less common in other races in the absence of HIV infection, and the prevalence of PsA in individuals with psoriasis may be less common. First-degree relatives of PsA patients have an elevated risk for psoriasis, for PsA itself, and for other forms of SpA. Of patientswithpsoriasis,upto30%haveanaffectedfirst-degreerelative.In monozygotic twins, the reported concordance for psoriasis varies from 35 to 72%, and for PsA from 10 to 30%. A variety of HLA associations have been found. The HLA-Cw*0602 gene is directly associated with psoriasis,particularlyfamilialjuvenile-onset(typeI)psoriasis.HLA-B27 is associated with psoriatic spondylitis (see below). HLA-DR7, -DQ3, and -B57 areassociated with PsA becauseof linkage disequilibrium with Cw6. Other associations with PsA include HLA-B13, -B37, -B38, -B39, -C12, and -DR4. A recent genome-wide scan found association of both psoriasisandPsAwithapolymorphismattheHCP5locuscloselylinked to


InternalMed_Harrison

InternalMed_Harrison. Cw6. Other associations with PsA include HLA-B13, -B37, -B38, -B39, -C12, and -DR4. A recent genome-wide scan found association of both psoriasisandPsAwithapolymorphismattheHCP5locuscloselylinked to HLA-B, and also to IL-23R, IL-12B (chromosome 5q31), IL-13, and several other chromosomal regions. Certain genetic loci are associated with PsA but not psoriasis, e.g., RUNX3 and IL-13.


InternalMed_Harrison

InternalMed_Harrison. The inflamed synovium in PsA resembles that of RA, although with somewhat less hyperplasia and cellularity than in RA. As noted with AS above, the synovial vascular pattern in PsA is generally greater and more tortuous than in RA, independent of disease duration. Some studies have indicated a higher tendency to synovial fibrosis in PsA. Unlike RA, PsA shows prominent enthesitis, with histology similar to that of the other spondyloarthritides.


InternalMed_Harrison

InternalMed_Harrison. PsA is almost certainly immune-mediated and probably shares pathogenic mechanisms with psoriasis. PsA synovium is characterized by lining layer hyperplasia; diffuse infiltration with T cells, B cells, macrophages, and NK receptor–expressing cells, with upregulation of leukocyte homing receptors; and neutrophil proliferation with angiogenesis. Clonally expanded T cell subpopulations are frequent and have been demonstrated both in the synovium and the skin. Plasmacytoid dendritic cells are thought to play a key role in psoriasis, and there is some evidence for their participation in PsA. There is abundant synovial overexpression of proinflammatory cytokines, and synovial tissue staining has identified an overexpression of monocyte-derived cytokines, such as myeloid-related protein (S100A8/A9). Interferon γ, TNF-α, and IL-1β, -2, -6, -8, -10, -12, -13, and -15 are found in PsA synovium or synovial fluid. TH17-derived cytokines are important in PsA, given the genetic association with


InternalMed_Harrison

InternalMed_Harrison. Interferon γ, TNF-α, and IL-1β, -2, -6, -8, -10, -12, -13, and -15 are found in PsA synovium or synovial fluid. TH17-derived cytokines are important in PsA, given the genetic association with genes in the IL-12/IL-23 axis and the therapeutic response to an antibody to the shared IL-12/23 p40 subunit (see below). TH17 cells have been identified from the dermal extracts of psoriatic lesions and the synovial fluid of PsA patients. The majority of these CD4+ IL-17+ T cells are of memory phenotype (CD4RO[+]CD45RA[–]CD11a[+]). Consistent with the extensive bone remodeling in PsA, patients with PsA have been found to have a marked increase in osteoclastic precursors in peripheral blood and upregulation of receptor activator of nuclear factor κβ ligand (RANKL) in the synovial lining layer. Increased serum levels of TNF-α, RANKL, leptin, and omentin positively correlate with these osteoclastic precursors.


InternalMed_Harrison

InternalMed_Harrison. In 60–70% of cases, psoriasis precedes joint disease. In 15–20% of cases, the two manifestations appear within 1 year of each other. In about 15–20% of cases, the arthritis precedes the onset of psoriasis and can present a diagnostic challenge. The frequency in men and women is almost equal, although the frequency of disease patterns differs somewhat in the two sexes. The disease can begin in childhood or late in life but typically begins in the fourth or fifth decade, at an average age of 37 years. The spectrum of arthropathy associated with psoriasis is quite broad. Many classification schemes have been proposed. In the original scheme of Wright and Moll, five patterns are described: (1) arthritis of the DIP joints; (2) asymmetric oligoarthritis; (3) symmetric polyarthritis similar to RA; (4) axial involvement (spine and sacroiliac joints); and (5) arthritis mutilans, a highly destructive form of FIGUrE 384-3 Characteristic lesions of psoriatic arthritis.


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InternalMed_Harrison. FIGUrE 384-3 Characteristic lesions of psoriatic arthritis. Inflammation is prominent in the distal interphalangeal joints (left 5th, 4th, 2nd; right 2nd, 3rd, and 5th) and proximal interphalangeal joints (left 2nd, right 2nd, 4th, and 5th). There is dactylitis in the left 2nd finger and thumb, with pronounced telescoping of the left 2nd finger. Nail dystrophy (hyperkeratosis and onycholysis) affects each of the fingers except the left 3rd finger, the only finger without arthritis. (Courtesy of Donald Raddatz, MD; with permission.) disease. These patterns frequently coexist, and the pattern that persists chronically often differs from thatofthe initialpresentation. A simpler scheme in recent use contains three patterns: oligoarthritis, polyarthritis, and axial arthritis.


InternalMed_Harrison

InternalMed_Harrison. Nail changes in the fingers or toes occur in up to 90% of patients with PsA, compared with 40% of psoriatic patients without arthritis, and pustular psoriasis is said to be associated with more severe arthritis. Several articular features distinguish PsA from other joint disorders;such hallmark featuresinclude dactylitis and enthesitis.Dactylitis occurs in >30%; enthesitis and tenosynovitis are also common and are probably present in most patients, although often not appreciated on physical examination. Shortening of digits because of underlying osteolysis is particularly characteristic of PsA (Fig. 384-3), and there is a much greater tendency than in RA for both fibrous and bony ankylosis of small joints. Rapid ankylosis of one or more proximal interphalangeal (PIP) joints early in the course of disease is not uncommon. Back and neck pain and stiffness are also common in PsA.


InternalMed_Harrison

InternalMed_Harrison. Arthropathy confined to the DIP joints occurs in about 5% of cases. Accompanying nail changes in the affected digits are almost always present. These joints are also often affected in the other patterns of PsA. Approximately 30% of patients have asymmetric oligoarthritis. This pattern commonly involves a knee or another large joint with a few small joints in the fingers or toes, often with dactylitis. Symmetric polyarthritis occurs in about 40% of PsA patients at presentation. It may be indistinguishable from RA in terms of the joints involved, but other features characteristic of PsA are usually also present. Almost any peripheral joint can be involved. Axial arthropathy without peripheral involvement is found in about 5% of PsA patients. It may be clinically indistinguishable from idiopathic AS, although more neck involvement and less thoracolumbar spinal involvement are characteristic,andnail changesarenot found inidiopathic AS.Asmall percentage of PsA patients have arthritis


InternalMed_Harrison

InternalMed_Harrison. idiopathic AS, although more neck involvement and less thoracolumbar spinal involvement are characteristic,andnail changesarenot found inidiopathic AS.Asmall percentage of PsA patients have arthritis mutilans, in which there can bewidespreadshorteningofdigits(“telescoping”),sometimescoexisting with ankylosis and contractures in other digits.


InternalMed_Harrison

InternalMed_Harrison. Six patterns of nail involvement are identified: pitting, horizontal ridging, onycholysis, yellowish discoloration of the nail margins, dystrophic hyperkeratosis, and combinations of these findings. Other extraarticular manifestations of the spondyloarthritides are common. Eye involvement, either conjunctivitis or uveitis, is reported in 7–33% of PsA patients. Unlike the uveitis associated with AS, the uveitis in PsA is more often bilateral, chronic, and/or posterior. Aortic valve insufficiency has been found in <4% of patients, usually after longstanding disease.


InternalMed_Harrison

InternalMed_Harrison. Widely varying estimates of clinical outcome have been reported in PsA. At its worst, severe PsA with arthritis mutilans is potentially at least as crippling and ultimately fatal as severe RA. Unlike RA, however, many patients with PsA experience temporary remissions. Overall, erosive disease develops in the majority of patients, progressive disease with deformity and disability is common, and in some largepublishedseries,mortalitywasfoundtobesignificantlyincreased compared with the general population. There appears to be a greater incidence of cardiovascular death in psoriatic disease. The psoriasis and associated arthropathy seen with HIV infection both tend to be severe and can occur in populations with very little psoriasis in noninfected individuals. Severe enthesopathy, dactylitis, and rapidly progressive joint destruction are seen, but axial involvement is very rare. This condition is prevented by or responds well to antiretroviral therapy.


InternalMed_Harrison

InternalMed_Harrison. Thereare nolaboratorytestsdiagnostic ofPsA.ESRandCRPareoften elevated.Asmallpercentageofpatientsmayhavelowtitersofrheumatoid factor or antinuclear antibodies. About 10% of patients have anti-CCP antibodies. Uric acid may be elevated in the presence of extensive psoriasis. HLA-B27 is found in 50–70% of patients with axial disease, but in ≤20% of patients with only peripheral joint involvement.


InternalMed_Harrison

InternalMed_Harrison. The peripheral and axial arthropathies in PsA show a number of radiographic features that distinguish them from RA and AS, respectively. Characteristics of peripheral PsA include DIP involvement, including the classic “pencil-in-cup” deformity; marginal erosions with adjacent bony proliferation (“whiskering”); small-joint ankylosis; osteolysis of phalangeal and metacarpal bone, with telescoping of digits; and periostitis and proliferative new bone at sites of enthesitis. Characteristics of axial PsA include asymmetric sacroiliitis. When compared with idiopathic AS, axial PsA manifests less zygapophyseal joint arthritis; nonmarginal, bulky, “comma”-shaped syndesmophytes that tend to be fewer and less symmetric and delicate than the marginal syndesmophytes of AS; fluffy hyperperiostosis on anterior vertebral bodies; severe cervical spine involvement, with a tendency to atlantoaxial subluxation but relative sparing of the thoracolumbar


InternalMed_Harrison

InternalMed_Harrison. syndesmophytes of AS; fluffy hyperperiostosis on anterior vertebral bodies; severe cervical spine involvement, with a tendency to atlantoaxial subluxation but relative sparing of the thoracolumbar spine;andparavertebralossification.UltrasoundandMRIbothreadily demonstrate enthesitis and tendon sheath effusions that can be difficult to assess on physical examination. A recent MRI study of 68 PsA patients found sacroiliitis in 35%, unrelated to B27 but correlated with restricted spinal movement.


InternalMed_Harrison

InternalMed_Harrison. Classification criteria for PsA were published in 2006 (Classification of Psoriatic Arthritis [CASPAR] criteria) that have been widely accepted (Table 384-2). The sensitivity and specificity of these criteria exceed 90%, and they are useful for early diagnosis. The the CaSpar (ClASSIfICatIOn CrIterIa fOr PSOrIatIC ARthrItIS) CrIterIaa


InternalMed_Harrison

InternalMed_Harrison. To meet the CASPAR criteria, a patient must have inflammatory articular disease (joint, spine, or entheseal) with ≥3 points from any of the following five categories: 1. Evidence of current psoriasis,b, c a personal history of psoriasis, or a family history of psoriasisd 2. Typical psoriatic nail dystrophye observed on current physical examination 3. A negative test result for rheumatoid factor 4. Either current dactylitisf or a history of dactylitis recorded by a rheumatologist 5. Radiographic evidence of juxtaarticular new bone formationg in the hand or foot aSpecificity of 99% and sensitivity of 91%. bCurrent psoriasis is assigned 2 points; all other features are assigned 1 point. cPsoriatic skin or scalp disease present at the time of examination, as judged by a rheumatologist or dermatologist. dHistory of psoriasis in a first-or second-degree relative. eOnycholysis, pitting, or hyperkeratosis. fSwelling of an entire digit. gIll-defined ossification near joint margins, excluding


InternalMed_Harrison

InternalMed_Harrison. of psoriasis in a first-or second-degree relative. eOnycholysis, pitting, or hyperkeratosis. fSwelling of an entire digit. gIll-defined ossification near joint margins, excluding osteophyte formation.


InternalMed_Harrison

InternalMed_Harrison. Source: From W Taylor et al: Arthritis Rheum, 54:2665, 2006.


InternalMed_Harrison

InternalMed_Harrison. criteria are based on the history, presence of psoriasis, characteristic 2177 peripheral or spinal joint symptoms, signs, and imaging. Diagnosis can be challenging when the arthritis precedes psoriasis, the psoriasis is undiagnosed or obscure, or the joint involvement closely resembles another form of arthritis. A high index of suspicion is needed in any patient with an undiagnosed inflammatory arthropathy. The history should include inquiry about psoriasis in the patient and family members. Patients should be asked to disrobe for the physical examination, and psoriasiform lesions should be sought in the scalp, ears, umbilicus, and gluteal folds in addition to more accessible sites; the finger and toe nails should also be carefully examined. Axial symptoms or signs, dactylitis, enthesitis, ankylosis, the pattern of joint involvement, and characteristic radiographic changes can be helpful clues. The differential diagnosis includes all other forms of arthritis, which can occur


InternalMed_Harrison

InternalMed_Harrison. ankylosis, the pattern of joint involvement, and characteristic radiographic changes can be helpful clues. The differential diagnosis includes all other forms of arthritis, which can occur coincidentally in individuals with psoriasis. The differential diagnosis of isolated DIP involvement is short. Osteoarthritis (Heberden’s nodes) is usually not inflammatory; gout involving more than one DIP joint often involves other sites and may be accompanied by tophi; the very rare entity multicentric reticulohistiocytosis involves other joints and has characteristic small pearly periungual skin nodules; and the uncommon entity inflammatory osteoarthritis, like the others, lacks the nail changes of PsA. Radiography can be helpful in all of these cases and in distinguishing between psoriatic spondylitis and idiopathic AS. A history of trauma to an affected joint preceding the onset of arthritis is said to occur more frequently in PsA than in other types of arthritis, perhaps reflecting the


InternalMed_Harrison

InternalMed_Harrison. and idiopathic AS. A history of trauma to an affected joint preceding the onset of arthritis is said to occur more frequently in PsA than in other types of arthritis, perhaps reflecting the Koebner phenomenon in which psoriatic skin lesions can arise at sites of the skin trauma.


InternalMed_Harrison

InternalMed_Harrison. Ideally, coordinated therapy is directed at both the skin and joints in PsA. As described above for AS, use of the anti-TNF-α agents has revolutionized the treatment of PsA. Prompt and dramatic resolution of both arthritis and skin lesions has been observed in large, randomized controlled trials of etanercept, infliximab, adalimumab, and golimumab. Many of the responding patients had long-standing disease that was resistant to all previous therapy, as well as extensive skin disease. The clinical response is often more dramatic than in RA, and delay of disease progression has been demonstrated radiographically. The potential additive effect of methotrexate to anti-TNF-α agents in PsA remains uncertain. As noted above, anti-TNF therapy, paradoxically, has been reported to trigger exacerbation or de novo appearance of psoriasis, typically the palmoplantar pustular variety. In some cases, the therapy can nevertheless be continued.


InternalMed_Harrison

InternalMed_Harrison. Ustekinumab, a monoclonal antibody to the shared IL-23/ IL-12p40 subunit, is an efficacious treatment for psoriasis and has shown promise in PsA in clinical trials. Other newer drugs that have shown efficacy for both psoriasis and PsA include the anti-IL-17 pathway agents, such as secukinumab and brodalumab, and an oral phosphodiesterase-4 inhibitor, apremilast. Data on the oral Jak inhibitor, tofacitinib, has been very limited but promising.


InternalMed_Harrison

InternalMed_Harrison. Other treatment for PsA has been based on drugs that have efficacy in RA and/or in psoriasis. Until recently, controlled clinical trial data on methotrexate in doses of 15–25 mg/week and sulfasalazine (usually given in doses of 2–3 g/d) suggesting clinical efficacy have been somewhat limited, but neither regimen effectively halts progression of erosive joint disease. A recent double-blind trial assessing methotrexate 15 mg weekly in PsA demonstrated no benefit to the joint-based inflammation, but improvement was seen in patient and assessor global scores and skin scores. Other agents with efficacy in psoriasis reported to benefit PsA are cyclosporine, retinoic acid derivatives, and psoralens plus ultraviolet A light (PUVA). There is controversy regarding the efficacy in PsA of gold and antimalarials, which have been widely used in RA. The pyrimidine synthetase inhibitor leflunomide has been shown in a randomized controlled trial to be beneficial in both psoriasis and PsA.


InternalMed_Harrison

InternalMed_Harrison. The Spondyloarthritides 2178 All of these treatments require careful monitoring. Immunosuppressive therapy may be used cautiously in HIV-associated PsA if the HIV infection is well controlled.


InternalMed_Harrison

InternalMed_Harrison. Many patients, usually young adults, present with some features of one or more of the spondyloarthritides discussed above. Until recently, these patients were said to have undifferentiated spondylo-arthritis, or simply spondyloarthritis, as defined by the 1991 European SpondyloarthropathyStudyGroupcriteria.Forexample,apatientmay present with inflammatory synovitis of one knee, Achilles tendinitis, and dactylitis of one digit. Some of these patients may have ReA in which the triggering infection remains clinically silent. In some other cases, the patient subsequently develops IBD or psoriasis, or the process eventually meets criteria for AS. This diagnosis of undifferentiated SpA was also commonly applied to patients with inflammatory back pain, who did meet modified New York criteria for AS. Most of these would now be classified under the new category of axial SpA (Table 384-1).


InternalMed_Harrison

InternalMed_Harrison. Comparable to the classification criteria for axial symptoms, the ASAS has recently formulated criteria for peripheral SpA. This is intended to exclude patients with axial symptoms and thus to divide the universe of patients with SpA into axial and exclusively peripheral subsets. These criteria are shown in Table 384-3. Approximately one-half of the patients with undifferentiated SpA are HLA-B27-positive, and thus the absence of B27 is not useful in establishing or excluding the diagnosis. In familial cases, which are much more frequently B27-positive, there is often eventual progression to classical AS.