Treatment:
Ankylosing spondylitis
Any management of AS should include an exercise program designed to maintain posture and range of motion. Until recently, nonsteroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of pharmacologic therapy for AS.These agents reduce pain and tenderness and increase mobility in many patients with AS. Moreover, in a recent 2-year randomized controlled study, radiographic progression of AS was significantly slower in patients taking daily NSAIDs than in those taking them only as needed for severe pain or stiffness. However, many patients with AS have continued symptoms and develop deformity despite NSAID therapy. Beginning in 2000, dramatic responses to anti-TNF-α therapy were reported in patients with AS and other spondyloarthritides. Patients with AS treated with either infliximab (chimeric human/mouse anti-TNF-α monoclonal antibody), etanercept (soluble p75 TNF-α receptor-IgG fusion protein), or adalimumab (human anti-TNF-α monoclonal antibody) have shown rapid, profound, and sustained reductions in all clinical and laboratory measures of disease activity. Patients with long-standing disease and even some with complete spinal ankylosis have shown striking 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. 9-2). Similar results have been obtained in large randomized controlled trials of all three agents and many open label studies. About half of the patients achieve a >50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI),the most commonly used measure of disease activity. Increased bone mineral density is found as early as 24 weeks after onset of therapy. Whether radiographic disease progression is slowed has not yet been determined definitively.
The dosages of these agents used in AS patients have usually been similar to those in RA. Infliximab is given as an intravenous infusion, typically at a dose of 3-5 mg/kg body weight, and then repeated 2 weeks later, again 6 weeks later, and then at 8-week intervals. Some success has been achieved with longer intervals, including infusion only upon recurrence of symptoms. Etanercept is given by subcutaneous injection in a dose of 25 mg twice weekly or 50 mg once weekly. Adalimumab is given by subcutaneous injection in a dose of 40 mg biweekly.
Although these potent immunosuppressive agents have so far been relatively safe, seven types of side effects are not rare: (1) serious infections, including disseminated tuberculosis; (2) hematologic disorders, such as pancytopenia; (3) demyelinating disorders; (4) exacerbation of congestive heart failure; (5) systemic lupus erythematosus-related autoantibodies and clinical features; (6) hypersensitivity infusion or injection site reactions;and (7) severe liver disease. Increased incidence of malignancy is of theoretical concern but has not been observed in AS patients treated for up to 5 years.
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 reactivity, and reactors (>5 mm) should be treated with anti-tuberculous 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 con-traindications.Continuation beyond 12 weeks of therapy requires a 50% reduction in BASDAI (or absolute reduction of 2 out of 10) and favorable expert opinion. 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-a.
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. A small number of 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 or even immunosuppressive drugs and rarely infliximab may be required in some cases.TNF inhibitors reduce the frequency of attacks of uveitis in patients with AS.A few individuals have developed new or recurrent uveitis subsequent to the use of a TNF inhibitor, especially etanercept.
Coexistent cardiac disease may require pacemaker implantation and/or aortic valve replacement. Management of osteoporosis of the axial skeleton is at present similar to that used for primary osteoporosis, since data specific for AS are not available.
Reactive Arthritis
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 spondy-loarthritis 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 spondyloarthritis, such as rheumatic fever or Lyme disease, are discussed in Chaps. 6 and 20.
Historic Background
The association of acute arthritis with episodes of diarrhea or urethritis has been recognized for centuries. A large number of cases during World Wars I and II focused attention on the triad of arthritis, urethritis, and conjunctivitis, which became known as Fiessenger-Leroy-Reiter syndrome, often with additional mucocutaneous lesions. These eponyms are now of historic interest only.
The identification of bacterial species capable of triggering the clinical syndrome and the finding that many patients possess the B27 antigen have led to the unifying concept of ReA as a clinical syndrome triggered by specific etiologic agents in a genetically susceptible host. A similar spectrum of clinical manifestations can be triggered by 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 part of the spectrum of the clinical manifestations of ReA. For the purposes of this topic, the use of the term ReA will be restricted to those cases of spondy-loarthritis in which there is at least presumptive evidence for a related antecedent infection. Patients with clinical features of ReA who lack evidence of an antecedent infection will be considered to have undifferentiated spondyloarthritis, discussed below.
Epidemiology
Following the first reports of association of ReA with HLA-B27, in most hospital-based series in which Shigella, Yersinia, or Chlamydia were the triggering infectious agents, 60-85% of patients were found to be B27 positive, with a lower prevalence in ReA triggered by Salmonella and Campylobacter. In more recent community-based or common source epidemic studies, the prevalence of B27 has often been below 50%, and in some instances not elevated at all.The most common age range is 18-40 years, but ReA can occur both in children over 5 years of age and in older adults.
The gender ratio in ReA following enteric infection is nearly 1:1, whereas venereally acquired ReA occurs predominantly in men. The overall prevalence and incidence of ReA are difficult to assess because of the variable prevalence of the triggering infections and genetic susceptibility factors in different populations. In Scandinavian countries, an annual incidence of 10-28/100,000 has been reported. The spondyloarthritides were formerly almost unknown in sub-Saharan Africa. However, ReA and other peripheral spondyloarthritides 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. Spondyloarthritis in Africans with HIV infection usually occurs in individuals with stage I disease (as classified by the World Health Organization). It is often the first manifestation of infection and often remits with disease progression. In contrast,Western Caucasian patients with HIV and spondyloarthritis are predominantly B27 positive, and the arthritis flares as AIDS advances.
Pathology
Synovial histology is similar to that of other spondyloarthri-tides. Enthesitis shows increased vascularity and macrophage infiltration of fibrocartilage. Microscopic histopathologic evidence of inflammation has occasionally been noted in the colon and ileum ofpatients with postvenereal ReA, but much less commonly than in postenteric ReA. The skin lesions of keratoderma blenorrhagica, which is associated mainly with venereally acquired ReA, are histologically indistinguishable from psoriatic lesions.
Etiology and Pathogenesis
Of the four Shigella species, S. sonnei, S. boydii, S. flexneri, and S. dysenteriae, S.flexneri has most often been implicated in cases of ReA, both sporadic and epidemic. Recent data suggest that S. sonnei and S. dysenteriae trigger some cases of ReA.
Other bacteria identified definitively as triggers of ReA include several Salmonella spp., Yersinia enterocolitica, Yersinia pseudotuberculosis, Campylobacter jejuni, and C. trachomatis. There is also increasing evidence implicating Clostridium difficile, Campylobacter coli, certain toxigenic Escherichia coli, and possibly Ureaplasma urealyticum and Mycoplasma genital-ium. Respiratory infection with Chlamydia pneumoniae has also been implicated. There are numerous isolated reports of acute arthritis preceded by other bacterial, viral, or parasitic infections, but whether the microorganisms involved are actual triggers of ReA remains to be determined.
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 fully elucidated in the case of any one of the known bacterial triggers. Most, if not all, of the triggering organisms produce lipopolysaccharide (LPS) and 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 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. The dor- 1 mant form of C. trachomatis that persists in synovium transcriptionally upregulates many genes orthologous to genes upregulated in persistent M. tuberculosis infection.
T cells that specifically respond to antigens of the inciting organism have been found in inflamed synovium but not in peripheral blood of patients with ReA. These T cells are predominantly CD4+, but CD8+ B27-restricted bacteria-specific cytolytic T cells have also been isolated in Yersinia- and C. trachomatis-induced ReA. A unique conserved T cell antigen receptor sequence has been identified in B27-restricted synovial T cells in ReA. Unlike the synovial CD4 T cells in RA, which are predominantly of the TH1 phenotype, those in ReA also show a TH2 phenotype. A T regulatory 1 (Tr1) phenotype with elevated IL-10 and TGF-β in T, B, and macrophage lineages has also been found in ReA synovium. IL-10 promoter haplo-types have been found to be significantly different in ReA patients than in B27+ controls.
HLA-B27 seems to be associated with more severe and chronic forms of ReA, but its pathogenic role remains to be determined. 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, may permit trafficking of infected leukocytes from the site of primary infection to joints, where a T cell response to persistent bacterial antigens may then promote arthritis.
Clinical Features
The clinical manifestations of ReA constitute a spectrum that ranges from an isolated, transient monarthritis 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. However, in a sizable minority, no clinical or laboratory evidence of an antecedent infection can be found. In many cases of presumed venereally acquired reactive disease, there is a history of a recent new sexual partner, even in the absence of laboratory evidence of infection.
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 period of 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 the most common sites of involvement, 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. Patients often cannot walk without support. Dactylitis, or “sausage digit,” a diffuse swelling of a solitary finger or toe, is a distinctive feature of ReA and other peripheral spondyloarthritides but can be seen in polyarticular gout and sarcoidosis. Tendinitis and fasciitis are particularly characteristic lesions, producing pain at multiple insertion sites (enthe-ses), especially the Achilles insertion, the plantar fascia, and sites along the axial skeleton. Spinal and low-back pain are quite common and may be caused by insertional inflammation, muscle spasm, acute sacroiliitis, or, presumably, arthritis in intervertebral articulations.
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 of the reactive phase of the disease. 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.
Mucocutaneous lesions are frequent. Oral ulcers tend to be superficial, transient, and often asymptomatic. The characteristic skin lesions, keratoderma blenorrhagica, consist of vesicles 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. Lesions on the glans penis, termed circinate balanitis, are common; these consist of vesicles that quickly rupture to form painless superficial erosions, which in circumcised individuals can form crusts similar to those of keratoderma blenorrhagica. Nail changes are common and consist of onycholysis, distal yellowish discoloration, and/or heaped-up hyperkeratosis.
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 3-5 months, but courses up to 1 year can occur. Chronic joint symptoms persist in about 15% of patients and in up to 60% in hospital-based series. Recurrences of the acute syndrome are also com-mon.Work disability or forced change in occupation are 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-induced arthritis have less chronic disease than those whose initial episode follows epidemic shigellosis.
Laboratory and Radiographic Findings
The ESR is usually elevated during the acute phase of the disease. Mild anemia may be present, and acute-phase reactants tend to be increased. Synovial fluid is non-specifically inflammatory. In most ethnic groups, about half the patients are B27 positive. It is unusual for the triggering infection to persist at the site of primary mucosal infection through the time of onset of the reactive disease, but it may occasionally be possible to culture the organism, e.g., in the case of Yersinia- or Chlamydia-induced disease. Serologic evidence of a recent infection may be present, such as a marked elevation of antibodies to Yersinia, Salmonella, or Chlamydia. Polymerase chain reaction (PCR) of first-voided urine specimens for chlamydial DNA is said to have high sensitivity.
In early or mild disease, radiographic changes may be absent or confined to juxtaarticular osteoporosis. With long-standing persistent disease, marginal erosions and loss ofjoint space can be seen in affected joints. Periostitis with reactive new bone formation is characteristic of the disease, as it is with all the spondyloarthritides. Spurs at the insertion of the plantar fascia are common.
Sacroiliitis and spondylitis may be seen as late sequelae. The sacroiliitis is more commonly asymmetric than in AS, and the spondylitis, rather than ascending symmetrically from the lower lumbar segments, can begin anywhere along the lumbar spine.The syndesmophytes may be coarse and nonmarginal, arising from the middle of a vertebral body, a pattern rarely seen in primary AS. Progression to spinal fusion is uncommon.
Diagnosis
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 sites of 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 molecular methods may help to identify a triggering infection.
Although typing for B27 is not needed to secure the diagnosis in clear-cut cases, 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, but a negative test is of little diagnostic value. HIV testing is often indicated and may be necessary in order to select appropriate therapy
It is important to differentiate ReA from disseminated gonococcal disease, 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, to lack back symptoms, and to 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 gonor-rhoeae and C. trachomatis may be helpful. Occasionally, only a therapeutic trial of antibiotics can distinguish the two.
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 no associated mouth ulcers, urethritis, or bowel symptoms.
Treatment:
Reactive Arthritis
Most patients with ReA benefit to some degree from 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.
Prompt, appropriate antibiotic treatment of acute chlamydial urethritis or enteric infection may prevent the emergence of ReA. However, several controlled trials have failed to demonstrate any benefit for antibiotic therapy that is initiated after onset of arthritis. 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 spondy-loarthritis. Another such study failed to demonstrate any long-term benefit.
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 d, or to methotrexate, up to 20 mg per week.Although no trials of anti-TNF-α in ReA have been reported,anecdo-tal evidence supports the use of these agents in severe chronic cases, although lack of response has also been observed.1
Tendinitis and other enthesitic lesions may benefit from intralesional glucocorticoids. Uveitis may require aggressive treatment with glucocorticoids to prevent serious sequelae. Skin lesions ordinarily require only symptomatic 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 ankylosing spondylitis.
Psoriatic Arthritis
Psoriatic arthritis (PsA) refers to an inflammatory arthritis that characteristically occurs in individuals with psoriasis.
Historic Background
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 spondyloarthri-tides because of features similar to those of AS and ReA.
