Page 805 - Clinical Immunology_ Principles and Practice ( PDFDrive )

776 Part six Systemic Immune Diseases

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systems. This is clearly an area where more work needs to CLINICAL FEATURES
be done.
Ankylosing Spondylitis
PATHOLOGY OF SPA Musculoskeletal Symptoms
One of the biggest problems with studies of the synovium KEY CONCEPts
in SpA and PsA is that most lesions are examined late in Clinical Features of Inflammatory Back Pain
the course of disease (i.e., in the hips), and this only at joint
replacement. Few data exist from early disease, and the dif- • Low-back pain that is present every day for at least 3 months
ficulty with tissue access further complicates this. 21,22 For the • Age of onset <45 years
most part, the synovium in SpA resembles that of rheumatoid • Morning stiffness in the back lasting at least 30 minutes
arthritis (RA), with some notable differences. The synovium in • Pain that is relieved by exercise and worsened by rest
SpA displays a tortuous vascular morphology compared with • Alternating buttock pain
• Relief with nonsteroidal antiinflammatory agents
the rheumatoid synovium, which is linear and has diminished
lymphoid aggregates. This may be caused by vascular endothelial
growth factor (VEGF) and the angiogenic growth factor Ang2,
the messenger RNA (mRNA) of which have been observed at The first symptoms of AS usually appear in adolescence or early
higher levels in the synovium in PsA compared with RA. VEGF adulthood and usually start before the age of 45 years. The
5
is particularly interesting because it can synergize with RANK hallmark of AS is the presence of inflammatory back pain, a
ligand (RANKL) to induce bone resorption and also synergize dull, persistent ache, usually in the buttocks or hips, that is worst
with bone morphogenetic proteins to trigger bone formation, in the early-morning hours (between 2 and 5 a.m.) and is associ-
both processes typical of the altered bone remodeling seen in PsA ated with morning stiffness lasting >30 minutes (and sometimes
and SpA. 21,22 several hours to all day). The pain is classically worsened by rest
Increased production of the scavenger receptor CD163 by or recumbency and improves with activity. One important
macrophages in both the lining and sublining layers is seen in component of inflammatory back pain is the striking improve-
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SpA compared with RA. Local production of soluble CD163 ment that results from the use of NSAIDs (usually in high doses).
inhibits synovial T-cell activation, and levels of synovial CD163 Although the pain may be unilateral or intermittent at first (in
5
fall with effective treatment. Increased expression of Toll-like fact, alternating buttock pain is a cardinal feature of the disease),
receptors 2 and 4 (TLR2, TLR4) has been shown in SpA on within a few months it usually becomes persistent and bilateral,
+
4,5
CD163 peripheral blood mononuclear cells in patients with and the lower lumbar area becomes stiff and painful. Occasion-
synovitis, which decreases with TNF-α blockade. This leads to ally, the first symptom of AS comes from extraspinal sources,
the speculation that SpA represents an exaggerated inflammatory such as AAU, peripheral arthritis, or enthesitis, especially in
response of the innate immune system in genetically susceptible patients with disease onset in childhood.
patients. 22 In patients with AS, the most commonly affected joints outside
22
Osteoclasts also appear to have a role and have also been the spine are the hips (in up to 50% of patients), with rapidly
+
observed at the bone–pannus junction in PsA. In addition, CD14 progressive destructive arthritis that necessitates joint arthroplasty
monocytes that are committed to becoming osteoclasts or at an early age. A characteristic radiographic finding is a fairly
osteoclast precursors are increased in the circulation of patients characteristic osteophytic collar that forms at the junction of
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with PsA compared with healthy controls and decline rapidly the femoral head and the neck. Peripheral arthritis other than
following treatment with TNF antagonists. The clinical improve- in the hips and shoulders is uncommonly seen in patients with
ment is accompanied by an MRI-defined reduction of bone AS but, when present, is typical of that seen in other types of
marrow edema. SpA, with an asymmetric oligoarthritis presenting predominantly
Even fewer data exist on enthesitis (the enthesium being the in the lower extremities.
insertion of tendons, ligaments, joint capsules, or fascia into Chest pain, often pleuritic, can be seen in patients with AS
bone). Pathological examination of enthesitis in AS demonstrates as a result of involvement of the costovertebral and manubri-
local inflammation, fibrosis, erosion, and ossification. Immu- osternal joints. This and progressive thoracic spinal involvement
nohistochemical staining for phosphorylated SMAD1/5 in may result in fusion of the costovertebral joints, with loss of
entheseal biopsies of patients with SpA reveals active bone chest expansion and a mechanical restrictive ventilatory defect.
morphogenetic protein signaling. 21 Enthesitis is a classic feature of AS and other SpA (Fig. 57.3).
The pathology of psoriasis consists of an inflammatory cell The most common (and most disabling) sites for enthesitis are
infiltration in the dermis, with localized increased cytokine in the foot, at the insertion of the Achilles tendon, and of the
production and hyperproliferation of keratinocytes (Chapter plantar fascia on to the calcaneus. 24
64). CD4 cells are prominent in the dermis, CD8 in the epi- Three physical measurements have been validated and rec-
dermis; Langerhans cells function as antigen-presenting cells ommended by an ASAS Working Group as useful for evaluating
(APCs). The synovium is infiltrated with CD8 T cells but patients with AS specifically and with inflammatory back pain
demonstrates less pronounced intimal lining layer hyperplasia in general. The Schober test is measured as the increase with
and fewer synovial T cells. It is more vascular than the synovium maximal forward spinal flexion with locked knees of a 10-cm
in RA, contains numerous B cells and macrophages, and has segment marked on the patient’s back with the inferior mark
upregulation of adhesion molecules, such as intercellular adhe- at the level of the posterosuperior iliac spines. The measured
sion molecule (ICAM)-1 and E-selectin, and overexpression distance should increase from 10 cm to at least 13.5 cm in an
of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, adult. Chest wall expansion with inspiration is measured with
and IL-18. 22 a tape measure placed circumferentially around the chest wall