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Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy

Sections Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy
Overview
Presentation
DDx
Workup
Treatment
Medication
Questions & Answers
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References

Treatment

Approach Considerations

No definite disease-modifying treatment exists for individuals with ankylosing spondylitis (AS) although biologic agents show evidence of such activity. Early diagnosis is important. As with any chronic disease, patient education is vital to familiarize the patient with the symptoms, course, and treatment of the disease. Treatment measures include pharmacologic, surgical, and physical therapy.

No drugs have been proved to modify the course of the disease, although tumor necrosis factor-α (TNF-α) inhibitors (TNHi) and IL-17 inhibitors (IL-17i) appear to have potential as disease-modifying agents.^[99]Symptoms are generally not affected by pregnancy or childbirth. Medical management of AS, including medications, must be adjusted during pregnancy in accordance with the specific pregnancy profiles of the medications.

Inpatient care is generally not necessary for patients with AS. The exceptions to this include patients with coexisting or extra-articular disease and those requiring surgery.

Extra-articular manifestations, which may necessitate specialist referral for appropriate care, include the following:

Acute anterior uveitis
Aortitis
Conduction defects
Pulmonary fibrosis
Amyloidosis
Neurologic deficits, including cauda equina
Associated inflammatory bowel disease

Disease progress and response to therapy can be monitored by following laboratory values, including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level.

Surgical treatment is geared toward resolution of the complications related to AS; it is occasionally used for repairing damaged peripheral joints and rarely used to correct spinal deformities as it involves significant morbidity. Patients with fusion of the spine secondary to AS who report a change in position of the spine should be treated cautiously and should be considered to have sustained a spinal fracture. Surgical intervention may be necessary to stabilize the fracture and prevent neurologic deficit.^{[100, 101]}

Outpatient care should be aimed toward providing adequate pain control and maximizing motion and functional ability. Such care includes pain medication, exercise programs, recreational therapy, and vocational therapy. Regular exercise helps reduce the symptoms and may slow the progress of the disease. Generally, no dietary restrictions are implemented for patients with AS; however, patients with coexisting diseases, such as inflammatory bowel disease (IBD), have dietary restrictions.

Peripheral spondyloarthritis

Pharmacologic treatment for peripheral spondyloarthritis includes the following:

Nonsteroidal anti-inflammatory drugs
Corticosteroid injections
Sulfasalazine
TNFi (infliximab, etanercept, adalimumab, certolizumab, golimumab)
IL-17i (secukinumab, ixekizumab)

In a study of adult patients with recent-onset peripheral spondyloarthritis (symptom duration < 12 weeks), early use of the TNFi golimumab resulted in sustained clinical remission in 49 of 60 patients (82%). Most patients (n=30) fulfilled criteria for sustained clinical remission by week 24. On follow-up at least 18 months after drug withdrawal, 26 of the 49 patients (53%) were still in drug-free remission.^{[102, 103]}Similar data have been seen with all the TNFi and IL-17i. IL-12/23i are effective in the peripheral arthritis and enthesitis of PsA but do not seem to be effective in axial disease such as is seen in AS.

Nonradiographic axial spondyloarthritis

In 2019, the US Food and Drug Administration (FDA) approved certolizumab for treatment of nonradiographic axial spondyloarthritis (nr-axSpA) with objective inflammation. Certolizumab is the first therapy approved for nr-axSpA. Approval was based on data from the phase 3 C-AXSPAND study, which favored certolizumab over placebo at both week 12 and week 52. At week 52, major improvement in the Ankylosing Spondylitis Disease Activity Score (ASDAS) had occurred in 42% of patients receiving certolizumab, compared with 7% of those receiving placebo.^[104]IL-17i, secukinumab and ixekizumab, are also FDA approved for the treatment of nr-axSpA.^{[105, 106]}Other TNFi and IL-17i have had similar results in patients with nr-axSpA.

Pharmacologic Therapy

Agents used in the treatment of AS include the following:

Nonsteroidal anti-inflammatory drugs (NSAIDs)
Sulfasalazine
Tumor necrosis factor–alpha inhibitors (TNFi)
Interleukin-17A (IL-17A) inhibitors
Corticosteroids
Janus kinase (JAK) inhibitors
Miscellaneous agents

Nonsteroidal anti-inflammatory drugs

NSAIDs improve the symptoms of the disease by reducing pain and decreasing inflammation. Numerous choices are available, and they are separated into different families of agents.^[107]If one NSAID is ineffective, another from a different family may provide relief.

Efficacy and adverse effect profiles differ among agents and families. Indomethacin may be more effective than other NSAIDs, although this potential advantage has not been proved. Salicylates seldom give adequate relief. Cyclooxygenase-2 (COX-2) inhibitors appear to be as effective as nonselective NSAIDs.^[108]

Sieper et al, in a randomized, double-blind, controlled study comparing two dosages of celecoxib (200 mg once daily and 200 mg twice daily) to diclofenac (75 mg twice daily), noted that both dosages of celecoxib were comparable to the diclofenac dosage with respect to global pain intensity.^[109]However, with respect to changes in disease activity, functional and mobility capacities, and adverse events, once-daily celecoxib was not as effective in reducing certain inflammation-associated parameters as twice-daily celecoxib and diclofenac were.

Give NSAIDs in full anti-inflammatory doses. Continuous treatment with NSAIDs appears to reduce radiographic progression in AS.^[108]Common toxicities involve the gastrointestinal (GI) tract (nausea, dyspepsia, ulceration, bleeding), the kidneys, and the central nervous system.

Sulfasalazine

Sulfasalazine is useful in AS patients who do not respond to or who have contraindications to NSAIDs, as well as in those with coexisting inflammatory bowel disease. In particular, it is often given to treat peripheral joint involvement, for which it has demonstrated efficacy. Sulfasalazine reduces spinal stiffness, peripheral arthritis, and the erythrocyte sedimentation rate (ESR), but there is no evidence that it improves spinal mobility, enthesitis, or physical function.^{[110, 111, 112]}In a randomized, double-blind study, treatment with sulfasalazine resulted in significantly lesser improvement when compared to treatment with the TNFi etanercept.^[113]Sulfasalazine toxicities include rash, nausea, diarrhea, and agranulocytosis (rarely).

Tumor necrosis factor–alpha inhibitors

TNF is a cytokine with two identified forms, which have similar biologic properties. TNF-α (cachectin) is produced predominantly by macrophages, and TNF-β (lymphotoxin) is produced by lymphocytes. TNF is but one of many cytokines involved in the inflammatory cascade that may contribute to AS.^{[114, 107]}

Agents that inhibit TNF-α have proved very effective in the treatment of AS.^[115]These TNFi have a fairly rapid onset of action (2 weeks), and have been shown to reduce the inflammatory activity of spinal disease as assessed with magnetic resonance imaging (MRI).^[116]

The European League Against Rheumatism notes that extensive MRI inflammatory activity, particularly in the spine, might be used as a predictor of good clinical response to TNFi treatment in patients with AS. Thus, MRI might aid in the decision of initiating TNFi, in addition to clinical examination and C-reactive protein (CRP) testing.^[91]

TNFi are indicated after NSAID therapy has failed (two different NSAIDs for one month each).^[99]The following TNFi have been approved by the US Food and Drug Administration (FDA) as therapies for AS:

Etanercept ^{[117, 118]}
Infliximab ^{[119, 120, 121]}
Adalimumab ^[122]
Golimumab ^[123]
Certolizumab pegol ^{[124, 125]}

TNFi are also approved for the treatment of rheumatoid arthritis and psoriatic arthritis. Other approved indications include the following:

Psoriasis (etanercept, infliximab, adalimumab, certolizumab pegol)
Juvenile idiopathic arthritis (etanercept, adalimumab)
Crohn disease (infliximab, adalimumab, certolizumab pegol)
Non-infectious uveitis (adalimumab)

Toxicities associated with TNFi include injection-site and infusion reactions. Increased risks of bacterial infections, reactivation of latent tuberculosis, and certain fungal infections (eg, histoplasmosis, coccidioidomycosis) have been observed.

There is some concern regarding an increased risk of malignancy in patients receiving TNFi. The most attention has been focused on lymphoma and non-melanotic skin cancers in patients with rheumatoid arthritis, although this has been difficult to document in such patients and has not been described in patients with AS. In rare cases, cytopenias have been associated with TNFi use.

Patients with rheumatoid arthritis who have recently started TNFi may be at increased risk for new-onset congestive heart failure even in the absence of any obvious risk factors for the disease. These agents should not be initiated in patients with uncompensated congestive heart failure.

Patients should be screened for latent tuberculosis, hepatitis B, and HIV infection before beginning TNFi therapy.^[126]Although these agents should not be used in patients with active hepatitis B, they appear to be safe in patients with chronic hepatitis C. Rarely, autoimmune syndromes (eg, a lupuslike illness) have been noted in patients receiving TNFi. More commonly, a positive antinuclear antibody (ANA) test result, in the absence of clinical disease, may occur during treatment.

Demyelinating syndromes have rarely been documented in patients receiving TNFi, though no direct link has been proved. These agents should not be used in patients with multiple sclerosis or other demyelinating diseases. New-onset psoriatic skin lesions have been documented after the initiation of TNFi.

In a prospective study of 334 patients with AS, response to treatment with TNFi was associated with a 50% reduction in the risk of radiographic progression of AS. However, nearly 4 years of treatment were necessary for the benefit to become apparent. Moreover, in patients who first began TNFi treatment 10 or more years after disease onset, AS progression was twice as likely as it was in patients who started treatment earlier.^{[127, 128]}

Interleukin-17A inhibitors

IL-17A is a proinflammatory cytokine that is involved in normal inflammatory and immune responses and also plays a key role in the pathogenesis of AS. Two human IgG monoclonal antibodies that target IL-17A are approved for use in AS and active non-radiographic axial spondyloarthritis: secukinumab and ixekizumab.

Secukinumab

Secukinumab (Cosentyx), a human IgG1 monoclonal antibody that selectively binds to and neutralizes IL-17A, was approved by the FDA for adults with active AS in 2016. In 2020, approval was expanded to include non-radiographic axial spondyloarthritis (nr-axSpA).

Approval of secukinumab for AS was based on 2 phase III trials (MEASURE 1 and 2). In MEASURE 1 (n=371), the Assessment of Spondyloarthritis International Society (ASAS20) response rates at week 16 for secukinumab (at a dose of 150 mg subcutaneously) versus placebo were 61% versus 29%, respectively (P < 0.001 for both comparisons with placebo). In MEASURE 2 (n=219), those rates were 61% and 28%, respectively (P < 0.001). The significant improvements were sustained through 52 weeks.^[129]

The approval of secukinumab for nr-axSpA was based on outcomes from the PREVENT phase III study (n = 555) in adults with active nr-axSpA who were biologic-treatment naïve or had an inadequate response or intolerance to an anti–TNF-α therapy. Of the 481 patients who completed 52 weeks of treatment, ASAS40 in TNFi-naïve patients was significantly higher with a loading dose (41.5%) at week 16 and without a loading dose (39.8%) at week 52 compared with placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05).^[105]

Ixekizumab

Ixekizumab (Taltz), a humanized monoclonal IgG4 antibody, also targets IL-17A. In 2019, ixekizumab was approved by the FDA for adults with active AS. In 2020, approval was expanded to include nr-axSpA. Approval was based on two phase III trials (COAST-V and COAST-W) that included 657 adults with active AS. In COAST-V, which included patients who had not been treated with biological DMARDs, at week 16, significantly more patients achieved improvement with ixekizumab than with placebo or adalimumab.^[130] In the COAST-W trial, patients with active AS with a previous inadequate response or intolerance to TNF inhibitors showed a statistical improvement at 16 weeks with ixekizumab, compared with placebo (30.6% versus 12.5%; P=0.003%).^[131]

Approval of ixekizumab for active nr-axSpA with objective signs of inflammation was based on the COAST-X phase III trial. The primary endpoint, the proportion of patients achieving ASAS40 at 52 weeks, was achieved in 30% of patients treated with ixekizumab versus 13% for placebo (P = 0.0045).^[106]

Corticosteroids

Oral corticosteroids are occasionally helpful in controlling AS symptoms. However, they should be used only for short-term management; long-term management carries a high risk of adverse effects. No evidence has shown that corticosteroids alter the outcome of the disease, and these agents are known to increase the tendency toward spinal osteoporosis.

Local corticosteroid injections are useful for symptomatic sacroiliitis, peripheral enthesitis, and arthritis, although the response is not typically as rapid as in patients with rheumatoid arthritis.

Janus kinase inhibitors

JAKs are intracellular tyrosine kinases that affect a range of intracellular activity, including the production of inflammatory cytokines. The JAK family contains four JAKs: JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2). Two JAK inhibitors, upadacitinib (Rinvoq) and tofacitinib (Xeljanz), are approved by the FDA for treatment of active AS in adults who have an inadequate response or are intolerant to one or more TNFi. Both are available as extended-release tablets.

Upadacitinib

Upadacitinib, a JAK1-selective inhibitor, was approved by the FDA for use in AS in April 2022. Approval was based on data from the phase III SELECT-AXIS 2 and the phase II/III SELECT-AXIS 1 clinical trials. SELECT-AXIS 2 evaluated upadacitinib in patients who had an inadequate response (IR) or intolerance to 1 or 2 biologic DMARDs (bDMARDs) and in patients with active non-radiographic axial spondyloarthritis (Nr-axSpA). At 14 weeks, significantly more patients from SELECT-AXIS 2 reached an Assessment of SpondyloArthritis international Society 40 (ASAS40) response versus placebo, the primary endpoint (45% versus 23%; P < 0.0001 in Nr-axSpA patients and 45% versus 18%; P < 0.0001 in bDMARD-IR patients).^[132]

In SELECT-AXIS 1, which comprised patients who had an IR or intolerance to at least 2 NSAIDs, the percentage of participants achieving the primary efficacy end point of ASAS40 at 14 weeks was significantly greater with upadacitinib than with placebo (52% vs 26%; P = 0.003).^[133]At week 14, patients in the placebo arm were switched to upadacitinib, and all patients continued in the open-label study extension and received upadacitinib up to week 104. At week 64, similar proportions of patients in either group (continuous upadacitinib or placebo-to-upadacitinib) achieved ASAS40 or ASDAS and showed low disease activity.^[134]

Tofacitinib

Tofacitinib, which inhibits JAK1 and JAK3, was approved by the FDA for use in AS in December 2021. Approval was based on data from a phase III, randomized, double-blind, placebo-controlled trial in patients who had an inadequate response or intolerance to 1 or more TNFi. At 16 weeks, the percentage of patients achieving an ASAS20 was significantly higher with tofacitinib than with placebo (56.4% vs 29.4%; P < 0.0001). Additionally, the ASAS40 response was significantly greater with tofacitinib vs placebo (40.6% versus 12.5%; P < 0.0001).^[135]

Other agents

Anecdotal reports suggest that other medications may be helpful in the treatment of AS, including methotrexate, azathioprine, cyclophosphamide, and cyclosporine. Methotrexate is of questionable benefit in AS; various studies have shown conflicting results.^[136]At present, it is reserved for patients with symptoms that are not adequately controlled with NSAIDs or sulfasalazine.

Leflunomide was evaluated in a randomized, double-blind, placebo-controlled study in active AS but was not found to be effective.^[137]Bisphosphonates may modestly affect clinical disease activity in AS. Anakinra, a recombinant human IL-1 receptor antagonist, may be effective in treatment-resistant AS.

Guideline-directed Therapy

Guidelines on treatment for ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (nr-axSpA) have been issued by the American College of Rheumatology.^[138]

In adults with active AS:

Strongly recommend treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) over no treatment with NSAIDs
Conditionally recommend continuous treatment with NSAIDs over on-demand treatment with NSAIDs
No recommendation for any particular NSAID as the preferred choice
Strongly recommend against treatment with systemic glucocorticoids

In adults with active AS despite treatment with NSAIDs:

Conditionally recommend treatment with sulfasalazine, methotrexate, or tofacitinib over no treatment with those medications; sulfasalazine or methotrexate should be considered only in patients with prominent peripheral arthritis or when a tumor necrosis factor inhibitor (TNFi) is not available.
Conditionally recommend treatment with a TNFi over treatment with tofacitinib
Strongly recommend treatment with a TNFi over no treatment with TNFi
No recommendation for any particular TNFi as the preferred choice
Strongly recommend treatment with secukinumab or ixekizumab over no treatment with those agents;
Conditionally recommend treatment with a TNFi over treatment with secukinumab or ixekizumab
Conditionally recommend treatment with secukinumab or ixekizumab over treatment with tofacitinib
In patients who have contraindications to TNFis, conditionally recommend treatment with secukinumab or ixekizumab over treatment with sulfasalazine, methotrexate, or tofacitinib
In patients with primary nonresponse to TNFi therapy, conditionally recommend treatment with secukinumab or ixekizumab over treatment with a different TNFi
In patients with secondary nonresponse to TNFi therapy, conditionally recommend treatment with a different TNFi over treatment with a non-TNFi biologic
In patients whose AS does not respond to treatment with the first TNFi used, strongly recommend against switching to treatment with a biosimilar of the first TNFi
In patients whose AS does not respond to treatment with the first TNFi used, conditionally recommend against the addition of sulfasalazine or methotrexate in favor of treatment with a new biologic
In adults with AS and isolated active sacroiliitis despite treatment with NSAIDs, conditionally recommend treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids
In adults with AS with stable axial disease and active enthesitis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids; however, peri-tendon injections of Achilles, patellar, and quadriceps tendons should be avoided
In adults with AS with stable axial disease and active peripheral arthritis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids
Strongly recommend treatment with physical therapy over no treatment with physical therapy
Conditionally recommend active physical therapy interventions (supervised exercise) over passive physical therapy interventions (massage, ultrasound, heat)
Conditionally recommend land-based physical therapy interventions over aquatic therapy interventions

In adults with stable AS:

Conditionally recommend on-demand treatment with NSAIDs over continuous treatment with NSAIDs
In patients receiving treatment with TNFi and NSAIDs, conditionally recommend continuing treatment with TNFi alone versus continuing both treatments
In patients receiving treatment with TNFi and a conventional synthetic antirheumatic drug, conditionally recommend continuing treatment with TNFi alone over continuing both treatments
In patients receiving treatment with a biologic, conditionally recommend against discontinuing it
In patients receiving treatment with a biologic, conditionally recommend against tapering of the biologic dose as a standard approach
In patients receiving treatment with an originator TNFi, strongly recommend continuing treatment with the originator TNFi over mandated switching to its biosimilar
Strongly recommend treatment with physical therapy over no treatment with physical therapy

In adults with active or stable AS:

Conditionally recommend against co-treatment with a TNFi and low-dose methotrexate
Conditionally recommend advising unsupervised back exercises
Conditionally recommend evaluation and counseling regarding falls
Conditionally recommend participation in formal group or individual self-management education
In patients with spinal fusion or advanced spinal osteoporosis,strongly recommend against treatment with spinal manipulation
In patients with advanced hip arthritis, strongly recommend treatment with total hip arthroplasty over no surgery
In patients with severe kyphosis, conditionally recommend against elective spinal osteotomy

In adults with AS-related comorbidities:

In patients with acute iritis, strongly recommend treatment by an ophthalmologist to decrease the severity, duration, or complications of episodes
In patients with recurrent iritis, conditionally recommend prescription of topical glucocorticoids over no prescription for prompt at-home use in the event of eye symptoms, to decrease the severity or duration of iritis episodes
In patients with recurrent iritis,conditionally recommend treatment with TNFi monoclonal antibodies over treatment with other biologics
In patients with inflammatory bowel disease, do not recommend any particular NSAID as the preferred choice to decrease the risk of worsening of inflammatory bowel disease symptoms
In patients with inflammatory bowel disease, conditionally recommend treatment with TNFi monoclonal antibodies over treatment with other biologics

Assessment of disease activity, imaging, and screening:

Conditionally recommend the monitoring of a validated AS disease activity measure at regular intervals
Conditionally recommend regular-interval monitoring of C-reactive protein (CRP) concentrations or erythrocyte sedimentation rate (ESR) over usual care without regular CRP or ESR monitoring
In adults with active AS, conditionally recommend against using a treat-to-target strategy using a target Ankylosing Spondylitis Disease Activity Score (ASDAS) of < 1.3 (or 2.1) over a treatment strategy based on physician assessment
Conditionally recommend screening for osteopenia/osteoporosis with dual-energy x-ray absorptiometry (DXA) scan over no screening
In adults with syndesmophytes or spinal fusion, conditionally recommend screening for osteoporosis/osteopenia with DXA scan of the spine as well as the hips, compared with DXA scan solely of the hip or other non-spine sites
Strongly recommend against screening for cardiac conduction defects with electrocardiograms
Strongly recommend against screening for valvular heart disease with echocardiograms
In adults with AS of unclear activity while on a biologic, conditionally recommend obtaining a spinal or pelvis MRI to assess activity
In adults with stable AS, conditionally recommend against obtaining a spinal or pelvis MRI to confirm inactivity
In adults with active or stable AS on any treatment, conditionally recommend against obtaining repeat spine radiographs at a scheduled interval (eg, every 2 years) as a standard approach

In adults with active nonradiographic axial spondyloarthritis (SpA):

Strongly recommend treatment with NSAIDs over no treatment with NSAIDs
Conditionally recommend continuous treatment with NSAIDs over on-demand treatment with NSAIDs
Do not recommend any particular NSAID as the preferred choice

In adults with active nonradiographic axial SpA despite treatment with NSAIDs:

Conditionally recommend treatment with sulfasalazine, methotrexate, or tofacitinib over no treatment with these medications
Strongly recommend treatment with TNFi over no treatment with TNFi
Do not recommend any particular TNFi as the preferred choice
Conditionally recommend treatment with TNFi over treatment with tofacitinib
Conditionally recommend treatment with secukinumab or ixekizumab over no treatment with secukinumab or ixekizumab
Conditionally recommend treatment with TNFi over treatment with secukinumab or ixekizumab
Conditionally recommend treatment with secukinumab or ixekizumab over treatment with tofacitinib
In patients who have contraindications to TNFi, conditionally recommend treatment with secukinumab or ixekizumab over treatment with sulfasalazine, methotrexate, or tofacitinib
In adults with active nonradiographic axial SpA and primary nonresponse to the first TNFi used, conditionally recommend switching to secukinumab or ixekizumab over switching to a different TNFi.
In adults with active nonradiographic axial SpA and secondary nonresponse to the first TNFi used, conditionally recommend switching to a different TNFi over switching to a non-TNFi biologic.
In adults with active nonradiographic axial SpA despite treatment with the first TNFi used, strongly recommend against switching to the biosimilar of the first TNFi.
In adults with active nonradiographic axial SpA despite treatment with the first TNFi used, conditionally recommend against the addition of sulfasalazine or methotrexate in favor of treatment with a different biologic.

Other recommendations for adults with nonradiographic axial SpA:

Strongly recommend against treatment with systemic glucocorticoids
In patients with isolated active sacroiliitis despite treatment with NSAIDs, conditionally recommend treatment with local glucocorticoids over no treatment with local glucocorticoids
In patients with active enthesitis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoid; however, peri-tendon injections of Achilles, patellar, and quadriceps tendons should be avoided
In patients with active peripheral arthritis despite treatment with NSAIDs, conditionally recommend using treatment with locally administered parenteral glucocorticoids over no treatment with local glucocorticoids
Strongly recommend treatment with physical therapy over no treatment with physical therapy
Conditionally recommend active physical therapy interventions (supervised exercise) over passive physical therapy interventions (massage, ultrasound, heat)
Conditionally recommend land-based physical therapy interventions over aquatic therapy interventions

In adults with stable nonradiographic axial spondyloarthritis (SpA):

Conditionally recommend on-demand treatment with NSAIDs over continuous treatment with NSAIDs
In adults receiving treatment with TNFi and NSAIDs, conditionally recommend continuing treatment with TNFi alone over continuing both medications
In patients receiving treatment with TNFi and a conventional synthetic antirheumatic drug, conditionally recommend continuing treatment with the TNFi alone over continuing treatment with both medications
In patients receiving treatment with a biologic, conditionally recommend against discontinuing it
In patients receiving treatment with a biologic, conditionally recommend against tapering of the biologic dose as a standard approach
In patients receiving treatment with an originator TNFi, strongly recommend continuation of treatment with the originator TNFi over mandated switching to its biosimilar

In adults with active or stable nonradiographic axial SpA:

Conditionally recommend against co-treatment with a TNFi and low-dose methotrexate

Assessment of disease activity and imaging:

Conditionally recommend monitoring of a validated AS disease activity measure at regular intervals
Conditionally recommend regular monitoring of the CRP concentrations or ESR over usual care without regular CRP or ESR monitoring
In adults with active nonradiographic axial SpA, conditionally recommend against using a treat-to-target strategy using a target of ASDAS < 1.3 (or 2.1) over a treatment strategy based on physician assessment
In adults with nonradiographic axial SpA of unclear activity while on a biologic, conditionally recommend obtaining a pelvis MRI to assess activity
In adults with stable nonradiographic axial SpA, conditionally recommend against obtaining a spinal or pelvis MRI to confirm inactivity
In adults with active or stable nonradiographic axial SpA on any treatment, conditionally recommend against obtaining repeat spine radiographs at a scheduled interval (eg, every 2 years) as a standard approach

Guidelines issued by an international task force on treating axial and peripheral spondyloarthritis to target include the following recommendations^[139]:

The treatment target should be clinical remission/inactive disease of musculoskeletal (arthritis, dactylitis, enthesitis, axial disease) and extra-articular manifestations.
The treatment target should be individualized on the basis of current clinical manifestations, and the treatment modality should be considered when defining the time required to reach the target.
Clinical remission/inactive disease is defined as the absence of clinical and laboratory evidence of significant disease activity; low or minimal disease activity may be an alternative treatment target .
Disease activity should be measured on the basis of clinical signs and symptoms, and acute phase reactants.
Validated measures of musculoskeletal disease activity and assessment of cutaneous and/or other relevant extra-articular manifestations should be used in clinical practice to define the target and to guide treatment decisions; the frequency of the measurements depends on the level of disease activity.
In axial spondyloarthritis, the Ankylosing Spondylitis Disease Activity Score (ASDAS) is a preferred measure.
The choice of the target and of the disease activity measure should take comorbidities, patient factors, and drug-related risks into account.
In addition to clinical and laboratory measures, imaging results may be considered in clinical management.
Once the target is achieved, it should ideally be maintained throughout the course of the disease.
The patient should be appropriately informed and involved in the discussions about the treatment target and the risks and benefits of the strategy planned to reach this target.

Joint guidelines on axial SpA (axSpA) issued by the Assessment of SpondyloArthritis international Society (ASAS) and the European League Against Rheumatism (EULAR) update and aggregate previous ASAS-EULAR guidelines on AS and ASAS guidelines on management of axSpA with TNFi into a single set of recommendations.^[99]

The ASAS-EULAR guidelines begin with the following five overarching principles:

AxSpA is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary management coordinated by the rheumatologist.
The primary goal of treating the patient with axSpA is to maximize long-term health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, and preservation/normalization of function and social participation.
The optimal management of patients with axSpA requires a combination of non-pharmacological and pharmacological treatment modalities.
Treatment of axSpA should aim at the best care and must be based on a shared decision between the patient and the rheumatologist.
AxSpA incurs high individual, medical, and societal costs, all of which should be considered in its management by the treating rheumatologist.

The ASAS recommendations are as follows:

The treatment of patients with axSpA should be individualized according to the current signs and symptoms of the disease (axial, peripheral, extra-articular manifestations) and the patient characteristics, including comorbidities and psychosocial factors.
Disease monitoring of patients with axSpA should include patient-reported outcomes, clinical findings, laboratory tests and imaging, all with the appropriate instruments and relevant to the clinical presentation. The frequency of monitoring should be decided on an individual basis, depending on symptoms, severity and treatment.
Treatment should be guided according to a predefined treatment target.
Patients should be educated about axSpA and encouraged to exercise on a regular basis and stop smoking; physical therapy should be considered.
Patients suffering from pain and stiffness should use an NSAID as first-line drug treatment up to the maximum dose, taking risks and benefits into account. For patients who respond well to NSAIDs and whose symptoms recur after stopping the NSAID or reducing the dose, continuous use is advised.
Analgesics, such as acetaminophen and opioid-(like) drugs, might be considered for residual pain after previously recommended treatments have failed, are contraindicated, and/or are poorly tolerated.
Glucocorticoid injections directed to the local site of musculoskeletal inflammation may be considered. Patients with axial disease should not receive long-term treatment with systemic glucocorticoids.
Patients with purely axial disease should normally not be treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs); sulfasalazine may be considered in patients with peripheral arthritis.
Biologic DMARDs (bDMARDs) should be considered in patients with persistently high disease activity despite conventional treatments; current practice is to start with TNFi therapy.
If TNFi therapy fails, switching to another TNFi or an anti–interleukin-17 (IL-17) therapy should be considered.
If a patient is in sustained remission, tapering of a bDMARD can be considered.
Total hip arthroplasty should be considered in patients with refractory pain or disability and radiographic evidence of structural damage, independent of age; spinal corrective osteotomy in specialized centers may be considered in patients with severe disabling deformity.
If a significant change in the course of the disease occurs, causes other than inflammation (eg, a spinal fracture) should be considered and appropriate evaluation, including imaging, should be performed.

Treatment of Uveitis

Acute anterior uveitis presents as a painful red eye that is associated with photophobia and often recurs. Untreated uveitis may lead to vision loss. Evaluation and treatment of uveitis should be performed under the guidance of an ophthalmologist.

Generally, patients respond well to topical corticosteroids, mydriatics, and artificial tears, with resolution of the attack over 2-3 months. Treatment occasionally requires topical NSAIDs, retrobulbar corticosteroid injections, or immunosuppressive drugs. TNFi may be helpful in selected cases. A study by van Denderen and colleagues reported a significant reduction in the recurrence rate of anterior uveitis in patients with AS who were treated with adalimumab.^[140] Adalimumab is FDA approved for treatment of noninfectious uveitis, including that associated with axial SpA.

Evaluation of Disease Activity and Treatment Response

Laboratory values, including the ESR and the C-reactive protein (CRP) level, are commonly employed to monitor the progression of the disease and the effectiveness of treatment. Guidelines from the European League Against Rheumatism (EULAR) recommend that conventional radiography of the sacroiliac (SI) joints, spine, or both may be used for long-term monitoring of structural damage, particularly new bone formation. If performed, it should not be repeated more frequently than every second year.^[91]

MRI may provide additional information. MRI of the SI joints and/or the spine may be used to assess and monitor disease activity in axial spondyloarthropathy. In general, short tau inversion recovery (STIR) sequences are sufficient to detect inflammation, and the use of contrast medium is not needed.^[91]

In addition, numerous tools have been developed to measure AS disease activity, especially in the setting of clinical trials.^{[141, 142, 143]}These tools include the following:

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) - A questionnaire that assesses fatigue, pain (in the neck, back, and hip), peripheral joint pain and swelling, discomfort, and severity and duration of morning stiffness
Bath Ankylosing Spondylitis Functional Index (BASFI) - A questionnaire of physical function that evaluates dressing, bending, mobility, standing, stairs, and full-day activities
Bath Ankylosing Spondylitis Metrology Index (BASMI) - A physical evaluation of range of motion (ROM) of the cervical and lumbar spine
Assessment in Ankylosing Spondylitis (ASAS) - The ASAS core set of domains (parameters) measures disease activity and includes patient global assessment of disease activity, patient assessment of back pain, BASFI, morning stiffness, synovitis and enthesitis score, ESR, CRP level, and fatigue

The ASAS response criteria are used to assess improvement in AS in clinical trials. Each of four domains is scored by the patient on a visual analog scale ranging from 0 to 10. The four domains are as follows:

Patient global assessment of disease activity for the past week
Patient assessment of back over the past week
Function (BASFI)
Inflammation (severity and duration of morning stiffness, average of items 5 and 6 in the BASDAI)

An ASAS20 response is defined as an improvement of at least 20% and an absolute improvement of at least 1 unit (on a 0-10 scale) in at least three of four domains, with no worsening of the remaining domain. An ASAS40 response is similar but requires a 40% improvement. An ASAS partial remission is defined as values of less than 2 for all four ASAS20 domains.

ASAS5/6 includes the four domains included in the ASAS20 plus spinal mobility (BASMI) and acute-phase reactants (CRP). An ASAS5/6 response is defined as improvement of at least 20% and an improvement of at least 1 unit in at least five of six domains, with no worsening of the remaining domain.

Surgical Correction and Stabilization

Surgical interventions for AS include the following:

Vertebral osteotomy
Fracture stabilization
Joint replacement

Vertebral osteotomy

Patients with fusion of the cervical or upper thoracic spine may have significant impairment in line of sight, eating, and psychosocial well-being. These patients may benefit from extension osteotomy of the cervical spine.^[13]This procedure is difficult and hazardous and should be performed only by surgeons specializing in spine surgery who have experience with the operation. The risk of major neurologic morbidity is significant; however, if the procedure is successful, it allows the patient to return to a more functional life.

Fracture stabilization

Many patients with advanced disease have fusion of the spine. If these patients report any change in position or movement of the spine, they should be assumed to have a spinal fracture because such an injury is the only way for a fused spine to move. Patients should be treated cautiously until fracture has been ruled out. If spinal fracture is present, surgical stabilization may be necessary.

Joint replacement

Patients with significant involvement of the hips may benefit from total hip arthroplasty^[14]; occasionally, total shoulder replacement may be indicated. These procedures may be very useful for reducing pain and improving function when the hip and shoulder joints become severely damaged. However, patients with AS at increased risk for complications after total hip arthroplasty, as the alteration in biomechanics resulting from spinal rigidity and kyphosis place higher demands on hip joints.^[144]

Heterotopic bone formation may occur after total joint replacement, especially around the hip. Heterotopic bone formation can be reduced by giving NSAIDs (eg, indomethacin) or employing radiation therapy postoperatively. In general, outcomes of total joint replacement in patients have been satisfactory.

Physical Therapy and Exercise

Physical therapy is important for maintaining function.^{[145, 146]}A proper exercise program is a crucial component of such therapy. Patients obtain a significant reduction in symptoms after exercising. Referral to physical therapy or to a rehabilitation specialist is useful in assisting patients to develop an appropriate exercise program.

Water therapy and swimming are excellent activities for maintaining mobility and fitness. In addition, a meta-analysis concluded that aquatic physical therapy can statistically significantly reduce pain and disease activity in patients with AS.^[147]

Postural training is also useful. Spinal extension and deep-breathing exercises help maintain spinal mobility, encourage erect posture, and promote chest expansion. Maintaining an erect posture during daily activities and sleeping on a firm mattress with a thin pillow also tend to reduce the tendency toward thoracic kyphosis.

Consultations

Consultations with the following specialists may be appropriate:

Rheumatologist - For evaluation and management of ongoing medical treatment of patients with AS; additional coexisting spondyloarthropathies can be assessed
Ophthalmologist - For patients with symptoms of acute anterior uveitis
Gastroenterologist - For patients with symptoms suggesting coexisting IBD
Cardiologist - For patients with cardiac involvement, including aortitis or heart block
Physical therapist or physical medicine and rehabilitation specialist - Indicated for all patients
Surgeon (orthopedic, neurologic, or both)
Support groups - Many patients benefit from various support groups, which can provide further education on the disease process and available treatment options

Medication

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Media Gallery

This 15-year-old female patient presented with recent onset of right-sided low back pain. Plain radiography findings were normal.
MRI of the same patient whose radiography findings were normal (previous image). She underwent further evaluation, including MRI. The MRI (short tau inversion recovery [STIR]) showed increased sinal intensity in the right sacroiliac joint, revealing sacroiliitis. Other laboratory study findings were essentially normal. The patient was started on indomethacin and rapidly improved.
Patient with ankylosing spondylitis affecting cervical and upper thoracic spine. The patient's spine has been fused in flexed position.
Posterior view of a patient with ankylosing spondylitis affecting cervical and upper thoracic spine. The patient's spine has been fused in a flexed position.
Anteroposterior radiograph of spine of a patient with AS. Ossification of annulus fibrosus can be observed at multiple levels, which has led to fusion of spine with abnormal curvature.
Anteroposterior radiograph of spine of a patient with AS.
Anteroposterior (left) and lateral (right) radiographs of a patient with AS.
Radiographs of hand (top) and arm (bottom) of a patient with peripheral involvement of AS. Fusion of joint spaces and deformity can be observed.
Sagittal MRI of thoracolumbar spine of a patient with AS. Syndesmophytes and anterior corner lesions can be seen.
Radiograph shows vertebral fracture in a patient with AS.
This radiograph of the lumbar spine of a patient with end-stage AS shows bridging syndesmophytes, resulting in bamboo spine.
This radiograph of the cervical spine of a patient with AS shows fusion of the vertebral bodies due to bridging syndesmophytes.
ASAS Classification Criteria for Axial Spondyloarthropathy.
ASAS Classification Criteria for Peripheral Spondyloarthropathy.
Family of spondyloarthropathies and HLA-B27 associated diseases
Bilateral symmetric sacroiliitis in a patient with AS showing blurring of the margins of the joints and pseudo-widening.
Bilateral symmetric sacroiliitis in a patient with AS with narrowing and sclerosis of the joints.
Bilateral sacroiliac joint fusion in a patient with AS.
Enthesitis at the site of the insertion of the annulus fibrosis on the corners of the vertebral bodies, shiny corner (Romanus) lesions.
CT scan of the pelvis in a patient with AS showing ankylosis of the sacroiliac joints.
CT scan of the L-spine in a patient with AS showing bony syndesmophytes.

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Table 1. Association of Spondyloarthropathies With HLA-B27

Population or Disease Entity	HLA-B27 –Positive
Healthy whites	8%
Healthy African Americans	4%
Ankylosing spondylitis (whites)	92%
Ankylosing spondylitis (African Americans)	50%
Reactive arthritis	60-80%
Psoriasis associated with spondylitis	60%
IBD associated with spondylitis	60%
Isolated acute anterior uveitis	50%
Undifferentiated spondyloarthropathy	20-25%

Table 2. Genetics of Ankylosing Spondylitis

Genes

Chromosome Location

Gene Product/Function

Definitely or probably associated

HLA-B27

HLA-B60

ERAP1 (ART1)

IL23R

IL-1 gene cluster

IL-1R2

STAT3

6p21.3

5q15

1p31.1

2q12.1

2q11-12

17q21

Antigen presentation

ER aminopeptidase 1

IL-23 receptor

Modulator of inflammation

Decoy receptor for IL-1

Signal transduction for IL-5, 6, 11

Probably associated

CYP 2D5

ANKH

TLR4

KIR (Killer Ig-like receptor)

MEFV

22q13.1

5p15

9q32

19q13.4

16p13.3

Metabolism about xenobiotics

Ectopic mineralization

Pattern recognition receptor forLPS

NK cell receptor

Pyrin, innate immunity

Not associated

TGF-ß, MMP3, IL-10, IL-6, Ig allotypes, TCR, TLR4, NOD2/CARD15, CD14, NFßBIL1, PTPN22, etc

Multiple

Table 3. Diagnostic Criteria for Undifferentiated Spondyloarthropathy Using Modified Amor Criteria

Inclusion Criteria		Exclusion Criteria
Inflammatory back pain	1 point	Diagnosis of specific spondyloarthropathy
Unilateral buttock pain	1 point	Sacroiliitis on radiograph = grade 2
Alternating buttock pain	2 points	Precipitating genitourinary/gastrointestinal infection
Enthesitis	2 points	Psoriasis
Peripheral arthritis	2 points	Keratoderma blennorrhagicum
Dactylitis (sausage digit)	2 points	Inflammatory bowel disease (Crohn disease or ulcerative colitis)
Acute anterior uveitis	2 points	Positive rheumatoid factor
HLA-B27 positive or family history of spondyloarthropathy	2 points	Positive antinuclear antibody, titer > 1:80
Good response to nonsteroidal anti-inflammatory drugs	2 points
Diagnosis of spondyloarthropathy with 6 or more points

Table 4. Clinical and Laboratory Features of Undifferentiated Spondyloarthropathy

Clinical or Laboratory Feature	Frequency
Inflammatory back pain	90%
Buttock pain	80%
Enthesitis	75%
Peripheral arthritis	40%
Dactylitis (sausage digits)	20%
Acute anterior uveitis	1-2%
Fatigue	55%
Elevated ESR	32%
HLA-B27 positive	25%
ESR = erythrocyte sedimentation rate.

Table 5. ESSG and Amor Criteria for Diagnosis of Spondyloarthropathy

ESSG Criteria	Amor Criteria*
Inflammatory spinal pain or synovitis and one of the following:	Inflammatory back pain	1 point
Alternating buttock pain	Unilateral buttock pain	1 point
Enthesitis	Alternating buttock pain	2 points
Sacroiliitis	Enthesitis	2 points
IBD	Peripheral arthritis	2 points
Positive family history of spondyloarthropathy	Dactylitis (sausage digit)	2 points
	Acute anterior uveitis	2 points
	HLA-B27 positive or family history of spondyloarthropathy	2 points
	Good response to NSAIDs	2 points
*Diagnosis of spondyloarthropathy with 6 or more points. European Spondyloarthropathy Study Group (ESSG); IBD = inflammatory bowel disease; NSAID = nonsteroidal anti-inflammatory drug.

Table 6. New York and Rome Criteria for Diagnosis of Ankylosing Spondylitis

New York Criteria	Rome Criteria
Low back pain with inflammatory characteristics Limitation of lumbar spine motion in sagittal and frontal planes Decreased chest expansion Bilateral sacroiliitis grade 2 or higher Unilateral sacroiliitis grade 3 or higher	Low back pain and stiffness for >3 months that is not relieved by rest Pain and stiffness in the thoracic region Limited motion in the lumbar spine Limited chest expansion History of uveitis
Definite ankylosing spondylitis when the fourth or fifth criterion mentioned presents with any clinical criteria	Diagnosis of ankylosing spondylitis when any clinical criteria present with bilateral sacroiliitis grade 2 or higher

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Author

Lawrence H Brent, MD Associate Professor of Medicine, Sidney Kimmel Medical College of Thomas Jefferson University; Chair, Program Director, Department of Medicine, Division of Rheumatology, Albert Einstein Medical Center

Lawrence H Brent, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Immunologists, American College of Physicians, American College of Rheumatology

Disclosure: Stock ownership for: Johnson & Johnson.

Coauthor(s)

Anand Patel, MD Fellow, Department of Rheumatology, Temple University Hospital

Anand Patel, MD is a member of the following medical societies: American College of Rheumatology, Pennsylvania Rheumatology Society, Philadelphia Rheumatism Society

Disclosure: Nothing to disclose.

Ruchika Patel, MD Attending Physician, Division of Rheumatology, Einstein Medical Center

Ruchika Patel, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Philadelphia Rheumatism Society

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

Rajni Kalagate, MD Resident Physician, Department of Internal Medicine, Albert Einstein Medical Center

Rajni Kalagate, MD is a member of the following medical societies: American Academy of Pediatrics, Indian Medical Association

Disclosure: Nothing to disclose.

Acknowledgements

Jason C Eck, DO, MS Assistant Professor, Department of Orthopedics and Physical Rehabilitation, UMass Memorial Medical Center

Jason C Eck, DO, MS is a member of the following medical societies: American Osteopathic Academy of Orthopedics, American Osteopathic Association, International Society for the Study of the Lumbar Spine, and North American Spine Society

Disclosure: Medtronic Honoraria Speaking and teaching

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Scott D Hodges, DO Consulting Surgeon, Department of Orthopedic Surgery, Center for Sports Medicine and Orthopedics

Scott D Hodges, DO is a member of the following medical societies: American Academy of Disability Evaluating Physicians, American Medical Association, American Osteopathic Association, American Spinal Injury Association, North American Spine Society, Southern Medical Association, Southern Orthopaedic Association, and Tennessee Medical Association

Disclosure: Medtronic Royalty Consulting; Biomet Spine Royalty Consulting

S Craig Humphreys, MD Orthopedic Spine Surgeon, Department of Orthopedic Surgery, Center for Sports Medicine and Orthopedics

S Craig Humphreys, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Orthopaedic Surgeons, American Medical Association, American Spinal Injury Association, North American Spine Society, Southern Medical Association, Southern Orthopaedic Association, and Tennessee Medical Association

Disclosure: Nothing to disclose.

James F Kellam, MD Vice-Chair, Department of Orthopedic Surgery, Director of Orthopedic Trauma and Education, Carolinas Medical Center

James F Kellam, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, Orthopaedic Trauma Association, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Kristine M Lohr, MD, MS Professor, Department of Internal Medicine, Center for the Advancement of Women's Health and Division of Rheumatology, Director, Rheumatology Training Program, University of Kentucky College of Medicine

Kristine M Lohr, MD, MS is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

William O Shaffer, MD Professor, Vice-Chairman and Residency Program Director, Department of Orthopedic Surgery, University of Kentucky at Lexington

William O Shaffer, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Orthopaedic Association, International Society for the Study of the Lumbar Spine, Kentucky Medical Association, Kentucky Orthopaedic Society, North American Spine Society, Southern Medical Association, and Southern Orthopaedic Association

Disclosure: DePuySpine 1997-2007 (not presently) Royalty Consulting; DePuySpine 2002-2007 (closed) Grant/research funds SacroPelvic Instrumentation Biomechanical Study; DePuyBiologics 2005-2008 (closed) Grant/research funds Healos study just closed; DePuySpine 2009 Consulting fee Design of Offset Modification of Expedium

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Sections Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy
Overview
Presentation
DDx
Workup
Treatment
Medication
Questions & Answers
Media Gallery
Tables
References

Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy Treatment & Management

Approach Considerations

Peripheral spondyloarthritis

Nonradiographic axial spondyloarthritis

Pharmacologic Therapy

Nonsteroidal anti-inflammatory drugs

Sulfasalazine

Tumor necrosis factor–alpha inhibitors

Interleukin-17A inhibitors

Corticosteroids

Janus kinase inhibitors

Other agents

Guideline-directed Therapy

Treatment of Uveitis

Evaluation of Disease Activity and Treatment Response

Surgical Correction and Stabilization

Vertebral osteotomy

Fracture stabilization

Joint replacement

Physical Therapy and Exercise

Consultations

References

Tables

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