Conventional (Nonbiologic) Therapy

Introduction

Evidence-based guidelines published by Assessment of Spondyloarthritis International Society (ASAS) and European League Against Rheumatism (EULAR) and the treatment recommendations developed as a joint effort by the American College of Rheumatology, the Spondylitis Association of America and SPARTAN have been discussed in the preceding sections. These recommendations, although quite similar to the ones published by ASAS/EULAR, are designed to reflect the clinical practice of rheumatology in North America. An important difference is that the North American recommendations provide no threshold values for the ankylosing spondylitis (AS) patient’s Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) or Ankylosing Spondylitis Disease Activity Score (ASDAS) scores to initiate anti-tumor necrosis factor (TNF) therapy.

The 3E (Evidence, Experts, Exchange) Initiative in Rheumatology, a multinational effort of rheumatologists with a special interest in clinical research, has published evidence-based statements (recommendations) without restricting the autonomy of treating physicians. The primary goal of AS treatment is to maximize long-term health-related quality of life through three objectives:

• Controlling symptoms and inflammation
• Preventing progressive structural damage
• Preserving or normalizing function and social participation.

The best treatment strategy incorporates:

• Individualized treatment based on the current disease manifestations, the level of current symptoms, clinical findings, disease activity and severity, functional status, deformities, general health status, comorbid conditions, prognostic indicators and the patient’s wishes and expectations.
• Patient and family education
• Lifestyle and workplace modifications
• Physical therapy
• Lifelong program of regular physical exercise
• Use of medications
• Monitoring of disease activity and adverse effects of drug therapies and when appropriate, referral to appropriate specialists.

Optimal management mandates a combination of nonpharmacologic and pharmacologic treatment, which should be clearly explained to the patients and they should be given relevant printed and/or online information to gain knowledge about their illness which will enhance their compliance with the recommended treatment. For best outcome, early referral of the patient to a rheumatologist is also needed.

Nonpharmacologic Management

Patient Education

Patient education and a lifelong appropriate regular exercise program are the cornerstones of nonpharmacologic treatment. Health education for self-management in patients with chronic arthritis produces sustained health benefits and reduces healthcare costs. Patients should be educated about the nature of their illness and their prognosis and should be encouraged to assume a central role in managing their illness. Self-help programs in patients with arthritis facilitate adherence to drug and physical exercise regimens and decrease pain.

The patient and their family members need to be educated about possible lifestyle and workplace modifications, a lifelong program of regular physical exercise, with consideration of individual and group physical therapy and interaction with patient associations and self-help groups. Smoking cessation should be urged because smokers have more severe illness and an increased incidence of respiratory complications, in addition to the numerous other adverse effects of smoking.

Patients should be advised to sleep on a firm mattress without a pillow, if possible, or with a thin pillow or a pillow that is suitably contoured to maintain neck extension and prevent spinal deformities from developing. They should be encouraged to walk erectly, keeping the spine as straight as possible while maintaining normal, reciprocal arm swing and rotational movements of the lower spine and pelvis during walking. Stooped postures such as slouching in chairs or leaning over a desk for prolonged periods should be avoided; adjustable swivel chairs with lumbar support and elevated and inclined writing surfaces may be helpful. Patients should maintain hip extension, e.g., by lying prone for a 15-minute period daily. Crossing roadways should be done with caution due to impaired neck mobility. Workplace needs should be evaluated, and appropriate modifications should be made. Changing position frequently and taking breaks for body stretching will improve endurance. Other aspects of patient education are discussed later in this section.

Exercise and Physical Therapy

Regular exercise and formal sessions of physical therapy are generally underutilized by patients and physicians, although they are an essential part of the patient management plan despite the dramatic clinical efficacy of biologic therapies. Patient should be referred to a physical therapist for specific instructions for spinal extension, deep breathing and range of motion exercises of the back, neck, hips and shoulders and other joints. Home-based regular exercise programs can be easily performed and are convenient and cost-free. Formal supervised physical therapy and, in most severe cases, inpatient rehabilitation may be needed. A yearly follow-up with a physical therapist can ensure that the physical exercises are being performed accurately; this can also help track any worsening of physical posture and mobility. A meta-analysis of 11 clinical trials has shown that exercise regimens should be individualized, a home exercise program is better than no program at all, supervised group physical therapy is better than home exercise and combined inpatient therapy followed by supervised weekly group physical therapy is the most effective program.

High-impact and contact sports activities and those that involve abrupt movement of the spine should be avoided, especially by patients who have axial disease with limited spinal mobility. Back stretching and deep breathing exercises, swimming and water aerobics, stationary bicycling and other appropriate recreational exercises are especially useful. They can help enhance general fitness, lung capacity, exercise capability, muscle strength and range of motion. They also increase cardiovascular (CV) conditioning and endurance. Patients with heart disease should be assessed by their physician and may require an exercise tolerance test before starting to exercise.

Patients usually feel that their back is too stiff to exercise in the morning, so they can choose a time of the day that works best for them. A warm shower before exercising tends to ease discomfort during exercise, promotes relaxation and helps in passive stretching of tight muscles. Therapeutic exercises must be tailored to the patient’s degree of spinal mobility or involvement and they should ideally be performed routinely.

A heated swimming pool or a spa helps to decrease pain and stiffness and therefore allows the patient to perform exercises that might be otherwise impossible because of pain and stiffness. Regular freestyle swimming is considered to be one of the best exercises for AS patients. The patient must be careful not to slip on wet surfaces in the pool area and also it is wise to avoid diving. It may be difficult for patients with rigid necks to swim freestyle, although the use of a snorkel may be helpful, provided the patient swims only under observation and near the edge of the swimming pool if it is deep. This precaution is necessary because patients with limited breathing capacity may not be able to blow out the water if it inadvertently enters the snorkel tube. In some European countries, professionally supervised special physiotherapy and hydrotherapy group sessions for AS patients have been organized by AS patient societies and group exercise sessions at a spa or hydrotherapy center are enjoyable and very helpful. Patients with psoriasis should avoid chlorinated water.

Figure 14-1 illustrates the physical limitations of an AS patient resulting from stiffening (ankylosis) of spine compared with the flexibility of a normal subject. The recommended physical exercises to help preserve good posture and retain good spinal mobility and chest expansion can be seen on web sites such as www.spondyloarthritis-international.org and exercise DVDs are sold on some other web sites such as www.spondylitis.org and www.bechterew.ch.

Enlarge  www.bechterew.ch . Source: Adapted from images from Dr. Heinz Baumberger." class="figure-img img-fluid">

Pharmacologic Therapy

NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for patients with symptomatic ankylosing spondylitis/axial spondyloarthritis (AS/axSpA), who seem to respond best if treated early in the course of disease. According to both the 2022 ASAS/EULAR and the 2019 ACR/SPARTAN management recommendations, NSAIDs should be considered first-line treatment for pain and stiffness in patients with active AS. These recommendations are based on the demonstrated efficacy of NSAIDs in multiple clinical trials of patients with AS. NSAIDs are effective for axial, peripheral and entheseal features of AS, although axial symptoms are most responsive. A majority of AS/axSpA patients show a very good (50% improvement or better) response to NSAIDs. Approximately 50% to 80% of patients benefit from treatment with NSAIDs according to a German cross-sectional study of 1,080 patients with AS; 20% showed complete response, 35% showed 50% response and 25% had 25% response. The desirable consequences far outweighed undesirable effects for the large majority of patients, but some patients are intolerant of or have contraindications to treatment with NSAIDs.

There is no significant difference between continuous NSAID treatment vs on-demand treatment. The decision to use NSAIDs continuously may vary depending on the severity and intermittency of symptoms, comorbidities and patient preferences. The dose may also be changed depending on symptom level.

Choice of NSAID should be based on consideration of the patient’s history of NSAID use, risk factors for adverse effects and comorbidities. Both traditional as well as selective cyclooxygenase-2 (COX-2) inhibitors have been shown to decrease axial and peripheral joint pain and improve function. The various NSAIDs are of comparable efficacy and there is no significant difference in efficacy between short-acting and long-acting agents or between COX-2 selective and nonselective agents. However, one study showed superiority of etoricoxib (not approved by the Food and Drug Administration (FDA) in United States) over naproxen. NSAIDs that are prescribed as a once- or twice-daily dose show enhanced patient compliance.

The effect of NSAIDs on radiographic progression of AS is a little controversial because continuous treatment with diclofenac over 2 years did not reduce X-ray progression compared to on-demand treatment. Correction for smoking status did not alter the results. But an earlier study of continuous treatment with celecoxib slowed radiographic progression of AS at 2 years when compared to on-demand (as needed) celecoxib. In another study, slowing down of X-ray progression was observed in those with baseline syndesmophyte and time-averaged elevated C-reactive protein (CRP) when treated with high-dose NSAID intake and not among those who were given low-dose treatment.

More than 20 types of NSAIDs are available. Some of the NSAIDs available in the United States include indomethacin (Indocin), naproxen (Naprosyn), diclofenac (Voltaren), ketoprofen (Orudis), tolmetin (Tolectin), oxaprozin (Daypro), piroxicam (Feldene), nabumetone (Relafen) and sulindac (Clinoril). Brand names may vary in different parts of the world. There are individual variations in response to different NSAIDs. Therefore, some patients may need to try more than one NSAID to find the most effective one before giving up on them for disease management. An adequate trial of NSAIDs, according to the recommendations, is a lack of response or intolerance to at least two different NSAIDs over 1 month or incomplete responses to at least two different NSAIDs over 2 months.

When selecting an NSAID in patients with AS, the patient’s individual Gastrointestinal (GI), cardiovascular (CV), hepatic and renal risks should be taken into consideration. There are some variations in their side effect profiles and drug interactions. For patients with a higher risk for GI tract complications, a selective COX-2 inhibitor could be used. Another way to reduce the risk for GI complications is to avoid smoking and alcohol intake and to use a GI-protective agent such as misoprostol or a proton pump inhibitor. There is limited evidence that NSAID use in AS precipitates first presentations of IBD or flares of preexisting disease. Inflammatory bowel disease (IBD) patients treated with NSAIDs should be monitored closely by both the prescribing doctor and a gastroenterologist. Diclofenac is the most commonly prescribed NSAID around the world, but it has higher pooled relative risk of CV events than naproxen. The CV toxicity seen with rofecoxib (Vioxx), which was taken off the market, has also been described in clinical trials of other selective COX-2 inhibitors, with some evidence suggesting that it may be an NSAID class effect. However, a meta-analysis did not reveal an increased risk of CV events with celecoxib.

DMARDs

Unlike in rheumatoid arthritis (RA), NSAIDs play a major role in the management of AS and there is no evidence to support efficacy of the conventional disease-modifying antirheumatic drugs (DMARDs), also called slow-acting antirheumatic drugs, for the treatment of axial manifestations of AS. The only DMARD to show limited efficacy is sulfasalazine (SSZ), but that may be useful only in treating patients with predominantly peripheral arthritis. In a randomized controlled trial of 423 patients with AS, psoriatic arthritis (PsA) and reactive arthritis demonstrated a very modest effect on peripheral arthritis on top of a placebo response of just over 40%.

In a randomized, double-blind trial in 566 patients, the tumor necrosis factor inhibitor (TNFi) etanercept was significantly more effective than SSZ for reducing the signs and symptoms of AS in both axial and peripheral sites. Methotrexate (MTX) has also failed to demonstrate significant benefit in AS in small controlled trials, and this lack of efficacy was confirmed in a 2013 Cochrane meta-analysis. An open-label study also showed no significant benefit with subcutaneous high-dose methotrexate in patients with active AS. It is unfortunate that despite the evidence, there is widespread use of SSZ and MTX for AS/axSpA, especially in Asia, Eastern Europe and Latin America. There is not sufficient evidence to support the mandatory use of DMARDs before or concomitant with anti-TNFi treatment in patients with active axial disease.

Leflunomide is also not effective in AS, and there are insufficient data to support the use of bisphosphonates in the treatment of active AS. However, bisphosphonates may be useful for the management of osteoporosis in AS. Thalidomide has a TNF inhibitory effect by decreasing the half-life of TNF-α messenger RNA and a 1-year open-label study of 30 Chinese AS patients who had failed conventional therapy and were treated with thalidomide showed moderate response but side effects were limiting factors. Apremilast inhibits phosphodiesterase-4 and increases cyclic adenosine monophosphate levels, which in turn, has anti-inflammatory effects and is currently approved by the FDA for active PsA and psoriasis, is the first oral small molecule to be evaluated in the treatment of AS. In a preliminary randomized, controlled trial of 36 patients, apremilast was associated with symptomatic improvement, although the primary endpoint of BASDAI response was not met.

Corticosteroids

Corticosteroid injections directed to the local site of musculoskeletal inflammation, such as some peripheral joints and entheses may be considered according to the ASAS/EULAR management recommendations. Topical glucocorticoids are very effective for the treatment of acute anterior uveitis. Local corticosteroid injection into the sacroiliac joints has demonstrated substantial efficacy in an open-label study, with >80% of patients attaining good or very good results. In a subsequent double-blind, placebo-controlled study involving 10 patients with spondyloarthritis (SpA) with 13 articulations associated with painful sacroiliitis, sacroiliac injections with corticosteroids (prednisone equivalent = 62.5 mg) was associated with relief in five of six injected sacroiliac joints (SIJs), but in none of seven joints injected with placebo (P <0.05).

Subsequent corticosteroid injections in six of seven joints in the placebo group and in two in the treatment group with failure and relapse yielded good results in 12 of 14 joints (86%) at 1 month. Results were still significant at 3 months in 62% of patients and at 6 months in 58% of patients. No notable complications were reported. But any use of systemic corticosteroids for axial disease is not supported by the available evidence and is not recommended. A placebo-controlled study showed that 50 mg oral prednisolone give for 2 weeks showed short-term response of patients with active AS despite treatment with NSAIDs. However, given its common and prominent untoward effects, such therapy will rarely be needed since the availability of biologic therapy.

Analgesics and Other Possible Medications

ASAS/EULAR recommendations suggest that analgesics such as acetaminophen (paracetamol) or tramadol may be considered for patients with residual pain (despite other recommended therapies) as an adjunctive short-term treatment until the inflammation is controlled, and it may require short-term use of opioid-like drugs. Extreme caution should be exercised when prescribing narcotics to avoid dependence and abuse. Low-dose tricyclics such as nortriptyline or amitriptyline may be a helpful adjunctive treatment to relieve pain and fatigue, especially in patients with sleep disturbances, but it may cause some untoward effects, such as drowsiness and dryness of the mouth.

Any comorbidities and associated diseases, such as psoriasis, chronic IBD and obstructive sleep apnea, need adequate management. Osteopenia and osteoporosis can occur relatively early in disease, and its prevention and treatment may help decrease the risk of compression fracture and worsening kyphosis. Vitamin D deficiency should be screened for and corrected if present. There is no role of special diet, and studies exploring a possible role of gut microbiome in AS/axSpA are not advanced enough to suggest any use of probiotics or other means to influence the microbiome in order to achieve a therapeutic benefit.

Biologic Therapy

After physical therapy and NSAIDs have failed to give sufficient relief to patients, there is a need to add treatment with biologics, as detailed in TNF Inhibitor Therapy and Biologics Targeting Interleukin-17.

Miscellaneous Management Issues

Patient Concerns and Questions

This subsequent section is primarily excerpted from the author’s previous two books on AS. It is not unusual for more than one person in a family to be affected with AS or related diseases, so the physician should ask in detail about the family history. The impact of the disease on the family should be discussed with patients and possibly family members. The patient may want to know the odds that his or her children will develop AS. Roughly 50% of the children of any HLA-B27–positive individual will inherit HLA-B27 from that parent. HLA-B27-positive children of such a patient will have an up to one in five chance of developing AS or related SpA during their lifetime. The other half of children who lack the gene carry virtually no increased risk unless other diseases that also predispose to AS (such as psoriasis or IBD) are present in the family. Thus, on average most (80%) of the HLA-B27–positive children in such families with a B27-positive parent suffering from AS are likely to remain unaffected.

Therefore, children in such families do not need to be tested for HLA-B27. Even among the 50% of children who are expected to inherit the B27 gene, most will remain unaffected during their lifetime and at present we do not know how to prevent AS. Parents and healthcare providers may unnecessarily get “HLA-B27-itis” every time the HLA-B27–positive child gets injuries and sprains. Knowing that the child has HLA-B27, the parents and healthcare providers might worry unnecessarily and symptoms unrelated to AS may be wrongly attributed to the fact that the child has inherited HLA-B27. The child may get an incorrect diagnostic label of AS, even though he or she is an unaffected individual who happens to have a normal gene called HLA-B27. Even a child who remains totally healthy may suffer indirectly in the future if the information about the HLA-B27 test result is on the medical chart and becomes available to health insurance companies or potential employers, who may misuse such information.

What if a child of a B27-positive affected parent develops symptoms (back pain and stiffness that is worsened with rest) that the parent suspects are due to early AS? The parent should raise this possibility with the child’s physician, and preferably be seen by a (pediatric) rheumatologist. The physician can conduct further investigation based on the results of clinical investigation and imaging studies and, when appropriate, may use HLA-B27 typing as an aid to early diagnosis. If the parent with primary AS does not have HLA-B27 (a 10% to 15% chance if he or she is white, and up to 50% chance if African American), then the risk of AS among the children is virtually nonexistent, unless any of the other diseases that also predispose to AS (as mentioned above) are present in the family.

Driving of Automobile

Many AS patients with a painful and stiff spine have difficulty driving a long distance and find it useful to stop after an hour or two to get out of the car, stretch the back and walk around for a few minutes. Patients must always wear seat belts and use proper head, neck and back support. It is better to avoid bucket seats. Patients should use headrests (head restraints) so that sudden slowing or stopping does not jerk the spine, including the neck; the stiff neck of an AS patient is more vulnerable to injury than a normal neck. The top of the headrest should be level with the top of the driver’s head and as close to the back of the head as possible.

Decreased range of motion of the cervical spine makes driving a real challenge. The use of side-angled mirrors increases the driver’s peripheral vision, making driving easier and safer. Patients may find it difficult to back the car into the garage and other tight parking spaces because they cannot turn their neck to look behind them. Special mirrors fitted onto the car can help; the patient should take a few practice sessions backing up the car in an open area to become comfortable using these mirrors. Disabled driver parking permits may be appropriate for patients who cannot walk very far, but this usually not a problem for most patients with early stages of AS and no involvement of hip joints.

Restrictions/Disability-Related Issues

Problems in performing activities of daily living should be identified and solutions should be sought to compensate for loss of motion and to improve functional capacity. Common functional difficulties include dressing, body transfers, lifting and carrying and endurance. Patients should be advised to make helpful home and workplace modifications. They should avoid prolonged immobility at home or at work and should change position frequently and take breaks for body stretching.

Postural changes that occur because the center of mass of the trunk is displaced can affect balance and pose safety concerns. It is important to take steps to prevent falls, such as avoiding loose carpets and installing night lights. Bathrooms should have non-slippery floors and should be equipped with features such as railings, grab bars and safety mats.

Patients with advanced disease may need assistive devices. These devices include walking aids if the patient has lower extremity joint problems, adjustable swivel chairs with lumbar support, elevated and inclined writing surfaces and long-handled devices for dressing and for reaching or picking up objects. Back splints, braces and corsets are not helpful and should be avoided.

Referrals/Consultations

In cases of acute anterior uveitis (AAU), ophthalmologic evaluation is urgently needed. For other extraskeletal complications, referral to a cardiologist, pulmonologist, or other specialist may be needed. Orthopedic consultation may be needed for total hip replacement in patients with advanced hip involvement who have severe pain or functional disability. Some patients have inadequate sleep due to worsened back pain and stiffness at night, and obstructive sleep apnea. Depression is not uncommon in patients with any chronic painful illness that impairs quality of life, and this includes AS. Depression is a treatable disease that has many underlying causes, and some individuals are genetically prone to depression.

Role of Surgery

Total hip replacement is indicated in patients with advanced hip involvement who have severe pain or functional disability. There is no significant increase in the incidence of heterotopic bone formation or ankylosis following this surgery, although some surgeons may use NSAIDs for 7 to 10 days, starting from the day of surgery. Similarly, the involvement of other joints, especially the knee, may require joint replacement in advanced cases. Other elective surgeries that might be indicated include corrective spinal wedge osteotomy to correct severe kyphosis and uncompensated loss of horizontal vision, and spinal fusion procedures for instability, including atlantoaxial subluxation, pseudarthrosis and fracture. Spinal pseudarthrosis should be differentiated from indolent infections.

Lumbar spinal anesthesia by lumbar puncture may not be possible due to spinal fusion and ligament ossification, although epidural block may be possible. General anesthesia can be a challenge for both the anesthesiologist and the surgeon. The anesthesiologist may have difficulty passing a breathing tube down the trachea so that the airway can be maintained during general anesthesia. This is a potential problem in patients with a rigid spine, especially if the patient also has forward stooping of the neck and a reduced jaw-opening capacity. Some patients with extreme neck deformity may require a tracheostomy.

The patient should discuss these issues with the surgeon and should have a preoperative consultation with the anesthesiologist. The patient should not assume that all health care providers are fully aware of the limitations due to AS. The anesthesiologist should examine the patient before surgery to identify any limitations and to allay any patient concerns. This should be done in the patient’s hospital room before he or she is taken to the operating room, and before any anesthetic premedications are given that reduce the patient’s alertness.

Patients with AS are also more like to have postsurgical lung complications due to their severely restricted chest wall movement and possible intubation difficulties resulting from cervical spinal ankylosis and flexion deformity, as well as severely restricted mouth opening due to temporomandibular joint involvement or presences of atlantoaxial subluxation. Heart complications may require aortic valve replacement or placement of a cardiac pacemaker. Scarring (fibrosis) and cavity (cyst) formation in the upper part (apex) of the lung is not easy to manage, and surgical resection may (rarely) be required.

Any new-onset neck or back pain in a patient with AS should be evaluated carefully for a spinal fracture or instability, even in the absence of obvious physical trauma or after a seemingly trivial injury, because paraplegia or quadriplegia may result. The back or neck should be immobilized in its usual alignment as a precaution pending musculoskeletal imaging if fracture is suspected; excessive straightening into a “normal” position can make a stable fracture unstable and may result in paralysis or death. The radiographic findings may be normal, and MRI, CT, or bone scan results may be more helpful in confirming or excluding spinal fracture.

Medical Alert Card

It is useful for patients with AS to carry a “Medical Alert” card that contains concise information about them—a proposed version of such a card is shown in Figure 14-2. The card should identify the degree of forward bending of the neck and the appropriate precautions that need to be taken in case of an emergency.

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