Why does a particular SpA patient not respond to a TNF antagonist?

A variety of factors are associated with a failure of treatment response to TNF antagonists in patients with SpA ( Table 1 ). It is imperative to determine the reason for the poor response given that treatment options outside the realm of TNF blockage are extremely limited. Optimally, one should focus on improving the response to a TNF antagonist by changing to a different drug in the class, adding another agent that may synergise with a TNF antagonist or breaking down treatment barriers (poor compliance, lack of insurance coverage or anxiety regarding potential side effects). A lack of response may be primary or secondary. Patients with no response to TNF antagonists are unusual and the more common scenario is a patient, who loses a response over time. For primary non-responders, consider an alternative diagnosis or barriers to treatment outlined above. Secondary non-response may arise from development of tolerance to the drug or onset of new manifestations that are thought to represent a disease flare.

Discontinuation of anti-TNF agents is frequently related to an adverse event and the different possibilities are listed in Table 2 . Infection is the most common side effect and, if not life-threatening, anti-TNF agents can be resumed once the infection has resolved. Other steps that can be taken for recurrent infections include addressing an anatomic cause for recurrent infections in the sinuses, lung or urinary tract, addition of a chronic suppressive antibiotic, lowering the dose of the anti-TNF agent or discontinuation of any other potentially immune-suppressive agents such as MTX or corticosteroids. Alternatively, another TNF antagonist may be associated with less immunosuppression. For example, patients who develop an infection on high-dose infliximab may tolerate etanercept, or recurrent urinary tract or skin infections in a patient on etanercept may resolve following a switch to a TNF antibody administered subcutaneously.

Cost is an important barrier to long-term use in many patients. In the US, cessation of a TNF antagonist may take place when insurance changes, or when a patient loses a job or switches to a Medicare policy on reaching 65 years of age that does not provide coverage for these medications. In Europe, these drugs are funded through government agencies that vary widely in providing patients with access to these medications and in eligibility requirements. The onset of uveitis or colitis in a SpA patient on a TNF antagonist may prompt a change in therapy. Some patients elect to stop TNF antagonists due to fear of side effects based on conversations with friends and colleagues or on information passed along on the Internet. Finally, some patients maintain extremely high expectations about treatment response. For example, failure to clear all psoriasis lesions despite a robust musculoskeletal response is not acceptable to some patients and results in the desire to switch to alternative therapies.

Interventions to consider when a patient with SpA fails a TNF antagonist

Once the reason for the failure of TNF antagonist therapy is ascertained, a series of interventions are available to the clinician ( Table 2 ). For patients who are extremely worried about potential side effects, a review of registry data combined with realistic reassurances can help place safety concerns in perspective. It is also important to frame risk-benefit issues in the context of a particular patient so they can better understand how treatment may affect them from a personal perspective. If unsure about the magnitude of treatment response, they can ask the patient to keep a diary that they can bring to the appointment for review. Pursue other reasons for non-compliance such as fear of needles, burning sensations during injection, inconvenience of injections or cutaneous reactions.

Loss of employment or change in insurance can lead to discontinuation of a TNF antagonist, particularly during times of economic downturns. In these cases, the physician can advocate for patients by contacting foundations that provide patient support, insurance companies or government agencies. In some cases, emphasis on specific outcome measures that have responded to the TNF antagonist (function, quality of life and participation), while underscoring the lack of alternative treatments, can help obtain approval or financial support .

A wide range of therapies, aside from DMARDs and biologic agents, are available for SpA patients. Consider different therapeutic modalities such as physical therapy or home exercise programmes, which can lessen pain and improve function . The injection of corticosteroids into the sacroiliac region can significantly reduce pain for months, and a recent study with ultrasound guidance showed that the analgesic response was the same whether or not the steroid reached the joint or adjacent soft tissues . In a multivariate analysis performed on AS subjects, helplessness and depression contributed to one-third of the variance in Bath Ankylosing Spondilytis Disease Activity Index (BASDAI), and it is well recognised that depressive symptoms can greatly amplify pain . Programmes and/or medications that can lessen stress, depression and anxiety may be effective for SpA patients. In addition, fatigue is a common complaint; hence, it is important to address the causes of disturbed sleep (sleep apnoea, primary sleep disorder, depression or nocturnal pain) .

A variety of systemic therapies have shown proven benefit in SpA patients. The NSAIDs can be extremely effective for control of pain and inflammation as monotherapy or in conjunction with TNF antagonists or DMARDS; the use of these agents in AS was recently reviewed . When possible, a switch to another TNF antagonist is preferred due to the high efficacy of these agents for patients with AS or PsA. In PsA, MTX and leflunomide have proven efficacy for peripheral arthritis but not for axial disease. Other biologics with efficacy in PsA include ustekinumab and abatacept. Oral corticosteroids can be used as a bridging agent for patients with peripheral arthritis, but long-term daily use for axial disease is not effective and is associated with serious side effects based on uncontrolled data . An uncontrolled study of pulse corticosteroids administered intravenously 1 g daily for 3 days to eight AS patients demonstrated a relatively rapid decline in acute phase reactants, but clinical responses lasted only about 8 weeks . In another study, 17 subjects with NSAID-refractory AS were randomised to receive 3 consecutive days of low-dose (375 mg) or high-dose (1000 mg) intravenous corticosteroids . The clinical outcome measures were not significantly different between the two groups, although the high-dose group reached pre-treatment pain levels at 347 days compared with 253 days in the low-dose group. It should be noted that additional therapies (analgesics and/or NSAIDs) were required within 8–28 days of the pulse therapy. Based on the lack of a placebo arm and the limited data available from these small pilot studies, the use of chronic oral or intravenous pulse steroids cannot be recommended at this time. In patients with psoriasis, corticosteroids have been associated with development of erythroderma and pustular psoriasis and long-term use is often complicated by metabolic, bone and cardiovascular side effects. For patients who do not respond to the interventions outlined above, the possibility of participation in a clinical trial can also be discussed.

Interventions to consider when a patient with SpA fails a TNF antagonist

Once the reason for the failure of TNF antagonist therapy is ascertained, a series of interventions are available to the clinician ( Table 2 ). For patients who are extremely worried about potential side effects, a review of registry data combined with realistic reassurances can help place safety concerns in perspective. It is also important to frame risk-benefit issues in the context of a particular patient so they can better understand how treatment may affect them from a personal perspective. If unsure about the magnitude of treatment response, they can ask the patient to keep a diary that they can bring to the appointment for review. Pursue other reasons for non-compliance such as fear of needles, burning sensations during injection, inconvenience of injections or cutaneous reactions.

Loss of employment or change in insurance can lead to discontinuation of a TNF antagonist, particularly during times of economic downturns. In these cases, the physician can advocate for patients by contacting foundations that provide patient support, insurance companies or government agencies. In some cases, emphasis on specific outcome measures that have responded to the TNF antagonist (function, quality of life and participation), while underscoring the lack of alternative treatments, can help obtain approval or financial support .

A wide range of therapies, aside from DMARDs and biologic agents, are available for SpA patients. Consider different therapeutic modalities such as physical therapy or home exercise programmes, which can lessen pain and improve function . The injection of corticosteroids into the sacroiliac region can significantly reduce pain for months, and a recent study with ultrasound guidance showed that the analgesic response was the same whether or not the steroid reached the joint or adjacent soft tissues . In a multivariate analysis performed on AS subjects, helplessness and depression contributed to one-third of the variance in Bath Ankylosing Spondilytis Disease Activity Index (BASDAI), and it is well recognised that depressive symptoms can greatly amplify pain . Programmes and/or medications that can lessen stress, depression and anxiety may be effective for SpA patients. In addition, fatigue is a common complaint; hence, it is important to address the causes of disturbed sleep (sleep apnoea, primary sleep disorder, depression or nocturnal pain) .

A variety of systemic therapies have shown proven benefit in SpA patients. The NSAIDs can be extremely effective for control of pain and inflammation as monotherapy or in conjunction with TNF antagonists or DMARDS; the use of these agents in AS was recently reviewed . When possible, a switch to another TNF antagonist is preferred due to the high efficacy of these agents for patients with AS or PsA. In PsA, MTX and leflunomide have proven efficacy for peripheral arthritis but not for axial disease. Other biologics with efficacy in PsA include ustekinumab and abatacept. Oral corticosteroids can be used as a bridging agent for patients with peripheral arthritis, but long-term daily use for axial disease is not effective and is associated with serious side effects based on uncontrolled data . An uncontrolled study of pulse corticosteroids administered intravenously 1 g daily for 3 days to eight AS patients demonstrated a relatively rapid decline in acute phase reactants, but clinical responses lasted only about 8 weeks . In another study, 17 subjects with NSAID-refractory AS were randomised to receive 3 consecutive days of low-dose (375 mg) or high-dose (1000 mg) intravenous corticosteroids . The clinical outcome measures were not significantly different between the two groups, although the high-dose group reached pre-treatment pain levels at 347 days compared with 253 days in the low-dose group. It should be noted that additional therapies (analgesics and/or NSAIDs) were required within 8–28 days of the pulse therapy. Based on the lack of a placebo arm and the limited data available from these small pilot studies, the use of chronic oral or intravenous pulse steroids cannot be recommended at this time. In patients with psoriasis, corticosteroids have been associated with development of erythroderma and pustular psoriasis and long-term use is often complicated by metabolic, bone and cardiovascular side effects. For patients who do not respond to the interventions outlined above, the possibility of participation in a clinical trial can also be discussed.