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Tumour necrosis factor alpha blockade for non-inflammatory pain: beyond inflammation?

Tumour necrosis factor alpha (TNF-α) is a proinflammatory cytokine involved in cell activation and inflammation. Inhibitors of TNF-α are currently available for various diseases including rheumatoid arthritis, psoriasis and uveitis. Besides its role as an inflammatory inducer, TNF-α is also known as a mediator of pain processing and sensation associated with hyperalgesia (1). Migraine has been reported to have a possible genetic susceptibility associated with TNF gene polymorphisms although it is generally believed to be a noninflammatory disease (2). Furthermore, a recent study demonstrated the skewed levels of TNF-α in migraineurs’ plasma (3). However, the effectiveness of anti-TNF-α therapy for migraine has been yet unknown. Here we report a case of 39-year-old female migraineur concomitant with ankylosing spondylitis (AS), who was treated with adalimumab, one of the anti-TNF-α monoclonal antibodies, resulting in the amelioration of both arthralgia and headache. The patient presented to our unit with polyarthralgia, systemic enthesopathy and lower back pain at rest in 2013. Since 2011, she had the unilateral and pulsating headache with photophobia characterized a maximum of up to a-three-day attack and was diagnosed with migraine with aura based on International Classification of Headache Disorders, 3rd edition (4). A radiography demonstrated erosive and sclerotic changes in the left sacroiliac joint, and blood test revealed a positivity of human leucocyte antigen-B27. She was thus diagnosed with AS. Although she was initially treated with non-steroidal antiinflammatory drugs, her symptoms persisted. We subsequently administered subcutaneous injection of 40 mg adalimumab every other week. Her symptoms were successfully relieved with the decline of Bath Ankylosing Spondylitis Disease Activity Index (Figure 1A). Surprisingly, her headache also ameliorated with the improvement of Headache Impact Test (HIT-6) score, a questionnaire for evaluating headache disability, as well as the decreased frequency of attacks and antimigraine agents use (Figure 1B). We performed resting state functional magnetic resonance imaging (rs-fMRI), and the extracted data were analysed using Statistical Parametric Mapping 12 software (Wellcome Department of Cognitive Neurology, London, UK) and the CONN toolbox (Whitfield-Gabrieli S and Nieto-Castanon A, 2012, www.nitrc.org/projects/conn, RRID:SCR_009550) implemented through MATLAB (Mathworks, Natick, MA, USA). The rs-fMRI analysis revealed that the atypical functional connectivity between nucleus accumbens and temporal pole, and between frontoparietal network in posterior parietal cortex and inferior temporal gyrus, whichwere reported to be associated with pain processing, cognition and hyperexcitability in migraineurs (5–7), was reduced after adalimumab administration (Figure 1C and Table 1). As long as she received adalimumab treatment, her pain due to spondyloarthritis and migraine were wellcontrolled. We first report that the possible effectiveness of antiTNF-α therapy for non-inflammatory pain. Considering the genetic susceptibility of TNF gene in patients with migraine and the involvement of TNF-α in pain processing (1, 2), it may be biologically plausible for the therapeutic efficacy of adalimumab in migraineurs. We showed that the patient’s subjective parameters associated with the severity of migraine were ameliorated by adalimumab. However, objective evaluation of the improvement of migraine is challenging. A recent study indicated fMRI as a useful tool for objectively evaluating pain with the findings that neuronal activities elicited by pain, were reduced along with the improvement of pain scale and disease activity in patients with rheumatoid arthritis (1). In addition, a case-controlled study revealed that the specific functional connectivity of the brain network was ameliorated after treatment in some migraineurs (6). In this case, we demonstrated the possible objective amelioration of abnormal brain functional connectivity related to pain processing in migraineurs (5–7). Of course, it is premature to narrate the definite efficacy of anti-TNF-α monoclonal antibodies to treat noninflammatory pain though this case report. To define a cause-effect relationship, further clinical research to confirm this novel insight of anti-TNF-α effect for noninflammatory pain itself is needed. Scand J Rheumatol 2019;48:513–515 513