TNF-alpha blockade may improve autonomic dysfunction in ankylosing spondylitis

Introduction Autonomic neuropathy is a significant risk predictor of sudden cardiac death in rheumatic disorders.1 However, there is no specific treatment for autonomic neuropathy in rheumatic disease. Treatment with TNFinhibitors (TNFi) has revolutionized the treatment of ankylosing spondylitis (AS). Their beneficial effects on musculoskeletal inflammation and endothelial dysfunction have also been reported.2 The present case study describes the improvement of autonomic neuropathy with infliximab in AS.


Introduction
Autonomic neuropathy is a significant risk predictor of sudden cardiac death in rheumatic disorders. 1owever, there is no specific treatment for autonomic neuropathy in rheumatic disease.Treatment with TNFinhibitors (TNFi) has revolutionized the treatment of ankylosing spondylitis (AS).Their beneficial effects on musculoskeletal inflammation and endothelial dysfunction have also been reported. 2The present case study describes the improvement of autonomic neuropathy with infliximab in AS.

Case report
A 36-year-old male patient diagnosed with AS around 2.6 years ago, presented with sacroiliac joint irregularity and marrow edema parallel to the joint (Figure 1).He was treated with TNFi-infliximab 5 mg/kg/dose as intravenous infusion at weeks 0, 2, and 6 along with sulfasalazine 500 mg thrice/day and etoricoxib 90 mg/day.In addition to inflammatory low back pain and joint pain, the patient complained about light headedness, and impaired sweating and bloating after eating a small meal.These symptoms were suggestive of autonomic dysfunction.High erythrocyte sedimentation rate (ESR) of 29 mm/1st hr, and high c-reactive protein (CRP) of 11mg/dl were noted.MRI of sacroiliac joints is depicted in figure 1. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis functional Index (BASFI) were also high (Table 1).The patient was normotensive and non-diabetic with high disease activity.Results of routine hematological and biochemical investigations were within the normal limits.He was also investigated for autonomic neuropathy before starting the therapy.Cardiovascular autonomic neuropathy (CAN) function was evaluated by conducting cardiovascular reflex tests (Table 1) according to Ewing and peripheral sympathetic autonomic function by FDA-approved Sudoscan (Sudoscan-Impeto Medical Device, EZS 01750010193, Paris-France). 3,4

Results and Discussion
The patient was diagnosed with HLA-B27+ve AS around 2.6 years ago.He was normotensive and non-diabetic with a history of synthetic disease modifying anti-rheumatic drug (DMARD) failure.The patient showed remarkable improvement in disease activity and biomarkers of inflammation (ESR and CRP) as well as parasympathetic, sympathetic, and peripheral sympathetic autonomic dysfunction in 2 weeks, and normalization of autonomic dysfunction after 6 weeks of treatment with infliximab (Table 1).Autonomic symptoms were also ameliorated after treatment with infliximab.6][7][8][9] The prevalence of autonomic neuropathy has been reported to vary from 24-

Abstract
The incidence of autonomic neuropathy in ankylosing spondylitis (AS) is well recognized.However, there are no studies demonstrating the therapeutic efficacy of TNF-alpha blockade in autonomic dysfunction of AS.We report here a case of a 36-year-old male of AS with high disease activity and autonomic symptoms, investigated for autonomic neuropathy.Noninvasive tests based on peripheral and cardiovascular autonomic neuropathy function were used for accurate assessment of autonomic neuropathy.The patient was treated with intravenous infusion of infliximab 5 mg/kg at weeks 0, 2, and 6.The 6 weeks therapy improved the disease activity, biomarkers of inflammation, and autonomic function.To the best of our knowledge, this is the first reported case of improvement in autonomic function associated with AS.  100% of patients with autoimmune rheumatic diseases. 6espite its massive prevalence, the pathogenesis of the autonomic neuropathy in rheumatic diseases is not clearly understood. 6There is also no known therapeutic strategy for the management of autonomic neuropathy in rheumatic disease.However, CAN is a significant risk predictor for sudden cardiac death in rheumatic patients.Hence, a precise treatment for this comorbidity is imperative.
In the present case study, the treatment using infliximab has significantly reduced the high disease activity, inflammation and abnormal cardiovascular autonomic neuropathy, and peripheral sympathetic dysfunction.
Hence it can be concluded that infliximab treatment may improve cardiovascular autonomic neuropathy and peripheral sympathetic dysfunction in AS.
The improvement of autonomic dysfunction by TNF-alpha therapy could be explained by the following theoretical evidence: Primarily, it has been reported that the inflammatory process itself might cause some autonomic abnormalities in AS patients. 5Secondly, the patients with raised ESR and increased CRP and high BASDAI score also have disturbances in the balance of the autonomic nervous system. 5Finally, there is numerous evidence for the contribution of the nervous system to inflammation. 5

Conclusion
To the best of our knowledge this is first reported observation of improvement in autonomic neuropathy with infliximab, in AS.In conclusion, the present case highlights two important findings.First, abnormal cardiovascular autonomic function and peripheral sympathetic neuropathy appeared to be rapidly improved after treatment with infliximab.Second, TNF-α blockade does not appear to be the cause of autonomic neuropathy.Further studies are warranted to confirm these observations and explore the role of infliximab and other therapeutic molecules on autonomic neuropathy in AS.

Figure 1 :
Figure 1: Sacroilitis of ankylosing spondylitis.MRI (axial T1W and STIR) images of the HLA B27 +ve patient with inflammatory back pain showing sacroiliac joint irregularity and marrow edema parallel to the joint