Neurological Syndromes May Be Associated with Anti-TNF Disease-Modifying Medication

Patient Expert

The biologic medications for rheumatoid arthritis and other autoimmune diseases have changed the face of disease for many patients.   We are fortunate to take advantage of disease-modifying medications which can slow down or halt the accumulation of damage and disability when we live with RA or other autoimmune disease.   And when you live with two (such as MS and RA as I do), it is even more important.

However, with powerful medications can come significant side-effects.   Not all patients will experience detrimental side-effects, but for those who do, it can shake up your world.   As a cruel joke, what if a medication caused an entirely different disease or syndrome as a rare side-effect?   That's something about which I would definitely want to know.

Patients living with multiple sclerosis and rheumatoid arthritis are somewhat limited in their choices of medications to take for RA.   Any person who already has a demyelinating disease must not use one of the anti-TNF (tumor necrosis factor) drugs.   It is strongly contraindicated, meaning the recommendation is that we do not take these medications.     Biological drugs which block the action of TNF-alpha, a pro-inflammatory immune system mediator (cytokine) produced by adipose tissue (ie. fat) in the body and other types of cells, include: Remicade (infliximab), Humira (adalimumab), Enbrel (etanercept), Simponi (golimumab), and Cimzia (certolizumab pegol).

I first learned of this contraindication from my own rheumatologist at our initial appointment.   She informed me of the different types of drugs approved for RA and why I couldn't use some of them.   Why is that?   Because I already had MS and didn't want to risk using one of these disease-modifying anti-rheumatic drugs (DMARDs) for fear that it could exacerbate my MS.

TNF-alpha blockers are known to potentially cause neurological symptoms which may be part of an MS-like syndrome or represent new inflammatory demyelinating disease.   While it is known that TNF-alpha inhibitor drugs can exacerbate multiple sclerosis (MS), there is a question whether this association actually represents an unmasking of pre-existing, pre-symptomatic cases of MS or the development of new demyelinating disease.

Besides learning this important information from my doctor and subsequently reading the "Important Safety Information" for most of the RA drugs, I had not read more than a few individual case studies of patients who developed MS (or something like it) while taking an anti-TNF drug.   Imagine my excitement to find a recent study in the Multiple Sclerosis Journal (published online 3 August 2011) which discusses "Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors."   (Solomon AJ, Spain RI, Kruer MC, and Bourdette D.)

The purpose of the study was two part: 1) to present ten new cases of neurological disease associated with the use of anti-TNF drugs, and 2) to present a review of the medical literature (via PubMed) regarding similar drug-related inflammatory neurological disease.   The 10 case studies include eight demyelinating central nervous system (CNS) syndromes and two peripheral nervous system syndromes associated with anti-TNF therapy.   The range of diseases in these cases included leukoencephalopathy,
transverse myelitis, optic neuritis, polycranial neuritis, multiple sclerosis, chronic inflammatory axonal polyradiculoneuropathy, and small fiber polyneuropathy.

The literature review included previous reports of 151 cases of neurological disease (including the 10 above) occurring in patients receiving TNF-alpha inhibitor therapy.   Not included in this study were 22 additional case reports where clinical information was inadequate.   Also not included is a recent case control study including 253 reported cases of demyelination in association with anti-TNF therapy and a report of 129 cases derived from limited data on post-marketing surveillance.   Thus, to date, more than 500 cases of neurological disease have been reported in association with anti-TNF therapy.

The 151 cases included in this report summarize 64 cases of central nervous system (CNS) syndromes, 18 cases of isolated optic neuritis, and 69 cases of neuromuscular syndromes.   The majority of reported cases included females (100/151, 66.2%) and patients living with rheumatoid arthritis (76/151, 50.3%).

For the CNS syndromes, onset was between the ages of 36 and 65 years in 84% of cases (with 63% between 36-50 years of age).   Because 84% of CNS cases began after the age of 36, the authors argue against coincidental unmasking of multiple sclerosis as they use a reference point of 25-35 years as being the typical peak incidence of MS.   Note that the National MS Society shares that the majority of MS cases are diagnosed between the ages of 20 and 50 years.**

Neurological symptom onset occurred within one year of beginning TNF-alpha inhibitor therapy in 72% of CNS cases, 88% of optic neuritis cases, and 81% of neuromuscular cases.   Etanercept (Enbrel ®) therapy was reported in the majority of cases of CNS syndromes (62%) and infliximab (Remicade ®) therapy in the majority of optic neuritis (65%) and neuromuscular syndromes (67%).   The smaller number of cases involving adalimumab (Humira ®) may reflect more recent approval by the FDA rather than a decreased risk associated with this treatment choice.

Clinical outcomes reported at follow-up in 56 CNS cases include: complete resolution of symptoms (25%), partial improvement (44.6%), unchanged or stable symptoms (12.5%), a relapsing-remitting course after initial presentation (16%), and one progressive disease course (0.02%).   Clinical outcomes reported in 17 optic neuritis cases include: complete resolution (35.3%), partial improvement (47.8%) and unchanged or stable symptoms (23.5%).   Clinical outcomes reported in 68 neuromuscular cases include: complete resolution (36.8%), partial improvement (45.6%), unchanged or stable symptoms (7.4%), and a relapsing-remitting course (10.3%).

The majority of reports (95/141, 67.4%) detailed significant disability at the time of follow-up.   However, most cases (100/122, 82%) had been followed for less than one year after onset of neurological disease.   Longer follow-up could reveal the emergence of a relapsing-remitting syndrome or a later full recovery without recurrence.     More detailed study is needed in future cases to better determine the natural course of disease development and to evaluate appropriate treatment interventions.

If you are a patient using a TNF-alpha inhibitor drug and you develop new neurological symptoms, please contact your rheumatologist immediately.

**Data found on PatientsLikeMe supports this statement.   Of 16,625 MS patients who have completed their profiles, 86% report disease onset between the ages of 20-49 years.   Onset for 32% began between 20-29 years, onset for 34% began between 30-39 years, and onset for 20% began between 40-49 years.