Rheumatic Diseases and Transverse Myelitis
Julius Birnbaum, MD
Johns Hopkins Clinic for Neurological Rheumatic Disease

1) Introduction: The importance of a broad surveillance for rheumatic diseases in all patients with TM

My background as both a rheumatologist and a neurologist has reinforced the importance of ruthlessly pursuing the myriad causes of transverse myelitis.  In most cases, transverse myelitis is “idiopathic,” meaning that there is no known identifying cause.  However, a subset of patients with transverse myelitis will have a background rheumatological disease, requiring a specific therapeutic strategy.  Systemic rheumatic diseases are clinical syndromes where the body’s immune system becomes maladaptive.  Normally charged with protecting vital organs from infection and cancers, the body’s immune system becomes a turncoat, ravaging the same vital organs.  When disease is truly systemic, causing obvious clinical distress, such as fever or weight loss, rashes, joint pains and swelling, or kidney failure, then the presence of these rheumatic diseases is promptly considered, with treatment and therapy depending on further diagnostic evaluation.  

At the Johns Hopkins Myelitis Center, I have established a Clinic devoted towards the care and evaluation of patients with neurological complications occurring in the context of systemic rheumatic disease.  In the past two years, I have cared for patients with transverse myelitis evolving in the context of a wide array of rheumatic syndromes.  In some cases, the background autoimmune disease is evident, for example, lupus can cause an inflammatory syndrome, which may include rashes, joint pains, and kidney damage.  When patients with this constellation of symptoms and signs present with transverse myelitis, then the physician may already suspect an underlying rheumatic disease.  However, in other cases, the symptoms suggestive of a rheumatic disease may be more circumspect and subtle.  

Many rheumatic diseases are associated with abnormal production of proteins, called “autoantibodies.”  Antibodies reflect the normal and elegant repertoire of our body’s capability to manufacture proteins capable of neutralizing a wide spectrum of infections.  In rheumatic diseases, autoantibodies are abnormal and maladaptive, attacking crucial proteins on the body’s cell and genetic material.   

In this article, I discuss our increasing understanding of an important class of autoantibodies, called “antiphospholipid antibodies” (referred to hereafter as aPL antibodies), which can be seen in patients with transverse myelitis.  I review specific clinical contexts in which aPL antibodies may be contributing to transverse myelitis. 
I emphasize the spectrum of treatment options which should be considered in patients with aPL antibodies.  Finally, I communicate to the Transverse Myelitis Community planned research studies that we will undertake, which will incorporate sophisticated neuroimaging studies, and which will help in disclosing the causes of transverse myelitis in patients with aPL antibodies. 

2) What are antiphospholipid antibodies, and what is antiphospholipid antibody syndrome?

As noted above, antibodies represent the sophistication of our biochemical machinery to neutralize damage from infections and cancers.  In systemic rheumatic disease, the orchestrated and controlled production of antibodies goes awry; there is proliferation of these same autoantibodies against our own cells.  Antiphospholipid antibodies  (aPL antibodies) target the cell layers which are involved in regulating the fluidity and clotting of blood.  These cell layers are called “phospholipids.”  Abnormal antibodies to these phospholipids increase the stickiness and likelihood of blood clots.  aPL antibodies target “phospholipids” on the surface of arteries and veins.  Furthermore, aPL antibodies may target proteins in the spinal cord or the brain, which can cause symptoms on MRI which can easily be confused with MS or “idiopathic” TM. 

Antiphospholipid antibody (aPL) syndrome is a disorder of abnormal clotting or obstetrical/pregnancy complications, which are believed to be caused by antiphospholipid antibodies.  Antiphospholipid antibody syndrome can be a “primary” autoimmune disease.  In other cases, it can occur as a “secondary” syndrome, with antiphospholipid antibodies generated as part of a “primary” autoimmune disease, such as lupus or Sjogren’s syndrome.  As transverse myelitis is such an example of a “primary” autoimmune disease, it is imperative that rheumatologists and neurologists check all patients with transverse myelitis for these antiphospholipid antibodies. 

3) When should the diagnosis of aPL syndrome be suspected? Examples of “red flags:”

In patients with transverse myelitis, the following are scenarios or “red flags,” in which the diagnosis of aPL syndrome should be especially considered.    

(A) History of obstetrical accidents or history of blood clots in veins or arteries  

aPL antibodies cause clots in larger arteries and veins, and is associated with complications of pregnancy.  Examples of these complications of pregnancies include recurrent episodes of spontaneous abortion; or episodes of pre-eclampsia (high blood pressure, sometimes with seizures, usually developing late in the third-trimester).   Although blood clots in the legs are more common in patients with myelitis because of immobility, a history of recurrent or multiple blood clots (i.e., otherwise referred to as “unprovoked” clots), should prompt blood tests for the aPL antibodies.

With increasing age, patients may develop heart attacks and strokes, especially when there are risk factors for atherosclerosis.  However, unexplained strokes or heart attacks in MS patients, especially when there are minimal to no risk factors for atherosclerotic disease (i.e., when there is no history of smoking, diabetes, high blood pressure, high cholesterol, or early family history of strokes/heart attacks), should prompt consideration of aPL syndrome.  

(B) Rashes  

aPL antibodies may be associated with different rashes.  One pattern is called “livedo reticularis.” I suggest that readers log onto the Internet, connect to Google, click the browser on Images, and type in “livedo reticularis.”  The rash of “livedo reticularis” presents as a mottling, faintly red, lace-like, reticular streaks, occurring more often on the legs than the arms.  In severe cases, livedo reticularis may be observed on the trunk.    The rash of livedo reticularis may be subtle, and require examination by physicians under proper lighting.  In this past year, we have identified more than 10 people with this livedo rash, who were unaware of subtle mottling on their arms!  Around the nails, the smallest blood vessels (called capillaries) may proliferate, causing a pattern of “corkscrewing.”  Under the nails, there may be tiny redness which look like splinters, and is therefore called “splinter hemorrhages.”

All of these rashes are nonspecific, meaning they can occur in different medical conditions other than aPL syndrome.  A subset of normal patients without any neurological disease can also have a livedo reticularis rash.  So the presence of these rashes is not diagnostic for aPL syndrome, but does suggest that an experienced neurologist consider testing for aPL antibodies.

(C) Presence of any “primary” autoimmne syndromes associated with aPL antibodies

aPL antibodies may be “primary” or occur in the absence of any provoking systemic diseases.  However, aPL antibodies also occur as a “secondary” autoimmune syndrome, occurring in the context of systemic autoimmune disease.  Aside from rheumatic diseases (SLE, Sjogren’s, rheumatoid arthritis, and vasculitis), other autoimmune diseases which have been associated with aPL antibodies includes inflammatory bowel disease (Crohn’s disease or ulcerative colitis) and Hashimoto’s thyroiditis.  Therefore, aPL antibodies should be checked in patients with a new diagnosis of transverse myelitis who have a history of other autoimmune diseases. 

4)  How do my physicians know when aPL antibodies are causing my signs or symptoms?

This is a notoriously difficult question and requires further research.  The mechanisms of how aPL antibodies cause neurological dysfunction are imperfectly understood.   However, a quandary in the care of patients with blood tests showing aPL antibodies is that aPL antibodies are often not associated with any symptoms or disease.  For example, aPL antibodies may be seen in up to 5 to 10 percent of normal, healthy people.  

Furthermore, in 3(C) above, I emphasized that aPL antibodies are seen in autoimmune diseases.  In some cases, aPL antibodies may reflect the manifestation of a global disturbance in the immunological system.  In such cases, autoantibodies are a marker of a heightened autoimmune response, without necessary causing autoimmune disease.    In other scenarios, aPL antibodies may directly contribute, if not cause, systemic damage, such as transverse myelitis.  In the latter scenario, when aPL antibodies directly cause symptoms, they are regarded as pathogenic.

The above paradox motivates questions frequently asked by transverse myelitis patients, and even by their referring neurologists:   How do I know whether the aPL antibodies are “innocuous” (i.e., an innocuous marker of an autoimmune disease such as transverse myelitis) versus “pathogenic” (and causing disease)?

This dilemna is the subject of planned ongoing research projects.  We should suspect that aPL antibodies are pathogenic:

(a) When you have any of the “red flags” listed in Section 3: (A) through (C) above;

(b) When you have a suboptimal treatment response to medicines used to treat TM.

5) Treatment for aPL antibody syndrome

Given our imperfect understanding of aPL antibody syndrome, there is no clear consensus regarding treatment in all situations.  In patients who have aPL antibodies and repeated blood clots or complications of pregnancy, it is incontrovertible that treatment should include “anticoagulation” or blood thinners.  Such treatment might include the pill Coumadin or an injectable form of Heparin. 

However, experts do not agree regarding treatment when there are abnormal blood tests showing aPL Abs, but without episodes of blood clots or pregnancy complications.  At the Johns Hopkins Transverse Myelitis Clinic, we consider recent studies suggesting that aPL antibodies might affect the clotting not only in larger vessels, but also in the smallest capillaries.  Treatment which target sludging and “stickiness” of cells in these smallest capillaries include Plaquenil, which is a medicine used in lupus patients, as well as “anti-platelet” agents (i.e., Aspirin, Plavix).

In patients with multiple episodes of transverse myelitis and aPL antibodies, a trial of “anticoagulation” may be reasonable.  In such instances, collaboration between neurologists and rheumatologists is crucial.  

6) Current research projects

As the above discussion suggests, improved diagnostic criteria, blood tests, and neuroimaging modalities are necessary to help clinicians understand how aPL antibodies cause neurological/rheumatic syndromes, not only transverse myelitis, but also multiple sclerosis, and inflammatory brain disease in lupus.  We are considering the use of Magnetic Resonance Spectroscopy (or MRS), as a neuroimaging tool to understand whether aPL antibodies are “pathogenic.”  MRS produces a biochemical and quantitative assessment of different molecules in the brain which may be affected differently in MS versus aPL syndrome.  

We hope that understanding these “biochemical signatures” will elucidate mechanisms of aPL syndrome.  We are also interested in the clinical evaluation of patients who may have received conflicting and discrepant diagnoses of whether transverse myelitis is caused by aPL antibodies; as well as rheumatic diseases versus MS.  In addition to immediate clinical and therapeutic benefit, our evaluation of these patients may pave the way for improved diagnostic criteria.   

Any members of the TM Community with known or suspected aPL syndrome, or with known or suspected co-existing rheumatic diseases, or those with any other questions should feel free to Email me at jbirnba2@jhmi.edu.