The Two Sides of CSF1 Receptor- Tenosynovial Giant Cell Tumour and Corticobasal Degeneration

A translocation in 1p13 leads to constitutional activation of Colony Stimulating Factor in a small proportion of synoviocytes in Tenosynovial Giant Cell Tumour (TGCT- previously called PVNS). They attract macrophages, which have the cognate receptor, CSF1R, leading to a proliferative state resembling a benign tumour in the synovium of joints or tendon sheath. The process can be localised, as in digits, or diffuse as in the knee.

So what happens if CSF1 is inactivated? The CSF1 receptor acts through and adaptor called DAP12 or TYROBP. This adaptor is also shared by another signalling entity called TREM2. When there is homozygous inactivation of either TREM2 or TYROBP, a condition called Nasu Hakola Disease results. This condition manifests as very early presenile dementia and bone cysts, often resulting in fractures. Death occurs around age 30.

Similarly, inactivating mutations of CSF1R results in a variant of Corticobasal Degeneration called Hereditary Diffuse Encepahalopathy with Spheroids.

Interestingly, heterozygous mutations in TREM2 leads to late onset Alzheimer's Disease.

Monoclonal Antibodies to CSF1R are in clinical trial for treating TGCT. The most well known is PLX3397 or Pexidartinib. A broader, more nonspecific inhibition is performed by the tyrosine kinase inhibitor Imatinib.

FcRn: Using IV Immunoglobulin to Treat Antibody Mediated Disorders

Intravenous Immunoglobulin (IVIG) is used to treat a variety of disorders. Among these conditions, a number are mediated by antibodies- such as Guillain Barre Syndrome, CIDP, Inflammatory Myositis, Multifocal Motor Neuropathy, Myasthenia Gravis & Rasmussen Syndrome.

But how do infusions of pooled antibodies from thousands of donors (each IVIG aliquot must be derived from at least a thousand donors) mitigate the consequences of pathogenic antibodies already present in the patient?

A number of mechanisms have been proposed, among them the presence of "anti-idiotype" antibodies in the infused IVIG. Thus, among the pooled antibodies, there will be a fraction that will treat the epitopes on pathogenic antibodies as "antigen" and thus neutralise them. Secondly, naive B cells binding to infused IgG through the B cell receptor will activate inhibitory ITIM motifs -"Immune Tyrosine Inhibitory Motif" and thus lead to B cell anergy. These B cells will no longer develop into memory B calls, and thus will not produce pathogenic antibodies.

While the above mechanisms are plausible, it does not explain why IVIg works well only for IgG mediated disorders such as the ones described above, but not for disorders mediated by IgM- such as MAG associated peripheral neuropathies seen in association with IgM paraprotein.

After the infusion of IVIg in subjects with pathogenic IgG antibodies such as Myasthenia Gravis, the putative IgG antibodies decline by up to 40% over a matter of several weeks. There is now sufficient evidence to suggest that this fall is due to increased degradation of these antibodies, rather than reduced production thereof.

But how does infusing IVIg increase the breakdown of intrinsic culprit antibodies?

The answer lies in a group of intracellular receptors called the "Neonatal Fc Receptor" or simply FcRn. While these were so named because they were first isolated in the gut of newborn rats, these receptors are in fact widely present in adults. The greatest concentration is in endothelial cells, but they are also found in antigen presenting cells. FcRn containing cells such as endothelial cells take up IgG by pinocytosis. In the acidic environment of endosomes-pH 6.0- FcRn binds to the Fc portion of IgG. The endosome than travels through the cell until it fuses with the cellular membrane to release the bound IgG back into the circulation. As long as sufficient FcRn receptors are available to take up circulating IgG, the effect is to recycle IgG and thus increase its half life in the circulation. However, FcRn does not bind IgM or IgA. This is the salient reason why IgG is the predominant antibody class in blood ahead of IgM and IgA- not because it's produced more, but because it is recycled repeatedly by FcRn receptors, increasing its half life, while no such thing happens with IgM or igA.


This principle is ingeniously exploited in antibody mediated diseases such as inflammatory myositides. When pooled human IVIg is infused, the "overload" of total IgG- in the infusate (more than 95% of infused IVIg is of IgG class) and intrinsic IgG- saturates the FcRn receptors. Thus, endosomal recycling is no longer possible. Instead the endosomes release pinocytosed IgG to lysosomes, where igG is degraded. Thus, infused igG leads to an overall increase in the breakdown of all IgG- including pathogenic antibodies, leading to a gradual and modest fall in the titre of pathogenic antibodies.

FcRn of course has other roles. Remember, it was first isolated in neonates. In the foetus, FcRn serves to transfer IgG across the placenta from the mother- again explaining why IgG is the only class of immunoglobulin to undergo transplacental transfer.

Recirculation of IgG has other benefits- when the amount of injected IgG is modest, i.e. the FcRn receptors are not saturated, it serves to extend the survival of monoclonal antibodies now in wide use inside the body. Again, it would not have escaped your notice that all monoclonal antibodies are of IgG class.

To summarise, FcRn explains the following observations:
1. Why IgG is the predominant class of antibody in blood
2. Infusion of IVIg reduces the level of pathogenic antibodies in humorally mediated disorders
3. Why IgG is the only class of immunoglobulin to be transferred from mother to foetus in utero
4. Why monoclonal antibodies are entirely of IgG derivation

The Fallacy of Diagnosing Cardiac Involvement in Inclusion Body Myositis

Unlike polymyositis and dermatomyositis, cardiac muscle involvement in inclusion body myositis (IBM) is uncommon, and any such involvement is unlikely to be due to IBM itself. Physicians routinely check cardiac troponins in subjects with putative inflammatory myositis and there is a risk of overdiagnosis of cardiac muscle involvement, primarily in IBM, but also in other skeletal muscle disorders.

This occurs when Troponin-T is used as the marker. Unlike Troponin-I, which is specific for the heart, Troponin-T is produced by regenerating skeletal muscle fibres, and therefore could be elevated with ongoing skeletal muscle damage (and regeneration).

The same applies to CK-MB, which is also produced by regenerating skeletal muscle, and therefore is not specific for cardiac damage when there is ongoing skeletal muscle destruction. The suspicion that such elevation- for Troponin-T or CK-MB- is not due to cardiac causes, is strengthened by a normal BNP or N-terminal ProBNP and a normal Echo.

Therefore, the only safe way to rule out cardiac muscle involvement in such patients is to test for Troponin-I. Unfortunately, many labs, including ours, routinely test for Troponin-T.

Think of Spinal Muscular Atrophy 3 or 4 in Subjects with Proximal Weakness, Raised CK, Areflexia and Tremor

What is the most common monogenic cause of infant mortality?

You would be surprised to know that it is Spinal Muscular Atrophy (SMA).

SMA has a carrier frequency of 1 in 53 and affects 1 in 11,000 births.

Based on age of onset and severity, it is classified into 5 types- 0,1,2,3 & 4.

Type 0 or the prenatal type, and type 1, the infantile type, are the most severe and affected children die of respiratory failure either at birth or within a few months. Type 1 is also known as Werdnig Hoffman disease.

Type 2, also known as Dubowitz disease, has onset before 18 months and affected subjects can live to 25 years, or rarely longer.

Type 3, known as Welander-Kugelberg syndrome, can start anytime between 18 months and adulthood, while type 4 mostly starts after 35 years of age and accounts for around 5% of cases of SMA. Survival is normal in these last two types and the disease is often non-progressive.

It is SMA types 3 & 4 that I will be dealing with here, as these are the ones who can occasionally present in the Rheumatology clinic.

So what determines the type of SMA?

SMA has autosomal recessive inheritance. The putative gene is called Survival Motor Neuron or SMN, and is loocated on chromosome 5q13. Due to gene duplication, there are two SMNs-SMN1 and SMN2, which are >99% similar. SMN1 sits telomeric to SMN2.

There are rare, non-5q varieties of SMA, but most have "5q disease".

In normal subjects or heterozygotes, SMN1 produces the functional protein. SMN2 is a "defective" gene, due to a single nucleotide substitution- T-->A in exon 7. Thus, SMN2 produces a truncated, non-functional protein due to defective splicing most of the time. However, 15% of SMN2 genes produce some functional protein. There are 4 to 8 copies of SMN2 in an individual.

In SMA, both alleles of SMN1 have deletion of exon 7 in 5q13, and do not produce any functional protein at all. Therefore the small amount of functional protein produced by 15% of SMN2 genes assumes added importance. It will not come as a surprise that the higher the copy number of SMN2 genes that an individual has, the milder is the phenotype of SMA expressed. Thus SMA types 0 or 1 have 1 or 2 copies of SMN2, SMA type 2 has 2 or 3 copies, while SMN3 or 4 have 3-8 copies.

SMA3 and SMA4 present with proximal muscle weakness, complete areflexia (resembling peripheral neuropathy), raised CK and absence of respiratory weakness. They may present with difficulty climbing stairs and sometimes with falls. One unexpected feature is a fine tremor of the extremities. This is the most useful clue to the underlying aetiology.

The diagnosis may be suggested by the presence of neurogenic pattern on EMG- sharp waves and fibrillation potentials, and prolonged, high amplitude motor units. Sequencing of the SMN1 alleles on 5q13 is diagnostic, and the copy number variants of SMN2 will accord with the prognosis and type of SMA.

Recently Nusinersen, an antisense oligonucleotide has won approval for SMA in USA and some countries in Europe. It is currently being assessed by NICE. It works by increasing the amount of functional protein produced by copies of SMN2.

Think of SMA3 or SMA4 in an adult with proximal muscle weakness, raised CK, areflexia, and tremor.

An Important Clue to Protein Losing Enteropathy Causing Hypogammaglobulinaemia

Occasionally one picks up hypogammaglobulinaemia unexpectedly in a young person. Most of them look well and give no history of serious infections. Some will have lymphangiectasia, but most will have a protein losing enteropathy due to malabsorption, caused by either Crohn's disease or coeliac disease.

An important clue in such cases is low IgG and IgA, in combination with a raised IgM. As far as I know, this does not happen in any other form of severe hypogammaglobulinaemia.

Use Both Arms for Bubble Contrast Study in Brain Abscess, Not Just the Right

Subjects with brain abscess without any other risk factors, or relatively young subjects with stroke are often suspected of having a right to left cardiac shunt and undergo a bubble contrast study with agitated saline.

A minority of such subjects have the rarest form of ASD- deroofing of the coronary sinus, accompanied by a left sided superior vena cava (SVC), draining into the coronary sinus. (The coronary sinus collects venous blood from the cardiac muscle and drains into the right atrium, but occasionally, the partition separating the coronary sinus from the left atrium is absent, creating continuity between the coronary sinus and left atrium. Such subjects usually have a left sided SVC, draining into the coronary sinus).

Under such subjects, bubble contrast injected only into the right arm will bypass the left sided sided SVC and will therefore appear in the right atrium long before the left atrium, suggesting an absence of shunt. On the other hand, bubble contrast injected into the left arm will traverse the left subclavian vein and make its way into the left sided SVC, the deroofed coronary sinus and will thus appear immediately in the left atrium, revealing the shunt and thus the cause for the putative brain abscess or stroke.

Persistent left sided SVC is rare, but is still the commonest venous anomaly, affecting 0.3% of subjects in the general population and 10% of subjects with congenital heart disease.

The Ross Procedure- An Alternative to Mechanical Aortic Valve Replacement in Young Patients

Consider this problem. A young or middle aged patient needs an aortic valve replacement. Perhaps she was born with a bicuspid valve, or perhaps she grew up in the East and had rheumatic heart disease. Regardless, her aortic valve is end stage and must be replaced. She may be pregnant. What do you do?

The current practice is to give these subjects a mechanical aortic valve. Older subjects would get a tissue (bioprosthetic) valve, but the latter have shorter lives and would almost certainly necessitate replacement after 10 years or so.

Therefore, despite the daunting prospect of lifelong anticoagulation, mechanical aortic valves are preferred in younger subjects.

Donald Ross, British cardiac surgeon, thought of an alternative in 1967. Working at Guy's Hospital, London, he replaced a diseased aortic valve with the patient's own pulmonary valve- an autograft. He then put in a homograft (a cadaveric valve of human origin rather than porcine valve) in the vacant pulmonary position to complete the switch.

His rationale was that a living valve would be physiologically more suitable, the pulmonary valve would share many of the aortic valve's attributes, there would be no immunologic rejection and anticoagulation would be avoided. The background to this was that Star & Edwards had pioneered the first mechanical aortic valve prosthesis in 1960 across the pond, and two years later, Ross himself had performed an aortic valve replacement with a cadaveric graft.

He wasn't happy though. The homografts simply did not last long enough in the aortic position.

Over the next few years, the Ross procedure gained acceptance and was performed in thousands of patients. However, it gained a reputation for being a technically challenging procedure and as the new generation of mechanical valves became available, it became less popular despite the fact that 80% of transplant recipients survived 20 years or longer without re-operation.

In the current issue of JAMA Cardiology, Mazine & colleagues publish a mata-analysis that looks back at five decades of the Ross procedure. Comparing around 1500 such procedures with just over 1900 mechanical valve replacements in young to middle aged patients, they found that the Ross procedure led to reduced all cause mortality, longer survival, better quality of life, haemodynamic performance and left ventricular function than mechanical valves. Rates of major bleeding & stroke were less frequent with the Ross procedure. As expected, re-operations were marginally less common with mechanical valves. These days, most such re-operations would be in the nature of modern percutaneous procedures- TAVR.

Despite the generally held view that the Ross procedure is technically more challenging, peri-operative mortality & morbidity did not differ in the 2 groups. Subjects who had mechanical valves were at a higher risk of needing a permanent pacemaker subsequently.

The Ross procedure cannot be performed in all patients. It is best avoided in those with familial aortopathy and in those with hereditary or acquired connective tissue disease.

It took a while, but after half a century, Donald Ross's groundbreaking procedure has been finally vindicated.