Seronegative Sjogren, what's new?

[pattismith]

Many people here on PR end with a SFN + Seronegative Sjogren Syndrome diagnosis, so while I'm waiting for my lip + skin biopsy date (in August), I have some time to read a bit about it…

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Sjogren diagnosis mostly requires positivity to anti-SSA or anti-SSB antibodies, so seronegative SS (SNSS) is not so easily reached.

Here some recent findings about neurological damages in SS:

This 2020 study (about SFN in SS patients) found that non length dependent pattern SFN was far more prevalent in SS than length dependent pattern.

Some insight about the different SFN patterns quickly explained by Dr Oaklander:

- Length-dependent SFPN starts distally, spreads proximally (Distal axons are targeted)
- Non-length dependent SFPN is proximal or patchy (Neuron cell bodies in trigeminal or spinal ganglia are targeted)

And this other 2020 study found that "Anti‐SSA/Ro and anti‐SSB/La autoantibodies might cause dysfunction in nodal and internodal region of the axon and small nerve fibers; meanwhile, autoreactive antibodies in seronegative primary SS mainly affect small nerve fibers.

Thus, the underlying pathophysiology for the two types of primary SS is different."


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2016 table diagnosis criteria:
"The classification of primary Sjögren's syndrome applies to any individual who meets the inclusion criteria*; does not have any of the conditions listed as exclusion criteria**; and has a score of ≥4 when the weights from the five criteria in the table are summed."

 

[wigglethemouse]

Do you have the early Sjogrens test available where you are?

Quest Diagnostics have a different antibody panel said to be earlier markers for Sjogren's, their 'Early Sjogren's Syndrome Profile' test, when the standard ANA and ENA panels aren't detecting positive results.
https://www.questdiagnostics.com/testcenter/BUOrderInfo.action?tc=93748&labCode=AMD
Can't find the reference paper offhand but another Quest paper said of this early panel;
[The current Ro and La antibodies can delay the diagnosis by over 6 years. Recently novel antibodies identified to salivary gland protein 1 (SP-1), carbonic anhydrase 6 (CA6) and parotid secretory protein (PSP) using western blot methodology. Further studies have shown that the isotype differentiation of the markers adds to the sensitivity of diagnosis of SS. These autoantibodies occurred earlier in the course of the disease than antibodies to Ro or La. In addition antibodies to SP-1, CA-6 and PSP were found in patients meeting the criteria for SS who lacked antibodies to Ro or La. Furthermore, in patients with idiopathic xerostomia and xerophthalmia for less than 2 years, 76% had antibodies to SP-1 and/or CA6 while only 31% had antibodies to Ro or La.
Antibodies to different isotypes (IgG, IgM & IgA of SP-1, CA6 and PSP are useful markers for identifying patients with SS at early stages of the disease or those that lack antibodies to either Ro or La.]

This Dysautonomia International article states that SSA and SSB can appear 10 years after the early markers appear.
https://www.dysautonomiainternation...sjogrens-antibodies-in-dysautonomia-patients/

I was positive for 2 out of the 3 early markers plus very positive skin biopsy for SFN.

my lip + skin biopsy date (in August),

Good luck!

 

[pattismith]

Do you have the early Sjogrens test available where you are?

This Dysautonomia International article states that SSA and SSB can appear 10 years after the early markers appear.
https://www.dysautonomiainternation...sjogrens-antibodies-in-dysautonomia-patients/

I was positive for 2 out of the 3 early markers plus very positive skin biopsy for SFN.

Good luck!

I guess my illness is so old (dry eyes for 33 years) that SSA or SSB would have shown up at a time or another. (The last negative control was in 2017).
Early antibodies however were not include in the 2016 international consensus diagnosis criteria, so I doubt any doc will do it in my country.
I feel doubtful about the Sjogren diagnosis for me, but I am curious about the lip biopsy result.
I suppose your lip biopsy was clearly positive for lymphocytic sialoadenitis?

 

[wigglethemouse]

I suppose your lip biopsy was clearly positive for lymphocytic sialoadenitis?

I'm too ill to travel to get one from the recommended specialist.

 

[pattismith]

I'm too ill to travel to get one from the recommended specialist.

But now that your doc found the early Ab and made the Sjogren diagnosis, and that your SFN is evident, do you have specific drugs to target those auto-immune diseases?
I think we already discuss about erythromelalgia, but can't remember if you have it, can you tell me?

 

[wigglethemouse]

But now that your doc found the early Ab and made the Sjogren diagnosis, and that your SFN is evident, do you have specific drugs to target those auto-immune diseases?

Yes the dual diagnosis opens up access to other drugs. But unless you can get to the root cause improvement is tough.

I think we already discuss about erythromelalgia, but can't remember if you have it, can you tell me?

I have palmar erythema

 

[pattismith]

Yes the dual diagnosis opens up access to other drugs. But unless you can get to the root cause improvement is tough.

I have palmar erythema

Do you feel your immunosupressive treatment helps your palmar erythema?

 

[wigglethemouse]

Do you feel your immunosupressive treatment helps your palmar erythema?

We are all different. So far I've not tried much, and react to a lot of medications which makes me particularly cautious.

Annie Oaklander wrote this paper on IVIG treatment of SFN. It seems it's a roll of the dice whether it will help significantly or not.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791555/

 

[pattismith]

We are all different. So far I've not tried much, and react to a lot of medications which makes me particularly cautious.

Annie Oaklander wrote this paper on IVIG treatment of SFN. It seems it's a roll of the dice whether it will help significantly or not.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791555/

If I had access to IVIG, I probably would do it, I wish you will get it.
I take methylprednisolone, it has shown anecdotal successes.
Did you try high magnesium for palmar erythema?

 

[wigglethemouse]

Did you try high magnesium for palmar erythema?

I seem to have electrolyte imbalance and high levels of one upsets the rest. Best not to mess.......

 

[pattismith]

it's a pity this study doesn't include discrimination between seronegative/seropositive sjogren...


Detection of nerve enlargement with ultrasound and correlation with skin biopsy findings in painful sensory neuropathy associated with Sjögren’s syndrome

Takeshi Yoshida ,Hiroyuki Nodera ,Yoshitaka Kumon,Saeko Osanai,Yuishin Izumi &Hiroki Mizukami
online: 13 Oct 2020

Abstract
Objectives

We evaluated usefulness of peripheral nerve ultrasound (US) in detecting abnormality in painful sensory neuropathy (PSN) associated with primary Sjögren’s syndrome (pSS), and associations among various clinical factors, US findings, and intraepidermal nerve fiber density (IENFD).

Methods

We conducted a retrospective, single-center, observational study of patients with pSS-PSN. US image was obtained to measure cross sectional area (CSA) of peripheral nerves and compared with matched pSS control
.
Results

We included 11 patients with primary Sjogren S-Peripheral Sensory Neuropathy (10 women; age 70.5 ± 5.66) and 17 pSS controls (15 women; age 62.5 ± 16.7).

Sural nerve Cross Sectional Area were significantly increased in pSS-PSN group (3.48 ± 1.0 mm2 vs 2.05 ± 0.65 mm2, p = .001).

UltraSound of sural nerve showed the area under the ROC curve of 0.872 (95% CI, 0.732 − 1).

Sural nerve CSA and IntraEpidermalNerveFiberDensity of lower leg showed positive correlation.

Compared with pSS-PSN patients with abnormal IENFD, those with normal IENFD showed significantly larger sural nerve CSA, and trends toward less systemic disease activity and small fiber impairment with sparing of large fibers.

Conclusion
US was useful in discriminating pSS patients with PSN from those without.
Additionally, US may disclose distinct subsets of pSS-PSN with different clinical findings and IENFD.

 

[Jjnz]

I'm Confused if I have sjogrens or just a type of dysautonomia that affects the saliva glands.
I get dry eyes and a dry nose, but it's on and off, it peaks and wanes. As does what I think is raynauds. I only get a dry mouth when I breath aggressively (exercising) but the eyes and nose are dry every morning. I'm seronegative for everything!

 

[pattismith]

I'm seronegative for everything!

And so am I

Seronegative Sjogren is when you don't have classical antibodies but your lip biopsy shows lymphocytic sialadenite.

 

[pattismith]

This is an old study, but a major peace explaining correlation between

-- seronegative Sjogren
-- Isolated SFN without large fiber alteration

MBL impairment is the key to understand it, it is inversely correlated to the severity of SS.

MBL low genotypes change the antibody profile of auto-immune diseases in general and in SS especially.

No patient with primary SS carrying the homozygous MBL-deficient genotype 0/0 had anti-Ro/SS-A or anti-La/SS-B antibodies, low C3/C4 levels or circulating cryoglobulins.

Mannose-binding lectin-low genotypes are associated with milder systemic and immunological disease expression in primary Sjögren's syndrome | Rheumatology | Oxford Academic (oup.com)

 

[Jjnz]

This is an old study, but a major peace explaining correlation between

Interesting , I've had low c3, which I also have a gene for
rs2230199(C;G) On a test I was producing about half of the lower limit, low c3 and lupus are supposedly correlated.
I had a quick look on my 23andme, which only caters for MBL2
I have
rs5030737(C;T) 14% pop
carrier of mannose binding deficiency but of low clinical importance
the rest look ok
rs11003125(C;C)
rs2099902(T;T)
rs11003124(T;T)
rs7096206(C;C)
rs2120132(T;T)
rs1800450(G;G)

 

[pattismith]

Inherited lack of functional MBL is conferred by

- LXPA/O (referred to also as LXA/O or XA/O) and
- O/O genotypes.

nucleotide polymorphisms (SNPs) of the MBL2 gene.

Two of them are localized in the promoter region:
550 G>C (rs11003125, commonly called H/L) and
221 C>G (rs7096206, called Y/X);

one to the 5′-untranslated region
+4 C>T, (rs7095891, called P/Q).

Among L,X and Q variants, only X really impairs MBL serum level

The coding region (exon 1) polymorphisms:

+223 C>T (Arg52Cys, rs5030737), called A/D or A/O
+230 G>A (Gly54Asp, rs1800450), called A/B or A/O
+239 G>A (Gly57Glu, rs1800451), called A/C or A/O

D, B, and C variants are collectively designated O and wild type allele is designed A

Promoter SNPs affect the gene expression level (and thus MBL concentration in serum),
while D/B/C alleles are related to markedly diminished ability to opsonize microbial cells and to activate complement.


.... the combination of the genetic alterations into both exon 1 and promoter results in 3 MBL genotype expression groups, which are associated with

high (YA/YA, YA/XA),
medium (XA/XA, YA/YO), and
low ( XA/XO, XA/YO, XO/XO, XO/YO, YO/YO)
MBL serum levels [5, 13, 19].

Interesting , I've had low c3, which I also have a gene for
rs2230199(C;G) On a test I was producing about half of the lower limit, low c3 and lupus are supposedly correlated.
I had a quick look on my 23andme, which only caters for MBL2
I have
rs5030737(C;T) 14% pop
carrier of mannose binding deficiency but of low clinical importance
the rest look ok

rs7096206(C;C)

rs1800450(G;G)

What you know from your MBL2 genome is:

Promotor:

rs7096206(C;C) Y/Y

Exon 1:

rs5030737(C;T) A/O
rs1800450(G;G) A/A
rs1800451 ?? this one is missing in 23andme


So your Haplotype could be YO/YA (also called O/A) or YO/YO (also called O/O) if I am correct , because I'm not familiar with haplotypes. Only YO/YO is considered a low genotype for MBL2 so you just don't know.

(@wigglethemouse maybe you could help us?)

Do you have SLE? Do you catch easily respiratory infections?

MBL2 Genotypes and Their Associations with MBL Levels and NICU Morbidity in a Cohort of Greek Neonates (nih.gov)

Mannose-binding lectin-low genotypes are associated with milder systemic and immunological disease expression in primary Sjögren's syndrome | Rheumatology | Oxford Academic (oup.com)

(PDF) Serum Mannose-Binding Lectin Concentration, but Not Genotype, Is Associated With Clostridium difficile Infection Recurrence: A Prospective Cohort Study (researchgate.net)

 

[Jjnz]

Thankyou @pattismith , much appreciated.
I used to get a lot (1 every 2 yrs) of chest infections but was also a smoker, oddly last 5 years since CFS- had none. I'm negative for ANA but I did wonder about lupus because
(Night time flu feelings
I get a myriad of chest pains with PEM and was thinking fluid around heart or lungs,
costochondritis like pain in chest/ribs
can remit for weeks/months)
However I'm inclined now to think the variance and sporadic nature of symptoms is simply PEM with a 2-3 day delay.

 

[wigglethemouse]

(@wigglethemouse maybe you could help us?)

I'm afraid I can't think clearly to help on this - it is very confusing. I can't even figure out how you guys decoded the rsID's. Sorry.

I am heterozyogus for rs5030737 (Exon1) but also heterozyogus for rs7096206 (promoter).

 

[pattismith]

I'm afraid I can't think clearly to help on this - it is very confusing. I can't even figure out how you guys decoded the rsID's. Sorry.

I am heterozyogus for rs5030737 (Exon1) but also heterozyogus for rs7096206 (promoter).

I suppose you need to be homozygous O for at less one low variant in the Exon 1 (BB, CC or DD) in order to get the label OO.

So your haplotype may be XA/YO also called XAO or XO or O/XA and you may have low MBL.

I am O/O so in the low bag as well, and negative for typical Sjogren Ab, like you and all the Sjogren with Low MBL in the study.

I bet I have found why our disease is a problem for docs. We have immunodeficiency + auto-immune disease, and the immunodeficiency makes our auto-immune disease "less severe" which makes it challenging for diagnosis.
The other problem is that associated immunodeficiency makes it more challenging for immunosuppressive treatment.
This is probably the reason why I got infectious side effects from taking corticosteroids...

IVIG is probably the best opportunity you have

 

[bread.]

how is seronegative ss diagnosed - and if it is just diagnosed with a Schirmer test, why would it be ss in the first place? That is a thinking that makes no sense in a way?