Immunosuppressive treatment for peripheral neuropathies in Sjogren’s syndrome – 2020

[pattismith]

Immunosuppressive treatment for peripheral neuropathies in Sjogren’s syndrome – a systematic review

ANDREEA CAMELIA HUMĂ1, EVELYN MARIA KECSKEȘ1, DELIA TULBĂ2,
PAUL BĂLĂNESCU1,3, CRISTIAN BĂICUȘ1,3
1 “Carol Davila” University of Medicine and Pharmacy, Faculty of Medicine, Bucharest, Romania
2 Neurology Department, Colentina Clinical Hospital, Bucharest, Romania
3 Internal Medicine Department, Colentina Clinical Hospital, Bucharest, Romania

Background.
Sjogren’s syndrome (SS) is among the most frequent autoimmune diseases and one of its most severe extraglandular manifestations is peripheral neuropathy.
There is no consensus about peripheral neuropathy treatment in SS.
Our aim is to identify studies proving the efficiency of immunosuppressive treatment on peripheral neuropathies in SS.

Methods.
The search was conducted on the PubMed (MEDLINE) database. Studies with
patients diagnosed with SS and peripheral neuropathy were included.

Treatment with one of the following was among inclusion criteria:
glucocorticoids (GC), rituximab (RTX), azathioprine (AZA), mycophenolic acid (MMF), cyclophosphamide (CP), methotrexate (MTX), plasmapheresis or iv immunoglobulins (IV IG).

Results.
A total of 116 results were found and abstracts were examined. 103 papers were excluded, and the remaining 13 papers were analyzed. They were 3 case series and 10 case reports, retrospective, totalizing 62 patients of which 22 (35.5%) received IV IG, 8 (13%) received RTX, 7 (11%) CP, and 5 (8%) received only GC.
Drug associations containing corticosteroids were frequent.

Of those 22 treated with IV IG, 18 patients improved (82%), and 4 stabilized (18%).
IV IG was useful in sensory, motor and sensorimotor neuropathies.
CP had good results in mononeuritis multiplex, while autonomic neuropathies responded well to GC or RTX.

AZA, RTX, MTX, MMF or plasmapheresis were not used alone.
Follow-up periods were heterogenous and the evaluation of the neuropathy was not systematic.

Conclusion.
There is only low level evidence (retrospective case reports and case series).
In most cases, IV IG treatment in patients with peripheral neuropathies and SS resulted in clinical improvement, while other therapies, such as RTX, corticosteroids and CP proved to be useful in a handful of cases.

 

[pattismith]

March 25, 2013


Prompt therapy provided successful outcomes for patients with neurosjögren



Aggressive early therapy with pulse corticosteroids and cyclophosphamide in patients presenting with neurosjögren resulted in successful recoveries in a recent study.

In a retrospective chart review, researchers in Singapore followed eight women (median age, 51 years) with primary Sjögren’s syndrome (PSS), including neurologic involvement, for a mean of 19 months since manifestation onset.

Six patients displayed neurologic symptoms at PSS diagnosis; the other two presented at 9 and 30 years after diagnosis.

Manifestations included longitudinally extensive transverse myelitis, ataxic sensory neuropathy, axonal sensimotor neuropathy, cranial neuropathy and organic brain syndrome.

The majority of patients did not voluntary offer sicca symptoms during consultation, though when directly questioned, some reported slight ocular dryness and others cited difficulty in swallowing that required fluid intake.

After a mean of 11 days post-consultation, all patients began intravenously administered or oral methylprednisolone, and six were given monthly intravenous cyclophosphamide at a median cumulative dose of 5.1 g.

At 19-month follow-up, five patients displayed complete recovery from neurologic symptoms, with the others achieving “good recovery” regardless of type or site involvement, immunoglobulin and complement levels or erythrocyte sedimentation rate.

Two patients with peripheral neuropathy exhibited mild paresthesias, while those with transverse myelitis showed quicker therapy response and full recovery at 5 months.

“Neurologic disease, when present, is a strong contributor to disease activity and damage [in patients with PSS],” the researchers concluded.

“Vigilance is needed when female patients present with new-onset unexplained neurologic syndromes, as the typical sicca complex may be absent.

“Seemingly benign PSS may evolve over time to affect the neurologic system. Continued follow-up and awareness for new neurologic symptoms facilitate early intervention.

It is likely that early initiation of treatment contributed to good recovery in our patients.”

 

[pattismith]

This 2015 article shows that Methylprednisolone/cyclophosphamide is the first line treatment in many cases of Sjogren neuropathy:

Fig. 4. Flowchart for the treatment of neurological systemic manifestations. PN, peripheral polyneuropathy; CNS, central nervous system; MS, multiple sclerosis; GC, glucocorticoids; MP, methylprednisolone; CYC, cyclophosphamide.

 

[Aubry]

Thanks for this information. I am recently diagnosed with Primary Sjogren Syndrome and Small Fiber Neuropathy via ankle biopsy. I had positive lip biopsy for Sjogren (focus score >2), highly elevated anti-SSA antibodies. I don't have SICCA symptoms. My rheumatologist concluded I suffer from neuro-sjogren.
I tried 8 months IVIG (payed myself) but I received too low dosages unfortunately (1g/kg every 6 weeks). One should get 1-1.5g/kg every 4 weeks... So now my new neurologist is trying to get approval for that treatment. I did feel better on IVIG but not significant enough (because too low dosages imo).
I am now trying the Coimbra (high dose vitamin D) protocol for auto-immune diseases. If that protocol doesn't give me some long lasting relief I will present my rheumatologist to give me cyclofosfamide and steroids.
First I wanna try Coimbra Protocol
Simultaneously hopefully soon again high dose IVIG
In last stage (if above fails): cyclofosfamide + steroids

 

[pattismith]

Hello @Aubry ,

you were "luckily" positive for SSA, which usually allows a quicker diagnosis.
I hope you will soon improve with IVIG!
(I still wait for skin and lip biopsy (after only 35 years illness) so not sure if I have it or not)

 

[Aubry]

Yes. But in fact the positive lip biopsy was was enough for a 100% sjogren diagnosis (golden standard test). Together with small fiber neuropathy was easy to make the link neuro+sjogren I still hope the Coimbra Protocol will work since IVIG is not a walk in the park either...

 

[pattismith]

Yes. But in fact the positive lip biopsy was was enough for a 100% sjogren diagnosis (golden standard test). Together with small fiber neuropathy was easy to make the link neuro+sjogren I still hope the Coimbra Protocol will work since IVIG is not a walk in the park either...

IVIG is less risky than long cortisosteroid use, so you are in good hands I think

 

[pattismith]

@Pyrrhus

I saw my new neurologist today (one of the few" SFN experts" we have in my country).

He told me that
-Small Fiber Neuropathy is mainly idiopathic (so looking for the cause is more or less useless)
-and that Sjogren peripheral neuropathy always involved large fibers (not SFN only)....
Needless I feel a bit disappointed by him and by his teachers (he is a young one)...

Of course some studies conclude on the contrary that Sjogren can be associated with isolated SFN, but I didn't contradicted him.

I still wait for my skin biopsy, but he told me my lips biopsy was negative for Sjogren, even though some inflammation showed up...

He agreed on the fact I took a lot of corticosteroids in the last year that could produce a false negative lip biopsy.

So I'm still at the zero level to know if my neuropathy is related to a Sjogren or not.

Neuro Sjogren here in my country would be my only opportunity to receive an immuno-suppressive treatment.

Here some studies about Sjogren SFN (it could be usefull to other SFN folks as well)


Painful small-fiber neuropathy in Sjögren syndrome 2005


Positive salivary gland biopsy, Sjögren syndrome, and neuropathy: Clinical implications 2003

Extreme efficacy of intravenous immunoglobulin therapy for severe burning pain in a patient with small fiber neuropathy associated with primary Sjögren’s syndrome 2009

Neurological manifestations of primary Sjogren's syndrome 2010

Small fibre neuropathy: Diagnostic approach and therapeutic issues, and its association with primary Sjögren's syndrome 2010

Peripheral neuropathy in an outpatient cohort of patients with Sjögren's syndrome 2006

Sjögren Syndrome-Associated Small Fiber Neuropathy
Characterization From a Prospective Series of 40 Cases 2013

Biopsy-Proven Small-Fiber Neuropathy in Primary Sjögren's Syndrome: Neuropathic Pain Characteristics, Autoantibody Findings, and Histopathologic Features 2019

 

[Pyrrhus]

Needless I feel a bit disappointed by him and by his teachers (he is a young one)...

I'm sorry to hear that. It's always disappointing when you are excited to see a new expert, but then it becomes clear that you may know more than them!

 

[pattismith]

I'm sorry to hear that. It's always disappointing when you are excited to see a new expert, but then it becomes clear that you may know more than them!

Well @Pyrrhus , I worked hard to understand my disease, so did you!
(I had no other choice in order to survive after 35 years visiting unhelpful docs.)

But I am overall happy that this SFN expert agrees that my disease is a pure SFN, and agreed to propose me some drug to improve it without waiting for the skin biopsy (believe me or not, but there's only one lab in France to perform the test and I may wait 3 to 6 months before I will get the result...)

He also admitted my SFN goes with an "unadvertised" dysautonomia..... (I'm smiling because the dysautonomia testing they performed on me was really succinct, I mean ridiculously perfunctory... mostly only a sudoscan test ...)

My happiness comes mainly from earing from my expert's mouth something that I already knew, it's strange but it's a real relief after all that time alone in my hell

 

[Pyrrhus]

My happiness comes mainly from earing from my expert's mouth something that I already knew, it's strange but it's a real relief after all that time alone in my hell

Oh, I know! I know...

You could write an article about how to access decent ME/CFS treatment in France! Perhaps others might benefit?

 

[pattismith]

Here a new article about Peripheral Neuropathic System involvement in Sjogren (PNS)

Frontiers | Peripheral Nervous System Involvement in Sjögren’s Syndrome: Analysis of a Cohort From the Italian Research Group on Sjögren’s Syndrome | Immunology (frontiersin.org)

"The most frequent types observed were pure sensory neuropathies and axonal sensorimotor polyneuropathies (SMP). Patients with PNS involvement exhibited a more active disease profile and were more frequently treated with immunosuppressants.

Intriguingly, clinical and serological negative prognostic factors, including purpura, extra-glandular manifestations, leukopenia, low complement and cryoglobulinemia, principally characterized patients with SMP, while subjects with pure sensory neuropathy displayed a milder phenotype."

These observations can also explain the higher need of GCs and IS therapy in patients with SMP and reinforce the hypothesis that SMP and pure sensory neuropathy patient subgroups may belong to a distinct disease phenotype which may reflect the existence of different pathogenic mechanisms underlying the high variability of disease-specific clinical and immunological features with consequent variable prognosis. Altogether, the results of our study may suggest that pSS patients with pure sensory neuropathy show an intermediate degree of disease severity between subjects with SMP and those with no PNS involvement.

In this setting, it has been long evident that anti-Ro/SSA and anti-La/SSB autoantibodies are associated with more diffuse glandular infiltrate and several extra-glandular manifestations, but not with PNS involvement (22). In fact, a recent analysis of the Big Data Sjögren Project Consortium international registry showed that anti-Ro/SSA and anti-La/SSB positive patients were characterized by higher frequency of activity in many ESSDAI domains except for PNS and CNS ones (18). Similarly, in a wide prospective Korean study, anti-Ro/SSA-negative patients were characterized by higher prevalence of PNS ESSDAI domain features in comparison to anti-Ro/SSA-positive subjects (23).

We confirmed a relatively high prevalence of pure sensory neuropathy (14–16, 21, 24–36). This manifestation may have a negative impact on disease outcome and patient quality of life due to disabling symptoms, often requiring immunosuppressive therapies (37–39). pSS subjects with evidence of pure sensory neuropathies, including SFN and DRG, are usually characterized by a low prevalence of serological markers of chronic B-cell activation, including ANA, anti-Ro/SSA, anti-La/SSB and rheumatoid factor (14–16, 21, 24–36).

The reason why we failed to confirm this observation is probably due to the low proportion of “seronegative” PSS patients and of patients – around 10% - who had the neurological diagnosis before pSS diagnosis in our cohort. In fact, pure sensory neuropathy can be characterized by sicca symptoms per se, which may represent a possible confounding factor for the diagnosis of pSS (33).

Thus, the unusual high proportion of “seronegative” pSS patients with pure sensory neuropathy reported in several studies may question the accuracy of pSS diagnosis. Our findings support the idea that pure sensory neuropathy developing in the course of pSS represents a distinct entity and is probably sustained by different pathogenic mechanisms compared to pure sensory neuropathy complicated by sicca syndrome, often erroneously diagnosed as “seronegative” pSS.

Our data confirm the hypothesis that SMP is mainly sustained by vasculitis and immune-complex deposition disease, while pure sensory neuropathy may be caused by a direct immune-mediated damage (19). This aspect also reflects on the treatment of the disease.

In fact, although immunosuppressive therapy was more prevalent in both our cohorts with PNS involvement, compared to subjects with no PNS disease, the recently published EULAR recommendations suggest first-line immunosuppressive therapy in case of SMP and DRG and symptomatic therapy in patients with axonal sensory polyneuropathy (40).

In this context, it is intriguing to analyze these data from a neurological perspective. In fact, the most common immune-mediated causes of SFN and DRG are represented by pSS and celiac disease (41–43). Since PNS manifestations, in particular SFN and DRG, represent typical clinical features of celiac disease which, in turn, has been recently shown to be closely associated with pSS (44), an intriguing and still unexplored common pathogenic network may be hypothesized.