Is CAR-T treatment hopeful as a cure for Sjögren's disease?

Sjögren's syndrome is an autoimmune disease characterized by inflammation of the exocrine glands, leading to symptoms such as dry eyes and dry mouth.   Neurological symptoms in Sjögren's syndrome can sometimes occur in the absence of the typical sicca (dryness) symptoms. This condition, often referred to as "neuro-Sjögren's," presents a challenge in diagnosis due to the atypical clinical manifestations.  Recent research shows that neuro-Sjögren's, is more common than was thought and one of the most common manifestations are "Sjögren's neuropathy", presenting as small fiber neuropathy causing pain and autonomic dysfunction, dysautonomia, POTS, and/or large fiber neuropathy causing sensory and motor impairments. Recently, due to a COVID-19 pandemic, the prevalence of POTS, MECFS and dysautonomia as part of the Long-COVID syndrome has risen, and the research to determine if the population of patients with POTS from autoimmune causes like Sjögren's, and population from COVID-19 due to Long-COVID, are differing in the etiology of the disease.

Sjögren's neurological symptoms can also affect the central nervous system (CNS).

 Studies have suggested that antibodies against specific G protein-coupled receptors (GPCRs), such as muscarinic acetylcholine receptors (M3 receptors), may be implicated in the pathogenesis of Sjögren's syndrome.   In the context of POTS and MECFS, the same autoantibodies have been investigated as well. Antibodies to beta-1, beta-2 adrenergic and muscarinic receptors have been identified in some individuals with POTS and ME/CFS. These autoantibodies can potentially interfere with the normal functioning of these receptors, contributing to the dysregulation of the autonomic nervous system and the characteristic symptoms of POTS.  The studies are ongoing to determine if GPCR autoantibodies play a role in Long COVID, Sjögren's  and POTS.

Common neurological symptoms in Sjögren's syndrome may include:

1. Peripheral Neuropathy: This can cause symptoms such as numbness, tingling, and pain in the extremities. Autonomic symptoms like Dysautonomia, POTS, autonomic neuropathy, NOH, Orthostatic Hypotension, AAG (Autonomic Autoimmune Ganglionopathy) are obseved manifestations.  There is also significant research and clinical experience that supports the observation that Sjögren's can cause ME/CFS in certain patients.

1. CNS Involvement: Sjögren's syndrome can affect the brain, leading to symptoms such as cognitive dysfunction, difficulty concentrating, memory problems, and, in some cases, more severe manifestations like seizures or mood disorders.
2. MS-like disease:  Brain MRI findings in Sjögren's syndrome may include white matter lesions, atrophy, and other abnormalities mimickng MS.
3. Cranial Neuropathies: Sjögren's syndrome can also cause inflammation of nerves in the head, leading to conditions such as trigeminal neuralgia or facial nerve palsies.
4. Myelitis: Inflammation of the spinal cord can occur, causing symptoms such as weakness, sensory disturbances, and problems with coordination.

It's important to note that neurological symptoms in Sjögren's syndrome can vary widely among individuals, and not everyone with Sjögren's will experience neurological complications. Neurological involvement in Sjögren's syndrome is thought to be due to inflammation and immune system activity affecting the nervous tissues.

Source: https://www.hopkinssjogrens.org/disease-information/sjogrens-syndrome/neurologic-complications/

While the exact mechanisms involved in Sjögren's syndrome are not fully understood, it is generally considered to be a B cell-driven disease. In the pathogenesis of Sjögren's syndrome, there is evidence of B cell hyperactivity, production of autoantibodies, and the formation of immune complexes. B cells play a role in the autoimmune response by producing antibodies that target the body's own tissues.

Also, the prevalence of Sjögren's syndrome in individuals with lupus varies in different studies. According to some estimates, approximately 15-20% of individuals with SLE also have Sjögren's syndrome.  

The animal lupus model, MRL/lpr Mouse Model is the model in which Dr Marko Radić tested CAR-T CD19 therapy for lupus in preclinical trials. The MRL/lpr model is considered an important animal model for Systemic Sjögren Syndrome because it contains also peripheral neuropathy and gland involvement (dryness/sicca), as discussed in the following research:

https://www.jrheum.org/content/47/1/157

 Of note, the MRL/lpr mouse model has also been historically identified as a pivotal model for neurological SLE, because of the neuropsychiatric/central nervous system (CNS) manifestations (which are not absent either in SS) seen in these mice. 

MRL/lpr mice also present with peripheral neuropathy, a particularly rare complication of SLE, but one of the most frequent in SS. Apart from these features, the clinical, biological, and histological phenotype of MRL/lpr mice encompasses the key features of SS: female sex predilection, decreased salivary flow rate (a feature erroneously noted as absent in all the review papers4 about animal models of SS, but which was noticed by us and other teams8 in MRL/lpr mice) and tear production, lymphocytic infiltrates in the salivary and lacrimal glands, and anti-Ro/SSA and anti-La/SSB autoantibodies production. Apart from the renal and CNS/peripheral nervous system manifestations, these mice also develop other manifestations resembling those of human patients with systemic SS, such as arthritis, pneumonitis, cryoglobulinemia, and signs of lymphoproliferation (lymphadenopathies, splenomegaly)7.

In general, plasma cells, which are differentiated forms of B cells, are responsible for producing antibodies. In the context of Sjögren's syndrome, elevated levels of plasma cells have been observed in the affected tissues, suggesting their involvement in the immune response.

BCMA (B-cell maturation antigen) is a receptor expressed on the surface of plasma cells. Targeting BCMA with CAR-T or CAR-NK cells could potentially be a strategy for treating diseases driven by plasma cells and has already been used for treating 3 patients with Sjögren's syndrome who also suffered from NMOSD (neuromyelitis optica spectrum diseases) and one case report of a patient who suffered from Sjögren's disease and INMN (myopathy).

CD19 is another B cell marker, and a CAR-T anti-CD19 therapy, has been successfully used in over 30 published cases of SLE (severe lupus with treatment resistant nephritis), and there has been one case report of a remission of Sjögren's in a woman treated for lymphoma.

All the above mentioned indicates that CAR-T treatment targetting B cells and plasma cells might be successful treatment for Sjögren's disease but studies are needed to determine efficacy and safety.

There have been curently 4 published case reports with Sjögren's disease patients successfully treated with CAR-T cell therapy. 

The first case report is of a 76-year-old woman with 10-year active Sjögren’s disease and diffuse large B-cell lymphoma, achieving complete remission by day 28. Post-treatment, she experienced a decrease in disease activity, evidenced by reduced EULAR score, improved symptoms, and normalized cytokine levels. Notably, autoantibodies turned negative for the first time since Sjögren’s diagnosis.

 IASO Bio company published 13 case series on BCMA targetted CAR-T therapy treating NMOSD spectrum diseases. 

Detailed information referring to co-existing autoimmune diseases

Of the 3 patients with Sjögren syndrome (SS), improvements in both clinical outcomes and laboratory measures were observed in 2 patients (Patient 12 did not reach her 12-week follow-up by the cutoff date). The levels of anti-SSA autoantibodies (a determined pathogenetic antibody in SS) decreased rapidly from 28.04 U/mL to below the minimum detection level in Patient 9 and to from 291.69 U/mL to 2.29 U/mL (indicating a negative status) in Patient 10 within 12 weeks. These signs of serologic remission were parallel to those of clinical remission. At enrolment and 12-week follow-up, the EULAR Sjögren's Syndrome patient reported index (ESSPRI) and EULAR Sjögren's syndrome disease activity index (ESSDAI) were calculated as previously defined.14 At week 12, a decrease was observed in the level of ESSPRI, from 11 to 3 in Patient 9 and from 17 to 8 in Patient 10. Similar changes were observed in the ESSDAI, with the score decreasing from 5 to 4 in Patient 9, and 11 to 8 in Patient 10. In correlation with these changes, the unstimulated salivary flow rate increased, together with tear breakup time and Schirmer’s test prolonged. 

4th case report also from IASO Bio with  highly refractory anti-SRP myopathy , accompanied by Sjogren's syndrome. 

 In the case of Lymphoma patient the patient experienced grade 2 CRS and grade 1 ICANS.  

Myopathy patient:

 Safety: The patient developed only grade 1 cytokine release syndrome (CRS), but had no immune effector cell-associated neurotoxicity syndrome (ICANS). Only transient hemocytopenia was observed.  

IASO Bio NMOSD :

2 patients had CRS 1, one patient had CRS 2, and no patients had ICANS.

Dr Donald Thomas: 

 However, I am concerned with Sjögren’s disease, which can have a high burden (large amounts) of B-cells. This could increase the risk for CRS and ICANS, as discussed above. CAR-T cell therapies showing low CRS and ICANS cases should be considered in Sjögren’s disease clinical trials. Such possible therapies that may not cause more side effects in those with a high B-cell burden include Descartes-08 and CAAR-T Therapy. https://www.lupusencyclopedia.com/car-t-cell-therapy-for-lupus/#process

 Sjögren's has no approved treatments due to high resistance of the disease to the standard treatments. This is perhaps not well knownn outside rheumatology ad patiets circles, but all thhe druugs approved for RA or SLE hav failed to show efficacy in Sjögren's . 

Some of which are: Hydroxychloroquine, Rituixmab, Belimumab (Benlysta), predisone, .. 

Otherhere is a great unmet need for effective treatment for Sjogrensr

The prevalennce: It is thhe seconnd most common autoimmune disease after hasimoto with 1% population

-: Sjögren's is highly B cell driven disease, with high invovlemnet of LLPC, making it so resistant to treatments that donnt target directly plasma cells and B cells. 

The Quality Of life in Sjögren's is shown to be lower than inn SLE and comparable to scleroderma (study)