Sjögren's syndrome—what more can we do?

Our understanding of the autoimmune basis of Sjögren's syndrome has evolved in the past several years, and this is offering new considerations for rational therapy that go beyond the old standard of care with its disappointing results. The authors of a paper recently published in the journal Arthritis Research & Therapy state:

"In vitro and in vivo experimental data have pointed to new immunopathogenic mechanisms in primary Sjögren's syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. This has taught us that the role of proinflammatory cytokines, in particular TNFα, is not crucial in the immunopathogenesis of pSS. B cells appear to play a major role, as depletion of B cells leads to restoration of salivary flow and is efficacious for treatment of extraglandular manifestations and mucosa-associated lymphoid tissue lymphoma. B cells also orchestrate T-cell infiltration and ductal epithelial dearrangement in the salivary glands. Gene profiling of salivary gland tissue in relation to B-cell depletion confirms that the axis of IFNα, B-cell activating factor, B-cell activation, proliferation and survival constitutes a major pathogenic route in pSS."

B cells are a kind of white blood cell (lymphocyte) that, when stimulated by an antigen, turn into plasma cells that produce antibodies that further attack that antigen. This is part of the humoral (versus cell-mediated) or Th2 (versus Th1) immune response. In addition to interferon alpha (IFNα) and B-cell activating factor, a study published in Clinical Immunology details the role of interleukin-14 alpha (IL-14a) in Sjögren's syndrome. The authors state:

"To evaluate the role of interleukin 14 alpha (IL-14a) in Sjögren's syndrome (SS), we evaluated the expression of IL-14a in the peripheral blood lymphocytes (PBL) of patients with primary and secondary SS and normal controls by quantitative RT-PCR."

They concomitantly examined transgenic IL-14a mice for both tissue and immune characteristics of Sjögren's syndrome. Interestingly...

"Patients with both primary and secondary Sjögren's syndrome expressed IL-14a at statistically higher levels in their peripheral blood compared to normal controls matched for age, sex and ethnic group. Transgenic mice in which IL-14a expression was increased constitutively were previously demonstrated to develop...all the clinical and immunological features of primary Sjögren's disease...Thus IL-14a is important in the pathophysiology of Sjögren's disease."

IL-14 alpha is a Th2 type cytokine that promotes B cell proliferation and maintenance. Based on these and related findings the use of biological therapy has emerged as a focus for treatment. (Biological therapy modulates immune system activity, often using agents that act as biological response modifiers.) Efforts have been made to exploit this understanding as documented in a paper published last year in Autoimmunity Reviews:

""Conventional therapy (moisturizers, pilocarpine, Cevimeline, local Cyclosporine, and hydroxychloroquine) remains the basis for the treatment of primary Sjögren's syndrome (pSS) but they do not modify the course of the disease. Rituximab is currently the most fully evaluated biologics in pSS. Open-label studies suggest that Rituximab is well tolerated (although infusion-related reactions and serum sickness remain possible), induces a rapid depletion of B cells in the blood and salivary glands, and could improve early active pSS or pSS with active extra glandular involvement. Two small double blind randomized studies have been conducted and now published, demonstrating its efficacy on fatigue and sicca syndrome in early disease."

Two larger studies were underway at the time the paper came out, and a paper just published in Expert Opinion on Biological Therapy reviews the evidence available at this time in regard to Sjögren's syndrome:

"Primary Sjögren's syndrome (PSS) is a relatively common immune-mediated condition characterized by oral and ocular dryness, fatigue, musculoskeletal pain and poor health-related quality of life. Other extra-glandular organs can also be affected and PSS is associated with a markedly increased risk of lymphoma. Furthermore, the health-economic cost for PSS is substantial. There is currently no effective treatment available. With better understanding of the pathophysiology of PSS and advances in technologies, it is now possible to develop biological therapies to target specific molecules or molecular pathways that are important in PSS pathogenesis. Indeed, a limited number of biological therapies have already been tested in PSS with mixed successes."

However, biological agents such as rituximab are not easy manage and come with the potential for serious side effects when B-cell activity, necessary for normal immunity, is blocked with a 'blunt instrument'. findings suggest that we shouldn't be 'putting all our eggs in one basket'. An overview of reviews published in the highly respected Cochrane Library highlights the concerns:

"Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates."

The authors investigated adverse effects from a number of biologics including tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) associated with 163 randomized controlled trials comprising 50,010 participants, and 46 extension studies with 11,954 more participants. Their data sound a cautionary note:

"Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events, number needed to treat to harm (NNTH) and withdrawals due to adverse events and an increased risk of TB reactivation compared to control."

Clinicians may wish to read the paper in its entirety to see the differences in this regard between the various biologics. The authors conclude:

"Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results...There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics."

What else can we do to modulate the course of the disease? Identifying and removing agents that trigger and amplify the inflammatory autoimmune activity is an important consideration. Abundant evidence has accumulated linking Sjögren's syndrome with gluten sensitivity. A study published in The American Journal of Gastroenterology draws attention to this association:

"Many autoimmune diseases occur concomitantly with celiac disease. We investigated prospectively the occurrence of celiac disease and small-bowel mucosal inflammation in patients with primary Sjögren's syndrome."

Clinicians know that when autoimmune activity has been set in motion there is rarely only one tissue target for the inflammatory attack. The authors examined 34 patients with primary Sjögren's syndrome and 28 controls by small bowel biopsy, the presence of intraepithelial lymphocytes (white blood cells within the intestinal lining), DQA and DQB genes for gluten sensitivity, serum antiendomysial and antigliadin antibodies. I find their data to be of special significance:

"Five (14.7%) of 34 Sjögren's syndrome patients were found to have celiac disease. The density of jejunal intraepithelial γδ+ T cells was increased in all celiac and in four nonceliac patients. All celiac patients, 69% of nonceliac Sjögren's syndrome patients, and 11% of control subjects showed enhanced HLA-DR expression. HLA DQ2 was present in 19 (56%) patients with Sjögren's syndrome, including all five with celiac disease."

A critical point is embedded here: non-celiac autoimmune manifestations of gluten sensitivity have become very common. While a modest percentage of the Sjögren's syndrome cohort had the celiac disease 'version' of gluten sensitivity, most showed activation of the HLA-DR and DQ genes expressing gluten sensitivity. The authors concluded:

"The findings show a close association between Sjögren's syndrome and celiac disease. Even among nonceliac patients with primary Sjögren's syndrome, an ongoing inflammation is often present in the small bowel mucosa."

Research published in the Scandinavian Journal of Gastroenterology adds more evidence to the connection between gluten sensitivity and Sjögren's syndrome, while cautioning that the gastrointestinal symptoms of celiac disease may not be present. The authors set out to...

"...evaluate the rectal mucosal response to gluten as an indication of gluten sensitivity in patients with primary Sjögren's syndrome (pSS)."

They exposed the rectal tissue of 20 patients with Sjögren's syndrome and 18 controls to wheat gluten. Fifteen hours later they measured the mucosal tissue release of nitric oxide (NO). What did they find?

"Five patients with pSS had a significant increase in the luminal release of NO after the rectal gluten challenge, indicating gluten sensitivity. All were HLA-DQ2 and/or -DQ8-positive. Two of the patients with increased NO had antibodies against transglutaminase and a duodenal biopsy showed an absolutely flat mucosa consistent with coeliac disease in one of the patients. Before gluten challenge, 15 of the Sjögren's syndrome (SS) patients reported gastrointestinal symptoms, and 8 reported intolerance to various food products. No correlation was found between gluten sensitivity and self-reported food intolerance or gastrointestinal symptoms."

Note again the last point that gluten sensitivity can manifest as an attack on a wide variety of tissue targets without gastrointestinal symptoms. The authors concluded:

"Rectal mucosal inflammatory response after gluten challenge is often seen in patients with pSS, signifying gluten sensitivity. However, this reactivity is not necessarily linked to coeliac disease."

The authors of a paper recently published in the Romanian Journal of Internal Medicine also comment:

"Celiac disease (CD) is an immune mediated enteropathy with an increasing prevalence worldwide...The clinically silent form affects the majority of patients. Hence, diarrhea, nutritional deficiencies and weight loss are symptoms which are not very often seen."

They further state:

"The high risk groups have been identified to be those patients suffering from autoimmune insulin-dependent diabetes mellitus, osteoporosis, Sjogren's syndrome and the first degree relatives of CD patients. Those patients should be screened for CD. The association of CD with several autoimmune ailments has various explanations ranging from common genotypes to systemic immune reactions triggered by food antigens."

A case report published in the journal Zeitshrift für Rheumatologie is worth noting in this context. The authors state:

"We report on a 26 year old woman with dermatitis herpetiformis Duhring, diagnosed at 10 years of age, who developed arthritis, symptoms of celiac disease, and Sjögren's syndrome 15 years later. Clinical symptoms, biopsies of duodenal mucosa and salivary glands as well as serological findings established the diagnoses."

Most importantly..."Gluten-free diet alleviated severity of clinical symptoms very quickly indicating the basic pathology of celiac enteropathy in the immunological disorders."A study published in the journal Clinical & Experimental Allergy alerts us to the fact that other food sensitivities can be involved with Sjögren's syndrome, in this case cow's milk protein. The authors note:

"Patients with primary Sjögren's syndrome (pSS) are reported to have a variety of gastrointestinal symptoms partly attributed to an overrepresentation of celiac disease. We have observed that irritable bowel syndrome (IBS)-like symptoms are frequent complaints in this patient group. Allergic manifestations to various drugs are also common in pSS. A role of food allergy in IBS has been proposed."

In this case the investigators examined the mucosal response to a rectal challenge with cow's milk protein (CM) in 21 patients with pSS and 18 healthy controls. Fifteen hours later they measured the mucosal production of nitric oxide (NO) and the release of myeloperoxidase (MPO) as indicators of a mucosal inflammatory reaction. They found that a significant percentage of Sjögren's syndrome subjects react to cow's milk protein:

"Eight out of 21 patients with pSS had a definite increase of mucosal NO synthesis and the luminal release of MPO after rectal CM challenge."

Interestingly...

"This sign of milk sensitivity was not linked to IgG/IgA antibodies to milk proteins."

Consider the clinical significance that there was an inflammatory response to cow's milk protein challenge in the absence of IgG and IgA antibodies. Furthermore...

"All patients who were CM sensitive suffered from IBS. In a small open study, patients reactive to CM reported an improvement of intestinal symptoms on a CM-free diet."

The authors conclude:

"A rectal mucosal inflammatory response after CM challenge is seen in 38% of patients with pSS as a sign of CM sensitivity. IBS-like symptoms were common in pSS, linked to CM sensitivity."

Taken together, this evidence suggests that it is very important for practitioners and patients both not to overlook the potential role of gluten and other food sensitivities as a causative factor in Sjögren's syndrome. Clinicians should note that a laboratory panel that does not include the full range of anti-gliadin and transaminase antibodies can be misleading and are urged to employ one that does. The scope of this post does not encompass the use of evidence-based natural agents to modulate immune system function within the functional medicine approach; practitioners are welcome to comment on this post or contact me personally for discussion. But I'll wrap this up with a study published not long ago in the journal Rheumatology in which the authors set out to...

"...investigate the immunomodulating role of fat-soluble vitamins in 25 patients with primary SS (pSS) and 15 healthy individuals...Nutritional defects, including vitamin deficiencies, are commonly associated with impaired immune responses..."

They measured plasma levels of vitamins A, D and E; natural killer [NK] T cells, T-cell subsets, B cells, IL-10 producing Tr1 cells, CD4+CD25+ Treg cells and Th17 cells, along with a number of Th1- and Th2-soluble and intracytoplasmic cytokines(IFN-γ, IL-4, -10 and -17. They then drew correlations between vitamin levels and immunological and clinical parameters.

"Vitamin A levels did not differ between patients and controls, yet in patients with extraglandular manifestations (EGMs) a significant decrease in vitamin A levels was apparent compared with pSS patients without EGMs. Vitamin E levels were increased in patients compared with controls, whereas vitamin D levels were similar in pSS and control subjects. In patients, vitamin A showed a positive correlation with both NK cell and Th17 cell, and a negative correlation with Schirmer’s test values [Schirmer’s test determines whether the eye produces enough tears to keep it moist.]. Positive correlation was found between vitamin E and NK cells, Th1 cells and the Th1/Th2 ratio. In the control group, we found correlation between vitamin E and serum IL-10 levels [immunoregulating]."

The authors sum up the significance of this in their conclusion:

"Our data suggest that fat-soluble vitamins may be important in immunoregulatory processes in patients with pSS."