Category Archives: Autoimmune

Patients on steroids must have Vit D levels checked

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A study just published in The Journal of Clinical Endocrinology & Metabolism alerts clinicians to the need for vigilance in attending to vitamin D levels for patients on chronic steroid medication. The authors state:

“In many disorders requiring steroid therapy, there is substantial decrease in bone mineral density. The association between steroid use and 25-hydroxyvitamin D [25(OH)D] deficiency has not been confirmed in large population-based studies, and currently there are no specific vitamin D recommendations for steroid users…The aim of the study was to evaluate the association of serum 25(OH)D deficiency [defined as 25(OH)D <10 ng/ml] with oral steroid use.”

They performed a cross-sectional analysis on a nationally representative sample of 22,650 U.S. children and adults from the NHANES study. (This is considered representative of 286 million U.S. residents.) It’s not clear why they set the bar so high, but their main outcome measure was serum 25(OH)D levels below 10 ng/ml which is a severe deficiency. What did the data show?

“A total of 181 individuals (0.9% of the population) used steroids within the past 30 d. Overall, 5% of the population had 25(OH)D levels below 10 ng/ml. Among steroid users, 11% had 25(OH)D levels below 10 ng/ml, compared to 5% among steroid nonusers. The odds of having 25(OH)D deficiency were 2-fold higher in those who reported steroid use compared to those without steroid use. This association remained after multivariable adjustment and in a multivariable model using NHANES III data.”

It’s a bit of a jolt to know that as many as 5% of the US population has 25(OH)D levels below 10 ng/ml. The risk is doubled for those on chronic steroids. The authors conclude:

“Steroid use is independently associated with 25(OH)D deficiency in this nationally representative cohort limited by cross-sectional data. It suggests the need for screening and repletion in patients on chronic steroids.”

Helicobacter pylori infection and autoimmune diseases

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Those managing cases of Helicobacter pylori infection (according to the World Health Organization the most common infection worldwide) should be alert to the association of Helicobacter infection and autoimmune diseases. The authors of a paper published in the journal Biomedicine & Pharmacotherapy discuss this connection, beginning with the autoimmune component of cardiovascular disease:

“In the last few years several studies have been performed on the association between H. pylori infection and a miscellany of extragastric disorders which also include autoimmune diseases. In particular, emerging evidence seems to give a potential role for H. pylori in ischaemic heart disease via a cross mimicry between antibodies against heat shock protein 65 which are produced in the consequence of infection, but which are also expressed in atherosclerotic lesions.”

They note that other autoimmune diseases have been recognized in this regard:

“In cases of healing of Sjogren syndrome and Schonlein-Henoch purpura have also been reported. A recent study, moreover, showed that eradication of H. pylori infection may be effective in the disappearance of autoimmune thrombocytopenia. Finally, a role for H. pylori has also been postulated in other autoimmune diseases such as membranous nephropathy and some acute immune polyneuropathies.”

We can also appreciate a paper just published in the journal Oral Diseases in which the authors observe:

“Helicobacter pylori (H. pylori) is a widely prevalent microbe, with between 50 and 80% of the population infected worldwide. Clinically, infection with H. pylori is commonly associated with peptic ulcer disease, but many of those infected remain asymptomatic.”

They proceed to elaborate on the implications for autoimmune disorders:

“H. pylori has evolved a number of means to affect the host immune response and has been implicated in many diseases mitigated by immune dysregulation, such as immune thrombocytopenic purpura (ITP), atrophic gastritis, and mucosa associated lymphoid tissue (MALT) lymphoma. Autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Sjogren’s syndrome, are the result of a dysregulated host immune system which targets otherwise healthy tissues…Because of its prevalence and ability to affect human immune function, many researchers have hypothesized that H. pylori might contribute to the development of autoimmune diseases. In this article, we review the available literature regarding the role of chronic H. pylori infection in various autoimmune disease states.”

Case management of H. pylori infection requires vigilance for the possibility of an autoimmune condition, and for those suffering an autoimmune diagnosis the possibility of infection should be ruled out.

Sjögren syndrome and autoimmune thyroiditis

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Although autoimmune diseases are labeled as separate diagnostic entities, it’s important to bear in mind that this nomenclature masks the fact that they are like branches growing from the same trunk. While the tissue targets of autoimmune inflammatory attack differ according to the individual, the underlying causal factors are similar. Moreover, if one tissue is under autoimmune attack, it is almost always that others are too. A report published in the Journal of Clinical Rheumatology draws attention to the association of autoimmune thyroid disease and Sjögren syndrome. The authors state:

“The thyroid, salivary, and lacrimal glands are susceptible to immunologic damage, which can be expressed as an organ-specific autoimmune disease such as thyroiditis, or a systemic autoimmune disease such as primary Sjögren syndrome (pSS). Sjögren syndrome is characterized by the progressive destruction of the exocrine parotid and lacrimal glands, causing mucosal and conjunctival dryness (sicca syndrome). The serology of patients with pSS often shows elevated levels of antibodies including antinuclear antibody, rheumatoid factor, Ro (SS-A), and La (SS-B). There is a growing body of literature suggesting an increased risk of autoimmune thyroid disease (AITD) in individuals with pSS and an increased risk of pSS in individuals with AITD.”

They continue to describe the case of a 41-year-old man suffering from autoimmune hypothyroid disease who was also found to have pSS after thyroid hormone replacement therapy was initiated. They elaborate the salient implications:

“Patients with one autoimmune disease are often at increased risk for developing another autoimmune disease. In the case of 170 Hungarian subjects with Hashimoto thyroiditis (HT), 17% had Sjögren syndrome. In a group of 176 Spanish patients with AITD…the prevalence of keratoconjunctivitis was 23% and that of xerostomia was 37%. In 2 smaller studies of patients with autoimmune thyroiditis and hypothyroidism, 22% to 58% had salivary gland abnormalities as demonstrated by parotid scintigraphy, sialometry, and/or salivary gland biopsies showing lymphocytic involvement.”

Furthermore…

“…patients with pSS may show higher rates of AITD. The largest retrospective study to date included 479 patients from Hungary with pSS, who had thyroid function testing every 3 to 6 months. The frequency of HT was 6%, which was greater than the 1% to 2% frequency in the general population…In other smaller studies, the prevalence of HT in patients with pSS ranged from 11% to 50%.”

The authors note a study in which the sera from 26 patients with pSS and 7 patients with hypothyroid were tested for antihuman thyroglobulin (antihTg) antibody activity. Interestingly, all of the pSS sera contained IgG and IgM antihTg autoantibodies, the antihTg autoantibodies in patients with pSS and HT overlapped in their reaction with a certain region on the thyroglobulin molecule. They conclude:

“As demonstrated in this case, primary Sjögren syndrome and AITD are often associated. Although not all studies consistently demonstrated an increased association, the number of positive studies and the larger studies suggest a true association…Rheumatologists and endocrinologists may miss the presence and association of these 2 autoimmune conditions, given several nonspecific and overlapping symptoms such as fatigue, weight gain, and diffuse myalgias. We therefore recommend that rheumatologists consider assessing patients with Sjögren syndrome with periodic thyroid function testing.”

Moreover, clinicians managing any autoimmune disease should be alert to the presence of autoimmune activity involving additional target sites. And of course we must bear in mind the necessity of going beyond symptom management to investigate and treat the underlying causal factors. Those with a particular interest may wish to read the earlier post on Sjögren syndrome.

Sublingual feverfew and ginger combination can abort a migraine

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It’s long been known that the herb feverfew (Tanacetum parthenium) can reduce the frequency and intensity of migraine attacks if taken ahead of time on a regular basis, but alternatives to triptan medications for acute application are in short supply. Therefore I’m glad to see a study just published in Headache: The Journal of Head and Face Pain offering evidence that the novel sublingual preparation of feverfew plus ginger LipiGesic M™ can rapidly abort or ameliorate a migraine headache. The authors state:

“Therapeutic needs of migraineurs vary considerably from patient to patient and even attack to attack. Some attacks require high-end therapy, while other attacks have treatment needs that are less immediate. While triptans are considered the “gold standard” of migraine therapy, they do have limitations and many patients are seeking other therapeutic alternatives. In 2005, an open-label study of feverfew/ginger suggested efficacy for attacks of migraine treated early during the mild headache phase of the attack.”

Pursuant to this they designed the double-bind placebo-controlled study reported here that included 60 patients who self-treated 221 attacks of migraine with either the sublingual feverfew/ginger preparation or placebo. Additionally…

“All subjects met International Headache Society criteria for migraine with or without aura, experiencing 2-6 attacks of migraine per month within the previous 3 months. Subjects had <15 headache days per month and were not experiencing medication overuse headache. Inclusion required that subjects were able to identify a period of mild headache in at least 75% of attacks. Subjects were required to be able to distinguish migraine from non-migraine headache.”

Subjects were randomized to receive either sublingual feverfew/ginger or a matching placebo, and told (but not required) to initiate treatment as soon as they recognized that a migraine was starting. What were the results?

“Sixty subjects treated 208 evaluable attacks of migraine over a 1-month period; 45 subjects treated 163 attacks with sublingual feverfew/ginger and 15 subjects treated 58 attacks with a sublingual placebo preparation…At 2 hours, 32% of subjects receiving active medication and 16% of subjects receiving placebo were pain-free. At 2 hours, 63% of subjects receiving feverfew/ginger found pain relief (pain-free or mild headache) vs 39% for placebo. Pain level differences on a 4-point pain scale for those receiving feverfew/ginger vs placebo were −0.24 vs −0.04 respectively. Feverfew/ginger was generally well tolerated with oral numbness and nausea being the most frequently occurring adverse event.”

This is clearly palliative treatment rather than therapy designed to address the underlying causes of migraine (see forthcoming posts regarding the functional medicine approach to migraine). However, an effective palliative that is wholesome and free of serious side-effects as implied in the authors’ conclusion is welcome news:

“Sublingual feverfew/ginger appears safe and effective as a first-line abortive treatment for a population of migraineurs who frequently experience mild headache prior to the onset of moderate to severe headache.”

 

Gluten sensitivity can increase suicide risk

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“When the gut is inflamed, the brain is inflamed” is a guideline that clinicians should bear in mind, and depression is one possible expression of brain inflammation. A study just published in the journal Digestive and Liver Disease offers evidence that inflammatory reactions to gluten can increase the risk for suicide. The authors state:

“Individuals with coeliac disease have increased risk of depression and death from external causes, but conclusive studies on death from suicide are missing. We examined the risk of suicide in coeliac disease and amongst individuals where the small intestinal biopsy showed no villous atrophy.”

The authors collected biopsy data on 29,083 individuals (from all 28 clinical pathology departments in Sweden) 1969–2007 who had celiac disease with villous atrophy (eroded gut lining), and another 13,263 who had non-celiac gluten sensitivity (inflammation but without villous atrophy), and 3719 subjects with positive coeliac disease lab results but normal mucosa. They the calculated Hazard ratios for suicide as recorded in the Swedish Cause of Death Register. What did their data show?

“The risk for suicide was higher in patients with coeliac disease compared to general population controls (HR = 1.55; based on 54 completed suicides). Whilst suicide was also more common amongst individuals with inflammation (HR = 1.96), no such increase was seen amongst individuals with a normal mucosa but positive coeliac disease serology.”

In other words, their data showed a 96% increase in risk for suicide among those with gluten sensitivity who had gut inflammation. These findings are in keeping with the extensive evidence for brain inflammation as a factor in depression and the linked between microinflammati0n in the gut and destructive glial activity in the brain. The authors conclude with an exhortation to practitioners:

“We found a moderately increased risk of suicide amongst patients with coeliac disease. This merits increased attention amongst physicians treating these patients.”

Note: Many diagnoses are missed due to inadequate laboratory resources. Only Cyrex Labs currently offers a complete gluten sensitivity test panel.

 

Microscopic blood in the urine can be a risk for severe kidney disease

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Trace amounts of blood cells in the urine without symptoms is often dismissed, but a study just published in JAMA (The Journal of the American Medical Association) offers evidence that asymptomatic microscopic hematuria can be a risk factor for serious kidney disease requiring dialysis and/or transplant. The authors set out to…

“…evaluate the risk of end-stage renal disease (ESRD) in adolescents and young adults with persistent asymptomatic isolated microscopic hematuria.”

They conducted a cohort study using medical data from 1,203,626 subjects, male and female, who were examined for for the Israeli military services, with reference to the Israeli treated ESRD registry. They were then able to estimate the hazard ratio (HR) of treated ESRD among those diagnosed as having persistent asymptomatic isolated microscopic hematuria. The outcome measure for ESRD was initiation of dialysis or kidney transplantation. What did the data show?

“A substantially increased risk for treated ESRD attributed to primary glomerular disease was found for individuals with persistent asymptomatic isolated microscopic hematuria compared with those without the condition (incidence rates, 19.6 vs 0.55 per 100 000 person-years, respectively; HR, 32.4).”

Although the overall incidence of ESRD among young adults is very low, when asymptomatic microscopic hematuria is detected by positive dipstick and confirmed by microscopic analysis, clinicians should be alert to the possibility of an underlying (likely autoimmune) process that could evolve into ESRD by bearing in mind the authors’ conclusion:

“Presence of persistent asymptomatic isolated microscopic hematuria in persons aged 16 through 25 years was associated with significantly increased risk of treated ESRD for a period of 22 years, although the incidence and absolute risk remain quite low.”

 

 

Inflammation caused by allergy promotes weight gain and obesity

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As clinicians and most lay readers know, healthy weight loss and weight maintenance require healthy insulin signaling. Insulin receptor resistance due to excessive glycemic stimulation results in higher compensatory insulin levels that force the storage of calories as fat. Inflammation also contributes to insulin resistance, with metabolic syndrome and its associated weight gain and eventual type 2 diabetes. A fascinating study just published in the journal Obesity describes how B cell-activating factor (BAFF) contributes to the development of insulin resistance. BAFF can be induced by food hypersensitivity and allergic reactions. The authors state:

“Visceral adipose tissue (VAT) inflammation has been linked to the pathogenesis of insulin resistance and metabolic syndrome. VAT has recently been established as a new component of the immune system and is involved in the production of various adipokines and cytokines. These molecules contribute to inducing and accelerating systemic insulin resistance. In this report, we investigated the role of B cell-activating factor (BAFF) in the induction of insulin resistance.”

They examined BAFF levels in the blood and visceral fat of obese mice, which they found to be increased compared to normal control mice…

“Next, we treated mice with BAFF to analyze its influence on insulin sensitivity. BAFF impaired insulin sensitivity in normal mice. Finally, we investigated the mechanisms underlying insulin resistance induced by BAFF in adipocytes. BAFF also induced alterations in the expression levels of genes related to insulin resistance in adipocytes. In addition, BAFF directly affected the glucose uptake and phosphorylation of insulin receptor substrate-1 in adipocytes.”

In other words, BAFF not only directly induced insulin resistance, but altered the expression of genes related to insulin receptor function and fat inflammatory cytokine (adipokine) production. The authors concluded:

“We propose that autocrine or paracrine BAFF and BAFF-receptor (BAFF-R) interaction in VAT leads to impaired insulin sensitivity via inhibition of insulin signaling pathways and alterations in adipokine production.”

We can also appreciate an earlier paper published in the journal Experimental & Molecular Medicine that also identifies BAFF as an adipokine that links inflammation with obesity. The authors state:

“In the current study, we verified that BAFF expression is increased during adipocyte differentiation…We sought to identify known BAFF receptors (BAFF-R, BCMA, and TACI) in adipocytes, and determined that all three were present and upregulated during adipocyte differentiation…BAFF-R and BCMA expression levels were upregulated under pro-inflammatory conditions…”

They also demonstrated that the BAFF receptors BAFF-R and BCMA were downregulated by rosigliatazone treatment. (Rosigliatzone, trade name Avandia, is a thiazolidinedione type anti-diabetic drug with anti-inflammatory properties whose use has been complicated by serious side effects.) In other words, inflammation associated with BAFF signaling promoted insulin resistance and obesity. The authors conclude:

“Taken together, our results suggest that BAFF may be a new adipokine, representing a link between obesity and inflammation.”

Incidentally, as the authors of a review just published in the Journal of Clinical Investigation note, obesity-associated inflammation has serious global effects:

“The obesity epidemic has forced us to evaluate the role of inflammation in the health complications of obesity…The reframing of obesity as an inflammatory condition has had a wide impact on our conceptualization of obesity-associated diseases.”

Moreover…

“The chronic nature of obesity produces a tonic low-grade activation of the innate immune system that affects steady-state measures of metabolic homeostasis over time…While transient inflammatory states such as sepsis can have multi-organ effects, few other chronic inflammatory diseases are characterized by the features of pancreatic, liver, adipose, heart, brain, and muscle inflammation as is seen in obesity.”

Clinicians should never overlook the role of the gut-associated immune tissue (GALT) in disorders of chronic inflammation. A paper just published in Current Opinion in Clinical Nutrition & Metabolic Care highlights this in the link between intestinal inflammation, obesity and insulin resistance. The authors state:

“Current views suggest that obesity-associated systemic and adipose tissue inflammation promote insulin resistance, which underlies many obesity-linked health risks. Diet-induced changes in gut microbiota also contribute to obesity…”

They go on to summarize…

“…the evidence supporting a role of intestinal inflammation in diet-induced obesity and insulin resistance and discusses mechanisms.”

Of course, food allergy and hypersensitivity are major causes of intestinal inflammation. Regrettably, many practitioners may wrongly assume that the phenomenon of inflammation triggered by food sensitivity is limited to the classically defined IgE-mediated acute hypersensitivity reaction. In fact, there are a number of pathways by which food sensitivity can elicit an inflammatory response. A very important study just published in Alimentary Pharmacology & Therapeutics makes this clear in regard to BAFF, which we now understand to be linked to obesity and insulin resistance. The authors first note that…

“Medically confirmed hypersensitivity reactions to food are usually IgE-mediated. Non-IgE-mediated reactions are not only seldom recognized but also more difficult to diagnose.”

They set out to…

“…examine B cell-activating factor (BAFF) in serum and gut lavage fluid of patients with self-reported food hypersensitivity, and to study its relationship to atopic disease.”

So they examined the gut lavage fluid obtained from 60 patients with self-reported food hypersensitivity and the serum from 17 others. From 20 healthy control subjects they obtained gut lavage fluid, along with serum from 11 of them. They then measured BAFF in both serum and the gut lavage fluid. Their findings are most interesting:

“B cell-activating factor levels in serum and gut lavage fluid were significantly higher in patients than in controls…There was no significant correlation between serum levels of BAFF and IgE.”

In other words, patients with food hypersensitivity produced significantly higher levels of BAFF–and IgE failed as an indicator of BAFF associated inflammation with food hypersensitivity. The authors add in their conclusion:

“The results suggest that BAFF might be a new mediating mechanism in food hypersensitivity reactions. Significantly higher levels in non-atopic compared with atopic patients, and no correlation between BAFF and IgE, suggest that BAFF might be involved particularly in non-IgE-mediated reactions.”

Unfortunately, food hypersensitivity is too often dismissed by many in the medical community as a poorly understood phenomenon that ends up being ignored in clinical practice. A clinical study review recently published in the Scandinavian Journal of Gastroenterology investigates this issue and observes the role of BAFF:

“Perceived food hypersensitivity is a prevalent, but poorly understood condition. In this review article, we summarize narratively recent literature including results of our 10 years’ interdisciplinary research program dealing with such patients.”

The studies included more than 400 adults who were referred to a university hospital because of gastrointestinal complaints that they attributed to food hypersensitivity. Most not only fulfilled criteria for irritable bowel syndrome…

“…In addition, most suffered from several extra-intestinal health complaints and had considerably impaired quality of life.”

Sadly…

“Despite extensive examinations, food allergy was seldom diagnosed…However, psychological factors could explain only approximately 10% of the variance in the patients’ symptom severity and 90% of the variance thus remained unexplained.”

Moreover…

“Intolerance to low-digestible carbohydrates was a common problem and abdominal symptoms were replicated by carbohydrate ingestion. A considerable number of patients showed evidence of immune activation by analyses of B-cell activating factor, dendritic cells and “IgE-armed” mast cells.”

Atopic dermatitis (the most common form or eczema, also linked to food sensitivity) has been shown to be associated with high levels of B cell-activating factor (BAFF) in a paper published not long ago in the journal Clinical and Experimental Dermatology. In order to investigate the role of BAFF in serum of patients with atopic dermatitis (AD)…

“Levels of serum BAFF, a proliferation-inducing ligand (APRIL) and total serum IgE level, and total eosinophil count were measured in 245 children.”

Their data showed a distinct association:

“Patients were characterized as having atopic eczema (AE); the remainder were healthy control subjects. Serum BAFF level in children with AE was significantly higher than in non-AE children or healthy controls.“

Not surprisingly considering immune function in the common mucosal barrier system, there is also evidence that B-cell activating factor is induced by airborne hypersensitivity reactions. A study published in The Journal of Allergy and Clinical Immunology documents the increased production of BAFF in the airway tissues after exposure to antigen.  The authors state:

“The objective of this study was to investigate the production of B cell-activating factor of the TNF family (BAFF), an important regulator of B cell survival and immunoglobulin class switch recombination, in bronchoalveolar lavage (BAL) fluid after segmental allergen challenge (SAC) of allergic subjects.”

They measured the amount of B cell-active cytokines including BAFF in bronchoalveolar lavage (BAL) fluid after 16 adult allergic subjects where challenged with allergens or saline. The data showed a clear result:

“BAFF protein was significantly elevated in BAL fluid after allergen challenge compared with those at saline sites…BAFF levels were also significantly correlated with other B cell-activating cytokines, IL-6 and IL-13.”

As in the gut, inflammation due to allergen exposure elevated BAFF levels. The authors conclude:

“These findings imply that exposure to antigen in the airway activates a process that stimulates the release of cytokines, including BAFF and others, that are known to promote CSR [class switch recombination = a change in antibody production by B cells] and immunoglobulin synthesis by B cells.”

Finally, B cell-activating factor expression due to gluten sensitivity deserves special mention because of the insidious and distinctively injurious nature of gluten reactions. An interesting study published in the Scandinavian Journal of Gastroenterology investigates this phenomenon, while referring to the link between celiac disease, BAFF and lymphoma. The authors state:

“The B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) was recently described as a critical survival factor for B cells, and its expression is increased in several autoimmune diseases. Abnormal production of BAFF disturbs immune tolerance allowing the survival of autoreactive B cells and participates in the progression of B-cell lymphomas. Coeliac disease (CD) is a common autoimmune disorder induced by gluten intake in genetically predisposed individuals, associated with autoantibody production and with an increased risk of lymphoma at follow-up. The purpose of this study was to investigate the possible implications of BAFF in CD.”

They examined serum BAFF levels, anti-transglutaminase (a-tTG) and endomysial antibodies in 73 patients with celiac disease confirmed by biopsy and laboratory tests before starting a gluten free diet (GFD), while using 77 blood donors as controls. Their data painted a most interesting and dramatic picture:

“Serum BAFF levels appeared to be significantly more elevated in CD patients than in controls and, compared with other autoimmune diseases where BAFF is increased, a much larger percentage (80.8%) of CD patients presented BAFF levels above the normal range. In addition, serum BAFF levels were found to correlate with a-tTG antibody levels…”

And happily…

“…there was a significant reduction of BAFF after introduction of a GFD [gluten-free diet].”

To summarize the significance for obesity and weight loss:

  1. B cell-activating factor (BAFF), triggered by food hypersensitivity and other allergic reactions, is associated with inflammation .
  2. BAFF induces insulin resistance; the resultant higher levels of insulin force the storage of calories of fat, promoting weight gain and obesity.
  3. A sucessful and physiologically sound weight loss and maintenance program should have a strategy to control inflammation and BAFF signaling. This includes the diagnosis of food allergy or sensitivity, with special emphasis on proper screening for reactions to gluten.

 

Sjögren’s syndrome—what more can we do?

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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.“

 

Are oats OK on a gluten-free diet?

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Apart from issues of contamination during transport, storage and processing, the safety of oats with a gluten-free diet (GFD) has been a topic of debate. A study recently published in GUT, An International Journal of Gastroenterology and Hepatology shows that the immunotoxicity of oats depends on the cultivar (the race or variety selected and maintained intentionally through cultivation). The authors state:

“Coeliac disease (CD) is triggered by an abnormal reaction to gluten. Peptides resulting from partially digested gluten of wheat, barley or rye cause inflammation of the small intestinal mucosa. Previous contradictory studies suggest that oats may trigger the abnormal immunological response in patients with CD. Monoclonal antibodies (moAbs) against the main immunotoxic 33-mer peptide (A1 and G12) react strongly against wheat, barley and rye but have less reactivity against oats. The stated aim of this study is to test whether this observed reactivity could be related to the potential toxicity of oats for patients with CD.”

For this study different varieties of oats were selected according to their protein patterns and controlled for purity. They examined differences in moAb (monoclonal antibody) G12 recognition and further determined immunogenicity by 33-mer concentration, T cell proliferation and interferon gamma production. Their findings are fascinating and of great importance to those who are sensitive to gluten:

“Three groups of oat cultivars reacting differently against moAb G12 could be distinguished: a group with considerable affinity, a group showing slight reactivity and a third with no detectable reactivity. The immunogenicity of the three types of oats as well as that of a positive and negative control was determined with isolated peripheral blood mononuclear T cells from patients with CD by measurement of cell proliferation and interferon γ release. A direct correlation of the reactivity with G12 and the immunogenicity of the different prolamins was observed.“

In other words, the authors were able to reliably pick out, according to the moAb reaction, an uncontaminated cultivar of oats with a distinct immunotoxic effect that expressed a proliferation of inflammatory white blood cells and cytokines. They also showed that another cultivar had only slight reactivity while the third had none at all. They have demonstrated that (1) oats, depending on the cultivar, can elicit an inflammatory reaction in those with gluten sensitivity, and (2) monoclonal antibodies can be used to distinguish which cultivars are safe.

“The results showed that the reactivity of the moAb G12 is proportional to the potential immunotoxicity of the cereal cultivar. These differences may explain the different clinical responses observed in patients suffering from CD and open up a means to identify immunologically safe oat cultivars, which could be used to enrich a gluten-free diet…This work should also be taken into consideration in food safety regulations, in particular labeling of gluten-free products that may contain oats.”

Until labeling for immunologic safety becomes standard practice, unless you know your oats, the only way to be sure of not having a reaction is to not eat them.

Chronic fatigue syndrome and the XMRV virus

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There are many ways to fall prey to simplistic linear thinking when desperately seeking solutions to complex problems. Chronic Fatigue Syndrome can be a devastating illness; as attractive as a viral culprit may be to some, there is abundant evidence that attributing this complex condition to a singular cause unrealistically ignores the complexity of CFS and related conditions. A study just published in the Journal of Virology is the most recent ‘nail in the coffin’ for the notion that CFS is caused by the XMRV virus. The authors state:

“Chronic fatigue syndrome (CFS) is a multi-system disorder characterized by prolonged and severe fatigue that is not relieved by rest…Recently CFS has been associated with xenotropic murine leukemia virus-related virus (XMRV) as well as other murine leukemia virus (MLV)-related viruses, though not all studies have found these associations.”

They analyzed blood samples from 100 CFS patients and 200 self-reported healthy volunteers using molecular, serological and viral replication assays. Interestingly, they also analyzed samples from patients in the original study that attracted so much media attention when it reported XMRV in CFS. What were the results?

“We did not find XMRV or related MLVs, either as viral sequences or infectious virus, nor did we find antibodies to these viruses in any of the patient samples, including those from the original study. We show that at least some of the discrepancy with previous studies is due to the presence of trace amounts of mouse DNA in the Taq polymerase enzymes used in these previous studies.”

Attention to their conclusion may prevent clinicians and CFS sufferers from a fruitless diversion:

“Our findings do not support an association between CFS and MLV-related viruses including XMRV and off-label use of antiretrovirals for the treatment of CFS does not seem justified at present.”

This is a thorough and detailed study, but is there any other evidence to support the assertion that we shouldn’t depend on XMRV as a linear viral cause for CFS? A study recently published in the journal Retrovirology also finds no association in cases across the US:

“Here we tested blood specimens from 45 CFS cases and 42 persons without CFS from over 20 states in the United States for both XMRV and MuLV. The CFS patients all had a minimum of 6 months of post-exertional malaise and a high degree of disability, the same key symptoms described in the Lombardi et al. study. Using highly sensitive and generic DNA and RNA PCR tests, and a new Western blot assay employing purified whole XMRV as antigen, we found no evidence of XMRV or MuLV in all 45 CFS cases and in the 42 persons without CFS. Our findings, together with previous negative reports, do not suggest an association of XMRV or MuLV in the majority of CFS cases.”

Additional research published shortly after in the same journal came up with the same negative results for both CFS and prostate cancer in Japan:

“To evaluate the risk of XMRV infection during blood transfusion in Japan, we screened three populations–healthy donors (n = 500), patients with PC (n = 67), and patients with CFS (n = 100)–for antibodies against XMRV proteins in freshly collected blood samples. We also examined blood samples of viral antibody-positive patients with PC and all (both antibody-positive and antibody-negative) patients with CFS for XMRV DNA.”

Their data led them to the following conclusion:

“Our data show no solid evidence of XMRV infection in any of the three populations tested, implying that there is no association between the onset of PC or CFS and XMRV infection in Japan.”

A study recently published in PLoS ONE (Public Library of Science) goes a step further in examining the issue. The authors state:

“The novel human gammaretrovirus xenotropic murine leukemia virus-related virus (XMRV), originally described in prostate cancer, has also been implicated in chronic fatigue syndrome (CFS). When later reports failed to confirm the link to CFS, they were often criticised for not using the conditions described in the original study. Here, we revisit our patient cohort to investigate the XMRV status in those patients by means of the original PCR protocol which linked the virus to CFS.”

In addition to the PCR protocol used in the original study, the authors also assayed the sera of CFS patients for the presence of both the xenotropic virus envelope protein and a serological response to it. What did their data show?

“The results further strengthen our contention that there is no evidence for an association of XMRV with CFS, at least in the UK.”

Subsequent research also conducted in the UK and published in PLoS examined a highly susceptible cohort of patients for XMRV virus:

“We extracted peripheral blood DNA from a cohort of 540 HIV-1-positive patients (approximately 20% of whom have never been on anti-retroviral treatment) and determined the presence of XMRV and related viruses using TaqMan PCR.”

Even for this very vulnerable group XMRV was not proven to be a concern:

“In view of these negative findings in this highly susceptible group, we conclude that it is unlikely that XMRV or related viruses are circulating at a significant level, if at all, in HIV-1-positive patients in London or in the general population.“

The authors of a study just published in the Annals of Neurology go a step further in investigating whether XMRV could be a causative agent in CFS. Having acknowledged the pre-existing research, they state:

“A useful next step would be to examine cerebrospinal fluid, because in some patients CFS is thought to be a brain disorder. Finding a microbe in the central nervous system would have greater significance than in blood because of the integrity of the blood–brain barrier.”

The brain is at the core of the experience of fatigue; if the virus were to show up anywhere it should be there. What did they find?

“We examined cerebrospinal fluid from 43 CFS patients using polymerase chain reaction techniques, but did not find XMRV or multiple other common viruses, suggesting that exploration of other causes or pathogenetic mechanisms is warranted.”

Just because a virus may be found in the body of a patient with CFS or any other condition does not mean that it is a significant causal factor for their complaint. The authors of a paper published in the British Medical Bulletin undertook a survey of…

“…All papers including the wording XMRV were abstracted from the NIH library of medicine database and included in the analysis.”

They make the point that…

“An increasing number of papers now refute the association of XMRV with human disease in humans although there is some evidence of serological reactivity to the virus. While it is unlikely that XMRV is a major cause of either prostate cancer or CFS, it can infect human cells and might yet have a role in human disease.”

But there is a big difference between being present in human cells and being a cause of disease. This is illustrated by a fascinating study published in the Journal of Virology showing that XMRV does not efficiently replicate and spread in human tissue. The authors state:

“To determine whether XMRV can replicate and spread in cultured PBMCs even though it can be inhibited by A3G/A3F, we infected phytohemagglutinin-activated human PBMCs and A3G/A3F-positive and -negative cell lines (CEM and CEM-SS, respectively) with different amounts of XMRV and monitored virus production by using quantitative real-time PCR.”

They summarize their findings by concluding:

“We found that XMRV efficiently replicated in CEM-SS cells and viral production increased by >4,000-fold, but there was only a modest increase in viral production from CEM cells (<14-fold) and a decrease in activated PBMCs, indicating little or no replication and spread of XMRV…Overall, these results suggest that hypermutation of XMRV in human PBMCs constitutes one of the blocks to replication and spread of XMRV.”

Wishing for a single linear cause that will lend itself to the discovery of a ‘magic bullet’ for conditions that are engendered by a multi-causal systemic web of factors is a flaw that has hindered progress in the treatment of chronic disease. In the case of CFS, dysregulation of the brain-immune axis is a core component. This demands that the clinician integrate a panoramic systems view with a nuanced investigation of individual functional elements. There is a world of science to delve into here; research just published in the journal NMR In Biomedicine offers a taste of the brain aspect. The authors in order to:

“…explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR [magnetic resonance] images has been extended to voxel-based regressions against clinical scores.”

The compared MR signal levels in 25 CFS subjects and 25 normal controls, including such clinical scores as fatigue duration, another score based on the 10 most common CFS symptoms, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24 hour blood pressure monitoring. What did their data show?

“In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1-weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction.”

In other words, there were strong correlations between CFS symptoms and pathological changes in the brain. The authors conclude:

“These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS).“

How might such neurodegenerative changes come about? A paper published earlier in Autoimmunity Reviews discusses the autoimmune component of CFS:

“The current concept is that CFS pathogenesis is a multifactorial condition. Various studies have sought evidence for a disturbance in immunity in people with CFS. An alteration in cytokine profile, a decreased function of natural killer (NK) cells, a presence of autoantibodies and a reduced responses of T cells to mitogens and other specific antigens have been reported. The observed high level of pro-inflammatory cytokines may explain some of the manifestations such as fatigue and flu-like symptoms and influence NK activity. Abnormal activation of the T lymphocyte subsets and a decrease in antibody-dependent cell-mediated cytotoxicity have been described. An increased number of CD8+ cytotoxic T lymphocytes and CD38 and HLA-DR activation markers have been reported, and a decrease in CD11b expression associated with an increased expression of CD28+ T subsets has been observed.”

The main point: practitioners and patients should not be seduced by the wish for a ‘magic bullet’ treatment of a single linear cause for complex conditions that require a systems biology perspective. In the case of chronic fatigue syndrome, the brain-immune axis comes to the fore, with all its multifaceted considerations for functional assessment and treatment.