Israel Medical Association Journal

In the absence of definitive anti-viral therapy, there is considerable interest in mitigating against severe inflammatory reactions in coronavirus disease-2019 (COVID-19) pneumonia to improve survival. These reactions are sometimes termed cytokine storm. PDE4 inhibitors (PDE4i) have anti-inflammatory properties with approved indications in inflammatory skin and joint diseases as well as chronic obstructive pulmonary disease (COPD). Furthermore, multiple animal models demonstrate strong anti-inflammatory effects of PDE4i in respiratory models of viral and bacterial infection and also after chemically mediated lung injury. The rationale for PDE4i use in COVID-19 patients comes from the multimodal mechanism of action with cytokine, chemokine, and other key pathway inhibition all achieved with an excellent safety profile. We highlight how PDE4i could be an overlooked treatment from the rheumatologic and respiratory armamentarium, which has potential beneficial immune-modulation for treating severe COVID-19 pneumonia associated with cytokine storms. The proposed use of PDE4i is also supported by age-related immune changes in inflammation severity in PDE4i modifiable pathways in primate coronavirus disease. In conclusion, over-exuberant anti-viral immune responses in older patients with COVID-19 may pose a substantial risk to patient survival and mitigation against such hyper-inflammation with PDE4i, especially with anti-viral agents, is a strategy that need to be pursed, especially in older patients

Background: Behçet's disease is a multi-systemic chronic relapsing inflammatory disease, classified among the vasculitides. The heterogeneity of clinical manifestations challenges the disease management.

Objectives: To assess efficacy and safety of adalimumab in patients with active persistent Behçet's arthritis who did not respond to disease-modifying anti-rheumatic drugs and to assess the impact of treatment on the cytokine milieu.

Methods: Our cohort comprised 10 patients with active arthritis who received adalimumab in a 24-week investigator-initiated prospective open-label study. Patients who relapsed within 12 weeks following adalimumab discontinuation could enter a 3-year extension study. The patients underwent a comprehensive assessment including questionnaires and measurement of inflammatory cytokines, adalimumab serum levels, and anti-drug antibodies.

Results: A significant improvement was observed in arthritis, disease activity visual analogue scales, Behçet's disease current activity form, and interleukin-6 (IL-6) levels, but not in health assessment questionnaire and functional assessment of chronic illness therapy fatigue scale questionnaire. Resolution of oral and urogenital ulcers was achieved in all patients. Significant reduction of pain was reported by 40% of patients. The disease relapsed in 9 of 10 patients, within 2–6 weeks following adalimumab discontinuation. Of the 7 patients who continued the study, arthritis was resolved in 5. Two patients with high neutralizing antidrug antibodies titer relapsed.

Conclusions: Adalimumab treatment achieved a significant improvement in arthritis, mucocutaneous manifestations, and IL-6 levels in all study patients but only 40% reported significant pain reduction. The arthritis relapsed in 90% of patients following adalimumab discontinuation and long-term treatment was required.

Background: Vitamin D insufficiency is associated with autoimmune and chronic inflammatory diseases such as tuberculosis and sarcoidosis. 

Objectives: To evaluate the vitamin D-dependent mechanisms of immunity and autoimmunity in different forms of pulmonary tuberculosis and sarcoidosis.

Methods: We measured the serum levels of 25(OH)D and 1,25(OH)2D, individual autoimmune profiles, plasma concentrations of cathelicidin, several hormones, and production of nine cytokines in patients with short- and long-duration tuberculosis and sarcoidosis.

Results: The level of 25(OH)D was significantly decreased in all patients. Concentration of 1,25(OH)2D was elevated only in sarcoidosis, prolactin content was augmented only in tuberculosis. We saw no expected increase of cathelicidin levels in tuberculosis and sarcoidosis. The individual mean immune reactivity levels of autoantibodies to 24 antigens were significantly lower in tuberculosis and sarcoidosis patients compared to healthy controls. Pronounced deviations from individual mean immune reactivity levels were found for several autoantigens in all patients. The induced production of interferon gamma-γ, interleukin (IL) 2, 17, and 8 by peripheral blood mononuclear cells was significantly increased in patients of both tuberculosis groups, but spontaneous production of tumor necrosis factor-α, IL-2, and IL-6 was lower in the tuberculosis patients than in healthy controls. We registered marked differences in the groups of tuberculosis patients. 

Conclusions: We demonstrated the role of vitamin D deficiency in poor cathelicidin response in  tuberculosis and sarcoidosis. Both diseases are accompanied by significant changes in the autoimmune profile, probably related to the status of vitamin D and cytokine regulation. 

 

Background: The activated NLRP3 inflammasome is associated with the etiology of fibrotic diseases. The role of inflammasomes in SSc is still poorly understood.

Objectives: To determine the expression of NLRP3 (nucleotide-binding domain, leucine-rich-repeat-containing family, pyrin domain-containing 3) in the skin of patients with systemic sclerosis (SSc) and its relationship with pro-inflammatory cytokines and vascular mediators expression.

Methods: Skin biopsies were taken from 42 patients with either limited or diffuse SSc (21 lcSSc and 21 dcSSc), and from 13 healthy individuals. Using real-time polymerase chain reaction (PCR), the relative expression of caspase-1, IL-1β, IL-18, IL-33, TGF-β, ET-1, iNOS and eNOS genes, were measured. The location of NLRP3 and IL-1β were also determined by immunohistochemistry. Clinical characteristics were evaluated.

Results: The mean age of the patients was 49.3 ± 12.9 (lcSSc), 44.6 ±1 3.8 (dcSSc), and 45 ± 14.1 (healthy individuals). Compared to healthy individuals, the skin of both subtypes of SSc showed a significant increase (P < 0.05) in NLRP3, caspase-1, IL-1β, IL-18 and ET-1. Samples of lcSSc also showed a significant increase of eNOS (P < 0.029), iNOS (P < 0.04) and TGF-β (P < 0.05). Dermal fibrosis evaluated by modified Rodnan skin score (MRSS) had significant correlation with NLRP3, IL-1β, IL-18, and ET-1. Immunohistochemical analysis showed stronger staining of NLRP3 and IL-1β cytoplasmic expression in the keratinizing squamous epithelium of skin from SSc patients compared to controls.

Conclusions: This study identified NLRP3 over-expression in skin of patients with SSc. Skin thickness correlates positively with the NLRP3 inflammasome gene expression and with the vascular mediator and pro-fibrotic ET-1, suggesting that NLRP3 inflammasome plays a role in the pathophysiology of skin fibrosis in human SSc.

Mesenchymal stem cells, or mesenchymal stromal cells, have emerged as a major new cell technology with a diverse spectrum of potential clinical applications. MSCs[1] were originally conceived as stem/progenitor cells to rebuild diseased or damaged tissues. Over the last 14 years, since the first report of MSC infusions in patients, the cells have been shown to suppress graft vs. host disease, stimulate linear growth in a genetic disorder of bone, and foster engraftment of haplo-identical hematopoietic stem cells. In all cases, few, if any, MSCs were identified at the site of clinical activity. This experience suggests a remarkable clinical potential, but a different general mechanism of action. Systemically infused MSCs seem to exert a therapeutic effect effect through the release of cytokines that act on local, or perhaps distant, target tissues. Rather than serving as stem cells to repair tissues, they serve as cellular factories that secrete mediators to stimulate the repair of tissues or other beneficial effects. Since both the tissue source of MSCs and the ex vivo expansion system may significantly impact the cytokine expression profile, these parameters may be critically important determinants of clinical activity. Furthermore, cell processing protocols may be developed to optimize the cell product for a specific clinical indication. For example, MSC-like cells isolated from placenta and expanded in a three-dimensional bioreactor have recently been shown to increase blood flow in critical limb ischemia. Future efforts to understand the cytokine expression profile will undoubtedly expand the range of MSC clinical applications.

Background: Multiple drug allergy syndrome is a rarely reported clinical condition characterized by an adverse reaction to more than one different class of pharmacologically and structurally unrelated drugs. The pathogenesis may involve immediate-type or delayed-type hypersensitivity.

Objectives: To further characterize patients with MDA[1] in terms of the type of CADR, drug intake and clinical drug suspicion.

Methods: The study group comprised 12 patients (6 males, 6 females) with CADRs[2] showing in vitro drug-induced IFNγ[3] release for multiple drugs, suggesting the presence of MDA. The diagnostic role of in vitro IFNγ release in identifying the culprit drugs was evaluated in terms of clinical data and the results of in vivo tests (withdrawal and/or challenge tests) with the offending drugs.

Results: Clinical relevance was attributed to in vitro drug-induced IFNγ release towards multiple drugs in this series of 12 patients with a variety of CADRs, implying MDA. The results of in vivo tests for the offending drugs confirmed the diagnosis. The main causative agents responsible were antibiotics and non-steroidal anti-inflammatory drugs.

Conclusions: The study further supports the role of a T cell-mediated mechanism in the pathogenesis of MDA. The in vitro drug-induced IFNγ release test may serve as a laboratory tool to identify the culprit drugs associated with this allergy.  

Background: Atherosclerosis is a chronic inflammatory process resulting in coronary artery disease.

Objectives: To determine the relationship between inflammatory markers and the angiographic severity of CAD[1].

Methods: We measured inflammatory markers in sequential patients undergoing coronary angiography. This included C-reactive protein, fibrinogen, serum cytokines (interleukin-1 beta, IL-1[2] receptor antagonist, IL-6, IL-8, IL-10) and tumor necrosis factor-alpha), all measured by high sensitivity enzyme-linked immunoabsorbent assay.

Results: There was a significant correlation between TNFα[3] and the severity of CAD as assessed by the number of obstructed coronary vessels and the Gensini severity score, which is based on the proximity and severity of the lesions. Patients had more coronary vessel disease (> 70% stenosis) with increasing tertiles of serum TNFα; the mean number of vessels affected was 1.15, 1.33, and 2.00 respectively (P < 0.001). IL-6 correlated with the Gensini severity score and coronary vessel disease (> 70% stenosis). A weaker correlation was present with IL-1 receptor antagonist. A significant correlation was not found with the other inflammatory markers. After adjustment for major risk factors, multivariate analyses showed that significant independent predictors of CAD vessel disease were TNFα (P < 0.05) and combined levels of TNFα and IL-6 (P < 0.05). IL-6 levels were independently predictive of Gensini coronary score (P < 0.05).

Conclusion: TNFa and IL-6 are significant predictors of the severity of coronary artery disease. This association is likely an indicator of the chronic inflammatory burden and an important marker of increased atherosclerosis risk.

Background: The global spread of tuberculosis necessitates the development of an effective vaccine and new treatment modalities. That requires a better understanding of the differences in regulation of the immune responses to Mycobacterium tuberculosis between individuals who are susceptible or resistant to the infection. Previous immune studies in young Ethiopian immigrants to Israel did not demonstrate anergy to purified protein derivative or a Th2-like cytokine profile.

Objectives: To evaluate the profile of Th1 and Th2 cytokine production in immigrant TB patients, in comparison with asymptomatic control subjects.

Methods: The present study included (part 1): 39 patients with acute TB[1] (group 1), 34 patients with chronic relapsing TB (group 2), 39 Mantoux-positive asymptomatic TB contacts (group 3), and 21 Mantoux-negative asymptomatic controls (group 4). Patients were mainly immigrants from Eastern Europe and Ethiopia. Levels of interferon gamma, interleukin 2 receptor, IL-6[2] and IL-10 were measured in serum and in non-stimulated and PPD[3]-stimulated peripheral blood mononuclear cell culture supernatants, using commercial ELISA kits. In addition (part 2), levels of IFNg[4] and IL-12p40 were evaluated in 31 immigrant Ethiopian patients and 58 contact family members.

Results: Patients with acute disease tended to secrete more cytokines than contacts, and contacts more than chronic patients and controls, without a specific bias. None of the patients showed in vitro anergy. Discriminant probability analysis showed that from the total of 12 available parameters, a cluster of 6 (IFNg-SER[5], IFNg-PPD, IL-2R[6]-SER, IL-10-SER, IL-10-NS[7] and IL-6-PPD) predicted an 84% probability to become a TB contact upon exposure, 71% a chronic TB patient and 61% an acute TB patient. Family-specific patterns of IFNg were demonstrated in the second part of the study.

Conclusions: Firstly, no deficiency in cytokine production was demonstrated in TB patients. Secondly, acute TB patients secreted more cytokines than contacts, and contacts more than unexposed controls. Thus, neither anergy nor a cytokine dysregulation explains susceptibility to acute TB disease in our cohort, although chronic TB patients produced less cytokines than did acute patients and less than asymptomatic contacts. Thirdly, a certain cytokine configuration may predict a trend of susceptibility to acquire, or not acquire, clinical TB. It is presently unclear whether this finding may explain the disease spread in large populations. Finally, the familial association of IFNg secretion levels probably points towards a genetic regulation of the immune response to Mycobacterium tuberculosis.