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ID PMID Title PublicationDate abstract
23833722 Ameliorative Effects of a Polyphenolic Fraction of Cinnamomum zeylanicum L. Bark in Animal 2013 Apr Cinnamon bark (Cinnamomum zeylanicum Syn C. verum, family: Lauraceae) is one of the oldest traditional medicines for inflammatory- and pain-related disorders. The objective of the present study was to evaluate the efficacy of the polyphenol fraction from Cinnamomum zeylanicum bark (CPP) in animal models of inflammation and rheumatoid arthritis. Dose-response studies of CPP (50, 100, and 200 mg/kg) used in a separate set of in vivo experiments were conducted in acute (carrageenan-induced rat paw edema), subacute (cotton pellet-induced granuloma), and sub-chronic (AIA, adjuvant-induced established polyarthrtis) models of inflammation in rats and the acetic acid-induced writhing model of pain in mice. Effects of CPP on cytokine (IL-2, IL-4, and IFNγ) release from Concanavalin (ConA)-stimulated lymphocytes were also evaluated in vitro. CPP showed a strong and dose-dependent reduction in paw volume, weight loss reversal effects against carrageenan-induced paw edema, and cotton pellet-induced granuloma models in rats. CPP (200 mg/kg p.o. for 10 days) showed a significant reduction in elevated serum TNF-α concentration without causing gastric ulcerogenicity in the AIA model in rats. CPP also demonstrated mild analgesic effects during acute treatment as evidenced by the reduction in the writhing and paw withdrawal threshold of the inflamed rat paw during the acetic acid-induced writhing model and Randall-Selitto test. CPP was found to inhibit cytokine (IL-2, IL-4, and IFNγ) release from ConA-stimulated lymphocytes in vitro. In conclusion, CPP demonstrated prominent action in animal models of inflammation and arthritis and therefore can be considered as a potential anti-rheumatic agent with disease-modifying action.
24932515 Chrysin alleviates testicular dysfunction in adjuvant arthritic rats via suppression of in 2014 Sep 1 Long standing rheumatoid arthritis (RA) is associated with testicular dysfunction and subfertility. Few studies have addressed the pathogenesis of testicular injury in RA and its modulation by effective agents. Thus, the current study aimed at evaluating the effects of two testosterone boosting agents; chrysin, a natural flavone and celecoxib, a selective COX-2 inhibitor, in testicular impairment in rats with adjuvant arthritis, an experimental model of RA. Chrysin (25 and 50mg/kg) and celecoxib (5mg/kg) were orally administered to Wistar rats once daily for 21days starting 1h before arthritis induction. Chrysin suppressed paw edema with comparable efficacy to celecoxib. More important, chrysin, dose-dependently and celecoxib attenuated the testicular injury via reversing lowered gonadosomatic index and histopathologic alterations with preservation of spermatogenesis. Both agents upregulated steroidogenic acute regulatory (StAR) mRNA expression and serum testosterone with concomitant restoration of LH and FSH. Furthermore, they suppressed inflammation via abrogation of myeloperoxidase, TNF-α and protein expression of COX-2 and iNOS besides elevation of IL-10. Alleviation of the testicular impairment was accompanied with suppression of oxidative stress via lowering testicular lipid peroxides and nitric oxide. With respect to apoptosis, both agents downregulated FasL mRNA expression and caspase-3 activity in favor of cell survival. For the first time, these findings highlight the protective effects of chrysin and celecoxib against testicular dysfunction in experimental RA which were mediated via boosting testosterone in addition to attenuation of testicular inflammation, oxidative stress and apoptosis. Generally, the 50mg/kg dose of chrysin exerted comparable protective actions to celecoxib.
24112447 Angiotensin II type 2 receptor correlates with therapeutic effects of losartan in rats wit 2013 Dec The angiotensin II type 1 receptor (AT1R) blocker losartan ameliorates rheumatoid arthritis (RA) in an experimental model. In RA, AT2R mainly opposes AT1R, but the mechanism by which this occurs still remains obscure. In the present study, we investigated the role of AT2R in the treatment of rats with adjuvant-induced arthritis (AIA) by losartan. Adjuvant-induced arthritis rats were treated with losartan (5, 10 and 15 mg/kg) and methotrexate (MTX; 0.5 mg/kg) in vivo from day 14 to day 28. Arthritis was evaluated by the arthritis index and histological examination. Angiotensin II, tumour necrosis factor-α, and VEGF levels were examined by ELISA. The expression of AT1R and AT2R was detected by western blot and immunohistochemistry analysis. After stimulation with interleukin-1β in vitro, the effects of the AT2R agonist CGP42112 (10(-8) -10(-5)  M) on the chemotaxis of monocytes induced by 10% foetal calf serum (FCS) were analysed by using Transwell assay. Subsequently, the therapeutic effects of CGP42112 (5, 10 and 20 μg/kg) were evaluated in vivo by intra-articular injection in AIA rats. After treatment with losartan, the down-regulation of AT1R expression and up-regulation of AT2R expression in the spleen and synovium of AIA rats correlated positively with reduction in the polyarthritis index. Treatment with CGP42112 inhibited the chemotaxis of AIA monocytes in vitro, possibly because of the up-regulation of AT2R expression. Intra-articular injection with CGP42112 (10 and 20 μg/kg) ameliorated the arthritis index and histological signs of arthritis. In summary, the present study strongly suggests that the up-regulation of AT2R might be an additional mechanism by which losartan exerts its therapeutic effects in AIA rats.
24712652 Methyl salicylate lactoside inhibits inflammatory response of fibroblast-like synoviocytes 2014 Jul BACKGROUND AND PURPOSE: Methyl salicylate 2-O-β-d-lactoside (MSL), whose chemical structure is similar to that of salicylic acid, is a natural product derivative isolated from a traditional Chinese herb. The aim of this study was to investigate the therapeutic effect of MSL in mice with collagen-induced arthritis (CIA) and explore its underlying mechanism. EXPERIMENTAL APPROACH: The anti-arthritic effects of MSL were evaluated on human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and CIA in mice in vivo by obtaining clinical scores, measuring hind paw thickness and inflammatory cytokine levels, radiographic evaluations and histopathological assessments. KEY RESULTS: Treatment with MSL after the onset of arthritis significantly prevented the progression and development of rheumatoid arthritis (RA) in CIA mice without megascopic gastric mucosa damage. In addition, MSL inhibited the production of pro-inflammatory mediators, the phosphorylation and translocation of NF-κB, and cell proliferation induced by TNF-α in FLS. MSL non-selectively inhibited the activity of COX in vitro, but was a more potent inhibitor of COX-2 than COX-1. MSL also inhibited the phosphorylation of inhibitor of NF-κB kinase, IκBα and p65, thus blocking the nuclear translocation of NF-κB in TNF-α-stimulated FLS. CONCLUSION AND IMPLICATIONS: MSL exerts therapeutic effects on CIA mice, suppressing the inflammatory response and joint destruction by non-selectively inhibiting the activity of COX and suppressing activation of the NF-κB signalling pathway, but without damaging the gastric mucosa. Therefore, MSL has great potential to be developed into a novel therapeutic agent for the treatment of RA.
23461924 [Giant Baker's cyst treated with intralessional methotrexate]. 2013 Jan INTRODUCTION: Synovial cyst is composed by a fibrous wall; lining by a thin layer of synovial cells containing synovial fluid, the prototype of these, in the knee is the Baker's cyst, which is located abnormally in the gastrocnemius semimembranous bursa. Baker's cyst prevalence ranges from 5 - 38%. Clinical diagnosis is supported by the presence of increased volume of soft tissues located in the popliteal region. CLINICAL CASE: A 74 year-old woman with longstanding active rheumatoid arthritis who developed a large, recurrent Baker's cyst. The Baker's cyst had two flare-ups of pain and soft tissue swelling which eventually limited knee movements; was treated with needle aspiration guided by ultrasound and synovectomy with methotrexate twice. At 18-months follow-up, the patient remains without evidence of recurrence. CONCLUSIONS: Local infiltration of methotrexate represents an alternative therapy for those refractory Baker's cyst with partial response to conventional treatment, where the surgical procedure carries a high risk.
25381730 Sonographic measurements of low-echoic synovial area in the dorsal aspect of metatarsophal 2015 May INTRODUCTION: Assessment of synovitis in the metatarsophalangeal (MTP) joints with ultrasound has been shown to improve the accuracy of assessment of rheumatoid arthritis (RA). However, the presence of intraarticular low-echoic synovial area (LESA) in the MTP joints in healthy subjects complicates the sonographic assessment of these joints. METHOD: Healthy subjects with no arthritic symptoms in their MTP joints were recruited. All subjects completed a questionnaire and underwent physical examination and sonographic assessment. LESAs in the dorsal aspect of all MTP joints were measured in the longitudinal view. RESULTS: One thousand non-arthritic MTP joints in 100 healthy subjects (female 73, mean age 41.0 years old) were evaluated. Measurable LESAs were identified in all joints assessed. Mean length of LESA in each of the 1st-5th MTP joints was 17.8, 13.9, 11.9, 10.6, and 9.2 mm, respectively, whereas mean thickness was 2.4, 2.4, 1.8, 1.2, and 0.8 mm, respectively. Multivariate linear regression models identified the difference between 1st and 5th MTP joints as the most independently influential factor on the measurement of LESA. CONCLUSIONS: Our data provide the normal reference values for the measurements of LESA in Japanese, which should be taken into consideration when the synovitis in MTP joints is evaluated with ultrasound.
24837400 Pathological findings from synovium of early osteoarthritic knee joints with persistent hy 2016 May AIM: Nonspecific chronic synovitis of the knee joint was reported by Pollard in 1962 and its pathogenesis is considered to be a physiological reaction to intra-articular disease. In this study, we evaluated the pathological findings of the synovium of early osteoarthritis (OA)-affected knee joints with hydrarthrosis in comparison to typical OA. METHODS: Synovial tissues were harvested from early OA knee joints with hydrarthrosis graded 0-2 according to the Kellgren and Lawrence classification and examined by histopathology. RESULTS: The synovial tissues showed proliferation of fibroblast-like synoviocytes (FLS) as if in rheumatoid arthritis (RA), and were immunohistochemically positive for matrix metalloproteinase 3, tumor necrosis factor α and interleukin 6. CONCLUSIONS: The histology of RA is characterized by marked proliferation of FLS. In this study, the synovial tissues of early OA with hydrarthrosis showed moderate FLS proliferation. They also expressed the cytokines that are detected in the synovial tissues of RA. We suggest long-term follow-up is needed because early OA with hydrarthrosis might progress to overt RA.
26107031 Management of Rheumatoid Arthritis-Related Peripheral Ulcerative Keratitis Using Glycerol- 2013 Sep PURPOSE: This study aimed to report the surgical outcome of patch grafts using glycerol-preserved corneas in perforated or near-perforated rheumatoid arthritis-related peripheral ulcerative keratitis (PUK). DESIGN: This is a retrospective chart review of a case series. METHODS: The medical records at a single institution were reviewed between July 2004 and July 2011. Of the 19 patients with PUK, 7 (36.8%) underwent glycerol-preserved cornea patch grafts for rheumatoid arthritis-related PUK. The clinical features, precipitating factors, adjuvant therapy, and therapeutic outcomes were analyzed. RESULTS: The age of patients ranged from 49 to 82 years (mean [SD], 64.43 [13.53] years) for the 4 women and 3 men with perforated or near-perforated PUK who were managed with systemic and local immunosuppressive therapy. A wound culture revealed 1 Staphylococcus aureus and 1 filamentary fungal infection. The mean (SD) area of the graft was 13.28 (6.11) mm; the mean (SD) time to reepithelializaiton was 7.0 (1.60) days. One patient had high intraocular pressure managed by topical medication; another had a complicated cataract formation. One graft melting was successfully managed by topical and systemic medication. CONCLUSIONS: Glycerol-preserved cornea patch grafts were successful in all patients and may be a viable option in perforated or near-perforated PUK, particularly when fresh donor corneas are neither available nor indicted.
23727938 Modulation by melatonin of the pathogenesis of inflammatory autoimmune diseases. 2013 May 31 Melatonin is the major secretory product of the pineal gland during the night and has multiple activities including the regulation of circadian and seasonal rhythms, and antioxidant and anti-inflammatory effects. It also possesses the ability to modulate immune responses by regulation of the T helper 1/2 balance and cytokine production. Autoimmune diseases, which result from the activation of immune cells by autoantigens released from normal tissues, affect around 5% of the population. Activation of autoantigen-specific immune cells leads to subsequent damage of target tissues by these activated cells. Melatonin therapy has been investigated in several animal models of autoimmune disease, where it has a beneficial effect in a number of models excepting rheumatoid arthritis, and has been evaluated in clinical autoimmune diseases including rheumatoid arthritis and ulcerative colitis. This review summarizes and highlights the role and the modulatory effects of melatonin in several inflammatory autoimmune diseases including multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes mellitus, and inflammatory bowel disease.
23382786 Small molecule inhibitors of CXCR4. 2013 CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. The SDF-1/CXCR4 axis is significantly associated with several diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus. For example, CXCR4 is one of the major co-receptors for HIV entry into target cells, while in cancer it plays an important role in tumor cell metastasis. Several promising CXCR4 antagonists have been developed to block SDF-1/CXCR4 interactions that are currently under different stages of development. The first in class CXCR4 antagonist, plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells and several other drugs are currently in clinical trials for cancer, HIV, and WHIM syndrome. While the long-term safety data for the first generation CXCR4 antagonists are not yet available, several new compounds are under preclinical development in an attempt to provide safer and more efficient treatment options for HIV and cancer patients.
23418376 Disease course, outcome, and predictors of outcome in a population-based juvenile chronic 2013 May OBJECTIVE: To investigate disease course, outcome, and predictors of outcome in an unselected population-based cohort of individuals diagnosed with juvenile chronic arthritis (JCA) followed for 17 years. METHODS: The cohort consisted of 132 incidence JCA cases identified 1984-1986 according to EULAR criteria. At 5-year followup, 129 individuals underwent joint assessment, laboratory measurements, radiographic examination, and medication and functional assessment. At 17-year followup, 86 were examined with joint assessment, laboratory measurements, medication assessment, Health Assessment Questionnaire (HAQ), Keitel functional test (KFT), and Medical Outcomes Study Short Form-36 (SF-36). RESULTS: At 17-year followup, 40% were in remission, 44% changed subgroups, median HAQ score was 0.0 (range 0.0-1.5), and median KFT was 100 (range 54-100). SF-36 scores were significantly lower compared to a reference group. Thirty-nine percent of those in remission at 5-year followup were not in remission at 17-year followup. In multivariate analyses of variables from the 17-year followup: remission was predicted by remission at 5-year followup (OR 4.8); HAQ > 0 by rheumatoid factor (RF)-positivity at 5-year followup (OR 3.6); KFT < 100 by nonremission (OR 11.3); and RF-positivity (OR 5.6) at 5-year followup; and the SF-36 physical component summary score above average of the reference group by remission at 5-year followup (OR 5.8). CONCLUSION: This longterm study of 86 individuals with JCA showed large variability of disease courses and of impaired health-related quality of life. Sixty percent were not in remission at 17-year followup. Longterm outcome was best predicted by and associated with characteristics at 5-year followup rather than those at onset.
25245537 Methotrexate: an old new drug in autoimmune disease. 2014 Nov Methotrexate (MTX) is currently considered, among disease-modifying anti-rheumatic drugs (DMARDs), the 'anchor-drug' in the treatment of rheumatoid arthritis. In the last 25 years, there has been a marked expansion in the use of MTX in different inflammatory diseases. Its low cost, associated to a good long-term efficacy and safety profile, justifies the use of MTX as a first-line disease-modifying drug or alternatively, a steroid-sparing medication in this field of medicine. Although new emerging options, including biological treatments, are being established in the therapeutic scenario, the good cost/benefit ratio of MTX supports the choice of this drug in combination with these newer therapies, enhancing the efficacy of these combination therapies and decreasing the risk of potential side effects.
23688955 Metabolomics in rheumatic diseases: the potential of an emerging methodology for improved 2013 Aug Metabolomics belongs to the family of "-omics" sciences, also comprised of genomics, transcriptomics, and proteomics, all of which share the advantage of a non-targeted approach for identifying biomarkers and profiling the patient. This means that they do not require a preliminary knowledge of the substances to be studied. Moreover, even small quantities of biological fluids or tissues may be utilized for analysis. Metabolomic procedure has become feasible only recently with the advent and accessibility of new high-throughput technologies, including mass spectrometry and nuclear magnetic resonance. The methodology generally involves three defining steps: 1) the acquisition of experimental data, 2) the multivariate statistical analysis, and 3) the projection of the acquired information (profiles) to construct the patient map. Metabolomic analysis has been applied to several disorders: as far as rheumatic diseases are concerned, a few studies have focused on rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, and osteoarthritis. Both murine models and clinical data have shown the potential of this novel tool to contribute to deciding a diagnosis, discriminate between patients based on disease activity, and even predict the response to a particular treatment. The present review fully reports these findings and offers a critical view of the challenges still to be met.
23430593 A mixed methods protocol to investigate medication adherence in patients with rheumatoid a 2013 BACKGROUND: Low adherence to medicines is an important issue as up to 40% of patients with chronic diseases do not take their medications as prescribed. This leads to suboptimal clinical benefit. In the context of rheumatoid arthritis, there is a dearth of data on adherence to disease-modifying antirheumatic drugs among minority ethnic groups. This study aims to assess the relationship between adherence to medicines and biopsychosocial variables in patients with rheumatoid arthritis of South Asian and White British origin. METHODS/ANALYSIS: A mixed methods approach will be used, encompassing a cross-sectional survey of 176 patients collecting demographic and clinical data, including information on adherence behaviour collected using a series of questionnaires. This will be followed by indepth qualitative interviews. ETHICS AND DISSEMINATION: This study has been approved by the South Birmingham (10/H1207/89) and Coventry and Warwickshire (12/WM/0041) Research Ethics Committees. The authors will disseminate the findings in peer-reviewed publications.
23206275 Surface modification of poly (l-lactic acid) microspheres for site-specific delivery of ke 2013 Apr The purpose of this research was to investigate the potential of surface modified Poly (l-lactic acid) (PLA) microspheres as a carrier for site-specific delivery of anti-inflammatory drug, ketoprofen, for the treatment of rheumatoid arthritis. Microspheres were prepared by solvent evaporation method using 20% w/w PLA in methylene chloride and 100 mL of a 2.5% poly vinyl alcohol (PVA) solution. Formulations were optimized for several processing parameters like drug to polymer ratio, stirring rate and volume of preparation medium etc. The surface of PLA microspheres was modified with gelatin to impart fibronectin recognition. The microspheres were characterized by surface morphology, size distribution, encapsulation efficiency, and by in vitro drug release studies. The prepared microspheres were light yellow, discrete, and spherical. Formulation with optimum drug to polymer ratio exhibited smallest vesicle size (43.02), high drug encapsulation efficiency (81.11) and better process yield (83.45). The release of drug was extended up to 24 h with Higuchi pattern of drug release. The in vivo results showed that the gelatin modified formulation reduced paw edema at greater extent than pure drug and PLA microspheres and it could be a promising carrier system for controlled and site-specific delivery of ketoprofen with possible clinical applications.
25455603 Autoimmunity: break-through in the diagnosis and treatment of immune-mediated inflammatory 2014 Dec The study of fundamental mechanisms of autoimmunity has been instrumental to clinical progress in the diagnosis and treatment of a range of immune-mediated inflammatory disorders. Dutch immunology has made major contributions to these developments, ranging from fundamental studies on immune cells, antibodies and cytokines to translational and clinical studies with targeted therapies in patients. In this paper we illustrate the progress made in our understanding of autoimmunity and the translational implications for human disease management by focusing on three areas: the autoantibody response in rheumatoid arthritis (RA), T-B cell interactions in Sjögren's syndrome (SS), and cytokine targeting in spondylarthritis (SpA).
24426869 First time myocardial infarction in a rheumatic patient after elective arthroplasty. 2013 Jul The management of perioperative cardiovascular risk in patients with rheumatoid arthritis (RA) is challenging due to the independent contribution to risk by high grade inflammatory mechanisms and the underestimation of risk by traditional cardiac risk factors alone. RA is associated with accelerated rates of subclinical atherosclerosis and markedly higher rates of both myocardial infarction and sudden cardiac death over non-RA controls. There is an absence of prospectively validated perioperative coronary heart disease (CHD) risk assessment tools for this unique patient population and available guidelines may fail to identify those patients most at risk. We examine a singular case of first time myocardial infarction after uncomplicated elective surgery in an adult RA patient with an unrevealing preoperative cardiac assessment. We also review the current literature for shared pathogenic mechanisms between systemic inflammation and atherosclerosis, discuss clinical and biologic markers such as C-reactive protein (CRP) in RA patients associated with heightened cardiac risk and discuss recommendations based on available evidence for cardiovascular risk management in this at risk cohort.
24418308 Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. 2014 Jun This review focuses on the biology of T helper 17 (Th17) and regulatory T (Treg) cells and their role in inflammatory diseases, such as rheumatoid arthritis. Th17 cells represent a pro-inflammatory subset whereas Treg cells have an antagonist effect. Their developmental pathways are reciprocally interconnected and there is an important plasticity between Th17 and Treg cells. These features implicate that the Th17/Treg balance plays a major role in the development and the disease outcomes of animal model and human autoimmune/inflammatory diseases. During these diseases, this balance is disturbed and this promotes the maintenance of inflammation. Targeting the Th17/Treg imbalance can be performed at different levels such as inhibition of pro-inflammatory cytokines and their receptors, of pathogenic cells or their specific signaling pathways. Conversely, direct effects include administration or induction of protective cells, or stimulation of their specific pathways. Several clinical trials are underway and some positive results have been obtained.
23754872 Minocycline-induced hyperpigmentation: comparison of 3 Q-switched lasers to reverse its ef 2013 Minocycline is a tetracycline derivative antibiotic commonly prescribed for acne, rosacea, and other inflammatory skin disorders. Minocycline turns black when oxidized, leading to discoloration of the skin, nails, bulbar conjunctiva, oral mucosa, teeth, bones, and thyroid gland. Hyperpigmentation has been reported after long-term minocycline therapy with at least 100 mg/day. Three types of minocycline-induced cutaneous hyperpigmentation can result. Type I is the most common, and is associated with blue-black discoloration in areas of previous inflammation and scarring. Type II most commonly affects the legs and is characterized by blue-gray pigmentation of previously normal skin. Type III is the least common and is characterized by diffuse muddy-brown discoloration predominantly on sun exposed skin. Minocycline-induced hyperpigmentation may be cosmetically disfiguring and prompt identification is essential. Without treatment, symptoms may take several months, to years to resolve, after discontinuation of the drug. However, the pigmentation may never completely disappear. In fact, there have been few reports of complete resolution associated with any therapeutic intervention. We report a case of a patient on long-term minocycline therapy utilized as an anti-inflammatory agent to control symptoms of rheumatoid arthritis, which led to minocycline-induced hyperpigmentation of the face. To remove the blue-gray cutaneous deposits, 3 Q-switched lasers (Neodymium: yttrium aluminum garnet (Nd:YAG) 1064 nm, Alexandrite 755 nm, and Ruby 694 nm) were used in test areas. The Alexandrite 755 nm laser proved to provide effective clearing of the minocycline hyperpigmentation requiring just 2 treatments, with minimal treatment discomfort and down time.
24646083 Towards inhibition of morbidity and mortality in Sjögren's syndrome: opportunities and ch 2014 Apr In recent years considerable progress has been made in our understanding of the immunopathology of primary Sjögren's syndrome. Several genetic and environmental risk factors as well as cellular and molecular pathways have been identified, providing multiple targets for therapeutic strategies. Establishment of disease activity scores allows careful monitoring of therapeutic strategies and has set the stage for definition of clinical response criteria. Early detection of autoimmune symptoms before the onset of primary Sjögren's syndrome might trigger early intervention strategies to prevent immunopathology. New studies that indicated a strong association between lymphoid neogenesis and development of lymphoma and extra-glandular manifestations indicate that future therapeutic strategies should perhaps be directed at patients at risk for more severe disease. Several challenges remain, such as dissecting the causes and consequences of several types of IFN signatures or elucidating how viral triggering of the immune system is involved and could be targeted. The biggest challenge may be prevention of dryness since the causes of dryness remain elusive and could include non-immunological ones. In the coming years it will become clear to what extent novel drugs can prevent immunopathology and clinical symptoms like dryness and fatigue.