My selection of ACR2012 Sjögren’s Syndrome Abstracts (2)
This year’s annual scientific meeting of the American College of Rheumatology (ACR) included 76 accepted abstracts on Sjögren’s Syndrome. In this blogpost I name a selection of them that may have clinical relevance for rheumatologists in daily practice together with a few more basic research oriented abstracts that I personally consider of interest.
ACR2012 abstracts on diagnosis and course of disease in Sjögren’s Syndrome
a) classification criteria sets
The 2002 American-European Consensus Group (AECG) and 2012 ACR criteria for SS identify mainly the same patient population (Kappa: 0.781), when applied to the Malmö SS registry containing 386 pSS and 264 sicca syndrome patients. A subgroup of patients lacking SSA/SSB antibodies can be catched only by the ACR criteria. This was concluded by Theander et al., from Skane University Hospital, Lund University, Malmö, Sweden. They added: On the other hand, several patients with high risk disease manifestations such as hypocomplementemia, GC formation or parotid swelling were missed using the ACR criteria because they lacked severe keratoconjunctivitis sicca. Sensitivity and specificity of the ACR criteria were 85% and 97% respectively. (Abstract #2202). Rasmussen et al. from Oklahoma Medical Research Foundation also studied the Effects of Reclassification Using the American College of Rheumatology Criteria On a Large cohort Sjögren’s Syndrome Patients (n=584) (Abstract #2203). Here it was concluded that When considering any subject who would meet classification for pSS by either set of criteria, only 75% would be so classified by both. Twenty five percent would be classified by only one set, leading to heterogeneity by either. This suggests that further refinement of the criteria is warranted. A 3rd abstract on classification criteria sets came from Martinez et al. from Instituto Nacional de Cardiologia Ignacion Chavez. Retrospectively 67 clinical charts with a biopsy report were reviewed by these authors. They concluded from their work that the agreement between a positive biopsy and having 4 of the 2002 criteria was low, and moderate when having 2 of the 20012 criteria. The agreement between the 2002 and the 2012 criteria was very good when PSS patients were included, however, it decreased when only the SSS patients were included(Abstract #2204). Personally I feel that everyone can judge for themselves and we are all still in an era of gaining wide consensus on how to define rheumatic diseases (not only Sjögren’s syndrome), in other words what do most physicians feel one can consider as Sjögren’s sydnrome and what not (and should be labeled sicca syndrome). I do notice however that there remains much more debate on how to define secondary Sjögren’s sydnrome (a term that I personally refuse to use, I would rather speak of having Sjögren’s syndrome or not, overlapping with another co-existent disease or not, I would rather use the term secondary sicca syndrome) then there is difficulty in obtaining consensus on what should be called (primary) Sjögren’s syndrome.
b) efforts on formulating disease activity scores
The most of the time stable, slowly progressive course of Sjögren’s syndrome makes it difficult to estimate disease activity at several time-points. This in turn makes it difficult to come up with evidence for beneficial effects of potential new treatment options in Sjögren’s syndrome. How should these effects be measuerd and quantified? An international collaborating group has been working on an attempt to define critertia for disease damage and disease activity to be implemented in future trials and research. This has resulted in a so-called EULAR SS Disease Activity Index (ESSDAI) and the EULAR SS Patient Reported Index (ESSPRI). On validation of these proposed tools, in Abstract #2551 from this multicenter european collaboration group it was concluded that both ESSDAI and ESSPRI had good construct validity, better than other scores. All scores were reliable. Systemic scores were sensitive to change in patient whose disease activity improves. Patient scores had a small sensitivity to change. However, ESSPRI in comparison was significantly better than completed Sicca Symptoms Inventory (SSI) or Profile of Fatigue and Discomfort (PROFAD) questionnaires by patients. The poor correlation between systemic and patients scores confirms that these 2 components are different and should be evaluated separately. Although the ideal parameters for assessing disease activity in Sjögren’s syndrome may still be lacking, it is better to have some tool for this purpose then having no tool at all and ending up with hard to compare studies with different sets of outcome parameters. The ESSDAI and ESSPRI will therefore both be used in every upcoming trial or other study, so it has been agreed upon by the collaborators. It will be interesting to see how this will evolve.
c) use of imaging techniques in Sjögren’s Syndrome
Luciano et al. from the Rheumatology Unit, University of Pisa, Italy presented an abstract on ultrasonography of salivary slands (# 126). They fund that parenchymal inhomogeneity of both parotid and submandibular glands correlated with antinuclear antibodies (ANA), anti-Ro/SSA, hypergammaglobulinemia and Rheumatoid Factor positivities. Patients with score 3 had significantly higher ESSDAI score (grade 3 vs 1, p=0.004; grade 3 vs 2, p=0.037) and showed trends towards lower salivary flow in comparison to other subgroups (grade 3 vs 1, p = 0.01; grade 3 vs grade 2, p= ns). When pSS patients where stratified according to parenchymal inhomogeneity, no difference was found in the presence of focal sialadenitis. The authors concluded in a more general way that major salivary glands US may be a specific tool in the diagnosis of pSS and that US abnormalities should be investigated particularly in pSS patients with positive serological markers. In a seperate ACR2012 session on the use of ultrasonography in distinct rheumatic conditions the current view on US use in Sjögren’s Syndrome was formulated as mentioned in this tweet:
d) follow-up / course of the disease in Sjögren’s Syndrome
Special focus in several accepted abstracts was noticed on (interstitial) lung disease (ILD) occurring in Sjögren’s Syndrome. From a population absed study Carlotta Nannini on behalf of authors from Prato Hospital, Prato, Italy, as well as Mayo Clinic, Rochester, MN, USA (Abstract #2175) the high incidence of ILD and the adverse effect on survival in patients with pSS were emphasised. Among pSS patients without prior ILD, the cumulative incidence of ILD in patients with pSS was 10% (± 3%) at 1 year after diagnosis of pSS and increased to 20% (± 4%) by 5 years after pSS. The development of lung disease in pSS was associated with poor survival with an hazard ratio of 2.16 (95%CI: 0.99, 4.74) adjusted for age, sex, and calendar year. According to the authors patients with pSS should be carefully assessed for diagnosis and treatment of ILD in order to improve the detrimental survival experience.
A Chinese reasearch group (Gao et al. from Peking University People’s Hospital) added that “the distribution of the abnormalities and severe parenchymal involvement are most pronounced in the lower lobes of pSS patients. Impaired diffusing capacity is the most significant PFT abnormalities. Hypoxia is not rare for pSS-association lung involvement patients. Corticosteroid therapy combined with hydroxychloroquine or intravenous cyclophosphamide is administered with a favorable response seen in the majority of patients. This should be further confirmed in a large cohort” (Abstract #2176).
Cohen et al. from Jean Verdier Hospital, Bondy, France added that 18-Fludeoxyglucose positron emission tomography (PET-scan) could be a valuable marker of activity of ILD in primary Sjögren’s Syndrome (Abstract #2078).
Baldini et al. from Rheumatology Unit, University of Pisa came with an abstract surveying prevalence of severe extra-glandular manifestations in a large cohort of patients with primary Sjögren’s Syndrome (Abstract #2185) and found that severe systemic manifestations may occur in about the 20% of the patients. Severe extraglandular manifestations included: active synovitis (11%), axonal sensory-motor neuropathy (2%), diffuse purpura or ulcers (6%) renal involvement (0.7%), myositis (0.5%), cerebral vasculitis (0.5%) and transverse myelitis (0.2%). Finally, 50 cases of non-Hodgkin lymphoma were documented. Shiboski et al. from University of California San Francisco also presented an abstract on the natural course of Sjögren’s Syndrome (Abstract #2174). However this study was limited by a very short follow-up period of only 2 years, which was acknowledged by the authors in their conclusion: “There was remarkable stability over a 2-year time period of both individual phenotypic features of SS and of SS status. This suggests that to fully characterize longitudinal outcomes and progression, a longer follow-up interval may be needed.”
Quartuccio et al. from Rheumatology Clinic, DSMB, University of Udine, Italy (Abstract #2183) described the prevalence of lymphoproliferative complications (defined as B-cell lymphoma or definite conditions predisposing to lymphoma, i.e, cryoglobulinemic vasculitis (CV) and major salivary gland swelling) in the course of primary Sjögren’s syndrome (pSS) in a large cohort of patients followed in five Rheumatologic Centres. In this study prevalence of lymphoma was noticed in 4.4% (51/1170), prevalence of CV was 3.9% (33/850), and prevalence of salivary gland swelling and/or myoepithelial sialadenitis (MESA) was 30.9% (362/1170). Salivary gland swelling and/or MESA, CV and lymphoma shared many laboratory features, i.e., positive rheumatoid factor, hypocomplementemia and leucopenia, as well as a the presence of purpura as clinical hallmark of the circulating immune complexes. Interestingly, polyclonal hypergammaglobulinemia was strictly associated with salivary gland swelling, but it was not associated with CV or lymphoma; on the other hand, serum monoclonal component was significantly associated with CV or lymphoma, but not with salivary gland swelling and/or MESA.
Ambrus et al. from State University of New York at Buffalo, USA, came up with a model for staging the disease (Abstract # 515) in which early injury to the submandibular and lachrymal glands is regulated by marginal-zone B-cells that produce IgM antibodies and lymphotoxin. Later development of IgG autoantibodies and parotid gland injury is dependent upon type 1 interferon. The authors conclude that further studies will be needed to investigate these observations in patients with SS.
ACR2012 abstracts on (possible) treatment options in Sjögren’s Syndrome
This is of course always the most interesting section for both doctors and patients. To date there is still not a single evidence-based / proven beneficial drug treatment for Sjögren’s Syndrome although components of the disease may be treated (e.g. pilocarpin or cevimelin for succa symptoms).
Data presented by Noaiseh et al. from University of Pennsylvania (Abstract #2191) suggests that patients with pSS who take secretagogues for xerostomia are more likely to continue cevimeline (very unfortunately this has never become available in Europe, MZ) than pilocarpine long-term. This is primarily due to a lower incidence of severe sweating (the most common side effect of therapy). However, therapeutic failure of one secretagogue did not predict similar results with the other.
Furthermore in daily clinical practice quite a lot of patients are prescribed hydroxychloroquin, an anti-malarial drug, although rheumatologists know that also for this drug therapy evidence-based literature is lacking. It is rather prescribed om empiric base, i.e. there are patients that report less joint symptoms when on hydroxychloroquin treatment. Coy et al. from Rheumatology Universidad Nacional de Colombia performed a meta-analysis on the use of antimalarials in Sjögren’s Syndrome (Abstract #2190). From 6 trials included it was confirmed that up to the moment the available evidence has poor quality. The best evidence did not identify a clear benefit of antimalarials in the reviewed outcomes. The analyzed data reported low incidence of adverse events.
The systemic approach in attempt to treat all symptoms of the syndrome at once remains a focus of current ongoing trials. Whereas a number of trials were aimed at anti-B-cell therapy, more recently also anti-T-cell therapy is subject of (ongoing) trials in Sjögren’s Syndrome. Whilst a study in Groningen, the Netherlands on the use of abatacept in Sjögren’s Syndrome is ongoing and hopefully presented at next years EULAR, Adler et al. from the University Hospital Bern presented a small pilot study investigating the effects of abatacept treatment in eleven Sjögren’s Syndrome patients (Abstract #2553). It was concluded that inhibition of T cell co-stimulation using CTLA4-Ig leads to a reduced inflammation in glandular tissue with a 50% decrease in FoxP3+ cells, to an expansion of peripheral naïve B cells and to an increase in saliva secretion in 70% of pSS patients. According to the authors, abatacept bears the potential of a disease-modifying biologic agent in pSS. It will be interesting to see whether the ongoing tsudy in Groningen can come up woth promising data as well.
Both rituximab as well as belimumab anti-B-cell treatment have been studied in Sjögren’s Syndrome and were presented in Abstracts #1751, #2554 (rituximab), #2189 and #2555 (belimumab) at ACR2012. Both studies on rituximab showed (in my opinion) rather disappointing results and confirm the current opinion of most rheumatologists in the field that were rituximab treatment can be beneficial in complicated cases of Sjögren’s Syndrome (e.g. with severe vasculitis) it has not gained a place for treatment in the general Sjögren’s Syndrome population. Early pilot studies with rituximab had provided promising data in the past, hopefully the early abatacept data do not encounter the same fate in follow-up studies.
In the two abstracts (by the same French-Italian collaborating group based in Paris and Udine) reporting on the use of belimumab in 30 Sjögren’s Syndrome patients data (that included the use of ESSDAI and ESSPRI) were however promising enough to continue further follow-up studies of this treatment modality.
Finally one abstract from Cinese authors reported on allogenic mesenchymal stem cells transplantation (via intravenous infusion) in Sjögren’s Syndrome (Abstract #2556). From data obtained in 24 treatedpatients the authors conclude that this procedure is safe and results in amelioration of disease activity (in terms of salivary flow rates, auto-antibody titers and decreased Th17 cells as well as increased Treg cells).
ACR2012 abstracts on the pathophysiology of Sjögren’s Syndrome
There were also numerous abstracts dealing with pathophysiological mechanisms in Sjögren’s Syndrome. Since during any scientific meeting a clinician gets overwhelmed by this “high-tec” basc reasearch work in laboratoria (don’t get me wrong, they are of crucial importance down the road in eventually developing enw treatment options) I always have difficulties in judging what is relevant for me as a rheumatologist, sometimes the abstracts are just too technical for me to understand at all. When I should pick out some of them my selection at this year’ s ACR on top of the 20 from 76 abstracts mentioned above contains Abstracts # 509, # 510 and # 519. The latter one caught my interest because it was the only abstract discussing sex-specific changes, athough in a mouse-mdoel. The role of the endocrine (estrogens) system in several rheumatic conditions, especially Sjögren’s Syndrome, keeps intriguing me. Abstract # 519 ended with the conclusion that the obtained data demonstrate that females harbor a population of lacrimal gland-protective Tregs that become dysfunctional in a male environment and suggest that dacryoadenitis in males is due to an underlying lacrimal gland-specific Treg defect. Studies to identify the sex-specific factors responsible for these findings are underway. Talking of Treg cells in Sjögren’s Syndrome, the other two selected basic research abstracts # 509 and # 510 are the result of Dutch work from colleagues at Utrecht University Medical Center and suggest that soluble human IL-7R /anti-IL-7 mAb blocks an autocrine function of IL-7 in B cells. This indicates that IL-7/IL-7R blockade, targeting not only T cells as previously shown, but also B cells, represents an interesting new therapeutic approach in pSS.
Well, that’s about it. And oh wait…despite what I wrote in part (1) taking notice of my converstaion with Dr Paul Sufka as presenetd on Storify by Ronan still adds valuable notes on what I wrote in this blogpost and could certainly be enjoyable for those interested, take a look here.