Chayawee Muangchan

The 15% Rule in Scleroderma: The Frequency of Severe Organ Complications in Systemic Sclerosis. A Systematic Review

Objective. The prevalence of organ complications in scleroderma (systemic sclerosis; SSc) varies by definition used. This study was done to determine the frequency of several features of SSc. Methods. A search of Medline-Ovid/Embase, PubMed, and Scopus databases from 1980 to November 30, 2011, was conducted to identify relevant articles with at least 50 patients with SSc extracting prevalence of each organ complication. Study quality was assessed using the STROBE (Strengthening The Reporting of OBservational studies in Epidemiology) checklist. Pooled prevalence was calculated using the random effects method. Heterogeneity was quantified using I2. Results. A total of 5916 articles were identified (913 from Medline-Ovid/Embase, 1009 from PubMed, and 3994 from Scopus); 5665 were excluded, leaving 251 articles for full-text review, with 69 included. Where available, frequencies were also included from the Canadian Scleroderma Research Group. Many severe complications in SSc occur about 15% of the time, including cardiac involvement (15%, 95% CI 6–24), diastolic dysfunction (16%, 95% CI 14–17), estimated pulmonary artery pressure > 40 mm Hg (18%, 95% CI 14–21), pulmonary arterial hypertension by right heart catheterization (15%, 95% CI 12–17), forced vital capacity (FVC) < 70% predicted (15%, 95% CI 12–17), FVC < 80% predicted (17%, 95% CI 12–21), myositis (13%, 95% CI 10–17), inflammatory arthritis (12%, 95% CI 9–16), Sjögren overlap (13%, 95% CI 10–16), and digital ulcers (DU; 15%, 95% CI 10–20); and 15% of DU have complications (amputations 12%, 95% CI 8–16, and hospitalizations 13%, 95% CI 6–21). Scleroderma renal crisis is uncommon but occurs in almost 15% (12%, 95% CI 5–19) of cases of disseminated cutaneous SSc. There is no 15% rule within skin and gastrointestinal tract for SSc. Conclusion. The “15%” rule for frequency of significant organ involvement in SSc is helpful.

Association of C-reactive protein with high disease activity in systemic sclerosis: results from the Canadian Scleroderma Research Group.

This study was performed to determine the prevalence of elevated C‐reactive protein (CRP) levels and the significance of CRP in clinical parameters in systemic sclerosis (SSc; scleroderma) patients.

Treatment Algorithms in Systemic Lupus Erythematosus

To establish agreement on systemic lupus erythematosus (SLE) treatment.

Interleukin 6 in Systemic Sclerosis and Potential Implications for Targeted Therapy

Objective. The purpose of this study was to review the potential importance of interleukin 6 (IL-6) in systemic sclerosis (SSc). Methods. PubMed and Scopus databases and American College of Rheumatology (from 2009–10) and European League Against Rheumatism abstracts (2009–11) were searched using keywords “scleroderma; SSc; cytokines; interleukins; interleukin 6” and publications were excluded if not pertaining to IL-6 in SSc. Data were extracted from selected articles to construct a cell interaction model of the effects of IL-6 in SSc. Results. A total of 416 reports were found (PubMed, n = 82; Scopus, n = 331; 3 abstracts); 372 were excluded (irrelevant) leaving 41 publications and 3 abstracts (39 from PubMed, 18 from Scopus; but 16 were repeated from PubMed search), where 40 suggested IL-6 was important in SSc and 4 did not. Effects of IL-6 in SSc were summarized schematically. Conclusion. Of the 44 publications, 40 suggested that IL-6 may be important in SSc, allowing for a conceptual framework within SSc including effects on macrophages, fibroblasts, plasma cells, monocytes, and extracellular matrix.

The frequency of and associations with hospitalization secondary to lupus flares from the 1000 Faces of Lupus Canadian cohort

Objectives Hospitalization is a major factor in health care costs and a surrogate for worse outcomes in chronic disease. The aim of this study was to determine the frequency of hospitalization secondary to lupus flare, the causes of hospitalization, and to determine risk factors for hospitalization in patients with systemic lupus erythematosus (SLE). Methods Data were collected as part of the 1000 Canadian Faces of Lupus, a prospective cohort study, where annual major lupus flares including hospitalizations were recorded over a 3-year period. Results Of 665 patients with available hospitalization histories, 68 reported hospitalization related to a SLE flare over 3 years of follow-up. The average annual hospitalization rate was 7.6% (range 6.6–8.9%). The most common reasons for hospitalization were: hematologic (22.1%), serositis (20.6%), musculoskeletal (MSK) (16.2%), and renal (14.7%). Univariate risk factors for lupus hospitalization included (OR [95% CI]; p < 0.05): juvenile-onset lupus (2.2 [1.1–4.7]), number of ACR SLE criteria (1.4 [1.1–1.7], baseline body mass index (BMI) (1.1 [1.0–1.1]), psychosis (3.4 [1.2–9.9]), aboriginal race (3.2 [1.5–6.7]), anti-Smith (2.6 [1.2–5.4]), erythrocyte sedimentation rate >25 mm/hr (1.9 [1.1–3.4]), proteinuria >0.5 g/d (4.2 [1.9–9.3], and SLAM-2 score (1.1 [1.0–1.2]). After multivariate regression only BMI, number of ACR criteria, and psychosis were associated with hospitalization for lupus flare. Conclusions The mean annual rate of hospitalization attributed to lupus was lower than expected. Hematologic, serositis, MSK and renal were the most common reasons. In a regression model elevated BMI, more ACR criteria and psychosis were associated with hospitalization.

Metabolic syndrome is associated with disease activity in patients with rheumatoid arthritis.

OBJECTIVE To investigate the association between metabolic syndrome (MS) and disease activity in patients with rheumatoid arthritis (RA). METHODS Siriraj Rheumatoid Arthritis registry is a prospective cohort study establishing since May 2011. A total of 267 patients who had complete data in February 2015 were included in these analyses. All clinical and laboratory data related to disease activity, functional status, and parameters of MS according to the 2001 National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) were collected. Univariate and backward stepwise multivariate analyses were performed to identify factors associated with MS. RESULTS Most (88%) were female with the mean age±standard deviation of 59±11.1 years old. MS was found in 43 patients (16%). Patients with MS had a significantly lower proportion of patients with remission (time-adjusted mean of disease activity score 28 or DAS28<2.6) than those with non-MS (2.3% vs. 16.5%, P=0.02). Multiple logistic regression analysis identified 3 independent factors associated with MS including body mass index [OR 1.2, 95% CI 1.1 to 1.3], educational level≤12 years [OR 5.92, 95% CI 1.47 to 23.83], and disease remission [OR 0.11, 95% CI 0.01 to 0.93]. This model correctly predicted 84% of cases. CONCLUSION Remission rate is significantly lower in RA patients with MS. Disease activity of RA, body mass index, and educational level are associated with metabolic syndrome in patients with RA.

2016 updated Thai Rheumatism Association Recommendations for the use of biologic and targeted synthetic disease‐modifying anti‐rheumatic drugs in patients with rheumatoid arthritis

In June 2015, the Thai Rheumatism Association (TRA) approved an update of its recommendation for the use of biologic disease‐modifying anti‐rheumatic drugs (bDMARDs) and targeted synthetic (tsDMARD) in the treatment of rheumatoid arthritis (RA) to cover those currently available in Thailand (etanercept, infliximab, golimumab, rituximab, tocilizumab, abatacept and tofacitinib).

Hydroxychloroquine treatment in SLE.

We appreciate the letter from Drs. Michaud and Caches that pertains to our SLE treatment article. We thank them for thoughtful comments and for reiterating the benefits of antimalarial treatment. The question of where HCQ belongs in the treatment armamentarium of SLE is a very good one. Part of the differing opinion could be due to the way the questions were asked in our study. Indeed, HCQ was considered as firstline immunotherapy (with or without steroids) for the treatment of SLE with constitutional symptoms, skin rashes, mild digital vasculitis, inflammatory arthritis, pericarditis, myocarditis, and antiphospholipid antibody syndrome (APS). In many cases, HCQ was first-line or adjunctive therapy. However, HCQ was not recommended as early line therapy in the treatment of other SLE organ involvement such as non-APS severe gangrene, various pulmonary complications (interstitial lung disease, alveolar hemorrhage, PAH), severe immune thrombocytopenia, active glomerulonephritis, and neurologic involvement such as mononeuritis, and central nervous system SLE. We did not question the treating physicians as to whether HCQ would be discontinued if SLE was stable, or if the patient was taking HCQ and had new active organ involvement. We speculated that in both scenarios, HCQ would be continued due to its well-known benefits, such as less flaring if continued in inactive SLE (1), improved lipid levels (2), less hypercoagulability (3,4), and potentially improved survival (4,5). However, finding improved survival in SLE patients who used antimalarials versus those who did not could be confounding by indication, where perhaps only those patients with mild SLE were prescribed antimalarials (i.e., those with skin and joint involvement, mucositis, and mild constitutional symptoms) compared to those presenting with major organ involvement who received strong immunosuppressives and high doses of steroids. We agree that clinicians should use knowledge from the literature and their clinical experience when treating SLE and recognize the benefits of antimalarial treatment, such as a steroid-sparing effect in a randomized trial (6). We recognize that trying to construct treatment pathways is somewhat artificial. Part of our research asking experts how to treat SLE patients assumed that in each case, there was an initial solo presentation within each organ and, considering that each treatment was available, tolerated at a full dose and with sufficient time to see an effect, and if there was not a full response to treatment, then the next step in the treatment algorithm would occur. For these reasons our research is flawed (patients often present with more than one active feature of SLE and often it is difficult to determine if infection is also present, which we said was ruled out prior to SLE treatment). However, it is unlikely that if an SLE patient presented with severe alveolar hemorrhage or very active lupus nephritis that the firstline treatment would be antimalarial therapy. That would not necessarily preclude the addition of antimalarial treatment once the patient was tolerating immunosuppression. This could be compared to considering when a bisphosphonate would be started in the above scenario. Likely after initial therapy was tolerated and the need for long-term steroids was determined, one would consider adding a bisphosphonate for the prevention or management of steroid-induced osteoporosis. The clinical reasoning could be that therapy is stratified as urgent treatment and then maintenance. In the latter phase of treatment, there would be considerations for antimalarial treatment in all SLE patients, reducing steroids to the minimum dose, treatment of cardiovascular risks (hypertension, lipids, smoking cessation, consideration of addition of aspirin), treatment of residual proteinuria with an angiotensin-converting enzyme inhibitor, and bone mass protection or treatment. Therefore, antimalarial treatment can be considered as an important part of maintenance therapy in SLE.

FRI0375 A Delphi Exercise for Treatment Algorithms for Systemic Lupus Erythematosus

Background Treatment for SLE is often organ based. The literature lacks trials and consensus for treatment in SLE when standard first or second line care is ineffective. Objectives To determine expert consensus for SLE treatment using case scenarios and especially for treatment beyond first line therapy. Methods SLE experts (n=69) were sent three surveys; writing therapies for SLE organ complications assuming inadequate response to each choice and providing a list of secondary choices. Results The response rate for the first survey where all treatment options were written by the experts was 54%. For each subsequent survey, the response rate decreased. For widespread DLE, first-line: topical steroids or tacrolimus+hydroxychloroquine (HCQ) ± glucocorticoids, then azathioprine (AZA) and switching to mycophenolate mofetil (MMF). For cutaneous vasculitis, first-line was GC ± HCQ ± methotrexate (MTX), followed by adding either AZA or MMF and then IV cyclophosphamide (CYC). For gangrenous vasculitis, first-line was glucocorticoids+CYC, then rituximab (RTX) or plasmapheresis and maintenance with AZA or MMF. For arthritis, first-line therapy was HCQ ± glucocorticoids; adding MTX and then RTX. For pericarditis refractory to NSAIDs, first-line was glucocorticoids ± HCQ, then adding AZA, MMF or MTX and then Belimumab (BLM) or RTX; and if needed pericardial window and/or aspiration. For ILD, induction was glucocorticoids+MMF or CYC, then RTX or IVIG; maintenance with AZA or MMF. For PAH, glucocorticoids+CYC or MMF+endothelin receptor antagonist, adding phosphodiesterase-5 inhibitor and then prostanoid and RTX. First-line therapy was anticoagulation ± HCQ for lupus associated antiphospholipid antibody syndrome. A direct thrombin inhibitor was second-line therapy for venous thrombosis, and adding low dose aspirin or another platelet aggregation inhibitor was a second-line option for arterial thrombosis. For mononeuritis multiplex, and CNS vasculitis, first-line induction was glucocorticoids+CYC followed by maintenance with AZA, or MMF and then RTX, IVIG or plasmapheresis. For LN type III/IV and V first-line was glucocorticoids+MMF, then adding RTX for LN type III/IV or switching to AZA, CYC or RTX for LN type V. Treatment algorithm for organ system involvements by systemic lupus erythematosus: Table 1 Organ involvement Treatment options Ancillary therapy % Agreement (median) 1st-line or Induction 2nd-line or failure of induction 3rd-line Maintenance 1. Constitutional symptoms GC, HCQ, IMM or combinations MMF Switching to RTX or BLM N/A N/A 60 2. Generalized DLE HCQ ± GC Adding AZA or switching antimalarial Switching AZA to MMF N/A Sun screening + Topical steroids or Topical tacrolimus 70 3. Uncomplicated digital/cutaneous vasculitis GC ± HCQ ± MTX AZA or MMF Switching to IV CYC N/A N/A 80 4. Gangrenous digital/cutaneous vasculitis GC + IV CYC Adding RTX or PLAX N/A AZA or MMF PGA 90 5. Non-erosive, non-deforming polyarthritis HCQ ± GC Adding MTX Adding RTX N/A N/A 80 6. Lupus pericarditis GC ± HCQ Adding MMF or AZA or MTX Adding BLM or RTX N/A Pericardiocentesis ± window 75 7. Lupus myocarditis GC + IV CYC ± HCQ Adding RTX or BLM or IVIG N/A MMF N/A 90 8. Lupus ILD GC + MMF or IV CYC Adding RTX or IVIG N/A AZA or MMF N/A 90 9. Lupus PAH GC + IV CYC or MMF + ERA Adding RTX, and PDE5i Adding PGA MMF N/A 80 10. Lupus thrombocytopenia GC ± HCQ Adding AZA or MMF Adding RTX or IV CYC or IVIG N/A Splenectomy 50 Conclusions Consensus for SLE treatment had variable agreement but some treatment consensus beyond first line therapy was obtained. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.2541

THU0249 C - reactive protein (CRP) is associated with high disease activity in SSC and ILD. Results from the canadian scleroderma research group (CSRG)

Background Elevated ESR in SSc is associated with morbidity yet little is known about the predictive value of C-reactive protein (CRP) in SSc. Objectives This study was done to determine the associations of CRP in SSc subsets (overall, early, late, dcSSc, lcSSc) and organ associations with CRP. Methods The CSRG is a large multi-site dataset comprised of patients with SSc where patient and physician reported measures and lab tests are performed annually. The frequency of elevated CRP and ESR and their relationships to clinical parameters, Scleroderma Disease Activity Score (SDAS), Scleroderma Disease Severity Score (SDSS), Health Assessment Questionnaire (HAQ) and changes between annual follow up were studied. Statistical comparisons were made for CRP in early (≤3 years from 1st non-RP symptom) vs. late SSc, diffuse cutaneous SSc (dcSSc) vs. limited cutaneous (lcSSc). CRP >8mg/L was the cut off for elevated as it was the value for 95th percentile for age and gender matched population norms. Results 1,043 patients aged 55.4±12.1 years, female predominant (86.1%), and disease duration of 11.0±9.5 years were analyzed of whom 38% had dcSSc, 62% had lcSSc and 10.6% were early dcSSc. Elevation of CRP occurred in 25.7% and ESR 38.2%. Baseline CRP in dcSSc (11.98±25.41 mg/L) was higher than in lcSSc (8.15±16.09 mg/L); p=0.016. SSc with disease duration ≤3 years had higher CRP (12.89±28.13 mg/L) than that with disease duration >3 years (8.60±17.06 mg/L); p=0.041. Though not be consistent in all subsets, CRP was significantly associated in overall group at p<0.01 for: ESR, MRSS, TLC<80%, FVC<80%, DLCO<75%, disease activity (SDAS), damage (SDSS), and HAQ. In early dcSSc, the frequency of elevated CRP and ESR was 41.5% and 44.2% respectively. CRP seemed to normalize in many SSc patients over time. Adding or withdrawing prednisone did not significantly change CRP but was underpowered. Table of Spearman Correlation with CRP Overall lcSSc dcSSc Early dcSSc Number 1,043 647 396 117 CRP vs. ESR 0.374** 0.333** 0.389** 0.461** CRP vs. MRSS 0.209** 0.120** 0.302** 0.203* CRP vs. SPAP 0.153** 0.157** 0.099 –0.121 CRP vs. TLC –0.247** –0.226** –0.245** –0.167 CRP vs. FVC –0.255** –0.232** –0.269** –0.353** CRP vs. DLCO –0.194** –0.209** –0.209** –0.290** CRP vs. CXR ILD 0.106** 0.130** 0.050 0.009 CRP vs. HRCT ILD 0.186** 0.186** 0.127* 0.162 CRP vs. SRC ever –0.010 0.020 –0.018 –0.205* CRP vs. arthritis 0.026 0.019 0.042 0.045 CRP vs. Tendon friction rubs 0.140** 0.062 0.178** 0.267** CRP vs. SDAS 0.229** 0.145** 0.343** 0.196 CRP vs. SDSS 0.213** 0.156** 0.289** 0.434** CRP vs. HAQ 0.280** 0.199** 0.341** 0.336** **p<0.01; *p<0.05; SRC is underpowered; Arthritis = 1 or more SJC AND TJC; SDAS = SSc Disease Activity Score; SDSS = SSc Disease Severity Score. Conclusions CRP is elevated in approximately one quarter of SSc patients, especially early disease. It is correlated with disease activity, severity and poor pulmonary function. Disclosure of Interest C. Muangchan: None Declared, S. Harding: None Declared, S. Khimdas: None Declared, A. Bonner: None Declared, M. Baron: None Declared, J. Pope Grant/Research support from: Support for the CSRG is from CIHR, Scleroderma Society of Canada, Scleroderma Society of Ontario