[Pancreatic panniculitis with polyarthritis: PPP syndrome]. / Polyartritis, panniculitis en pancreatitis.

BACKGROUND: Diseases of the pancreas may present with extrapancreatic symptoms, such as (poly)arthritis or necrosis of subcutaneous fat. A combination of pancreatitis, panniculitis and (poly)arthritis is referred to as the PPP syndrome, which is associated with acute and chronic pancreatitis, as well as pancreatic malignancies. CASE DESCRIPTION: This article describes a patient which was admitted to our hospital with severe polyarthritis and panniculitis. A meticulous work-up revealed an underlying focal alcoholic pancreatitis. The clinical course in our patient illustrates the severity of the PPP syndrome and emphasizes the need of a multidisciplinary approach. CONCLUSION: Panniculitis and/or (poly)arthritis may be the first symptom of underlying pancreatic disease. Timely recognition and diagnosis is imperative for successful treatment and outcome. The multi-organ involvement in the PPP syndrome requires close collaboration across different medical departments.

Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-Act-Early and CAMERA-II treat-to-target trials.

OBJECTIVES: Methotrexate (MTX), often combined with low moderately dosed prednisone, is still the cornerstone of initial treatment for early rheumatoid arthritis (RA). It is not known how this strategy compares with initial treatment with a biological. We therefore compared the effectiveness of tocilizumab (TCZ), or TCZ plus MTX (TCZ+MTX) with MTX plus 10 mg prednisone (MTX+pred), all initiated within a treat-to-target treatment strategy in early RA. METHODS: Using individual patient data of two trials, we indirectly compared tight-controlled treat-to-target strategies initiating TCZ (n=103), TCZ+MTX (n=106) or MTX+pred (n=117), using initiation of MTX (n=227) as reference. Primary outcome was Disease Activity Score assessing 28 joints (DAS28) over 24 months. To assess the influence of acute phase reactants (APRs), a disease activity composite outcome score without APR (ie, modification of the Clinical Disease Activity Index (m-CDAI)) was analysed. Secondary outcomes were remission (several definitions), physical function and radiographic progression. Multilevel models were used to account for clustering within trials and patients over time, correcting for relevant confounders. RESULTS: DAS28 over 24 months was lower for TCZ+MTX than for MTX+Pred (mean difference: -0.62 (95% CI -1.14 to -0.10)). Remission was more often achieved in TCZ+MTX and in TCZ versus MTX+pred (p=0.02/0.05, respectively). Excluding APRs from the disease activity outcome score, TCZ-based strategies showed a slightly higher m-CDAI compared with MTX+pred, but this was not statistically significant. Other outcomes were also not statistically significantly different between the strategies. CONCLUSIONS: In patients with early RA, although TCZ-based strategies resulted in better DAS28 and remission rates compared with MTX+pred, at least part of these effects may be due to a specific effect of TCZ on APRs.

Validation of quantitative salivary gland scintigraphy in relation to the American-European concensus criteria for Sjögren's syndrome.

PURPOSE: The aim of this retrospective study was to evaluate the diagnostic value of semiquantitative parameters in salivary gland scintigraphy (SGS) in the diagnostic work-up of primary Sjögren's Syndrome (SS) using the American-European consensus criteria (AECC) as the gold standard. PATIENTS AND METHODS: 99mTc-pertechnetate-SGS was performed in 110 patients with suspected primary SS. Uptake ratios (URs) and excretion fractions (EFs) for all parotid and submandibular salivary glands were calculated. Patients were divided into SS-positive, SS-negative, and SS-equivocal groups on the basis of the AECC criteria. SGS semiquantitative parameters were compared per group and cut-off values were defined. RESULTS: Ninety-six (87%) women and 14 (13%) men with a mean age of 51 years (range: 18-77 years) were included. All patients underwent SGS, labial biopsy, Schirmer's test, and antibody tests (anti-SS-A and anti-SS-B). Twenty-four patients were SS positive, 56 patients were SS negative, and 30 patients were SS-equivocal.UR of the parotid glands did not differ between SS-positive and SS-negative groups [mean (range): 3.4 (1.4-6.9) and 3.9 (2.2-6.5), respectively], whereas UR of the submandibular glands were significantly lower in SS-positive patients [mean (range): 2.7 (1.1-5.6) and 3.5 (2.3-5.3), respectively]. EF in both parotid and submandibular glands was significantly lower in SS-positive patients compared with SS-negative patients: parotid 24% (range: -4 to 53%) and 36% (range: 15-58%), respectively; submandibular 16% (range: -5 to 46%) and 29% (range: 9-49%), respectively.On the basis of a cut-off value of 2.0 for UR and 20% for EF, the sensitivity, specificity, positive predictive value, and negative predictive value were 0.67, 0.86, 86, and 67%, respectively. Of 30 SS-equivocal patients, 15 had a positive SGS, whereas the other 15 were SGS negative. In both, there was no correlation with the AECC criteria IV (histopathology) and VI (antibodies). In these cases, the SGS result was decisive. CONCLUSION: Quantitative SGS is a valuable tool in the diagnostic management of patients with suspected primary SS, especially in those in whom the nonscintigraphic AECC criteria are not conclusive. The straightforward quantitative analysis of SGS used in this study can be implemented in any nuclear medicine department.

Ascending Aortic Aneurysm Secondary to Isolated Noninfectious Ascending Aortitis.

Isolated noninfectious ascending aortitis (I-NIAA) is increasingly diagnosed at histopathologic review after resection of an ascending aortic aneurysm. PubMed was searched using the term aortitis; publications addressing the issue were reviewed, and reference lists of selected articles were also reviewed. Eleven major studies investigated the causes of an ascending aortic aneurysm or dissection requiring surgical repair: the prevalence of noninfectious aortitis ranged from 2% to 12%. Among 4 studies of lesions limited to the ascending aorta, 47% to 81% of cases with noninfectious aortitis were I-NIAA, more frequent than Takayasu arteritis or giant cell arteritis. Because of its subclinical nature and the lack of "syndromal signs" as in Takayasu arteritis or giant cell arteritis, I-NIAA is difficult to diagnose before complications occur, such as an aortic aneurysm or dissection. Therefore, surgical specimens of dissected aortic tissue should always be submitted for pathologic review. Diagnostic certainty requires the combination of a standardized histopathologic and clinical investigation. This review summarizes the current knowledge on I-NIAA, followed by a suggested approach to diagnosis, management, and follow-up. An illustrative case of an uncommon presentation is also presented. More follow-up studies on I-NIAA are needed, and diagnosis and follow-up of I-NIAA may benefit from the development of diagnostic biomarkers.

Rheumatoid factor isotype and Ro epitope distribution in primary Sjögren syndrome and rheumatoid arthritis with keratoconjunctivitis sicca.

Primary Sjögren syndrome (pS) is associated with autoantibodies such as rheumatoid factor (RF) and anti-nuclear antibodies such as anti-Ro (SS-A) and/or La (SS-B). Recent developments within autoimmune diagnostics allow quantitation of RF subclasses and anti-Ro epitopes. Will this refinement by autoimmune diagnostics help predicting development of extraglandular manifestations (EGM) in pS patients? A cohort of pS and rheumatoid arthritis (RA) patients with keratoconjunctivitis sicca (n = 35 and 16, resp) was included. Of the pS patients, 54% developed one or more EGM. Antibodies quantitated were IgM-RF, IgA-RF, IgG-RF, anti-Ro52, and anti-Ro60. Upon analysis of RF isotypes, pS patients generally displayed higher IgA-RF concentrations than RA patients (126 versus 49 U/ml, p = 0.015), while the dominant RF isotype in RA patients was IgM-RF (82.5 versus 38 U/ml, p = 0.012). No differences were observed regarding IgG-RF concentrations. In pS without/with EGM, the median RF IgM concentrations were similar, while RF IgA and IgG concentrations tended to be lower in pS patients with EGM > 1. Both Ro epitopes were strongly recognized by almost all pS patients, independent from EGM, while these antibodies were absent in RA patients. Primary Sjögren syndrome and RA patients have distinct serological profiles when analysing RF and Ro-specific antibodies. A longitudinal study of switched RF isotypes in pS patients is worthwhile from an immunological point of view, but its value is limited regarding identification of pS patients prone to developing EGM or RA patients prone to developing secondary sicca symptoms.

Is extra-glandular organ damage in primary Sjögren's syndrome related to the presence of systemic auto-antibodies and/or hypergammaglobulinemia? A long-term cohort study with 110 patients from the Netherlands.

AIM: To test the hypothesis that systemic auto-antibodies or hypergammaglobulinemia are related to the prevalence of extra-glandular tissue organ damage (EGOD) in primary Sjögren's syndrome (SS). METHODS: A real practice-based investigation of a relatively large (n = 110) Dutch cohort of primary SS patients systematically followed up in a large non-academic hospital. RESULTS: After a follow up of mean 8.2 years a significant correlation was found between disease duration and the prevalence of EGOD. We did not observe a relationship between the total number or type of systemic auto-antibodies or hypergammaglobulinemia and the total number of EGOD. However, there was a correlation between the prevalence of polyneuropathy (PNP) and antinuclear antibodies (ANA) as well as anti-Ro/SS-A positivity and there was an inverse relationship between the presence of anti-Ro/SS-A antibodies and primary biliary cirrhosis (PBC). All PBC cases were anti-Ro/SS-A and anti-La/SS-B negative but ANA positive. There was a trend for a higher occurrence of pleuro-pulmonary disease in the ANA negative cases. CONCLUSIONS: Although we did not find a relationship between the total number or type of systemic auto-antibodies and the total number of EGOD, there were correlations between specific systemic auto-antibodies and specific types of EGOD. The presence of ANA and anti-Ro/SS-A was associated with the occurrence of PNP, as well as was the absence of anti-Ro/SS-A with PBC.

Necessity of TNF-alpha inhibitor discontinuation in rheumatoid arthritis is predicted by smoking and number of previously used biological DMARDs.

OBJECTIVES: Despite the success of TNF-alpha inhibitor (TNFi) treatment in rheumatoid arthritis (RA), a substantial number of patients necessitate discontinuation. Prediction thereof would be clinically relevant and guide the decision whether to start TNFi treatment. METHODS: Data were used from the observational BiOCURA cohort, in which patients initiating biological treatment were enrolled and followed up for one year. In the model development cohort (n=192), a model predicting TNFi discontinuation was built using Cox-regression with backward selection (p<0.05). The parameters of the model were tested again in a model refinement cohort (n=60), for significance (p<0.05) and consistency of effect. In addition, we performed a systematic review to put our study results into perspective. RESULTS: Of the 252 patients who initiated TNFi treatment, 103 (41%) had to discontinue treatment. Discontinuation was predicted at baseline by female gender, current smoking, high visual analogue scale of general health, and higher number of previously used biological disease-modifying anti-rheumatic drugs (bDMARDs). At refinement, smoking status and number of previously used bDMARDs remained with re-estimated hazard ratios (HRs) in the total cohort of 1.74 (95%-CI 1.15-2.63, p<0.01) and 1.40 (95%-CI 1.1-1.68, p<0.01), respectively. Using these two predictors, we developed a simple score predicting discontinuation (PPV=72.3%). From literature, predictors were pack years of smoking, number of previously used bDMARDs, lack of any concomitant DMARD therapy and in particular lack of concomitant methotrexate (MTX). CONCLUSIONS: TNFi discontinuation is predicted by current smoking and number of previously used bDMARDs, as well as by pack years of smoking and lack of any concomitant DMARD/MTX therapy.

Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial.

BACKGROUND: For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug [DMARD]), versus initiation of methotrexate monotherapy in line with international guidelines. METHODS: We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov, number NCT01034137. FINDINGS: Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72-78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk [RR] 2·00, 95% CI 1·59-2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48-2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00-1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01-1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 [16%] of 106 patients in the tocilizumab plus methotrexate arm vs 19 [18%] of 103 in the tocilizumab arm and 13 [12%] of 108 in the methotrexate arm), and no deaths occurred during the study. INTERPRETATION: For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. FUNDING: Roche Nederland BV.

[A woman with a swelling of the right elbow]. / Een vrouw met een zwelling aan de rechter elleboog.

A 74-year-old woman with longlasting rheumatoid arthritis came to our clinic because of a swollen bursa olecrani. Aspiration of the swelling yielded a yellow fluid; polarized light microscopy showed cholesterol crystals.

[A man with a red ear]. / Een man met een rood oor.

A 80-year-old man had a red and painful ear with an repeating interval of 1 week. He had a history of COPD, an aortic valve and mitral valve replacement with a bioprosthesis and anterior uveitis. Histological examination of the ear showed relapsing polychondritis.

[Painful, swollen hand after carpal tunnel surgery]. / Pijnlijke, gezwollen hand na carpaletunneloperatie.

A 45-year-old man presented at the rheumatology outpatient department with a painful swollen hand after carpal tunnel surgery. This is a complication in approximately 2% of all patients due to complex regional pain syndrome.

Look beyond the disease activity score of 28 joints (DAS28): tender points influence the DAS28 in patients with rheumatoid arthritis.

OBJECTIVE: To explore the influence of tender points (TP) on the Disease Activity Score assessing 28 joints (DAS28) in patients with rheumatoid arthritis (RA). METHODS: In 200 consecutive patients with RA from the outpatient clinic, DAS28 and its components, tender and swollen joint counts (TJC, SJC, respectively), visual analog scale (VAS) for patient's general health (GH), and erythrocyte sedimentation rate (ESR), along with a tender point count (TPC) were assessed. Patients were categorized according to 4 TPC classes: zero, 1-5, 6-10, and ≥ 11 TP. The influence of TPC classes on DAS28 and its individual components was determined with Kruskal-Wallis tests and correlations between TP and DAS28 and its components were calculated. RESULTS: In 196 eligible patients, 70% were female, mean age was 59 years, and median disease duration was 3.9 years; median DAS28 was 3.1; and 49% had active disease, defined as DAS28 > 3.2. In 15% of patients, the TPC was ≥ 11, in 12% 6-10, in 30% 1-5, and in 43% zero. TPC significantly influenced the DAS28 and its less objective components TJC and VAS-GH (i.e., based on patient's report), but not the more objective DAS28 components SJC and ESR (i.e., observer- and laboratory-based). CONCLUSION: DAS28 is influenced by tender points, even in the non-fibromyalgia range, falsely suggesting higher disease activity and decreasing the sensitivity of the DAS28 criterion of low disease activity or remission. When applying DAS28-guided "tight control" or "treat-to-target" treatment strategies in RA, evaluation of not only the DAS28, but also its individual components along with a full joint and physical evaluation including assessment of TP is required to reliably estimate the individual's disease activity, which guides therapeutic decisions.

[A man with calcifications in his legs]. / Een man met calcificaties in de onderbenen.

A 70-year-old man had ulcers on his right lower leg for a year; he also had pitting oedema. On X-ray of his legs soft tissue calcifications were seen. These were caused by venous insufficiency.

Relation of systemic autoantibodies to the number of extraglandular manifestations in primary Sjögren's Syndrome: a retrospective analysis of 65 patients in the Netherlands.

OBJECTIVES: Extraglandular manifestations (EGM) are often seen in patients with primary Sjögren's syndrome and are probably due to a (more) disturbed immune system. Their relation to systemic autoantibodies remains controversial. We hypothesized that positive serology as reflected by the presence of 1 of more systemic autoantibodies is related to the number of EGM. METHODS: To this purpose, all patients, visiting a large nonacademic teaching hospital, with primary Sjögren's syndrome, according to the revised American-European classification criteria of 2002, were retrospectively analyzed. RESULTS: In this group of 65 patients, systemic autoantibodies were abundant: anti-Sjögren syndrome A antigen (SSA) and/or anti-Sjögren syndrome B antigen (SSB) (80%), immunoglobulinM-Rheumatoid factor (IgM-RF) (68%), and anti-nuclear antibodies (ANA) (77%). Their presence was often found together and correlated to the presence of hypergammaglobulinemia. There was a statistically significant correlation between the number of systemic autoantibodies and the total number of EGM (P = 0.025). Anti-SSA was the strongest predictor of the presence of EGM (OR = 4.67, P = 0.024). CONCLUSIONS: These findings indicate that a more disturbed immune system, as reflected by B-cell hyperactivity, with autoantibody formation and hypergammaglobulinemia, is associated with more systemic manifestations in patients with primary Sjögren's syndrome.