Development of new extra-glandular manifestations or associated auto-immune diseases after establishing the diagnosis of primary Sjögren's syndrome : A long-term study of the Antonius Nieuwegein Sjögren (ANS) cohort.

To investigate in a long-term study, the development of new extra-glandular manifestations (EGM) or associated auto-immune diseases (AID) from 1 year after establishing the diagnosis of primary Sjögren's syndrome (pSS). The primary goal was to examine the frequency and type of these manifestations and to find out which demographic, clinical and serological profile was most at risk. All outpatients diagnosed with primary Sjögren's syndrome were included in a retrospective study, with at least one check-up per year, from June 1991 until August 2015. Patients also fulfilling the criteria for concomitant connective tissue disorders were excluded. Data were collected with respect to the cumulative prevalence of a new EGM or associated AID. 140 patients were included in the final analysis. After 10 years of follow-up, the cumulative incidence of a new EGM or associated AID was 30.7%. The most frequent events were polyneuropathy, interstitial lung disease, (poly)arthritis, discoid lupus erythematosus (LE)/subacute cutaneous LE and Hashimoto's disease. Non-Hodgkin lymphoma was not diagnosed during the follow-up. Patients without chronic benign pain syndrome (CBP) (HR 2.13; 95% CI [0.94-4.76]; p = 0.061), but in particular those with cryoglobulins (HR 2.87; 95% CI [1.20-6.86]; p = 0.013), developed more events. Age at diagnosis, gender, the presence of ANA, anti-Ro/SSA, anti-La/SSB, IgM-RF, decreased levels of C3 or C4, or hypergammaglobulinaemia did not show any statistically significant differences. The burden of disease in pSS is higher than expected due to the development of EGM or associated AID. Therefore, we recommend long-term follow-up of all pSS patients, particularly those with cryoglobulinaemia.

Lower prevalence of extra-glandular manifestations and anti-SSB antibodies in patients with primary Sjögren's syndrome and widespread pain: evidence for a relatively benign subset.

OBJECTIVES: To investigate in primary Sjögren's syndrome, the differences between patients with and without widespread pain (WSP) with respect to the cumulative prevalence of extra-glandular manifestations (EGMs) and systemic auto-antibodies. METHODS: All outpatients diagnosed with primary Sjögren's syndrome (2) were included in a prospective follow-up, with at least one check up each year, from June 1991 until November 2011. Patients who also fulfilled criteria for concomitant connective tissue disorders were excluded. Widespread pain was defined as the presence of long-lasting (>one year) diffuse pain in all four body quadrants. Data were collected with respect to the cumulative prevalence of systemic auto-antibodies (anti-nuclear antibodies [ANA], anti-Sjögren syndrome A antigen [anti-SSA], anti-Sjögren syndrome B antigen [anti-SSB] and immunoglobulin M-Rheumatoid factor [IgM-RF]) and EGMs related to primary Sjögren's syndrome. RESULTS: Eighty-three patients were included in the final analysis. Thirty-nine (34.9%) patients had widespread pain. Anti-SSB was found less frequently (p<0.05) in patients with WSP than in patients without WSP. The WSP-positive patients were more frequently negative for all four tested autoantibodies (p<0.05). The patients with WSP had fewer EGMs than the patients without WSP (p<0.01); more specifically, polyneuropathy occurred less frequently (p<0.05) in the patients with WSP. Cytopenia, uveitis, pericarditis, pleuritis, interstitial lung disease, vasculitis, monoclonal gammapathy of unknown significance and non-Hodgkin lymphoma only occurred in the patients without WSP. CONCLUSIONS: Primary Sjögren's patients with WSP form a benign subgroup, with a lower prevalence of anti-SSB and EGMs (in particular polyneuropathy). We suggest a shorter period of follow-up for this subset than for the WSP-negative patients.

Rituximab in life threatening antisynthetase syndrome.

This case study reports a patient with severe interstitial pneumonitis, mild polyarthritis and polymyositis, accompanied by the presence of anti-Jo-1 antibodies diagnosed as antisynthetase syndrome. The concurrence of anti-Jo-1 with anti-Ro/SSA antibodies leads to a more severe form of interstitial lung disease. This patient was referred to our hospital because of life threatening respiratory failure. He was refractory to glucocorticoids and cyclophosphamide, but was successfully treated with two sequential infusions of rituximab. Clinical condition improved very rapidly. Response to treatment was well correlated with a fall of levels of serum soluble IL2-receptor. A decrease in pulmonary disease activity was visualized on PET-scans before and after two sequential rituximab infusions.

Relationship between histological subtypes and clinical characteristics at presentation and outcome in biopsy-proven temporal arteritis. Identification of a relatively benign subgroup.

Temporal arteritis (TA) may offer major complications, whilst high dosage of prednisone may result in serious side effects. We tried to identify a subgroup of TA, which can be treated with a lower dosage of prednisone. Retrospectively, clinical and laboratory data were studied at presentation, as well as the outcome in 44 consecutive patients with biopsy-proven temporal arteritis. These data were related to three particular histological subgroups, (a) classical giant cell arteritis, (b) atypical arteritis, and (c) 'healed arteritis', defined according to Allsop and Gallagher (The American Journal of Surgical Pathology 5:317-332, 1981). At presentation in subgroup c, erythrocyte sedimentation rate was lower and the level of haemoglobin was higher than in the other two subgroups. During follow-up in the healed arteritis group, reactivation, recurrence, or early death were not observed, whilst prednisone dosage after 2 and 3 years was lower compared to subgroup b. Major complications (permanent blindness and cerebrovascular accident) were only observed in subgroups a and b. We believe that the healed arteritis subgroup represents a relatively benign subgroup with a mild clinical presentation and a good prognosis. Therefore, a much lower initial prednisone dosage (15 mg/day) is suggested for patients in subgroup c than in the other two subgroups (40-60 mg/day).

Extremely high serum ferritin levels as diagnostic tool in adult-onset Still's disease.

The diagnosis of adult-onset Still's disease (ASD) is difficult to establish due to the nonspecific clinical and laboratory findings. A markedly raised serum ferritin level is a typical finding, although it is not well understood why ferritin levels are extremely high in ASD. We discuss several possible explanations leading to the extremely high levels of ferritin.

Nocardiosis: a case series and a mini review of clinical and microbiological features.

Infections caused by Nocardia species are uncommon and have a wide variety of clinical manifestations in immunocompetent and immunocompromised patients. The diagnosis of nocardiosis can easily be missed because there are no characteristic symptoms. We present one case of a Nocardia infection in detail and give a brief description of eight other cases, including a relatively unique type of Nocardia veterana, diagnosed in our hospital during a five-year period. The diversity of clinical manifestations, microbiological identification and general principles of treatment of nocardiosis are reviewed.

Polyarthritis in primary Sjögren's syndrome represents a distinct subset with less pronounced B cell proliferation a Dutch cohort with long-term follow-up.

The primary goal was to investigate the differences in patients with and without polyarthritis (PA) in primary Sjögren's syndrome (pSS) in a clinical-based (real-life) setting, with respect to demographic characteristics, cumulative prevalence of other extra-glandular manifestations (EGM), hypergammaglobulinaemia and serological profile. The secondary goal was to describe the characteristics of polyarthritis in our pSS cohort. Patients diagnosed with pSS and polyarthritis but without rheumatoid arthritis (RA)-like changes on X-rays were followed up prospectively from June 1991 until August 2014, with at least one check-up each year. Patients fulfilling the criteria for concomitant connective tissue disorders were excluded. Data were collected with respect to the prevalence of systemic auto-antibodies (anti-nuclear antibodies (ANA), anti-Sjögren's syndrome-related antigen A (anti-SSA), anti-Sjögren's syndrome type B (anti-SSB) and immunoglobulin M-rheumatoid factor (IgM-RF)) and other EGM related to pSS. A total of 134 patients were included for the final analysis. The median follow-up was 86 months (range 0-368 months). Twenty-two patients (16.4 %) had polyarthritis. The prevalence of systemic auto-antibodies including rheumatoid factor did not differ between the two groups. Anti-cyclic citrullinated peptide (CCP) occurred much more frequently in the polyarthritis-positive (PA+) patients (13.7 vs 0.9 %; p = 0.015). Hypergammaglobulinaemia (p = 0.002) and increased levels of IgG (p = 0.013) occurred much less frequently in the PA+ group compared to the polyarthritis-negative (PA-) group. The mean total number of EGM or of any specific EGM did not differ between the two groups. Most patients had a mild, symmetrical PA predominantly involving the finger joints (proximal interphalangeal joints/metacarpophalangeal joints (PIP/MCP)) and/or wrists and/or metatarsophalangeal (MTP) joints. Significant morning stiffness lasting ≥1 h was found infrequently (32 %). All patients were treated with a classic (c) disease-modifying antirheumatic drug (DMARD), but in two cases, treatment was necessary with a tumour necrosis factor (TNF) inhibitor. PA+ pSS patients are more frequently anti-CCP positive and have a less pronounced B cell proliferation than PA- patients. PSS patients with PA seem to have a relatively mild articular expression with a favourable course.

[A patient with sclerosing autoimmune pancreaticocholangitis as the cause of recurrent cholangitis following a pylorus-sparing pancreaticoduodenectomy]. / Een patient met scleroserende auto-immune pancreaticocholangitis als oorzaak van recidiverende cholangitis na pylorussparende pancreaticoduodenectomie.

A pylorus-sparing pancreaticoduodenectomy was performed in a 67-year-old man because of indications for a carcinoma of the distal common bile duct. Histology of the postoperative specimen, however, revealed a sclerosing inflammation of the distal common bile duct and the surrounding pancreatic parenchyma. Initial postoperative recovery was followed by recurrent cholangitis. Stenosis of the choledocho-jejunostomy could not be demonstrated. Instead, repeated endoscopic retrograde cholangiopancreaticography revealed extensive sclerosis of the intrahepatic bile ducts, which suggested a sclerosing cholangitis associated with an autoimmune pancreatitis: sclerosing autoimmune pancreaticocholangitis. This disorder was recently described; it is characterised by a disorder in the pancreas that is indistinguishable from malignancy by imaging techniques and that is followed by a sclerosing inflammation of the bile ducts. The disease responds well to steroids. The patient described demonstrated a complete clinical and biochemical recovery after initiation ofprednisone therapy.

Pulmonary function in systemic lupus erythematosus is related to distinct clinical, serologic, and nailfold capillary patterns.

PURPOSE: The purpose of this study was to investigate whether systemic lupus erythematosus (SLE) patients with interstitial lung disease represent a particular subset of patients characterized by the presence of clinical, serologic, and nailfold capillary patterns overlapping scleroderma. PATIENTS AND METHODS: In 57 consecutive patients with SLE, a standardized detailed history was obtained and a physical examination performed, directed at signs and symptoms of connective tissue diseases, in particular scleroderma. Additionally, pulmonary function testing, chest radiography, radionuclide transit studies of the esophagus, nailfold capillary microscopy, and detailed serologic studies directed at the antigenic specificities of antinuclear antibodies were performed. Patients were divided into three groups based on the results of pulmonary function testing, i.e., normal lung function, restriction, or isolated impairment of diffusion. Clinical, serologic, and nailfold capillary microscopic findings were compared among these three groups. RESULTS: Twenty patients had normal lung function, 19 had restrictive lung function loss, and 9 had an isolated impairment of the diffusing capacity (T1,CO). Patients with obstructive lung disease (n = 9) were excluded from analysis. Sclerodermatous changes of the hands were associated with a restrictive lung function pattern. Interstitial changes on chest radiograph were associated with isolated impairment of T1,CO. Nailfold capillary abnormalities correlated with decreased T1,CO and Dm, the component of T1,CO representing the diffusing capacity of the alveolocapillary membrane. Antibodies to U1-RNA were associated with restrictive lung function and decreased T1,CO. CONCLUSION: We conclude that interstitial lung disease is present in a subset of SLE patients characterized by an increased prevalence of scleroderma traits and anti-(U1)RNA antibodies. Microvascular changes may contribute to the development of interstitial lung disease in SLE as well as in scleroderma.

Pulmonary diffusing capacity disturbances are related to nailfold capillary changes in patients with Raynaud's phenomenon with and without an underlying connective tissue disease.

PURPOSE: The aim of this study was to evaluate whether pulmonary microvascular damage is part of a more generalized involvement of the microvasculature in the spectrum of scleroderma (Scl)-like syndromes. PATIENTS AND METHODS: We studied four groups of patients, all with Raynaud's phenomenon (RP), distinguished by the extent and nature of their underlying connective tissue disease. Twenty-two patients had primary RP (pRP), another 22 patients had RP and an undifferentiated connective tissue disease (uCTD), 15 patients had Scl, and eight patients had the CREST syndrome (CREST). Pulmonary vascular damage in these groups was assessed by measuring the pulmonary diffusing capacity (T1,CO) and its components: the diffusing capacity of the alveolocapillary membrane (Dm) and the pulmonary capillary blood volume (Vc). Results were compared with morphologic abnormalities of the nailfold capillaries, as determined by nailfold capillary microscopy, and related to the presence of antinuclear antibodies. RESULTS: Vc was below normal in 38% and 43% of patients with pRP and uCTD, respectively (versus 52% in patients with Scl or CREST combined). In contrast, Dm was below normal in only 5% and 26% of patients with pRP and uCTD, respectively (versus 61% in patients with Scl or CREST combined). In patients with Scl and CREST, Dm was significantly decreased as compared with the former groups (p less than 0.01). Dm was also the pulmonary function parameter that correlated most strongly with both nailfold capillary abnormalities and the presence of antinuclear antibodies, whereas Vc did not. CONCLUSION: Early pulmonary involvement in Scl syndromes is functionally characterized by a lowered Dm, correlating with morphologic changes of the nailfold capillaries. Decreased Vc is probably a reflection of RP of the pulmonary vasculature.

Serial nailfold capillary microscopy in primary Raynaud's phenomenon and scleroderma.

Eighty-four patients with long-standing Raynaud's phenomenon (RP) were evaluated by nailfold capillary microscopy (NCM) in a cross-sectional and longitudinal study. The patients were classified in five diagnostic groups: primary familial RP (n = 16), primary nonfamilial RP (n = 20), possible scleroderma (n = 27), scleroderma (n = 16), and the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome (n = 8). In the cross-sectional study, NCM showed gradually decreasing numbers of capillary loops and increasing numbers of widened and giant loops in the following order: primary RP, possible scleroderma, and scleroderma/CREST, suggesting that these diseases are part of a continuing spectrum of RP. In the longitudinal study there was a decrease in the total number of nailfold capillary loops in scleroderma/CREST but not in primary RP and possible scleroderma.

Clinical associations of antiribonucleoprotein antibodies in patients with systemic lupus erythematosus.

The authors undertook a cross-sectional study to investigate the clinical associations of antiribonucleoprotein (anti-RNP) antibodies in 49 patients with systemic lupus erythematosus (SLE) without other concomitant connective tissue disorders. The traditional counterimmunoelectrophoresis (CIE) and the immunoblotting (IB) technique were compared. Clinically, special attention was given to the identification of sclerodermalike features. All patients completed a detailed questionnaire, physical examination, and additional investigations including pulmonary function tests, chest roentgenogram, radionuclide transit studies of the esophagus, and nailfold capillary microscopy. Pulmonary function testing and radionuclide transit studies of the esophagus were very sensitive for the detection of (subclinical) pulmonary and esophageal involvement, respectively. Within the relatively homogeneous SLE population, a subset was recognized that was characterized clinically by the presence of sclerodermalike features such as Raynaud's phenomenon, sclerodactyly, interstitial changes on chest roentgenogram, and decreased numbers of nailfold capillary loops, and serologically by the presence of anti-RNP antibodies. IB was somewhat more sensitive than CIE for the detection of anti-RNP (anti-Sm/anti-nRNP) antibodies but did not identify other clinical associations. Thus, anti-RNP antibodies in SLE are associated with scleroderma-associated features. For clinical practice, CIE is the technique recommended for their detection.

Detection of autoantibodies to ribonucleoproteins by counter-immunoelectropheresis, immunoblotting and RNA-immunoprecipitation: comparison of results.

Counterimmunoelectropheresis (CIE), immunoblotting (IB) and RNA-immunoprecipitation (RNA-IP) were compared for their potential to detect antibodies to U1RNP, Sm and SS-B in sera from 50 patients with SLE and 18 with MCTD. Anti-SS-B were detected in 6 SLE-sera (12%) and one MCTD-serum (6%) by all three techniques. Anti-Sm were present in 7 SLE-sera (14%) by RNA-IP and IB; 3 of these sera showed identity with a-Sm and 4 with a-U1RNP by CIE. Antibodies precipitating U1RNA were present in 8 SLE sera (16%); 4 of these sera were positive for anti-U1RNP by CIE (8%) and 4 sera recognized one or more of the U1RNA-associated proteins by IB (8%). All MCTD-sera were positive for anti-U1RNP by RNA-IP including one serum negative by IB and CIE. RNA-IP allowed the detection of antibodies precipitating U1-U2RNA in 4 sera; in IB, the U2RNA specific protein B" was recognized by 3 sera. RNA-IP appears to be a sensitive method for detecting anti-URNP's.

The prognostic value of the antiperinuclear factor, anti-citrullinated peptide antibodies and rheumatoid factor in early rheumatoid arthritis.

OBJECTIVE: To study the prognostic value of the antiperinuclear factor (APF), determined by an indirect immunofluorescence test (IIF) and a recently developed anti-citrullinated cyclic peptide (CCP) ELISA, in combination with rheumatoid factor (RF) status, in early RA (< 1 year). METHODS: A total of 249 participants in a randomized trial of treatment strategies were divided into 4 groups according to their APF (or CCP) and RF status at baseline. Differences in disability, joint involvement and radiological damage over a 3-year period were analysed. RESULTS: APF-IIF results differed from CCP-ELISA in 42 cases (17%); 38 of the 42 had a positive IIF and negative ELISA value. Disability after 3 years did not differ significantly between the RF and APF groups. APF- patients had significantly lower Thompson joint scores compared to APF+ patients (6 vs 24 for CCP-ELISA; 2 vs 24 for IIF). RF+APF+ patients exhibited more radiological damage compared to RF-APF- patients. RF+APF- and RF-APF+ patients had intermediate scores. Within the RF+ and RF- groups, APF+ was associated with more radiological damage and thus yielded prognostic information in addition to RF. In this respect, the results of ELISA and IIF were comparable. Thirty percent of the RF+APF+ patients had a radiological score higher than 45, compared to 13% of the RF+APF-, none of the RF-APF+, and 2% of RF-APF- patients (p < 0.001). In addition, more large joints were affected in APF+ than in APF- patients, while no difference was observed between RF+ and RF- patients. CONCLUSION: APF has prognostic value in addition to RF for joint involvement and radiological damage in early RA. The CCP-ELISA technique for APF assessment may facilitate its use in clinical practice. However, the prognostic value of the two tests lies in their ability to predict mild disease. Reliable identification at baseline of individual patients with progressive disease is still not possible.

Ileal pouch arthritis: a case report.

A patient is described with arthritis of both wrists and tendinitis of one achilles tendon in the presence of severe pouchitis. The rapid disappearance of arthritis and tendinitis after removal of the pouch strongly suggests their relationship. The pathogenesis of arthritis in pouchitis has not been elucidated but may be the same as in ulcerative colitis. Rheumatologists should be aware of the occurrence of arthritis in patients with ulcerative colitis after the construction of an ileo-anal anastomosis with a so-called pouch.

Unexpected severe reversible cyclosporine A-induced nephrotoxicity in a patient with systemic lupus erythematosus and tubulointerstitial renal disease.

We describe a patient with systemic lupus erythematosus and impaired renal function probably mainly due to tubulointerstitial disease. After a six-week course of low-dose cyclosporine A, she developed a severe but reversible loss of glomerular filtration rate and effective renal plasma flow despite of low cyclosporine A plasma levels. Based upon the observed fall of the filtration fraction, the rise in the relative clearance of 99Tc-dimercaptosuccinic acid and the increase in proteinuria, we suggest that in this case the tubules and/or interstitium are the main targets for cyclosporine A nephrotoxicity. Neither our patient's clinical symptoms nor her serologic parameters improved possibly because of the low dosage and/or short duration of cyclosporine A treatment. We conclude that one should be cautious when treating patients with systemic lupus erythematosus and pre-existing renal disease with cyclosporine A especially when tubulointerstitial abnormalities are present and/or other nephrotoxic drugs are used.

High frequency of hysterectomies and appendectomies in fibromyalgia compared with rheumatoid arthritis: a pilot study.

We investigated, in retrospect, if there were differences in the frequency and types of abdominal surgery between newly diagnosed female fibromyalgia (n = 80) and rheumatoid arthritis (n = 47) patients performed before the formal diagnosis. There was no difference in the total number of abdominal operations between both groups. In the rheumatoid arthritis group more cholecystectomies (p = 0.01) were performed, probably due to the older age of these patients (58.5 vs 48.5 years). However, in the fibromyalgia group there were more hysterectomies (p = 0.04) and appendectomies (p = 0.05) than in the rheumatoid arthritis group.

Arterial thrombotic manifestations in young women associated with the lupus anticoagulant.

To demonstrate the wide variety of clinical syndromes associated with the lupus anticoagulant (LAC), we report the case histories of three young females with arterial thrombosis in whom LAC was demonstrated. Two patients had a diagnosis of systemic lupus erythematosus and mixed connective tissue disease respectively; the other patient had no signs of underlying auto-immune disease. Arterial thrombotic events in young females should arouse suspicion of the presence of LAC although its pathophysiological significance is not established.

Liver cirrhosis due to methotrexate in a patient with rheumatoid arthritis.

A 49-year-old female with rheumatoid arthritis developed liver cirrhosis after a cumulative dosage of 6 g methotrexate (MTX). There were mild liver enzyme abnormalities, decreased liver synthesis function and possible signs of portal hypertension. After stopping MTX all laboratory abnormalities disappeared except for a mild thrombocytopenia. Risk factors and guidelines for monitoring liver toxicity during MTX treatment in rheumatoid arthritis are discussed.

Treatment of primary Sjögren's syndrome with D-penicillamine: a pilot study.

BACKGROUND: Up to now no satisfying systemic treatment is available for patients with primary Sjögren's syndrome. METHODS: In a prospective, open study we investigated the effect of D-penicillamine (first three months 250 mg/day, next three months 500 mg/day) on clinical and immunological parameters in 19 patients with primary Sjögren's syndrome and a mean disease duration of 3.8 years. RESULTS: Eight patients had to stop treatment mainly due to severe (reversible) loss of taste. Clinically, a statistically significant increase in basal salivary flow was observed after three months (p<0.05). In addition, improvement was noted in the Schirmer test and stimulated parotid salivary flow after six months, but these differences were not statistically significant. Laboratory values showed a decrease in ESR (p<0.05) and levels of IgA and IgM (both p<0.02) after six months, a decrease in levels of IgA-Rf and IgM-Rf after three months (both p<0.05), and an increase in haemoglobin level (p<0.05). CONCLUSION: From this pilot study we conclude that the treatment of primary Sjögren's syndrome with D-penicillamine has only marginal beneficial effects. Together with its clear side effects this means that D-penicillamine is unsuitable for this indication.