Thorough assessment of the effectiveness of belimumab in a large Spanish multicenter cohort of systemic lupus erythematosus patients.

OBJECTIVES: To provide an overview on the current use of belimumab (BLM) in SLE patients in clinical practice and to examine its efficacy in terms of standardized outcomes, drug survival, as well as patient and safety profiles. METHODS: A longitudinal retrospective multicentre cohort including SLE patients treated with BLM at 18 Spanish centers. Data was collected upon initiation of BLM, at 6 and 12 months after initiation, and at the last recorded visit. Changes in SLEDAI-2K, the proportion of patients who achieved LLDAS and DORIS 2021, and number of flares were compared between visits. Changes in damage, glucocorticoids use and employment status pre-BLM and post-BLM were also assessed. RESULTS: A total of 324 patients were included with a mean follow-up of 3.8 (±2.7) years. LLDAS was attained by 45.8%, 62% and 71% of patients, and DORIS by 24%, 36.2% and 52.5% on successive visits, respectively. Twenty-seven-point two percent of patients were in DORIS ≥ 50% of the visits and a 46% in LLDAS-50. Flares and number of flares were significantly lower one year after treatment with BLM and no changes in damage accrual were observed. Mean (±SD) prednisone dose was significantly reduced over time, with 70 (24%) patients discontinuing GC. CONCLUSION: Our study not only demonstrates belimumab´s efficacy in attaining treat-to-target goals in SLE patients, but also confirms its GC-sparing effect, and its prevention of flares and organ damage accrual.

Cryoglobulinaemic vasculitis at diagnosis predicts mortality in primary Sjögren syndrome: analysis of 515 patients.

OBJECTIVE: To evaluate the fulfilment of classification criteria for cryoglobulinaemic vasculitis (CV) at diagnosis in a large cohort of patients with primary SS and their correlation with poor outcomes. METHODS: We included 515 consecutive patients tested for serum cryoglobulins who fulfilled the 2002 classification criteria for primary SS. CV classification criteria and serum cryoglobulins at diagnosis were assessed as predictors of death and lymphoma using Cox proportional-hazards regression analysis adjusted for age and gender. RESULTS: Positive serum cryoglobulins were detected in 65 (12%) patients, of whom 21 (32%) fulfilled CV classification criteria. Compared with patients positive for cryoglobulins who did not fulfil CV criteria, patients with CV had a higher frequency of type II cryoglobulinaemia (86% vs 43%, P = 0.04), a higher mean cryocrit level (6.58% vs 1.25%, P < 0.001) and a higher cumulated mean EULAR-SS disease activity index score (35.3 vs 16.2, P < 0.001). After a mean follow-up of 110 months, 45 (9%) patients developed B-cell lymphoma and 33 (6%) died. Compared with patients without cryoglobulins, patients with cryoglobulins who fulfilled [hazard ratio (HR) = 7.47, 95% CI: 3.38, 16.53] and did not fulfil (HR = 2.56, 95% CI: 1.03, 6.35) CV criteria both showed a higher risk of B-cell lymphoma in the univariate analysis, but not in the multivariate models. Compared with patients without cryoglobulins, patients with CV had a higher risk of death in both the univariate (HR = 11.68, 95% CI: 4.44, 30.74) and multivariate (HR = 4.36, 95% CI: 1.32, 14.47) models. CONCLUSION: Patients with primary SS who fulfilled criteria for cryoglobulinaemic vasculitis at diagnosis are at higher risk of death.

Classification and characterisation of peripheral neuropathies in 102 patients with primary Sjögren's syndrome.

OBJECTIVES: This paper aims to analyse the etiology, characterisation and outcomes of the different types of peripheral neuropathy in patients with primary Sjögren's syndrome (SS) and their association with clinical and immunological disease expression. METHODS: A total of 563 consecutive patients diagnosed with primary SS were evaluated. We retrospectively assessed the results of nerve conduction studies carried out in patients with suspected peripheral nervous system involvement. Peripheral neuropathies were classified into mononeuropathy, mononeuropathy multiplex, polyneuropathy and neuronopathy according to the patterns evidenced by electrodiagnostic studies. RESULTS: Nerve conduction studies were carried out in 158/563 (28%) SS patients. The results were normal in 49 and abnormal in 109 patients, in whom peripheral neuropathy was diagnosed in 102. After excluding patients with neuropathy associated with other diseases and patients with entrapment mononeuropathies, 55/563 (10%) patients were classified as having SS-related peripheral neuropathy, including axonal sensorimotor polyneuropathy (n=24), pure sensory neuronopathy (n=15), mononeuropathy multiplex (n=15) and demyelinating polyradiculoneuropathy (n=1). In spite of therapy, clinical progression measured by the MOHS scale was observed in 12% of patients with axonal polyneuropathy, 13% of those with mononeuropathy multiplex and 47% of those with neuronopathy. Survival was significantly reduced in patients with peripheral neuropathy (especially in those with mononeuropathy multiplex and axonal polyneuropathy) in comparison with the control group (log rank =0.001). CONCLUSIONS: We found a prevalence of SS-related peripheral neuropathy of 10%. Classification of neuropathy according to the clinical presentation and electrodiagnostic tests may be useful in determining the functional outcome, therapeutic response and survival.

Monoclonal gammopathy related to Sjögren syndrome: a key marker of disease prognosis and outcomes.

OBJECTIVE: To analyze the monoclonal expression of SS through the detection of serum monoclonal immunoglobulins (mIgs) in a large series of patients with Sjögren syndrome (SS), focusing on the etiology, characterization and evolution of the monoclonal band and the association with SS clinical expression and outcomes. METHODS: Serum immunoelectrophoresis (IE) was performed to 408 consecutive patients who were evaluated by our unit between 1992 and 2011: 221 patients who fulfilled the 2002 American-European criteria for primary SS, 122 primary SS patients who fulfilled exclusively the 1993 European criteria and 65 patients with SS-associated hepatitis C virus infection. IE was performed at diagnosis and every year during the follow-up. RESULTS: Of the 221 patients with primary SS, 48 (22%) had monoclonal gammopathy. In the control groups, the prevalence was 16% in patients with SS who fulfilled the 1993 criteria (p > 0.05) and 52% in SS-HCV patients (p < 0.001). Monoclonal bands were characterized in 47/48 patients with primary SS: IgG (n = 21), IgM (n = 16), IgA (n = 5) and free light chains (n = 5); the light chain was κ in 28 patients and λ in 19 (κ:λ ratio 1.5). Primary SS patients with monoclonal gammopathy had a higher prevalence of parotidomegaly (38% vs 20%, p = 0.021), vasculitis (21% vs 6%, p = 0.003), neurological involvement (42% vs 23%, p = 0.016), higher mean values of circulating gammaglobulins (23.4 vs 20.6%, p = 0.026), ESR (56.6 vs 37.6 mm/h, p = 0.003), a higher prevalence of RF (69% vs 50%, p = 0.022), low C3 levels (24% vs 11%, p = 0.028), low C4 levels (24% vs 7%, p = 0.003), low CH50 activity (28% vs 11%, p = 0.008) and cryoglobulins (23% vs 8%, p = 0.012) compared with those without monoclonal gammopathy. Of the 48 patients with primary SS and monoclonal gammopathy, 8 developed hematologic neoplasia after a mean follow-up of 10 years, a higher prevalence than observed in patients without monoclonal gammopathy (17% vs 5%, p = 0.009). Survival rates according to the presence or absence of monoclonal gammopathy were 83% and 97%, respectively (log rank 0.004). CONCLUSION: Monoclonal gammopathy was detected in 22% of patients with primary SS fulfilling the 2002 criteria, with mIgGκ being the most frequent type of band detected. In HCV-associated SS patients, the prevalence was higher (52%) with IgMκ being the most prevalent band detected. Monoclonal gammopathy was associated with a higher prevalence of parotid enlargement, extraglandular features, hypergammaglobulinemia, cryoglobulinemia and related markers (rheumatoid factor, hypocomplementemia), and with a poor prognosis (development of neoplasia and death).

Etiopathogenic role of surfactant protein d in the clinical and immunological expression of primary Sjögren syndrome.

OBJECTIVE: To analyze the etiopathogenic role of genetic polymorphisms and serum levels of surfactant protein-D (SP-D) in primary Sjögren syndrome (pSS). METHODS: We analyzed 210 consecutive patients with pSS. SFTPD genotyping (M11T polymorphism rs721917) was analyzed by sequence-based typing and serum SP-D by ELISA. RESULTS: Thirty-two patients (15%) had the Thr11/Thr11 genotype, 80 (38%) the Met11/Met11 genotype, and 96 (46%) the Met11/Thr11 genotype; 2 patients could not be genotyped. Patients carrying the Thr11/Thr11 genotype had a higher prevalence of renal involvement (13% vs 1% and 4% in comparison with patients carrying the other genotypes, p = 0.014). Serum SP-D levels were analyzed in 119 patients (mean 733.94 ± 49.88 ng/ml). No significant association was found between serum SP-D levels and the SP-D genotypes. Higher mean values of serum SP-D were observed in patients with severe scintigraphic involvement (851.10 ± 685.69 vs 636.07 ± 315.93 ng/ml, p = 0.038), interstitial pulmonary disease (1053.60 ± 852.03 vs 700.36 ± 479.33 ng/ml, p = 0.029), renal involvement (1880.64 ± 1842.79 vs 716.42 ± 488.01 ng/ml, p = 0.002), leukopenia (899.83 ± 661.71 vs 673.13 ± 465.88 ng/ml, p = 0.038), positive anti-Ro/SS-A (927.26 ± 731.29 vs 642.75 ± 377.23 ng/ml, p = 0.006), and positive anti-La/SS-B (933.28 ± 689.63 vs 650.41 ± 428.14 ng/ml, p = 0.007), while lower mean values of serum SP-D were observed in patients with bronchiectasis (489.49 vs 788.81 ng/ml, p = 0.019). CONCLUSION: In pSS, high SP-D levels were found in patients with severe glandular involvement, hypergammaglobulinemia, leukopenia, extraglandular manifestations, and positive anti-Ro/La antibodies. The specific association between SP-D levels and pulmonary and renal involvements may have pathophysiological implications.

Factors influencing dry mouth in patients with primary Sjögren syndrome: usefulness of the ESSPRI index.

OBJECTIVE: To evaluate health-related quality of life in a large series of primary SS patients using the recently-proposed ESSPRI questionnaire and to evaluate the relationship between the intensity of oral dryness and other signs and symptoms frequently found in these patients. METHODS: We evaluated 90 primary SS patients seen consecutively; all fulfilled the current classification criteria. All patients completed the ESSPRI questionnaire. We compared the mean values of the ESSPRI-dry mouth item with other ESSPRI items related to sicca features, general symptoms, quality of life, quality of sleep, psychological and psychiatric features, extraglandular involvement, laboratory features and immunological markers and cardiovascular risk factors. Multivariate regression analysis with a backwards stepwise selection method was performed to identify those variables that were independently associated with dry mouth. RESULTS: Mean intensity of oral dryness measured by the corresponding ESSPRI item was 7.17±0.23. Oral dryness correlated with age both at diagnosis and at study inclusion (p=0.013), but not with gender or with time of disease evolution. No significant correlation was found with the SF-36, HAQ and FIQ questionnaires. We found a significant correlation between the intensity of oral dryness and the quality of sleep (p=0.001), anxiety and depression measured by the GH28 (p=0.004 and 0.024, respectively), and a statistically-significant trend for anxiety and depression measured by the HADS (p=0.08 and 0.07, respectively). No significant correlation was found with the main extraglandular and immunological features; however, a significant correlation between oral dryness and hypertension (p=0.019), type II diabetes mellitus (p=0.005) and hypercholesterolemia (p=0.011) was found. Multivariate regression analysis shows that fatigue measured by ESSPRI (p=0.049), sleep quality (p=0.008) and hypercholesterolemia (p=0.008) were independently associated with dry mouth. CONCLUSION: We report on the usefulness of the ESSPRI index in evaluating HRQOL associated with oral dryness in primary SS patients. Oral dryness correlated with age and the other sicca symptoms measured by ESSPRI, but not with the main systemic and immunological SS features. In contrast, oral dryness was strongly correlated with fatigue, pain, psychological distress, poor sleep and vascular risk factors. A multidisciplinary therapeutic approach may be the best way of minimizing oral dryness and its consequences in primary SS patients.