A. Tavoni

A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis

OBJECTIVE To conduct a long-term, prospective, randomized controlled trial evaluating rituximab (RTX) therapy for severe mixed cryoglobulinemia or cryoglobulinemic vasculitis (CV). METHODS Fifty-nine patients with CV and related skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy were enrolled. In CV patients who also had hepatitis C virus (HCV) infection, treatment of the HCV infection with antiviral agents had previously failed or was not indicated. Patients were randomized to the non-RTX group (to receive conventional treatment, consisting of 1 of the following 3: glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) or the RTX group (to receive 2 infusions of 1 gm each, with a lowering of the glucocorticoid dosage when possible, and with a second course of RTX at relapse). Patients in the non-RTX group who did not respond to treatment could be switched to the RTX group. Study duration was 24 months. RESULTS Survival of treatment at 12 months (i.e., the proportion of patients who continued taking their initial therapy), the primary end point, was statistically higher in the RTX group (64.3% versus 3.5% [P < 0.0001]), as well as at 3 months (92.9% versus 13.8% [P < 0.0001]), 6 months (71.4% versus 3.5% [P < 0.0001]), and 24 months (60.7% versus 3.5% [P < 0.0001]). The Birmingham Vasculitis Activity Score decreased only after treatment with RTX (from a mean ± SD of 11.9 ± 5.4 at baseline to 7.1 ± 5.7 at month 2; P < 0.001) up to month 24 (4.4 ± 4.6; P < 0.0001). RTX appeared to be superior therapy for all 3 target organ manifestations, and it was as effective as conventional therapy. The median duration of response to RTX was 18 months. Overall, RTX treatment was well tolerated. CONCLUSION RTX monotherapy represents a very good option for severe CV and can be maintained over the long term in most patients.

Recommendations for the management of mixed cryoglobulinemia syndrome in hepatitis C virus-infected patients.

OBJECTIVE The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. METHODS Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. RESULTS An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild-moderate HCV-related MCS. Prolonged treatment (up to 72 weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low-medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild-moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. CONCLUSION Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS.

Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: Results of multicenter cohort study and review of the literature

OBJECTIVE Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune-complexes, mainly the cryoglobulins. B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by hepatitis C virus (HCV) infection. The treatment of MCs syndrome is generally based on antiviral drugs and/or immunosuppressors, among which rituximab, an anti-CD20 monoclonal antibody, has been usefully employed for both cutaneous and visceral MCs organ involvement. This multicenter study retrospectively evaluated the effects of rituximab in a large series of patients with active MCs. The observed results were compared to those emerging from the updated review of the literature on this topic. METHODS The study included 87 patients (male/female 19/68, mean age 62.3±11.4SD years, mean disease duration 9±6.2SD years, HCV infection in 92% of cases) with active cryoglobulinemic vasculitis evaluated before rituximab monotherapy and after 6-month follow-up by means of main clinico-serological parameters. A PubMed search up to May 31, 2011, was done to find published clinical studies, including case reports of MCs treated with rituximab. RESULTS A significant clinical improvement was observed in a relevant percentage of cases, regardless the presence/absence of associated HCV infection; namely, complete/partial remission of pre-treatment active manifestations was observed in 74% of skin purpuric lesions, up to 87% of non-healing vasculitic leg ulcers, and 44% of the peripheral neuropathy, mainly paresthesias (patients visual analogical scale from 62±25 to 37±27; p≤.0001). Moreover, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases (serum creatinine from 1.8±1.1SD to 1.4±0.8SD mg/dl, p≤.0001; 24-hour proteinuria from 2.2±2.1SD to 0.9±1.7SD g/24h, p≤.0001), with complete remission in the 50%. Among 6 patients with complicating non-Hodgkins B-cell lymphoma a complete or partial remission was observed in 5/6. A complete remission of abdominal vasculitis was also observed in one patient. These beneficial effects were mirrored by the improvement of cryoglobulinemic serological hallmarks, namely cryocrit and low complement C4, in half cases. The safety of rituximab was confirmed by the small number of side effects recorded during the 6-month follow-up. On the whole, the results of the present study are in keeping with those reported in 39 papers present in world literature, including a total of 279 MCs patients. CONCLUSIONS Rituximab may be regarded as useful and safe pathogenetic treatment of cryoglobulinemic vasculitis. The actual role of this drug should be definitely confirmed by randomized controlled trials, as well as its position in the therapeutical strategy, mainly with respect to antiviral treatment in HCV-associated MCs.

Undifferentiated connective tissue diseases: the clinical and serological profiles of 91 patients followed for at least 1 year

The objective of this work was to evaluate the clinical and serological profiles of patients with undifferentiated connective tissue diseases (UCTD) who had been followed for at least 1 year. The retrospective analysis (1974–95) was based on UCTD patients diagnosed on the basis of clinical manifestations suggestive of a connective tissue disease, and the presence of at least one non-organspecific autoantibody. A total of 91 patients were evaluated. The condition of 79 remained stable during the follow up, while in 12 the UCTD evolved to systemic lupus erythematosus (SLE) within a mean period of 3 years (min. 1 year, max. 8 years, median 2 years) after the onset of the disease. At baseline none of the variables, considered alone, showed an association with the future development of SLE. Multiple regression analysis, however, suggested that the association of sicca symptoms, Raynauds phenomenon and/or photosensitivity was inversely correlated with the development of SLE (P = 0.0012, Fishers exact test). The most common clinical manifestations of UCTD included arthritis, arthralgias, Raynauds phenomenon, xerostomia, xerophthalmia and leukopenia. The stable UCTD patients showed a simple autoantibody profile characterized by a single autoantibody specificity in 82% of the cases 30% with anti-Ro/SSA alone and 28% with anti-RNP alone. This profile remained stable during the follow up. Anti-RNP antibodies alone correlated with the presence of Raynauds phenomenon and arthritis (P < 0.001 and P < 0.01, respectively), while anti-Ro/SSA antibodies alone correlated with xerostomia and xerophthalmia (P < 0.01). In conclusion, the UCTDs in most of our patients seem to represent distinct clinical entities with a limited autoimmune repertoire rather than the early phases of definite connective tissue diseases. They could therefore provide an ideal model for the study of the clinico-serological correlations in autoimmune diseases.

Evaluation of s-adenosylmethionine in primary fibromyalgia: A double-blind crossover study

The effect of S-adenosylmethionine (SAMe) and placebo was evaluated in a short-term crossover study of 17 patients with primary fibromyalgia. Eleven of 17 patients had a significant depressive state as assessed by either the Hamilton Depression Rating Scale or the Scala di Autovalutazione per la Depressione (SAD) rating scale. The number of trigger points plus painful anatomic sites decreased after administration of SAMe (p less than 0.02) but not after placebo treatment. In addition, scores on both the Hamilton and SAD rating scales improved after SAMe administration (p less than 0.05 and p less than 0.005, respectively), whereas they did not significantly change after placebo treatment. In all the patients, there was a good correlation between scores on the Hamilton rating scale and the number of trigger points. Thus, this preliminary study confirms the close relationship between primary fibromyalgia and psychologic disturbances, particularly with regards to a depressive state. SAMe treatment, by improving the depressive state and reducing the number of trigger points, seems to be an effective and safe therapy in the management of primary fibromyalgia.

Preliminary classification criteria for the cryoglobulinaemic vasculitis

Background To develop preliminary classification criteria for the cryoglobulinaemic syndrome or cryoglobulinaemic vasculitis (CV). Methods Study part I developed a questionnaire for CV to be included in the formal, second part (study part II). Positivity of serum cryoglobulins was defined by experts as an essential condition for CV classification. In study part II, a core set of classification items (questionnaire, clinical and laboratory items, as agreed) was tested in three groups of patients and controls—that is, group A (new patients with the CV), group B (controls with serum cryoglobulins but lacking CV) and group C (controls without serum cryoglobulins but with features which can be observed in CV). Results In study part I (188 cases, 284 controls), a positive response to at least two of three selected questions showed a sensitivity of 81.9% and a specificity of 83.5% for CV. This questionnaire was employed and validated in study part II, which included 272 patients in group A and 228 controls in group B. The final classification criteria for CV, by pooling data from group A and group B, required the positivity of questionnaire plus clinical, questionnaire plus laboratory, or clinical plus laboratory items, or all the three, providing a sensitivity of 88.5% and a specificity of 93.6% for CV. By comparing data in group A versus group C (425 controls), the same classification criteria showed a sensitivity 88.5% and a specificity 97.0% for CV. Conclusion Classification criteria for CV were developed, and now need validation.

Low-antigen-content diet in the treatment of patients with mixed cryoglobulinemia

PURPOSE The effects of a low-antigen-content diet (LAC diet) versus a standard normocaloric diet on the signs and symptoms of mixed cryoglobulinemia (MC) were compared in a crossover randomized study. PATIENTS AND METHODS The study consisted of 24 outpatients with MC, and was carried out in a 48-week period. After 18 weeks of either the LAC or the placebo diet, patients returned to a totally unrestricted diet for 12 weeks (washout period) and crossed over to the second half of the study for the other 18 weeks. RESULTS After three weeks of the restricted LAC diet, the cryocrit decreased from 3.5 +/- 3.4% (mean +/- SD) to 2.3 +/- 2.0% (p less than 0.01), and the circulating immune complex levels decreased from 48 +/- 30% to 39 +/- 34% (p less than 0.01). At the same time, the purpura score (p less than 0.05), glutamic pyruvic transaminase level (p less than 0.01), and gamma glutamyl transferase level (p less than 0.001) significantly improved. Splenic reticuloendothelial function, measured as the half-life of heat-damaged autologous red cells, decreased from 41 +/- 21 minutes to 21 +/- 10 minutes (p less than 0.005). In contrast, no significant parallel clinical, biochemical, and immunologic changes occurred in the same patients during the placebo (standard normocaloric) diet. CONCLUSION These data show that an LAC diet decreases the amount of circulating immune complexes in MC and can modify certain signs and symptoms of the disease. These effects of the LAC diet may be explained by postulating a functional restoration of the mononuclear phagocytic system.

Fibromyalgia Features in Patients with Primary Sjögren's Syndrome: Evidence of a Relationship with Psychological Depression

The prevalence of musculoskeletal complaints suggestive of the fibromyalgia syndrome (FS) was evaluated in 30 patients with primary Sjögrens syndrome (1 degree SS) and in two control groups of patients with osteoarthritis (OA) and diabetes mellitus (DM). In addition, the presence of depressive state was investigated in patients and controls using the Hamilton rating scale and an Italian self-evaluating test. Fibromyalgia features were found in 14 1 degree SS patients (47%), in 21 OA (70%) and in 10 DM (33%) controls. 1 degree SS patients showed the highest prevalence (47%) of moderate-severe depression with respect to OA (20%) and DM (7%) groups (p less than 0.01). Furthermore, while FS features correlated closely with both tests for depression in 1 degree SS (p less than 0.001), this correspondence was absent or much less significant in the other disease groups. Finally, neither psychopathological features nor FS complaints appeared to be related to the other clinical and serological findings of 1 degree SS.

Validation of the classification criteria for cryoglobulinaemic vasculitis

OBJECTIVE The aim of this study was to validate the classification criteria for cryoglobulinaemic vasculitis (CV). METHODS Twenty-three centres were involved. New patients with CV (group A) and controls, i.e. subjects with serum cryoglobulins but lacking CV based on the gold standard of clinical judgment (group B) and subjects without cryoglobulins but with clinical features that can be observed in the course of CV (group C), were studied. Positivity of serum cryoglobulins was necessary for CV classification. Sensitivity and specificity of the criteria were calculated by comparing group A vs group B. The group A vs group C comparison was done to demonstrate the possible diagnostic utility of the criteria. RESULTS The study included 268 patients in group A, 182 controls in group B and 193 controls in group C (small vessel vasculitis, 51.8%). The questionnaire (at least 2/3 positive answers) showed 89.0% sensitivity and 93.4% specificity; the clinical item (at least 3/4 clinical involvement) showed 75.7% sensitivity and 89.0% specificity and the laboratory item (at least 2/3 laboratory data) showed 80.2% sensitivity and 62.4% specificity. The sensitivity and specificity of the classification criteria (at least 2/3 positive items) were 89.9% and 93.5%, respectively. The comparison of group A with group C demonstrated the clinical utility of the criteria in differentiating CV from CV mimickers. CONCLUSION Classification criteria for CV were validated in a second, large, international study confirming good sensitivity and specificity in a complex systemic disease.

Predictors of renal outcome in diffuse proliferative glomerulonephritis in systemic lupus erythematosus

The occurrence of nephritis is considered to be the most important factor influencing the prognosis in systemic lupus erythematosus (SLE). Despite the apparent histological similarity of the lesions, however, patients with diffuse proliferative glomerulonephritis (DPGN) may exhibit different outcomes. A retrospective study was carried out on 81 SLE patients with DPGN to evaluate the prognostic significance of different clinical, serological and histological variables; in particular, 95 renal biopsies were re-evaluated and the activity and chronicity indices for the patients were determined. A positive correlation was observed between the presence of chronic lesions on renal biopsy and a poor renal outcome (<0.001). Moreover, in the repeat biopsies the patients with a poor outcome showed a higher degree of chronic lesions. Active lesions and other clinical and serological parameters did not correlate with the outcome.