Elsevier

Autoimmunity Reviews

Volume 14, Issue 11, November 2015, Pages 1072-1078
Autoimmunity Reviews

Review
Rituximab in the treatment of patients with systemic sclerosis. Our experience and review of the literature

https://doi.org/10.1016/j.autrev.2015.07.008Get rights and content

Abstract

Background

The treatment of systemic sclerosis (SSc) represents a great clinical challenge because of the complex disease pathogenesis including vascular, fibrotic, and immune T- and B-lymphocyte-mediated alterations. Therefore, SSc should be treated by combined or sequential therapies according to prevalent clinico-pathogenetic phenotypes. Some preliminary data suggest that rituximab (RTX) may downregulate the B-cell over expression and correlated immunological abnormalities.

Methods

Here, we describe a series of 10 SSc patients (4 M and 6 F, mean age 46 ± 13.5SD years, mean disease duration 6.3 ± 2.7SD years; 5 pts had limited and 5 diffuse SSc cutaneous subset) treated with one or more cycles of RTX (4 weekly infusions of 375 mg/m2). The main indications to RTX were interstitial lung fibrosis, cutaneous, and/or articular manifestations unresponsive to previous therapies; ongoing treatments remained unchanged in all cases. The effects of RTX were evaluated after 6 months of the first cycle and at the end of long-term follow-up period (37 ± 21SD months, range 18–72 months). An updated review of the world literature was also done.

Results

RTX significantly improved the extent of skin sclerosis in patients with diffuse SSc at 6 months evaluation (modified Rodnan skin score from 25 ± 4.3 to 17.2 ± 4.6; p = .022). A clinical improvement of other cutaneous manifestations, namely hypermelanosis (7/7), pruritus (6/8), and calcinosis (3/6) was observed. Moreover, arthritis revealed particularly responsive to RTX showing a clear-cut reduction of swollen and tender joints in 7/8 patients; while lung fibrosis detected in 8/10 remained stable in 6/8 and worsened in 2/8 at the end of follow-up. Pro-inflammatory cytokines, namely IL6, IL15, IL17, and IL23, evaluated in 3 patients with diffuse cutaneous SSc, showed a more or less pronounced reduction after the first RTX cycle.

These observations are in keeping with the majority of previous studies including 6 single case reports and 10 SSc series (from 5 to 43 pts), which frequently reported the beneficial effects of RTX on some SSc manifestations, particularly cutaneous sclerosis, along with the improvement/stabilization of lung fibrosis. Possible discrepancies among different clinical studies can be related to the etiopathogenetic complexity of SSc and not secondarily to the patients' selection and disease duration at the time of the study.

Conclusion

The present study and previous clinical trials suggest a possible therapeutical role of RTX in SSc, along with its good safety profile. The specific activity of RTX on B-cell-driven autoimmunity might explain its beneficial effects on some particular SSc clinical symptoms, namely the improvement of skin and articular involvement, and possibly the attenuation of lung fibrosis.

Introduction

Systemic sclerosis (SSc) is a connective tissue disease characterized by specific autoimmune abnormalities, diffuse microangiopathy, and accumulation of collagen and other matrix constituents in the skin and target internal organs [1], [2]. Clinically, SSc appears as multifaceted disorder consequent to the variable contribution of the above pathogenetic mechanisms, through a multistep process responsible for different clinical phenotypes. These latter represent a variable combination and degree of typical SSc symptoms: from vascular manifestations, i.e. skin ulcers, pulmonary arterial hypertension, and/or renal scleroderma crisis, to fibrotic cutaneous and visceral organ involvement [1], [2], [3], [4]. Abnormal humoral and cellular immune activation may decisively contribute to both vascular and fibrotic SSc manifestations [1], [2], [3], [4]; however, the complex and pleiotropic nature of the immune response in SSc constitutes a great therapeutic challenge [1], [2], [3], [4], [5], [6]. The effects of nonselective immunosuppressive treatments, usually employed during the early phases of SSc to control skin and lung inflammation, are often unpredictable. In addition, they tend to lose their efficacy once the disease enters a chronic phase, and consequently their long-term treatment is not recommendable considering their potential severe side-effects [4].

Given the close interrelationship between altered immune response and initiation/propagation of the other SSc pathogenetic events, the usefulness of novel immunomodulating therapies targeting specific cellular and/or molecular immune effectors requires to be carefully investigated [6]. In particular, the rationale for the use of rituximab (RTX), able to downregulate the B-cell over expression, is largely demonstrated in different autoimmune diseases [7], [8], [9], [10], [11], [12], [13], [14]; moreover, some important experimental data suggested a key role for B cells in regulating both inflammatory and fibrotic alterations that characterize several SSc manifestations [4], [6], [15], [16]. On the basis of laboratory investigations, during the last years preliminary clinical trials have suggested the therapeutical usefulness of RTX also in SSc [17], [18].

Here we report our experience with RTX treatment in a series of SSc patients along with the updated review of the world literature on this topic.

The present study included 10 SSc patients (4 M and 6 F, mean age 46 ± 13.5SD years, mean disease duration 6.3 ± 2.7 SD years) treated with one or more cycles of RTX and evaluated during a mean follow-up period of 37 ± 21SD months, range 18–72 months (Table 1). All patients, followed at our University-based Rheumatology Unit, satisfied EULAR/ACR 2013 criteria for SSc classification [19].

Scleroderma cutaneous and visceral organ involvement, including pulmonary, cardiac, renal, and gastrointestinal alterations, as well as routine blood chemistry, urinalysis, and immunological alterations were evaluated according to previously described methodologies [3], [5]. The following serological markers were detected by means of standard techniques: anti-nuclear (ANA), anti-centromere (ACA), anti-nucleolar (ANoA), and anti-extractable nuclear antigen (ENA) antibodies; these latter included anti-Scl70, -Sm, -RNP, -SSB, -SSA, -PCNA, -SL, and Jo1 [3].

In addition, standard pulmonary function tests (PFTs), namely FVCnd a DLCO, 6-minute walking test, high-resolution computed tomography (HRCT), trans-thoracic echo-color-Doppler cardiography (ECHOcg), and nailfold videocapillaroscopy were performed in all patients at baseline, after 6 months of RTX treatment, and at the end of follow-up. With the same timing, an experienced physician evaluated, in a blinded fashion, the extent of skin thickening measured by modified Rodnan skin score (mRSS), the presence and severity of skin ulcers, melanodermia, teleangectasias, calcinosis, pruritus, and tender and/or swelling joints. Four patients with abnormally increased pulmonary arterial systolic pressure at ECHOcg underwent to right heart catheterization.

At the starting of RTX treatment, the patients showed one or more active SSc clinical manifestations, scarcely responsive to previous and/or ongoing treatments (Table 1). Patients were treated with one or more cycles of RTX; each cycle included 4 infusions of RTX 375 mg/m2 of body surface area once weekly, always in combination with other ongoing therapies (iloprost, calcium-channel blockers, steroids and/or bosentan). Nine patients underwent to a second RTX cycle after 6 months; moreover, in 4/9 subjects RTX was repeated once yearly for a total of 3–5 cycles. In only one patient the initial RTX cycle was interrupted after the first two infusions because of severe sepsis. Besides routine laboratory examinations, at baseline and after six months of RTX therapy, circulating CD19-positive cell count were carried out in all cases by flow cytometry; moreover, serum levels of some pro-inflammatory interleukins were measured in 3 patients by means of commercially available assays (Human IL6, IL15, IL17, and IL23 Quantikine ELISA Kits).

Adverse events attributable to RTX were also recorded; they were classified as adverse events that occurred during RTX infusion or that appeared within the next 12 months after the RTC cycle and requiring hospitalization and/or intravenous antibiotics in case of infection.

A throughout search in PubMed, Embase, Scopus, Web of Science, Asian Science Citration Index (ASCI), IranMedex, Scientific Information Database (SID), PaKMediNet, IndMed, and Index Medicus for the World Health Organization Eastern Mediterranean Region (IMEMR) regarding SSc patients treated with RTX up to June 2015 was done, using the key words scleroderma, systemic sclerosis, rituximab, and anti-CD20.

Statistical analysis was performed by means of univariate analysis of variance (ANOVA), Student's t-test, and Fisher's exact test. Values are given as mean ± SD for normally distributed variables, or as median (range) for not normally distributed variables; P values  0.05 were considered statistically significant.

Demographic and clinico-epidemiological features of 10 SSc patients treated along with the main indications to RTX therapy are shown in Table 1. Five patients presented limited cutaneous scleroderma with serum ACA, while the other five showed a diffuse cutaneous involvement with circulating anti Scl-70 in 4 and ANoA in one. The most frequent symptoms were arthritis (8 pts), lung fibrosis (9 pts) associated to PAH in 4; pruritus (7 pts), melanodermia (7 pts), skin ulcers (8 pts), calcinosis (6 pts), and dysphagia (5 pts). RTX treatment was decided because of the failure or low responsiveness to other previous combined treatments (Ca-channel blockers, iloprost, bosentan, hydroxychloroquine, leflunomide, and/or immunosuppressors). At baseline the patients showed a variable combination of SSc clinical manifestations; the main indications to RTX are shown in Table 1.

After 6 months from the first RTX cycle, the patients showed a clear-cut clinical improvement of both articular and skin SSc manifestations. In particular, the number of swollen and tender joints markedly reduced in 7/8 patients, as well as the patient's pain VAS that medially decreased 66 ± 19.5 to 39 ± 9.9 (p = 0.017). At the end of follow-up, the clinical improvement of arthritis showed a complete remission in 6/7 and remained stable in 1/7.

Similarly, mRSS was significantly lower after RTX (from 15.3 ± 11.5 to 11 ± 7.3; p = 0.042); skin sclerosis improvement was particularly evident considering the five patients with diffuse cutaneous involvement (mRSS from 25 ± 4.3 to 17.2 ± 4.6; p = .022). At the end of follow-up, the extent of skin sclerosis in the five patients with diffuse cutaneous subset remained stable or showed a moderate progression in some individuals (19.6 ± 7.1; Wilcoxon test: p = 0.071; Fig. 1).

After RTX treatment the majority of subjects showed (Table 1) a clinical improvement of other cutaneous manifestations, such as hypermelanosis (7/7), pruritus (6/8), and calcinosis (3/6), with the exception of digital ulcers resulting scarcely responsive in all cases (6/6) (Table 1).

Similarly, other important SSc manifestations were poorly responsive to RTX treatment; in particular lung fibrosis detected in 8/10 remained stable in 6/8 and worsened in 2/8 at the end of follow-up (Table 1); moreover, three individuals (pts no. 1, 2, and 4) deceased because of PAH progression (Table 1).

As expected, the number of circulating B-lymphocytes significantly decreased in all patients after RTX treatment, while no variations of serum levels of immunoglobulins, autoantibodies, ESR, and C-reactive protein were observed.

Moreover, serum levels of pro-inflammatory cytokines, namely IL6, IL15, IL17, and IL23, measured at baseline in 3 patients with diffuse cutaneous SSc, were abnormally increased in all cases compared to the median values detectable in our healthy controls; these cytokines showed a more or less pronounced reduction after 6-month period from the first RTX cycle (Table 2).

With regards to the safety of RTX, only few and generally mild side-effects were recorded after treatment. In particular, infusion-related reactions were observed in 2/10 patients, i.e. hypotension, mild urticaria, and serum sickness-like reaction. Only one patient developed bacterial infection of the urinary tract that needed the hospitalization and intravenous antibiotics, with RTX cycle discontinuation.

Available data from the world literature regarding the RTX treatment in SSc patients comprises 15 reports [17], [18], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], which are carefully summarized in the Table 3. It includes 6 single case reports [17], [22], [24], [25], [26], [29] and 9 open-label, uncontrolled trials [18, 20, 21, 23, 27, 28, 30–32]; these latter generally reported small patients' series (from 5 to 20 pts), with the exception of one multicentre study reporting the effects of RTX in a large series scleroderma patients [31]. The indications to RTX treatment were generally lung fibrosis and/or skin sclerosis, and less frequently severe calcinosis or arthritis (Table 3); while, the dosage and modalities of drug administration and the number of RTX cycles, as well as the duration of patient's clinical follow-up after RTX treatment largely varied among different studies (Table 3).

Following the first description of a patient with lung fibrosis improvement by McGonagle et al. in 2008 [17], the majority of studies focused on the significant reduction of skin sclerosis and/or improvement/stabilization of interstitial lung fibrosis after RTX treatment (Table 3).

The improvement of lung fibrosis was observed in one randomized controlled trial including a small series of SSc patients [23]; in addition, RTX was able to reduce the scores of skin sclerosis, even if cutaneous improvement was comparable to that observed in the control group of patients receiving standard treatment alone [23]. More recently, two studies reported the effects of RTX treatment in SSc patients showing a positive response of both cutaneous and pulmonary involvement [31], [32]. In particular, Bosello et al. demonstrated a clear-cut reduction of skin fibrosis and disease activity/severity indexes after RTX in the majority of patients unresponsive to recent treatment with cyclophosphamide [32]. Moreover, pulmonary function tests remained stable throughout the long-term clinical follow-up. The Authors hypothesized that these findings, especially the skin fibrosis improvement might be correlated to the significant decline in IL-6 serum levels after RTX treatment as observed in a previous study of the same group [20]. In a multicentre study by the European Scleroderma Trial and Research (EUSTAR) the efficacy and safety of RTX were analyzed in 63 patients using a nested case-control design [31]. The mRSS was available in 46 patients, showing a significant reduction in the RTX-treated group compared to matched controls (N = 25; − 24.0 ± 5.2% vs − 7.7 ± 4.3%; p = 0.03). Moreover, in RTX-treated patients, the mean mRSS was significantly reduced at the follow-up compared with baseline (26.6 ± 1.4 vs 20.3 ± 1.8; p = 0.0001). In addition, in a limited number of patients with documented interstitial lung disease, RTX was able to prevent a further decline of FVC compared with controls (N = 9; 0.4 ± 4.4% vs − 7.7 ± 3.6%; p = 0.02). The safety measures showed a good profile of RTX in SSc patients consistent with previous studies in other autoimmune rheumatic diseases [31], [7], [8], [9], [10], [11], [12], [13].

Contrarily, Lafyatis et al. did not confirm the above positive results in a study evaluating the effects of a single RTX cycle in a series of 15 patients with diffuse cutaneous SSc; no significant variations of both cutaneous and lung involvement were observed, regardless the complete depletion after 6-months from RTX cycle of the modest B cell infiltrates present in most skin biopsies at baseline [18].

On the whole, these cohort studies demonstrated the frequent reduction of skin fibrosis as well as the improvement/stabilization of lung fibrosis after RTX, while data regarding the beneficial effects on other SSc manifestations such as calcinosis, arthritis, and skin ulcers remains still anecdotal.

Section snippets

Discussion

The results of the present study seem to confirm the clinical usefulness of RTX treatment in SSc patients, particularly for some disease manifestations. The B cell depletion was able to significantly improve the extension and severity of skin sclerosis, clearly evident in patients with diffuse cutaneous involvement; similarly, other skin manifestations, such as melanodermia, pruritus, and calcinosis ameliorated in the majority of individuals. Another valuable effect of RTX was the recovery of

Take-home messages

  • B-cell overexpression represents one of the most important pathogenetic mechanisms of SSc.

  • The usefulness of rituximab on some SSc manifestations has been previously reported.

  • In our SSc pts, anti-CD20 therapy was able to improve both cutaneous and articular involvement.

  • These findings are in keeping with the updated review of the world literature on this topic.

  • Rituximab represents a promising treatment of SSc skin sclerosis and arthritis, and possibly lung involvement.

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