Efficacy and safety of rituximab in treatment of systemic... : Indian Journal of Drugs in Dermatology (2024)

INTRODUCTION

Systemic sclerosis (SSc) is an autoimmune connective tissue disease with complex pathogenesis.[¹] It is clinically characterized by a variable combination of cutaneous and internal organ fibrosis, along with articular and vascular involvements. Its importance is underlined by the fact that despite being rare, it is the leading cause of mortality among all connective tissue disorders.[²] Its incompletely understood pathogenesis involves interplay between alterations in adaptive and innate immunity and vasculopathy, which finally leads to fibrosis.[^3–6-]

The ideal treatment for SSc is still not available. Conventional treatment employed includes measures for symptom control and broad-spectrum immunosuppression.[⁷] The latter often fails to offer satisfactory and sustained disease control. In addition, adverse effects related to chronic use of cytotoxic immunosuppressants add to the morbidity faced by the patients.[⁶]

With advancement in the understanding of the immune alterations and interactions of cytokines with fibroblasts, the development of targeted and pathogenetically relevant therapeutic interventions is becoming increasingly possible.[⁸] B-lymphocytes have a critical role in the pathogenesis of SSc. They not only produce the autoantibodies associated with SSc but are also involved in key immunoregulatory pathways, cytokine production, and interaction with effector cells. Rituximab (RTX), an anti-CD 20 monoclonal antibody, is effective in downregulating B-lymphocytes and has been successfully used in the management of more than one connective tissue disease.[^9–17-] Its utility in the treatment of SSc is also emerging. In our study, we have analyzed the results of the use of RTX in SSc in a group of patients at our center.

MATERIALS AND METHODS

Thirteen SSc patients fulfilling the EULAR/ACR 2013 SSc diagnostic criteria, who had received RTX between January 2019 and June 2020 at a teaching hospital, were selected for this retrospective study. Only those patients whose relevant data were available and had a minimum follow-up of 12 months were included. Eleven patients had diffuse cutaneous SSc, and two patients had limited cutaneous SSc. Except one, all patients were female with a median age of 36 years (range, 10–53 years) and had median disease duration of 10 years (range, 6 months to 18 years). Relevant data at three time points, pretreatment and 6- and 12-month posttreatment, were extracted.

Cutaneous fibrosis was assessed in terms of modified Rodnan skin score (mRSS). Additional signs of cutaneous fibrosis noted were reduced mouth opening and presence of Ingram sign. Presence of melanoderma, pruritus and calcinosis were recorded. Frequency and duration of Raynaud’s phenomenon, and number and severity of digital ulcers were also noted.

Counts of swollen and tender joints at baseline and follow-up visits were documented. Clinical features suggestive of pulmonary, renal, cardiac, and gastrointestinal tract (GI) involvement were obtained.

Complete blood count, metabolic profile, and urinalysis were done in all patients at baseline and follow-up visits.

Pulmonary function test (PFT) and echocardiogram had been done in all patients at baseline. High-resolution computed tomography scan (HRCT) of the chest had been done in 11 patients. PFT was repeated at 6 months and at the end of the follow-up period. HRCT was repeated at 1 year in those with abnormal baseline findings. Upper GI endoscopy was done only in the six patients who had severe gastroesophageal reflux symptoms and was not repeated in any of the patients.

All patients as an institutional protocol had a Health Associated Questionnaire-Disability Index (HAQ-DI) assessment before RTX institution and at the end of follow-up.[¹⁸]

In 9 of 10 adult patients, the indication of RTX was inadequate response to oral corticosteroids and/or steroid-sparing immunosuppressants and vasodilators. One patient also had uncontrolled hyperglycemia while on steroid. On the other hand, in one adult (27 years old with 3-year disease duration) and three adolescent patients (with maximum 1-year disease duration), RTX was given as a first-line treatment. One of the adolescent patients had diffuse rapidly progressive skin sclerosis, whereas another with limited cutaneous sclerosis exhibited a reduction in forced vital capacity (FVC) along with evidence of fibrosis on HRCT lung early in her disease course.

Standard pretreatment written consent had been provided by all patients. Patients received one cycle of RTX treatment comprising four 500 mg infusions at 2-weekly intervals. Conventional treatments such as oral steroid, steroid-sparing immunosuppressants, peripheral vasodilators, and proton pump inhibitors were continued and modified as per requirement throughout the study period.

Statistical analysis

Wilcoxon signed rank test with two-tailed P value of less than 0.05 was used to test the level of significance.

RESULTS

Baseline clinical and demographic profiles of patients are shown in Table 1. The patients (12 female and 1 male) had a median age of 36 years (range, 10–53 years). Two of the thirteen patients had limited cutaneous involvement with presence of anti-centromere antibody and the other11 had diffuse cutaneous involvement with serological positivity for anti-Scl 70 antibody in 8 of these patients. All patients had classical features of cutaneous fibrosis along with Raynaud’s phenomenon. Other frequent symptoms were hypermelanosis (13/13), digital ulcers (12/13), pruritus (7/13), dyspnea (11/13), dysphagia (7/13), arthritis (6/13), and retrosternal burning sensation (6/13).

All patients showed significant clinical improvement in cutaneous manifestations as early as 6 months from completion of the RTX treatment cycle [Table 2]. The baseline mRSS of 22.2 ± 7.97 declined by about 20% to 17.7 ± 9.8 at 6 months (P < 0.05) and by 37% at 12 months to 14 ± 7.12 (P < 0.05 vs. both baseline and 6 months) [Figure 1]. A more impressive improvement in mRSS of about 60% was seen in the three adolescent patients with the improvement commencing as early as 2 months. In the adult patients with longer disease duration, improvement in mRSS was 36% by the end of 1 year follow-up period. The skin pliability was maintained throughout the follow-up period.

Mouth opening increased from a baseline value of 2.29 ± 0.49 fingers to 3.43 ± 0.83 fingers (P < 0.05) at the end of follow-up due to improvement in fibrosis. A representative clinical photograph of the latter is presented in Figure 2. All affected patients showed improvement in hypermelanosis and pruritus. Skin ulcers improved in most adult patients but improvement of ulcers was seen as early as 2 months post-RTX infusion in the two adolescent patients with short disease duration. Reduction in frequency and duration of Raynaud’s phenomenon was seen in 9/10 adult and three adolescent patients.

Six patients with articular involvement showed a decrease in the number of swollen and tender joints along with improvement in visual analog scale for joint pain at 6 months follow-up. At the end of follow-up, complete remission in arthritis was seen in all six patients affected at baseline.

Dyspnea improved by at least one class in all our affected patients (11/11) by the end of the follow-up period. Percentage predicted FVC increased from 70 ± 9.09 to 76.54 ± 7.5(P < 0.05) at the end of 1 year [Figure 3]. HRCT chest scan showed improvement in 7/11 patients whose scan was done. The improvement in quality of life was documented by a decrease in HAQ-DI from 1.77 ± 0.53 to 0.75 ± 0.23 (P < 0.05). Further, no patient had any serious adverse effects due to RTX.

Oral steroid could be stopped in the adolescent patients after 4 months. One of these three patients was subsequently off all immunosuppressants, whereas the others needed to remain on weekly methotrexate in the follow-up period. All other patients were on at least 20–30 mg prednisolone daily for 6 months post-RTX infusion, whereas after 6 months, they were on 10 mg/day prednisolone along with immunosuppressants apart from vasodilators. There was at least a 50% reduction in the dose of oral corticosteroid 3 months post-RTX infusion.

DISCUSSION

SSc is a serious autoimmune disease with significant morbidity and mortality.[¹⁹] Available conventional treatment options fail to adequately halt or reverse the ubiquitous fibrosis seen in this life-threatening disease. The European Scleroderma Observational Study evaluated treatment outcomes with oral steroid and various other immunosuppressants in SSc.[²⁰] In this study, the treatment benefits were found to be modest and the need for better and more targeted treatment was emphasized. The use of immunosuppressants early in the disease course was also suggested by the authors.[²⁰]

It has been appreciated that agents, which act on the initial steps in the pathogenesis, for example, a B-cell depleting drug like RTX, may help alleviate the unmet needs in treating SSc more effectively. In this context, evidence is accruing that RTX is indeed an important component in the armamentarium of drugs for SSc.[²¹]

Studies on the use of RTX have shown benefits predominantly in the form of improvement in skin sclerosis and stabilization/improvement of lung fibrosis. The RTX nested control study, as part of the larger European Scleroderma Trial and Research (EUSTAR) multicentre study, analyzed the effect of RTX in a large number of patients and showed that RTX was effective in reducing skin sclerosis with the baseline mRSS decreasing from 18 ± 1.6 to 14.4 ± 1.5 (P = 0.0002) at the end of follow-up.[²²] Moreover, in contrast to the group on conventional treatment, the RTX-treated group showed a greater absolute change in mRSS from baseline (6.3 ± 1.4 vs. −1.9 ± −1.6; P = 0.02). Similarly, the absolute change in percentage predicted FVC at the end of follow-up was statistically significant in favor of the RTX-treated group compared with the group on conventional treatment (0.8 ± 2.2 vs. −4.8 ± 1.7; P = 0.01).[²²] This was because the FVC remained stable in the RTX group but declined in the conventional group.[²²]

Other published studies have also shown similar improvement in skin score and lung function.[^23,24] A recently published meta-analysis of 14 studies of RTX in SSc has documented a significant and progressive improvement in skin fibrosis over a 2-year duration accompanied by a stabilization of lung function.[²⁵]

In the current retrospective study, RTX was used in 13 patients with SSc. We found significant improvement in important cutaneous and systemic features when RTX was added to conventional treatment. Overall, the therapeutic benefit of RTX was more prominent in cutaneous and articular features compared with pulmonary fibrosis and vascular symptoms such as Raynaud’s phenomenon and digital ulcers. The improvement of mRSS in our study, from a baseline of 22.2 ± 7.97 to 14 ± 7.12 at 12 months (P < 0.05) at the end of the follow-up, was in consonance with the nested control EUSTAR study and other published case series.[^{22,23,24,25,26,27}] There was no deterioration of FVC in any of our patients and statistically significant improvement in FVC in the group as a whole was achieved at 12 months follow-up. The adolescent patient with reduced FVC early in her disease also showed improvement in FVC as well as HRCT lung findings. The utility of RTX in stabilizing/improving lung fibrosis has been reported in other studies.[^23–27-]

The adolescent patients in whom RTX was administered as a first-line treatment showed greater improvement. Studies in support of early use of RTX for greater efficacy have been published earlier.[²⁸]

The overall improvement in the quality of life of patients was evidenced by the significant improvement in HAQ-DI with RTX treatment in our study. This has been reported earlier also.[²⁸]

In conclusion, our experience with the use of RTX in the treatment of SSc showed significant improvement in cutaneous, pulmonary, and articular features along with an improvement in the quality of life without any major safety concern. The greater response with use of RTX in the three treatment-naive adolescent patients is in line with the suggestion of the use of RTX as a first-line treatment option.[²⁸] Rituximab and other B-cell targeting agents under development as well as drugs directed at other important pathogenetic targets in systemic sclerosis would improve the efficacy of treatment available for this serious autoimmune condition.[¹⁸]

Authors’ contributions

A.S.: concept and design of study, and interpretation of data. U.K.U.: acquisition of data. P.K.T.: acquisition of data, analysis, and interpretation of data. G.P.: acquisition of data. A.K.J.: final approval of the version to be published. M.Z.: final approval of the version to be published. S.S.:acquisition of data, analysis, and interpretation of data.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Ethical committee clearance

The study was cleared by the Institutional Ethics Committee.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgement

The authors appreciate and acknowledge the contribution of Dr. Anil Kumar Singh in reviewing the manuscript

REFERENCES