Subcutaneous immunoglobulin therapy for refractory skin thickening in rapidly progressive systemic sclerosis: A case report and literature review

Abstract

The use of immunoglobulin is a therapeutic option with increasing evidence of efficacy for different rheumatologic autoimmune systemic diseases. Some studies concerning immunoglobulin use in systemic sclerosis have been published with encouraging results. We present the case of a young woman diagnosed with rapidly progressive diffuse cutaneous systemic sclerosis, refractory to therapy with methotrexate and rituximab, which presented a relevant skin improvement after one year of subcutaneous immunoglobulin (2 g/kg cumulative monthly dose, refracted in weekly administrations). Furthermore, a narrative literature review of the evidence for alternative treatments with a focus on immunoglobulin use for systemic sclerosis skin involvement was carried out.

Introduction

Systemic sclerosis (SSc) is a complex multisystem connective tissue disorder, characterized by autoimmune phenomena and vascular injury followed by defective neovascularization and impaired vessel remodeling, resulting in progressive tissue fibrosis. ¹ The most evident aspect of SSc is skin involvement and, apart from Raynaud’s phenomenon (RP), it represents the most frequent presenting symptom. Early cutaneous manifestation is exemplified by scleredema, clinically apparent as puffy fingers, evolving into sclerodactyly, and potentially progressing proximally with skin fibrosis. Skin involvement occurs in almost all patients and may represent a sufficient criterion for diagnosis of SSc, according to 2013 EULAR/ACR classification criteria, although there is a great heterogeneity of clinical manifestations and a condition of SSc sine scleroderma may occur.^2,3,4 Cutaneous manifestations allow subclassification of SSc into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) subsets consistently with the distribution of cutaneous involvement and disease progression pattern. Peculiarly, in dcSSc, skin thickening extends proximal to the elbows and may involve the whole trunk, disease progression is rapid, and may reach a plateau within the first years from disease onset.^5,6 Specific treatment for SSc skin involvement reported in the last updated guidelines refers to methotrexate (MTX) as the first choice therapy, but evidence for other treatment alternatives in this subset of patients is scarce. ⁴

We report the clinical case of a young lady diagnosed with rapidly progressive SSc and extensive skin involvement, refractory to MTX and off-label use of rituximab (RTX), and then positively responding to subcutaneously administered immunoglobulin (Ig) therapy. Furthermore, a literature review of dcSSc evidence-based treatments with a focus on the use of Ig was also performed.

Case description

A 39-year-old female patient affected by rapidly progressive SSc was referred to our attention in October 2019. She reported the first appearance of the RP in January 2019 and developed within few weeks digital ulcers at the tip of the second and third digits, bilaterally. Scleredema of the arms and forearms was also present. Prompt use of iloprost and topical interventions for wound care allowed healing of the lesions within 2 months, without recurrence during summer.

When she arrived at our rheumatologic outpatient clinic, she complained of new digital ulcers appearance, arthralgia, and noticed progressive skin thickening. At our physical examination, diffuse fingers sclerodactyly and scleredema of the hands, upper arms, face, and the trunk were found, her modified Rodnan skin score (mRSS) was 8. We could also note mild face telangiectasias and an eczematous rash of the dorsum of both hands. After a comprehensive clinical, laboratory, and instrumental evaluation, we confirmed the diagnosis of dcSSc subset. Of note, antinuclear antibody (ANA) positivity (1:320) with a nuclear speckled pattern and the presence of ENA-Ro52 antibodies were detected. Nailfold videocapillaroscopy (NVC) was suggestive of a secondary RP, compatible with an active-late scleroderma pattern according to Cutolo et al.^7,8,9 Spirometry values were within the physiological range for diffusing capacity for carbon monoxide (DLCO), total lung capacity (TLC), and forced vital capacity (FVC), while at high-resolution computed tomography (HRCT) of the thorax, subpleural limited (10%) reticulations with ground glass appearance were present.

In the light of the clinical and instrumental findings observed, we promptly established a combination therapeutic regimen based on bosentan (125 mg BID), nifedipine (30 mg/day), low-dose prednisone (7.5 mg/day), MTX (15 mg weekly), folic acid (24 h after MTX, 10 mg weekly), and RTX (2000 mg refracted in two 1000 mg doses 2 weeks apart, every 6 months). ¹⁰

Despite good therapeutic adherence, we noticed worsening of cutaneous manifestations, evident as thickening of the skin presents at the dorsum of both hands where the eczematous rash was once present; overall, the mRSS increased up to 15 after 3 months (Figure 1(a)). A total body computed tomography (CT) scan was performed, and no signs of organ involvement or space-occupying lesions were detected. To obtain an echographic assessment of skin involvement, we also performed a shear wave elastography with ultrasound (SWE-US) of the right distal third forearm of our patient, in the proximity of the wrist (Figure 2(a)). SWE-US is a new noninvasive diagnostic technique employed also in SSc for measuring skin body stiffness, with good sensitivity and reproducibility.^11,12

Figure 1.

Picture of right hand and wrist before (a) and after (b) one year of subcutaneous (sc) immunoglobulins (Ig) administration. In (a), scleredema and sclerodactyly are representative of skin involvement with a total mRSS of 15. In (b), the same anatomical region after 1 year of sc Ig therapy with a total mRSS of 4.

Figure 2.

Shear wave elastography with ultrasound (SWE-US) longitudinal scan of the right distal third forearm, in proximity to the wrist, (a) at baseline and (b) after 1 year of sc Ig therapy. Colors are representative of the tissue elasticity/stiffness with a semiquantitative scale: blue, green, or red describe increasing elasticity or decreasing stiffness.^11,12

The pictures document the improvement in the skin and subcutaneous tissue elasticity, evidenced by the reduction of stiff (blue) areas in the same anatomical region from (a) 5.2 cm² to (b) 2.9 cm².

During the follow-up visit, our patient reported an onset of nausea, vomiting, and abdominal pain lasting 3 days after each MTX administration, causing discontinuation of the drug. Within 4 weeks, she noticed itching and progressive skin thickening. Considering the young age and the pregnancy desire of the patient, we evaluated possible treatment strategies and decided to propose Ig therapy, the alternative with the most promising risk-to-benefit ratio. The coronavirus disease 2019 (COVID-19) pandemic brings us to limit inpatient admissions, therefore, after written informed consent and off-label approval, we started subcutaneous administration of Ig International Nonproprietary Names (INN)-human normal Ig, 2 g/kg cumulative monthly dose, refracted in 2 weekly administrations). Within 2 weeks, the patient reported a subjective improvement, and after 4 weeks, we noticed a striking decrease in mRSS and ameliorated clinical conditions of our patient.

During monthly follow-up visits after the beginning of sc Ig therapy, we observed the progressive improvement of cutaneous conditions, with no appearance of new digital ulcers. Notably, overall quality of life, despite progressive steroid tapering up to its discontinuation, was ameliorated. After 6 months, we performed another SWE-US of the same anatomical region (Figure 2(b)) to evaluate the change and we observed a reduction in the superficial dermal thickness and skin stiffness (see Figure 2). Extension of cutaneous involvement was strikingly decreased, as documented by mRSS reduction up to a value of 6 and regression of trunk and upper limbs scleredema.

This treatment option was well tolerated and effective in stopping disease progression in our patient non-responder to suggested treatment protocols according to the latest guidelines. Notably, skin involvement assessed by mRSS after 1 year of sc Ig therapy was 4, lower than the baseline value when our patient was first seen and visited (Figure 1(b)).

Discussion

Despite the discovery of new classes of molecules effective in various rheumatologic diseases, treatment of SSc is still challenging. Effective specific disease-modifying therapy is lacking, partly due to the heterogeneous nature of SSc and its complex pathophysiology. Notwithstanding great improvements, SSc remains a major medical challenge with high mortality and morbidity. ¹³ Recently, the introduction of organ-based treatment strategies provided valuable new insights concerning improved patient care, research, and drug development. ¹⁴

One of the main pathogenetic aspects of SSc is impaired fibrogenesis, with altered collagen turnover balance, leading to the build-up of closely packed collagen bundles and abnormally cross-linked fibrils and secondary loss of vessels and appendages. ¹⁵ The fibrotic process usually originates in the connective tissue of the septae in the subcutaneous layer, also known as panniculus adiposus. ¹⁶ Skin changes over time have been shown to correlate with indexes of disease activity and internal organs involvement. ¹⁷

In our patient, we described the off-label use of MTX and RTX according to EULAR recommendations and evidence from some clinical trials. ⁴

The use of MTX for the treatment of cutaneous manifestations is supported by the results on mRSS in two independent randomized control trials (RCTs). In the first RCT, intramuscular MTX at a dose of 15 mg/week for 24 weeks showed a trend toward improvement of the total skin score (p = 0.06 vs placebo). ¹⁸ In the second RCT, orally given MTX at a dose of 10 mg/week for 12 months improved mRSS compared with placebo in an intention-to-treat analysis. ¹⁹ The beneficial effect of MTX over placebo on skin manifestations was confirmed by a re-analysis of the trial using a Bayesian methodology, ²⁰ but positive effects on other organ manifestations have not been established.

RTX is a monoclonal chimeric antibody against CD20 that depletes peripheral B cells. It was first approved for indolent non-Hodgkin lymphoma treatment in 1994 ²¹ and rheumatoid arthritis in 2006. ²² RTX has been proposed for the treatment of different rheumatological diseases, and its use in SSc has been tested for the growing evidence of B cells involvement in SSc. ²³ The role of RTX in SSc treatment has been questioned in multiple clinical trials in recent years with some evidence supporting its use in dcSSc, even if not so consistent to be adopted by guidelines. ²⁴ Two uncontrolled studies evaluated the clinical efficacy of RTX in SSc skin involvement. In the first one, skin fibrosis as assessed clinically and histologically improved significantly in the RTX-treated patients. ²⁵ In the second one, skin biopsies from RTX-treated patients exhibited a significant reduction in the myofibroblast score. ²⁶ According to another study, all included SSc patients treated with RTX experienced an improvement in the skin score, activity index, severity index, health assessment questionnaire (HAQ), and general health status during the follow-up if compared to pre-treatment values. ²⁷ With regards to safety, few and mild side effects were recorded after treatment, most commonly infusion-related reactions. In conclusion, RTX represents a plausible treatment for SSc skin sclerosis and arthritis, and possibly lung involvement with acceptable toxicity. ²⁸

Alternative treatments for skin involvement in refractory patients to MTX and RTX include cyclophosphamide (CYC), azathioprine (AZA), mycophenolate mofetil (MMF), and tocilizumab with some evidence of efficacy and also for safety issues and contrasting results their placement in SSc skin involvement treatment is still debated. ²⁹

Promising findings for the use of Ig to treat SSc cutaneous manifestations have been published as early as 2000. ³⁰ Igs are molecules physiologically produced by activated B cells and plasma cells in response to antigens exposure, with multiple non-specific mechanisms of action, including a potent immunomodulatory effect through neutralization of autoantibodies, inhibition of inflammatory mediators, and blockage of Fc receptors on the surface of B cells. ³¹ Among the approved anti-fibrotic drugs used to target the cutaneous component of SSc, none has been described as successful and all showed limited effectiveness. ³² Igs have been variably used in the last 20 years in SSc, but despite positive and encouraging results present in the literature, there are no guidelines suggesting their use.^33,34

From a molecular perspective, Ig activity may positively regulate pathological mediators involved in SSc pathogenesis, such as interleukin (IL)-6 and IL-13, B cells, and transforming growth factor beta (TGF-β) that may constitute substrates for Ig therapy activity.^35,36 The efficacy of Igs in SSc is partly due to their ability to neutralize pathogenic autoantibodies. ³⁷ It has been shown that IgG from SSc patients with severe gastrointestinal involvement can inhibit contractions of colonic smooth muscle cells in vitro through antibodies directed against type 3-muscarinic receptors (M3R); ³⁸ adding normal Igs to the culture medium results in a lower fixation of SSc IgG on M3R, probably through neutralization of pathogenic anti-M3R antibodies in SSc sera. ³⁹ A similar phenomenon could occur with SSc autoantibodies associated with fibrosis, in particular those targeting fibroblasts.^40,41

Many studies that investigated the use of Ig in treating SSc are small uncontrolled studies reporting different doses and infusion schedules (1–2 g/kg of body weight, administered over 2–5 days).^29,31 One of the largest studies to date involved 30 dcSSc patients who were on concomitant immunosuppressives with refractory disease. They showed improvement in skin involvement at 12 months compared with historical controls from negative clinical trials. ³³ More clinical studies reporting their use are required to improve awareness about the real-life use of Igs, their effectiveness, and their safety profile.

According to published protocols concerning Igs use in SSc, it is advisable to start therapy in some specific subsets of SSc patients such as: early-stage skin disease (mRSS < 22 points) refractory to corticosteroids, in the dcSSc subset; severe arthritis refractory to anti-rheumatic medications; myositis refractory to corticosteroids; and severe gastrointestinal symptoms. Apart from effectiveness, Igs are also characterized by a verified safety profile with a low incidence of adverse events, mostly mild and transient. ³¹

In SSc, the use of intravenous (IV) Igs is supported by several studies with effective results in cases refractory to conventional therapy. Most relevant proofs of Igs efficacy were shown when administered for refractory gastrointestinal involvement, such as severe dysphagia and life-threatening dysbiotic intestinal pseudo-obstruction.^42,43 Studies evaluating the long-term efficacy of Ig therapy confirm the amelioration of some key clinical aspects in refractory SSc patients both with upper and lower gastrointestinal manifestations.^44,45

Consistently, there is also evidence of IV Igs efficacy in treating SSc-related arthropathy, assessed as differences in the number of swollen and tender joints and improved joint functionality, in particular of the hands.^46,47 In a randomized double-blind placebo-controlled study assessing skin involvement at 60 weeks in refractory dcSSc patients, there was evidence of progressive improvement as assessed by mRSS after administration of one or two courses of Igs. ⁴⁸

Noteworthy, some RCTs evaluating the role of Igs for treatment of skin involvement in dcSSc patients have been carried out and are registered on ClinicalTrials.gov. One of them, which aimed to assess the efficacy and safety of intravenous Ig therapy at 48 weeks (NCT04138485), was withdrawn for business reasons, not because of any safety issues. Another open label trial (NCT04137224) has been completed to investigate the safety, tolerability, and pharmacoki-netics of subcutaneous Ig and intravenous Ig in subjects with diffuse cutaneous systemic sclerosis.

Conclusion

Our clinical case represents an example of clinical management with different therapeutic alternatives, nowadays available, to treat dc involvement in an SSc patient refractory to the recommended agent. This is a complicated issue considering the urge to stop disease progression before irreversible damage is established.

Improved management of SSc patients relies on the acknowledgment of new therapeutic alternatives, which could broaden the array of available drugs to target specifically and effectively different aspects of the disease. Ig treatment is reaching increasing evidence and may represent a valid therapeutic option for SSc treatment. Unfortunately, the complex manufacturing procedures to obtain Igs from blood donors and their relative costs are a relevant limit to the availability of this agent in clinical practice.

Nevertheless, the potential effect on multisystem involvement of different rheumatic diseases, and specifically for SSc, may justify Igs use mainly for the treatment of patients with refractory and/or multiorgan manifestations.