Treatment Approach in Systemic Lupus Erythematosus

Introduction

There is currently no known cure for systemic lupus erythematosus (SLE); therefore, the treatment of this chronic autoimmune disorder is focused on long-term management of disease activity, keeping flares at a minimum and preventing organ damage accrual. The marked heterogeneity of SLE presentation necessitates that management strategies involve both general approaches and strategies tailored to the specific tissue, organ, or organ system involved. Nevertheless, five general goals of SLE management apply to all patients with the disease: 1) control of disease activity, 2) flare prevention, 3) minimization or avoidance of drug toxicity, 4) prevention of damage accrual and, ultimately, 5) quality of life improvement and survival extension. As shown in Figure 7-1, these five goals are interrelated.

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General Approaches to Treatment

Like in other chronic inflammatory disorders, achieving disease activity control in SLE requires the application of the treat-to-target strategy. This approach requires setting clear treatment targets and continuous evaluation in the form of regular monitoring and treatment modification in response to changes. Setting treatment goals is itself a challenge in a disorder whose heterogeneity makes disease activity difficult to assess. Several disease assessment tools have been developed over the last four decades for use in clinical trials that can also be applied in clinical practice to set treatment goals; these tools are briefly reviewed in the Measures of Disease Activity section below. Two targets are considered acceptable in SLE treatment: remission and low disease activity (LDA). The final agreement on the definition of SLE remission by the Definition of Remission in SLE (DORIS) group and the validation of Lupus Low-Disease Activity State (LLDAS) definition represent two major achievements that are likely to provide feasible targets for SLE treatment in clinical practice. According to the DORIS group, overall clinical remission should be defined by no or low disease activity by the following disease activity measure scores:

• Clinical SLE Disease Activity Index (SLEDAI): Score of 0
• Physician Global Assessment (PGA, scale 0-3): Score of <0.5
  • Irrespective of serological findings
  • The patient may be receiving antimalarials, low-dose glucocorticoids (prednisolone ≤5 mg/day), and/or stable immunosuppressives including biologics.

Because remission remains difficult to achieve, LDA is an alternative treatment target. Low disease activity is in most cases formally defined as LLDAS, which requires:

• SLEDAI-2K: Score of ≤4 with no activity in major organ systems
• No new SLE disease activity compared to the previous assessment
• Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (PGA, scale 0-3) ≤1
• Current prednisone (or equivalent) dose ≤7.5 mg daily
• Good tolerance of standard maintenance doses of classic and biologic immunosuppressive agents

Achieving and maintaining LLDAS is associated with reduction in overall organ damage. Organ-specific manifestations of SLE may have specific measures of remission and response. For example, response in lupus nephritis (LN) is often defined in terms of proteinuria or glomerular filtration rate, while an instrument called the Cutaneous Lupus Erythematosus Disease Activity and Severity Index (CLASI) is often used to assess mucocutaneous involvement.

A generalized management strategy applicable to all patients with SLE is presented in Table 7-1. All patients should be receiving hydroxychloroquine (HCQ; see Hydroxychloroquine), with additional immunosuppressive agents added according to need to control disease activity (see the Overview of the Armamentarium section below). In addition to pharmacological management of disease activity, patients should take care to limit exposure to environmental risk factors (e.g., avoiding UV light, quitting smoking, increasing physical activity) and monitor for and act to prevent emergent complications and comorbidities (e.g., keeping up with vaccinations, screening for bone density loss, screening for antiphospholipid antibodies). Since SLE predominantly occurs in women of reproductive age, family planning should comprise part of disease management, including pregnancy risk quantification (estimated on the basis of maternal characteristics, disease characteristics and pharmacotherapy) and adjustment of therapeutic strategy (e.g., to favor immunosuppressants of low teratogenic potential and low fetotoxicity).

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Measures of Disease Activity

As we have seen, measuring disease activity is essential for the implementation of the treat-to-target strategy in the management of SLE. Several validated instruments have been designed and implemented for use in clinical trials and clinical practice since the 1980s. Such instruments may be either global score systems (assessing overall disease activity) or individual organ or organ system assessment scales. A few of the most widely used disease activity assessment instruments are briefly presented here.

The British Isles Lupus Assessment Group (BILAG) is an organ-based instrument originally published in 1988 and updated in 2004 (Figure 7-2). It evaluates 9 systems on an ordinal scale, with 106 total items which can be rated 0 (not present), 1 (improving), 2 (same), 3 (worse) and 4 (new). The total score for each organ domain is then converted into an ordinal alphabetic level: (A) severe disease; (B) moderate disease; (C) mild persistent disease; (D) no longer active disease; and (E) never active. Because it includes so many items, the BILAG is not practical for clinical use and has largely remained restricted to clinical trials.

Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is global activity index first developed in 1985. The original SLEDAI contained 24 items organized in 9 organ systems, each with an attributed weight based on the severity of disease manifestation, with the total score giving a degree of overall disease activity. The SLEDAI received two modification since its introduction. The Safety of Estrogens in Lupus Erythematosus-National Assessment (SELENA)-SLEDAI, shown in Figure 7-3, modified the definitions of several descriptors to improve clarity. The SELENA-SLEDAI also contains the Physician’s Global Assessment (PGA) Visual Analog Scale (VAS) instrument, which evaluates SLE disease activity, as estimated by a physician, on a scale of 0 to 3. The PGA has never been standardized and because it largely depends on individual judgment, it should be scored by experienced physicians. The SLEDAI-2K, introduced in 2002, modified several descriptors from both the original SLEDAI and SELENA-SLEDAI in order to further optimize and simplify scoring. Although originally designed to allow scoring of items only if they were present 10 days or less prior to assessment, the SLEDAI-2K was subsequently modified to extend this period to 30 days, as most clinical trials have a monthly visit schedule. The current (2010) version of the SLEDAI-2K is shown in Figure 7-4. Because of its binary scoring system and alignment with organ system-based questions that practitioners use with patients to assess disease activity, the SLEDAI has been incorporated in many electronic health record systems.

Two composite responder indices – the SLE Responder Index (SRI-4) and the BILAG-based Composite Lupus Assessment (BICLA) – were developed more recently to combine global assessment scores and organ-based indices. The SRI-4 classifies an individual as a responder if they satisfy the following criteria:

• ≥4 point reduction in the SELENA-SLEDAI Index
• No new severe disease activity (BILAG A) or ≥1 new moderate organ score (BILAG B)
• ≤10% deterioration from baseline in PGA scale

The BICLA response is defined as the following:

• BILAG improvement (all A scores at baseline improved to B/C/D, all B scores improved to C/D)
• No new BILAG A or ≥1 BILAG B
• No worsening of total SLEDAI-2K
• ≤10% deterioration from baseline in PGA scale
• No treatment failure (initiation of non-protocol treatment)

While these composite responder indices have readily been employed in clinical trials, they both incorporate BILAG and are thus impracticable for clinical use.

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Overview of the Armamentarium

Since the middle of the 20^th century, the pharmacological armamentarium for the treatment of SLE has increased considerably. No single agent, however, can be considered a “silver bullet” for disease activity control. The available options are shown in Figure 7-5, organized by disease severity from mild (constitutional symptoms/mild arthritis/rash ≤9% body surface area [BSA]/platelets 50-100,000 per mm³; SLEDAI ≤6; BILAG C or ≤1 BILAG B manifestation) to moderate (RA-like arthritis/rash 9-18% BSA/cutaneous vasculitis <18% BSA; platelets 20-50,000 per mm³/serositis; SLEDAI 7-12; ≥2 BILAG B manifestations) to severe (major organ-threatening disease – nephritis, cerebritis, myelitis, pneumonitis, mesenteric vasculitis; thrombocytopenia with platelets <20,000 per mm³; thrombotic thrombocytopenic purpura-like disease or acute hemophagocytic syndrome; SLEDAI >12; ≥1 BILAG A manifestation).

Hydroxychloroquine is the pharmacotherapeutic agent which all patients with SLE should be taking, at a maximum dose of 5 mg/kg real body weight. Glucocorticoids are also useful for patients will all levels of disease severity, both as induction therapy (often intravenous pulses) and as maintenance therapy (typically oral); however, to control adverse reactions associated with the chronic use of GCs, during maintenance they should be minimized to <7.5 mg of prednisone equivalent per day, and ideally eventually stopped. A number of immunosuppressive agents are available for each level of SLE severity. Azathioprine and methotrexate are appropriate options for refractory mild disease and as first line immunosuppressants in moderately severe disease. Mycophenolate is an option for moderate disease and as a first-line agent for severe systemic disease and for LN. Calcineurin inhibitors can be used in SLE of moderate severity; the newest agent in this class – voclosporin – is specifically approved for the treatment of LN. Cyclophosphamide is typically reserved for severe SLE and in cases refractory to all other immunosuppressive agents. Three biologic agents – the monoclonal antibodies rituximab , belimumab and anifrolumab – can be used for disease refractory to classic immunosuppressants, with rituximab reserved for refractory severe disease. Belimumab is also approved for use in patients with LN, in combination with standard therapy (most often MMF).

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