Systemic Lupus Erythematosus and Sjögren's Syndrome: Highlights From ACR 2007
Robert I. Fox, MD, PhD Disclosures
Introduction
The recent American College of Rheumatology (ACR) Annual Meeting was held in Boston, Massachusetts, November 6-11, 2007. Over 15,000 people attended with a range of interests, including basic research, practicing clinicians, researchers in the pharmaceutical industry, and even investment bankers.
The dramatic successes with biologic agents in treating rheumatoid arthritis (RA) have led to a search for therapies that will show similar "remissions" in systemic lupus erythematosus (SLE) and related disorders. However, the results of clinical trials in SLE or Sjögren's syndrome (SS) have not yet matched the breakthrough successes in RA patients achieved with tumor necrosis factor (TNF) inhibitors. Although we are impatient for such breakthroughs, it reminds us that SLE and related disorders, such as SS, are now the "next" frontier for focused attention for new therapy.
SLE and SS have many clinical similarities (as well as genetic and biomarkers) that were reported, and patients with each condition have responded to similar medications, such as antimalarials and antimetabolites. Thus, therapeutic agents that have been found useful in SLE are also likely to be effective in SS. However, many more trials are currently in progress for SLE, particularly involving SLE nephritis, a condition in which it is relatively easy to establish endpoints for flare or clinical response.
SS and nonrenal SLE patients have encountered a higher level of difficulty in establishing definitive endpoints for clinical study, as discussed below. This partly reflects the significant role of fatigue or "fibromyalgia" in influencing the global evaluation of both patient and physician. Thus, new therapies can show statistically significant changes in a variety of clinical parameters or biomarkers, but not exhibit the dramatic impact on improved quality of life that we have come to expect from biologic agents used in RA.
Summary of SLE Presentations
Abstracts presented at the meeting are available online at: http://www.rheumatology.org/annual. On this Web page, choose "Abstracts" in the upper left-hand corner of the page.
Presentations on SLE covered 3 key broad areas:
The risks and benefits of "older" agents, such as cyclophosphamide and mycophenolic acid, that comprise the "comparator" standard therapy for the biologic agents;
Reports on longer-term studies with biologic agents, such as rituximab, and continued safety reports on how to minimize serum sickness reactions; and
Results with newer agents, including anti-B-cell activation factor (anti-BAFF [BLyS]) antibody and an antibody to interferon (IFN) type I.
A great deal of the impetus in current clinical trials of biologic agents has been directed toward finding an alternative to intravenous cyclophosphamide. Therefore, it was interesting to hear the following results of the Johns Hopkins SLE Renal Cohort treated with cyclophosphamide by Abou-Khamis and colleagues[1]:
Monthly intravenous cyclophosphamide (MIC) according to standard National Institutes of Health (NIH) protocol was compared with high-dose immunoablative cyclophosphamide (HDIC) regimen (200 mg/kg) alone or with stem cell rescue therapy; and
22% of SLE patients on HDIC and 64% on MIC achieved complete response in 1 year (P = .048).
The study authors concluded that the traditional NIH regimen is superior to HDIC, both in terms of achieving a complete renal response and in maintaining the complete response during follow-up. Younger patients tend to do better than those 30 years or older.
These results strongly suggest that the initial cyclophosphamide regimen for lupus nephritis should remain the traditional NIH monthly one, with high-dose cyclophosphamide (with or without stem cell rescue) being reserved as a rescue regimen.
Presentations also emphasized the role of atherosclerosis as a significant risk factor in long-term outcomes. Urowitz and colleagues[2,3] presented a study documenting atherosclerotic risk factors by ethnicity over a period of 3 years. It was demonstrated that inadequately treated hypertension and elevated cholesterol were the key risk factors in all ethnic groups and require closer attention by rheumatologists, who may assume that the primary care physicians are following these important variables. Thus, lupus patients should receive active therapy to control disease activity and therapy directed to minimize coronary artery disease.
Mycophenolate Mofetil
In recent years, mycophenolate mofetil (MMF) has been shown in several clinical trials to be an effective and well-tolerated treatment for lupus nephritis.[4] MMF has since been increasingly used for the treatment of lupus nephritis in a maximum dose of 3 g/day.
Amoura and colleagues[5] reported that low mycophenolic acid levels, as determined by the "area under the curve," are associated with increased SLE activity. However, patient characteristics, such as age, race, sex, and weight, did not allow prediction of the area under the curve or the efficacy, toxicity, and tolerability of MMF.
Silva-Fernández and colleagues[6] found that neither body weight nor ethnicity significantly affected gastrointestinal or leukopenia adverse events:
In the discussion period, several groups agreed that the efficacy of MMF for lupus nephritis is dose-related;
MMF should be used at the maximum tolerated dose, up to 3 g/day;
The risk for herpes zoster infection seems to increase at dose levels above 2 g/day, which is similar to clinical experience with MMF over 25 years ago when the drug was introduced for psoriasis[7]; and
Dose adjustments may be required with increasing age and in women with marked neutropenia.
A series of case reports have also reported the benefit of MMF in SLE-related thrombocytopenia, neuropsychiatric disorders, and hemolytic anemia.[6,8,9]
15-Deoxyspergualin
The ability of 15-deoxyspergualin (DSG) to suppress SLE flares has been shown in animals and humans in observational trials[10,11]:
DSG has been approved as an orphan drug for therapy of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis[12,13]; and
DSG exerted no nephro- or hepatotoxicity, but reversibly induces leukopenia.
Lorenz and colleagues[14] presented a study and evaluation of the safety and efficacy of DSG in SLE glomerulonephritis in SLE and SS:
Twenty patients with active biopsy-proven lupus glomerulonephritis (proteinuria > 1 g and/or active urinary sediment and/or impaired renal function) after prior treatment with at least 1 immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of 1 week; and
These cycles were repeated to a maximum of 9 cycles.
The study was open-label to assess safety, but the early indications suggest that the efficacy-safety profile warrants double-blind studies.
Rituximab for SLE
Amoura and colleagues[15] reported the results of their study investigating the efficacy of rituximab in SLE. In this study, 18 women and 4 men received rituximab for:
Lupus nephritis refractory to conventional immunosuppressants (n = 6; 4 class IV and 2 class III);
Refractory autoimmune hemolytic anemia (n = 4);
Severe thrombocytopenia refractory to splenectomy (n = 1) or high-dose steroids (n =2);
Thrombotic thrombocytopenic purpura resistant to plasmapheresis (n = 2);
Systemic cryoglobulinemia (n =1);
Hemophagocytic syndrome (n = 1);
Severe polyarthritis associated with cutaneous lupus refractory to conventional treatment (n = 3); and
Antiphospholipid antibody syndrome with repeated thrombosis despite an accurate anticoagulation treatment (n = 1).
Doses of rituximab were 375 mg/m2/week x 4 (n = 16), 750 mg at day 1 and day 15, or 1000 mg on day 1 and day 15. Rituximab was used without immunosuppressants and/or immunomodulating drugs (n = 9), and with intravenous cyclophosphamide (n = 2), MMF (n = 5), plasmapheresis (n = 3), or intravenous immunoglobulin (n = 2).
In 18 cases (81%), outcome was considered as favorable as assessed by the physician in charge of the patient. All of the hematologic manifestations improved; platelet counts and hemoglobin levels returned to the normal range, and Willebrand protease inhibitor and cryoglobulinemia disappeared. Four nephritis patients (66%) improved with a ≥ 50% decrease of the daily proteinuria at 6 months. One patient evolved to end-stage renal disease. In a separate presentation in regard to these patients, hematologic manifestations, including thrombocytopenia, were responsive to rituximab.
A long-term follow-up of rituximab-treated SLE patients was also reported by Tanaka and colleagues[16]:
Rituximab (375 mg/m2) was administered weekly for 2 weeks in 19 patients (18 female and 1 male; average age, 33 years) with refractory SLE, despite intensive treatments, including 12 cases with neuropsychiatric SLE and 10 with lupus nephritis (7 were type IV);
All 19 patients were ranked as category A of the British Isles Lupus Assessment Group (BILAG) score, and average of SLE Disease Activity Index (SLEDAI) was 17;
Rituximab resulted in rapid improvement in clinical manifestations, especially symptoms and signs of neuropsychiatric SLE and urinary protein levels in lupus nephritis, as evidenced by a reduced SLEDAI score from 17.1 to 8.4 at day 28; and
Fourteen (74%) of 19 cases were induced into remission (SLEDAI = 0) following rituximab within 1-17 months.
Henriksson and colleagues[17] presented the results of the study involving patients with severe SLE, refractory to conventional immunosuppressive drugs, who were treated with the combination of rituximab (375 mg/m2 x 4) plus cyclophosphamide (500 mg/m2 x 2) plus a glucocorticoid taper:
Among 20 treated patients, improvements were seen in most dimensions of the health related quality of life questionnaire (HRQOL); and
The study authors found a statistically significant improvement for social function and vitality as measured by the 36-Item Short-Form Health Survey (SF-36), fatigue as measured by Functional Assessment of Chronic Illness Therapy (FACIT), and global health by visual analog scale (VAS).
BAFF and BLyS
Several presentations described the long-term follow-up with the inhibitor of BAFF (also known as BLyS). BAFF is a TNF family member that promotes B-cell survival by inhibiting apoptosis. Elevated BAFF is correlated with increased SLE disease activity. Two compounds are in phase 2/3 development binding to BAFF:
Belimumab, a human monoclonal antibody; and
Atacicept, a recombinant hybrid molecule that binds to both BAFF and APRIL.
Petri and colleagues[18] presented an update on a study of belimumab (anti-BAFF antibody) that included a 1-year initial study plus a 24-week extension. The study authors used a novel combined endpoint that demonstrated:
Less than 4-point improvement in the Safety of Exogenous Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI score;
No new BILAG 1A/2B flares (in which a 1A is one severe organ and a 2B is 2 moderate organs); and
No worsening in Physician Global Assessment (<>
At week 52, the belimumab-treated population had fewer shifts to worse BILAG organ scores (joint, muscle, neurologic) and fewer BILAG flares. A combined response was observed in serologically active subjects at week 52 (46% belimumab vs 29% placebo). The response improved to 56% at week 76. The discussion was rather animated as to the significance of how to reinterpret data that previously did not meet its primary endpoint initially, and had a low patient retention rate. The dose-response curves were also unclear for all 3 doses (1 mg, 4 mg, and 10 mg) that gave virtually superimposable curves. Other data drawn from the same study pool showed normalization of complement levels.[19]
Merrill and colleagues[20] reported that belimumab is well tolerated in combination with SLE standard-of-care therapy during long-term (2-year) exposure:
The incidence rates of adverse events, serious adverse events, and malignancies were comparable to placebo (ie, usual standard of care) per 100 subject-years of exposure; and
The overall incidence rate of adverse events remained similar or decreased over time during and up to 2.5 years of exposure to belimumab.
Wallace and colleagues[21] presented data from a phase 1 dosing study of an antibody to type I IFN:
A total of 51 patients were randomized into the blinded phase of the study;
Fifty patients were treated with 1 of 5 doses of the experimental compound MEDI-545 (0.3 [n = 6], 1.0 [n = 6], 3.0 [n = 6], 10.0 [n = 7], or 30.0 [n = 8] mg/kg) or placebo [n = 17);
Most patients were white women, with a median age of 44 years; and
Dose-dependent inhibition of type I IFN-inducible genes was seen in whole blood samples, with corresponding inhibition of type I IFN-inducible genes in skin samples.
Compared with placebo, patients receiving MEDI-545 had a greater reduction in average SLEDAI as assessed through study day 56. The safety profile of MEDI-545 was acceptable, and MEDI-545 was well tolerated. Although this is a phase 1/2 dosing trial, the preliminary results suggest that MEDI-545 inhibits type I IFN and shows evidence of clinical activity in patients with SLE.
Summary of SS Presentations
Daniels and colleagues[22] and Ramos-Casals and colleagues[23] presented their clinical experience in each registry of over 500 SS patients. During the discussion periods, they pointed out the highly significant impact of dry mouth and periodontal disease on quality of life and the associated high financial expense of dental care.
Artificial salivas remain only partially helpful because they may be poorly tolerated due to their flavoring, viscosity, and their failure to adequately and comfortably adhere to buccal mucosa.
At different times in a patient's clinical course (including use of concurrent medications with anticholinergic side effects or even seasonal changes in dryness), patients may find different products more tolerable. Thus, patients should be encouraged to think of these oral care products in a manner similar to "changing clothes to fit the environment."
Both study authors emphasized that the goal of dentistry for SS patients is to keep the carious teeth "in full view" where "areas of decay" can be carefully followed for treatment and not covered by full veneer crowns. Also, it is essential to make certain that decay and tooth loss will not progress undetected.
As an interesting bridge between SLE and SS, Fabbri and colleagues[24] reported that treatment of periodontal disease was an important factor in exacerbating other systemic manifestations of SLE and SS. The discussion further emphasized that rheumatologists do not normally look for periodontal problems as a source of continuing immune stimulation -- and should more closely follow the lead of radiation therapists in their assessment and treatment of periodontal disease. Rheumatologists should assess their patients for bleeding gums and estimate the level of gingival recession and possible infections on the basis of erythema or purulent discharge.
Shiozawa and colleagues[25] reported the result of their study investigating the effect of nizatidine, an H2-receptor antagonist in patients with SS:
A total of 22 primary SS and 17 secondary SS patients were included in the study. Patients in the experimental group received nizatidine (n = 24, 150 mg twice daily), and those in the control group received famotidine (n = 15, 20 mg twice daily).
VAS scores suggested that nizatidine provides mild relief of xerostomia, but the effect was not statistically significant.
However, the preliminary study did suggest an increase in salivary gland flow.
St. Clair and colleagues[26] reported the results of the open-label trial for rituximab in patients with SS:
The study included 12 subjects with primary SS who were all women and had a median age of 51 years (range, 34-69 years), with a median disease duration of 6.5 years;
Of the 12 eligible subjects at screening, 10 had VAS scores of > 50 mm for fatigue and 9 had joint pain;
Three subjects had severe parotid gland swelling;
Four subjects had peripheral neuropathy;
One subject had interstitial lung disease; and
One subject had purpura.
The results showed that rituximab produced rapid depletion of circulating CD19+ B cells in all patients. A significant decrease was observed between baseline and week 26 for both the physician global (median change, -29.0 mm) and subject global (median change, -9.0 mm) assessment VAS scores. No significant changes were observed between baseline and week 26 for most of the ocular and oral symptoms of dryness and the unstimulated and stimulated salivary flow rates.
Dass and colleagues[27] reported the findings from their study on the effect of rituximab on fatigue in SS:
Eighteen SS patients were randomized to infusions with either 1 g rituximab or placebo on days 1 and 15 with 100 mg methylprednisolone prior to each infusion (9 patients were randomized to each group); and
Patients also received oral prednisone 60 mg daily on days 2-7 and 30 mg daily on days 8-14.
The primary endpoint was 20% reduction in fatigue VAS at 6 months. Secondary endpoint included 20% improvement in somatic fatigue, mental fatigue, and sicca mean scores. Results suggested that rituximab may improve fatigue and systemic symptoms without influencing immunoglobulin (Ig)G levels. The steroids/placebo effect was quite marked with considerable variability in responses in both groups.
Conclusion
SLE is an autoimmune connective tissue disorder with a wide range of clinical features, which predominantly affects women, with increased severity in some ethnic groups. Diagnosis is based on clinical assessment supported by investigations, including the finding of autoantibodies. The outcome measures are still being refined, and the lack of biomarkers to clearly identify subsets limits the ability to rationally set up and evaluate clinical trials. Treatments presented at the recent ACR meeting ranged from antimalarial agents to corticosteroids and immunosuppressive agents. Clinical manifestations, including cardiovascular risks, lupus nephritis, central nervous system disease, the antiphospholipid syndrome, assessment of disease activity and damage, and pregnancy related- and quality-of-life issues, were all presented.
Trials of SS therapy parallel those for SLE. However, the endpoints of improved tear flow or salivary flow have been difficult to achieve even with potent biologic agents. Even when significant increases are obtained, the patient's evaluation of improvement is rather limited. Manifestations of SS (such as rash of mixed cryoglobulinemia, hematologic features, and glandular swelling) appeared responsive to rituximab. The key issues that "drive" the quality of life in both SS and SLE patients are fatigue and cognitive "fuzziness," which correlate poorly with acute-phase reactants or biomarkers. Some improvement with rituximab was noted, but the results were modest and the risk for serum sickness continues to be a concern.
This activity is supported by an independent educational grant from Abbott, Bristol-Myers Squibb, Forest, and Genentech.
Gracias Dr. José Manuel Ferrer Guerra
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