Rheumatology

Systemic lupus erythematosus

Article Name:  Mycophenolate Mofetil versus Cyclophosphamide for Induction Treatment of Lupus Nephritis
URL: https://jasn.asnjournals.org/content/20/5/1103.long
Journal and year of publication: Journal of American Society of Nephrology, 2009
Trial Design: Randomized clinical trial
Population: 370 patients  
Key inclusion criteria:

– Aged 12 to 75 years, diagnosed with SLE
– Patients with class III or V LN must have had proteinuria (at least 2 g/d)
Key exclusion criteria:

– Treatment MMF or IVC in the previous year
– Continuous dialysis for >2 wk before randomization or anticipated duration longer than 8 wk
Intervention Studied:  Mycophenolate Mofetil (MMF)
Control:  Cyclophosphamide
Outcomes:
– Response rates: MMF: 56.2% patients responded  vs IVC: 53.0% patients responded
– No significant differences in the rates of adverse events, serious adverse events, or infections between both groups

The authors concluded that “Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis”
Citation: Appel GB, Contreras G, Dooley MA, Ginzler EM, Isenberg D, Jayne D, Li LS, Mysler E, Sánchez-Guerrero J, Solomons N, Wofsy D; Aspreva Lupus Management Study Group. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103-12. doi: 10.1681/ASN.2008101028. Epub 2009 Apr 15. PMID: 19369404; PMCID: PMC2678035.
Article Name:  Mycophenolate versus Azathioprine as Maintenance Therapy for Lupus Nephritis
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1014460
Journal and year of publication: NEJM, 2011
Trial Design: Randomized clinical trial
Population: 370 patients  
Key inclusion criteria:

– Kidney biopsy within the 6 months prior to first randomization with a histologic diagnosis of lupus nephritis
– Active nephritis at screening
Key exclusion criteria:

– Previous kidney transplant or planned transplant 
– Autoimmune condition, or its treatment, that  may affect the study assessments or outcomes
Intervention Studied:  Mycophenolate Mofetil (MMF)
Control:  Azathioprine
Outcomes:
– Mycophenolate mofetil was superior to azathioprine with respect to the primary endpoint, time to treatment failure: Hazard ratio: 0.44 (95% CI: 0.25 to 0.77), P=0.003
– Time to renal flare and time to rescue therapy: Hazard ratio: <1.00; P<0.05

The authors concluded that “Mycophenolate mofetil was superior to azathioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy.”
Citation: Dooley MA, Jayne D, Ginzler EM, Isenberg D, Olsen NJ, Wofsy D, Eitner F, Appel GB, Contreras G, Lisk L, Solomons N; ALMS Group. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011 Nov 17;365(20):1886-95. doi: 10.1056/NEJMoa1014460. PMID: 22087680.

Rheumatoid Arthritis

Article Name:  Infliximab and Methotrexate in the Treatment of Rheumatoid Arthritis
URL: https://www.nejm.org/doi/full/10.1056/NEJM200011303432202
Journal and year of publication: NEJM, 2000
Trial Design: Randomized clinical trial
Population: 428 patients  
Key inclusion criteria:

– Active RA despite treatment with at least 12.5 mg of methotrexate/week for 3 months at least with no break for more than 2 weeks
Key exclusion criteria:

– Using a DMARD other than methotrexate
– Intraarticular, IM, or IV corticosteroids in the 4 weeks
Intervention Studied:  Infliximab + Methotrexate
Control:  Placebo + Methotrexate
Outcomes:
– Clinical response: Infliximab + methotrexate: 51.8% vs Methotrexate alone: 17.0% (P<0.001)
– Quality of life: Significantly better with infliximab + methotrexate, vs Methotrexate alone
– Radiographic evidence of joint damage: Increased in those given methotrexate alone. Not increased in those given infliximab and methotrexate

The authors concluded that “In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.”
Citation: Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN; Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000 Nov 30;343(22):1594-602. doi: 10.1056/NEJM200011303432202. PMID: 11096166.
Article Name:  Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial
URL: https://onlinelibrary.wiley.com/doi/full/10.1002/art.21405
Journal and year of publication: Arthritis and Rheumatology, 2005
Trial Design: Randomized clinical trial
Population: 508 patients  
Key inclusion criteria:

– Age ≥18 years with early and active RA
– Disease duration of ≤2 years
Key exclusion criteria:

– Using a DMARD other than methotrexate
– Intraarticular, IM, or IV corticosteroids in the 4 weeks
Intervention Studied:  
Group 1: Sequential DMARD monotherapy
Group 2: Step-up combination therapy
Group 3: Initial combination therapy with tapered high-dose prednisone
Group 4: Initial combination therapy with Infliximab
Control:  See above
Outcomes:
– Time to functional improvement: Achieved earlier in groups 3 and 4, in comparison to groups 1 and 2.
– Mean scores of the Dutch version of the Health Assessment Questionnaire (D-HAQ) at 3 months: Groups 1 and 2: 1.0 vs Groups 3 and 4: 0.6  (P < 0.001)

The authors concluded that “In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.”
Citation: Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005 Nov;52(11):3381-90. doi: 10.1002/art.21405. PMID: 16258899.
Article Name:  Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa032534
Journal and year of publication: NEJM, 2004
Trial Design: Randomized clinical trial
Population: 161 patients  
Key inclusion criteria:

– At least 21 years of age, with active RA despite treatment with at least 10 mg of methotrexate per week.
– Seropositive for rheumatoid factor
Key exclusion criteria:

– Other autoimmune disease (except concurrent Sjögren’s syndrome)
– American Rheumatism Association functional class IV disease
– Rheumatoid vasculitis
Intervention Studied:  
1) Methotrexate (control)
2) Rituximab (1000 mg on days 1 and 15)
3) Rituximab plus cyclophosphamide (750 mg on days 3 and 17)
4) Rituximab plus methotrexat
e
Control:  See above
Outcomes:
– Achieving 50% improvement in disease symptoms (At week 24):
– Methotrexate alone: 13% 
– Rituximab–methotrexate combination: 43% (P=0.005)
– Rituximab–cyclophosphamide combination: 41% (P=0.005)
– All ACR responses were maintained at week 48 in rituximab–methotrexate group

The authors concluded that “In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.
Citation: Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2572-81. doi: 10.1056/NEJMoa032534. PMID: 15201414.

Vasculitis

Article Name:  A Randomized Trial of Maintenance Therapy for Vasculitis Associated with Antineutrophil Cytoplasmic Autoantibodies
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa020286
Journal and year of publication: NEJM, 2003
Trial Design: Randomized clinical trial
Population: 144 patients  
Key inclusion criteria:

– Diagnosis of Wegener’s granulomatosis, microscopic polyangiitis, or renal-limited vasculitis
– Renal involvement, other threatened loss of function of a vital organ
– ANCA positivity  OR  ANCA-negative +  histologic confirmation of vasculitis
Key exclusion criteria:

– Another multisystem autoimmune disease
– Hepatitis B e antigenemia, hepatitis C, or HIV
Intervention Studied: After remission, substitute regimen of azathioprine
Control: After remission, continued cyclophosphamide therapy
Outcomes:
– Relapses: Azathioprine: 15.55 of patients vs Cyclophosphamide:13.7% (P=0.65)
– Lower with microscopic polyangiitis patients than those with Wegener’s granulomatosis (P=0.03)

The authors concluded that ” In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.
Citation: Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniené J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C; European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003 Jul 3;349(1):36-44. doi: 10.1056/NEJMoa020286. PMID: 12840090.
Article Name:  Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0909905
Journal and year of publication: NEJM, 2010
Trial Design: Randomized clinical trial
Population: 197 patients  
Key inclusion criteria:

– Diagnosis of Wegener’s granulomatosis or  Microscopic polyangiitis
– Positive serum assay for PR3-ANCA or MPO-ANCA
Key exclusion criteria:

– Churg-Strauss syndrome or anti-glomerular basement membrane disease
– Alveolar hemorrhage severe enough to require mechanical ventilation
– Active systemic infection
Intervention Studied: Rituximab
Control: Cyclophosphamide
Outcomes:
– Reaching the primary endpoint (remission of disease without the use of prednisone at 6 months): Rituximab: 64% of patients vs Cyclophosphamide: 53% of patients (Noninferiority P<0.001)
– Inducing remission of relapsing disease: Rituximab: 67% of patients vs Cyclophosphamide: 42% of patients (P=0.01)

The authors concluded that “Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease.”
Citation: Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905. PMID: 20647199; PMCID: PMC3137658.
Article Name:  Azathioprine or Methotrexate Maintenance for ANCA-Associated Vasculitis
URL: https://www.nejm.org/doi/full/10.1056/NEJMoa0802311
Journal and year of publication: NEJM, 2008
Trial Design: Randomized clinical trial
Population: 159 patients  
Key inclusion criteria:

– Newly diagnosed Wegener’s granulomatosis or microscopic polyangiitis
Key exclusion criteria:

– Cancer not in remission for more than 3 years 
– HIV, HBV, HCV infection
Intervention Studied:
1) Azathioprine
2) Methotrexate
Control: See above
Outcomes:
– Primary end point occurrence (adverse event requiring discontinuation of the study drug or causing death): Azathioprine: 7 patients vs Methotrexate: 12 patients (P=0.21)
– No difference in relapses or adverse events

The authors concluded that “These results do not support the primary hypothesis that methotrexate is safer than azathioprine. The two agents appear to be similar alternatives for maintenance therapy in patients with Wegener’s granulomatosis and microscopic polyangiitis after initial remission.”
Citation: Pagnoux C, Mahr A, Hamidou MA, Boffa JJ, Ruivard M, Ducroix JP, Kyndt X, Lifermann F, Papo T, Lambert M, Le Noach J, Khellaf M, Merrien D, Puéchal X, Vinzio S, Cohen P, Mouthon L, Cordier JF, Guillevin L; French Vasculitis Study Group. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008 Dec 25;359(26):2790-803. doi: 10.1056/NEJMoa0802311. PMID: 19109574.

Do you think there are some important trials we should add to our site? Please contact us at landmarktrials@gmail.com with the trial name, link, and why you think it is a landmark paper!

Disclaimer: Please note that articles mentioned on this site are the property of their respective journals. The information from these articles was presented on this site under the Fair Use legal doctrine (Section 107 of the Copyright Act) as the data shared was limited in quantity, factual in nature, already published, and for the purpose of relaying and teaching socially beneficial medical knowledge. The work was attributed to the journals that published them with citations and links provided.

%d bloggers like this: