Mycobacterium tuberculosis infection is a major problem in the application of biologics. In addition to the tuberculin pure protein derivative (PPD) test and X-ray chest radiograph, the gamma-interferon release assay (IGRA) has been used to screen for latent tuberculosis but is not widely used.
One study included 205 patients with rheumatic diseases, and IGRA, PPD test and X-ray chest radiographs were given before the patients received biologics. The results were that of the 19 patients tested for latent TB by IGRA, only 3 were positive for PPD, 1 chest radiograph was suggestive of TB, and 14 (74%) were negative for PPD and chest radiograph. This study confirmed that IGRA is more reliable for screening for latent TB.
Our authors reported that 40 RA patients with a history of hepatitis B and normal liver function did not have abnormal liver function after 26 weeks of infliximab (IFX) + methotrexate (MTX) application.
TNF-α antagonists
After IFX, etanercept and adalimumab (ADA), certolizumabpegol and golimumab were also approved by the U.S. Food and Drug Administration (FDA) for the treatment of RA in 2009.
The FDA approved golimumab (50 mg monthly, subcutaneously) for the treatment of moderate-to-severe RA, active psoriatic arthritis and AS, with the main adverse effects being upper respiratory tract infection, sore throat, nasal congestion and injection site erythema.
One study reported that after 4 weeks of treatment with MTX + golimumab in RA patients, inflammation-related indicators were significantly reduced, and their RA symptoms improved significantly after 16 weeks, which could achieve the expected efficacy.
Another study reported that in RA patients with poor long-term maintenance treatment with IFX, an increase in dose (from 3 mg/kgq8w to 5 mg/kgq8w) did not improve the efficacy but increased adverse effects, suggesting that the dose should not be increased blindly when IFX is not effective.
The BeSt study found that early application of IFX+MTX was beneficial in patients with risk factors for RA [positive rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide (CCP) antibodies, C-reactive protein (CRP) >35 mg/L, and high baseline x-ray score]. A Belgian study with a 7-year follow-up reported that IFX+MTX was effective in the treatment of RA with no serious adverse effects.
Several studies have reported that IFX or ADA treatment is effective in patients with autoimmune disease-associated uveitis who have failed to respond to conventional drug therapy, and that long-term remission can be maintained by discontinuing the drug after 6 months of clinical remission.
IL-1 and IL-6 receptor antagonists
Anakinra is an interleukin (IL)-1 receptor antagonist. Anakinra 1.0 mg/(kg・d) is safe and effective in the treatment of juvenile rheumatoid arthritis (JRA). Anabolic acid (100 mg/d, subcutaneous injection) has been reported to reduce hand pain and improve function in patients with erosive osteoarthritis over 3 months of treatment. Another study reported that anabolic acid intra-articular injection treatment was ineffective in knee osteoarthritis.
Tocilizumab is the main IL-6 receptor antagonist. Tocilizumab + MTX is more effective than MTX in RA, with rapid improvement in signs and symptoms, significant inhibition of bone destruction, and a better safety profile at 2-year follow-up.
Tocilizumab has also been shown to be effective in other rheumatic diseases. One study reported significant efficacy of Tocilizumab in RA peripheral neuritis and skin ulcers. Another study found moderate results for juvenile idiopathic arthritis (JIA).
T-cell-targeted biologics
Abatacept is a recombinant cytotoxic T-lymphocyte-associated antigen 4 (CTLA4). For RA where TNF antagonists and MTX are ineffective, Abatacept is effective and can significantly improve patients’ quality of life without increasing the risk of serious infections; it has a higher safety profile compared to IFX.
B-cell targeted biologics
Rituximab
There are numerous clinical studies on rituximab for the treatment of rheumatic diseases, and opinions are not uniform in some aspects.
Other drugs
In addition to rituximab, other biologics that act on CD20+ B cells include the humanized monoclonal antibodies Ofatumumab and Ocrelizumab and the small molecule single chain peptides TRU-015 and SBI-087, which are currently in Phase II or Phase III clinical trials for the treatment of RA. Ocrelizumab clinical trials for RA have recently met the primary endpoint of improving RA signs and symptoms.
Atacicept, a fully humanized recombinant receptor-immunoglobulin fusion protein (TACI-Ig) that inhibits soluble B lymphocyte-stimulating factor (BLyS) and proliferation-inducing ligand (APRIL), was effective in SLE and RA, with dose-dependent reductions in immunoglobulin and inflammatory marker levels and in the number of mature B cells, and was well tolerated by patients.
Belimumab, a humanized monoclonal antibody that inhibits BLyS and APRIL, has good biological activity against SLE with few adverse effects. Patients in the belimumab-treated group showed significant improvement in serologic parameters compared with controls, but their lupus activity was not significantly reduced.
The therapeutic effect of belimumab, as well as other agents such as epratuzumab (anti-CD22 monoclonal antibody), BLyS receptor fusion protein (BR3-Fc) and peptide fusion protein (A-623), on RA remains to be further investigated. However, phase II clinical trials have confirmed that epalizumab is more effective than placebo in the treatment of SLE.
Other
Pamapimod is a p38 mitogen-activated protein kinase inhibitor. The latest study on its comparison with methotrexate (MTX) reported that Pamapimod was less effective than MTX in RA after 12 weeks of application, and its efficacy was dose-dependent, with a significantly higher incidence of side effects in the 300 mg/d group than in the 50 mg/d, 150 mg/d and MTX groups.
CP-690550 is an inhibitor of JAK-3 (an intracytoplasmic tyrosine kinase). Phase II clinical trials suggest that CP-690550 is safe and effective for moderate-to-severe RA in monotherapy or in combination with MTX.
PHA-408, a highly selective inhibitor of nuclear factor-κB kinase (IKK)-2, reduced joint swelling and prevented bone destruction in an animal model of arthritis.
New therapeutic targets and drugs
As an upstream regulator of TNF-α and interleukin (IL)-1 inflammatory mediators, macrophage movement inhibitory factor (MIF) may be a therapeutic target for RA, ankylosing spondylitis (AS) and SLE.
Mucin C and TLR4 may be new therapeutic targets for RA, as high expression of mucin C in the joints was found to activate the immune system to produce an inflammatory response, and the switch molecule is TLR4. The study found that LY2439821 (an anti-IL-17 antibody) is effective in treating RA that is resistant to at least one relieving anti-rheumatic drug (DMARD) and is well tolerated by patients.
After pregabalin and duloxetine, the US FDA approved minazepam (50 mg Bid) for the treatment of fibromyalgia syndrome in 2009.
Denosumab (60 mg subcutaneously twice a year), a fully humanized monoclonal antibody targeting nuclear factor-κB receptor activator ligand (RANKL) to regulate osteoclast function, was effective in osteoporosis. Studies have reported that interferon gamma has a promotive effect on osteogenic differentiation of mesenchymal stem cells and may be a new target for the treatment of osteoporosis.
Cell therapy
A follow-up of 900 patients with autoimmune disease who underwent autologous hematopoietic stem cell transplantation (HSCT) found that the 5-year survival and progression-free survival rates were 85% and 43%, respectively, and that transplant-related mortality was related to experience and disease type at each center. Autologous HSCT induces long-term remission in refractory autoimmune diseases, and it is the disease type, not the transplantation technique, that determines efficacy.
Bone marrow mesenchymal stem cell transplantation (MSCT) has been used to treat autoimmune diseases such as SLE. One study reported an increase in circulating regulatory T cells (Treg) in 2 SLE patients after 14 weeks of autologous MSCT, but no disease remission. Nanjing Drum Tower Hospital in China reported that after 1 year of allogeneic MSCT in 13 patients with refractory SLE, 7 patients had complete remission, 12 patients had reduced LN, and 1 of the 2 relapsed patients still had remission after receiving retransplantation, confirming that MSCT is a new approach for the treatment of autoimmune diseases.
Based on the above understanding that vascular lesions in autoimmune diseases may be caused by abnormal endothelial progenitor cells in the circulation, the therapeutic idea of transplanting mononuclear cells from patients’ bone marrow or peripheral blood to the ischemic site has been proposed.
Immunosuppressive agents
A retrospective study found that mortifamol ester (MMF) resulted in a significant reduction in the relapse rate of SLE and a reduction in the maintenance dose of prednisone. In proliferative LN, the efficacy of MMF was comparable to CTX and the safety profile appeared to be higher. MMF resulted in improved skin scores, peripheral vascular damage and health status in patients with systemic sclerosis (SSc) with no worsening of pulmonary function. MMF combined with intravenous gammaglobulin significantly relieved polymyositis/dermatomyositis where corticosteroids and other immunosuppressive agents were ineffective.
Cyclosporine A (CsA) was found to control symptoms and renal pathology in patients with LN who were not effective with other immunosuppressants, reduce proteinuria in patients with proliferative nephritis and membranous nephritis, and small doses of CsA reduced corticosteroid dosage. Studies on LN have found higher remission and recurrence rates in the CsA-treated group than in the CTX-treated group.
In active RA where infliximab was not effective, imipramine + MTX resulted in a significant reduction in the Disease Activity Score of 28 joints (DAS28). Imiparibine increases salivary secretion in SS patients and is indicated for early onset. Imipramine has been reported to be effective in refractory polymyositis and may reduce prednisone dosage.
The application of tacrolimus (FK506) 1.5-2 mg/d in RA patients with ineffective MTX and TNF-α antagonists resulted in significant improvement in symptoms and X-ray progression without serious adverse effects.
Rapamycin (everolimus, sirolimus) is a novel immunosuppressant of proliferation signaling inhibitors (PSI). It has been found that the efficiency of such drugs in the treatment of refractory autoimmune diseases (SLE, RA, etc.) is about 50%, and can be used in autoimmune diseases where other immunosuppressive agents are ineffective.