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 Table of Contents  
Year : 2019  |  Volume : 3  |  Issue : 1  |  Page : 47-56

Disease-modifying antirheumatic drugs – Old and new: A brief overview

Department of General Medicine, Amrita Institute of Medical Sciences, Kochi, Kerala, India

Date of Web Publication14-Feb-2019

Correspondence Address:
Raghuveer S Prabhu
Department of Medical Oncology and Hematology, Amrita Institute of Medical Sciences, Ponekkara, Kochi - 682 041, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/CDR.CDR_50_18

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Rheumatological disorders comprise a vast subset of conditions with differing manifestations but overlap in pathogenesis. Disease-modifying antirheumatic drugs (DMARDs) are a diverse group of medications which aim at the various pathogenic factors leading to these disorders. DMARDs are of three broad subtypes: the conventional synthetic DMARDs, the biologicals, and Janus kinase inhibitors. Here, we give a brief overview of the various DMARDs with an emphasis on their practical use.

Keywords: Biologicals, disease-modifying antirheumatic drugs, hydroxychloroquine, methotrexate

How to cite this article:
Baliga VD, Prabhu RS. Disease-modifying antirheumatic drugs – Old and new: A brief overview. Clin Dermatol Rev 2019;3:47-56

How to cite this URL:
Baliga VD, Prabhu RS. Disease-modifying antirheumatic drugs – Old and new: A brief overview. Clin Dermatol Rev [serial online] 2019 [cited 2023 Jan 29];3:47-56. Available from: https://www.cdriadvlkn.org/text.asp?2019/3/1/47/252315

  Introduction Top

Disease-modifying antirheumatic drug (DMARD) as an acronym was first used in the 1980s for a group of drugs which can slow the natural progression and occasionally even induce remission of rheumatoid arthritis (RA). From the 1990s, the use of the acronym DMARD became common. From development of injectable gold in the 1930s, hydroxychloroquine (HCQ) in the 1950s, azathioprine in the 1960s to methotrexate (MTX) and sulfasalazine (SSZ) in the 1980s, armamentarium of DMARDs expanded considerably when 1998 ushered in the era of targeted monoclonal antibodies with the Food and Drug Administration (FDA) approval of etanercept, and a year later with approval of infl iximab. These targeted antibodies against cytokines came to be known as Biologics. In 2012, oral drug targeting Janus kinases (JAK) 1 and 3, tofacitinib got approval from the US FDA.

From the 1990s onward, DMARDs have been increasingly used in rheumatic disorders other than RA. HCQ, MTX, mycophenolate, and cyclophosphamide are used in systemic lupus erythematosus (SLE). Azathioprine and MTX have been used in systemic sclerosis (SSc). Recently, belimumab, a monoclonal antibody against B-lymphocyte stimulator, has been approved for resistant lupus.

This review focuses on the classification of DMARDs and profile of individual drugs and briefly regarding the treatment of common rheumatic disorders.

  Classification of Disease-Modifying Antirheumatic Drugs Top

  • Conventional DMARDs: Synthetic DMARDs such as MTX and SSZ and antimalarials such as HCQ and leflunomide (LEF)
  • Kinase inhibitors: JAK1 and JAK3 inhibitor such as tofacitinib
  • Biologic DMARDs: Infliximab, etanercept, rituximab, adalimumab, certolizumab, anakinra, and abatacept.

Conventional disease-modifying antirheumatic drugs


MTX remains the cornerstone therapy for patients with RA. Clinical and radiological results indicate the benefits of MTX monotherapy and in combination with other agents.

MTX interferes with folate metabolism by competitive inhibition of dihydrofolate reductase. It also results in increased extracellular concentration of adenosine which has anti-inflammatory role. It has also been suggested that MTX interferes directly with the binding of interleukin-1 (IL-1) beta to the IL-1 receptor on target cells and thereby inhibits the cellular responses to IL-1.[1]

MTX can be administered by oral, subcutaneous, and intramuscular routes.

MTX administered weekly in low doses is a mainstay in the therapy of RA. The bioavailability of oral MTX varies considerably between individuals.

It is usually started at 7.5–15 mg once weekly and then increased depending on disease activity, adverse effects, and renal and liver functions.

Absolute contraindications include severe renal or hepatic impairment, immunodeficiency or active immunosuppression, severe anemia, leukopenia and thrombocytopenia, concomitant antifolate drugs such as trimethoprim, sulfamethoxazole, and co-trimoxazole, pregnancy and lactation, and men who are actively trying for progeny.

Regular monitoring for efficacy as well as side effects is recommended. Baseline monitoring includes chest X-ray, renal function test, liver function test (LFT), and complete blood count. Blood counts are repeated every week for 1 month thereafter monthly for 3 months and then at least every 3 months. LFT is repeated monthly for the first 3 months and thereafter every 3 months.[2] The common toxicities related to MTX are gastrointestinal symptoms such as nausea, loose stools and stomatitis, hepatotoxicity and pulmonary toxicity in the form of fibrosis, headache, fatigue, alopecia, and hematologic abnormalities. MTX is contraindicated in pregnancy.

If MTX has to be continued beyond a certain cumulative dose (more than 3.5–4 g in healthy individuals and 1.5 g in compromised individuals), a liver biopsy has to be performed to rule out fibrosis.[3]

Folic acid supplementation[4]

To reduce the risk of MTX toxicities, folic acid supplementation is indicated in patients on continuous low-dose MTX. There are various regimens. Folic acid is either given 1 mg daily, except on days of MTX administration, or as 5 mg once a week after 1–3 days of MTX intake. This helps in combating hepatic and gastrointestinal toxicity to some extent, though its role on hematological toxicity is debatable;[4] folinic acid (leucovorin) also reduces MTX toxicity; it is used in the case of patients with unsatisfactory response to folic acid and also as a rescue factor in acute toxicity.


SSZ is a prodrug, reduced to its metabolites – sulfapyridine and 5-aminosalicylic acid in the colon by the coliform bacterial enzyme azoreductase.

Sulfapyridine is the active moiety which may have disease-modifying effects.[5]

Dosing the patient has to undergo pretreatment evaluation of complete blood count, liver enzymes, and renal function tests. The therapy is initiated at a dose of 500 mg daily for the first week, and subsequently, the dose is increased by 500 mg daily every week, till a dose of 2 g is achieved. If there is no significant response to this dose, the dose can be increased to 3 g daily in divided doses. If the patient develops toxicity, the dose can be accordingly lowered to 1500 mg or 1000 mg/day.

Common side effects of SSZ are gastrointestinal symptoms, leukopenia, agranulocytosis, hemolytic anemia, liver function abnormalities, and skin reactions such as toxic epidermal necrolysis and Stevens–Johnson syndrome.


LEF which acts by inhibiting pyrimidine synthesis has an immunomodulatory and immunosuppressive effect. It decreases the synthesis of ribonucleotide uridine monophosphate pyrimidine through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase, blocking the replication of rapidly dividing cells.

It is well absorbed following oral administration, the active metabolite teriflunomide undergoes extensive enterohepatic recirculation, and plasma levels of the active metabolite may persist for up to 2 years.

Dosing LEF is taken once daily. The usual dose is 20 mg, administered orally, once daily, irrespective of whether a loading dose was given. Lower dose is sometimes used in patients treated with a combination of MTX and LEF or in patients with gastrointestinal intolerance to the usual dose.

In some preliminary findings, the dose escalation of LEF to 40 mg/day seemed to increase the effectiveness of the treatment in a number of patients with RA. The adverse events of the dose escalation which appeared in 4 of 11 patients were mild and reversible. If confirmed in larger studies, the dose escalation of LEF might be especially valuable for patients with RA who tolerate LEF at the standard dose of 20 mg/day but show insufficient response. For them, the dose escalation might be a way to further improve disease activity and an alternative to an early switch to DMARD combination treatment or treatment with biologics.[6]

LEF may potentiate the action of warfarin as a result of its mutual competition at the level of cytochrome metabolism.[7]

Adverse effects include hypertension, gastrointestinal intolerance, diarrhea and nausea, hepatotoxicity, risk of fetal and neonatal toxicity, peripheral neuropathy, rash, and alopecia. To prevent fetal risk during pregnancy due to potential drug exposure, accelerated elimination of the drug can be achieved through the administration of cholestyramine. LEF should be avoided in patients with known interstitial lung disease or a history of MTX-induced lung toxicity. Patients on LEF should be monitored with regular complete blood count, LFTs, and renal function tests. It is contraindicated in pregnancy and lactating females, in preexisting liver disease. Live vaccines should not be administered to patients being treated with LEF.


Antimalarials such as HCQ and chloroquine (CQ) have been used in the treatment of SLE and RA for several years. HCQ has been extensively used for SLE, for effective control of symptoms of Sjogren's syndrome (SS), for preventing thrombosis in antiphospholipid antibody syndrome. HCQ is the cornerstone of the medical management of SLE. It has been shown in multiple SLE populations to be associated with improved survival and specifically has been found to be effective in the treatment of cutaneous disease.[8]

These drugs are relatively well absorbed orally and have good bioavailability and variable plasma terminal elimination half-lives. They have multiple actions which may be responsible for their immunomodulatory effects. Antimalarials are weak bases that accumulate in the lysosomes and autophagosomes of phagocytic cells. They affect MHC Class II expression and antigen presentation. They have actions related to control of toll-like receptor-9 activation.[9]

According to a randomized control trial, dose loading with HCQ has shown to improve the rate of response in early, active RA.[10]

The use of a weight-based dosing regimen of HCQ with a maximum dose of 400 mg per day is recommended, except in the case of renal insufficiency, when the dose should be reduced to 200 mg/day and for those on dialysis, who should be on 200 mg three times per week.[11]

The most common adverse effects are gastrointestinal symptoms such as nausea, vomiting, and diarrhea; dermatologic reaction such as pruritic maculopapular rash; CNS side effects such as headaches, lightheadedness, tinnitus, insomnia, toxic neuropathy, and cardiomyopathy; and ocular effects such as corneal deposits and retinopathy. Retinopathy is the most important ophthalmic complication of antimalarial therapy. The occurrence of ocular adverse reactions can be minimized by proper drug dose titration with regular retinal examination.

HCQ and CQ can pass through the placenta. However, teratogenicity has not been reported in association with the use of HCQ in pregnant women with SLE. It might be beneficial to the mother with SLE and her child by controlling the maternal disease activity and ensuring a successful pregnancy outcome.


Azathioprine is a purine analog which is metabolized to 6-mercaptopurine (6-MP) through reduction by glutathione and other sulfhydryl-containing compounds and then enzymatically converted into 6-thiouric acid, 6-methyl-MP, and 6-thioguanine. Azathioprine can then become incorporated into replicating DNA and can also block the de novo pathway of purine synthesis.

Few clinical trials have shown azathioprine toxicity to be higher and more serious than that observed with other DMARDs.[12] Hematological toxicity is the most important one. Neutropenia has been observed in up to 28% of RA patients on azathioprine. Thiopurine methyltransferase (TPMT) mutation testing can help to identify those at increased risk of developing neutropenia or thrombocytopenia with azathioprine. Dose reduction is required in those with absent or low TPMT activity.

Chronic immunosuppression with azathioprine can lead to an increased risk of malignancies, but this is especially seen in posttransplant use of azathioprine or in those with inflammatory bowel disorders.

Dosage is 1-3 mg /kg/day given as a single dose or divided q12h. Initially started in low dose of 0.5 mg/kg body weight, and increased by 0.5 mg/kg/day every 4 weeks, upto the maximum dose.


Cyclosporine has potent immunosuppressive properties, reflecting its ability to block the transcription of cytokine genes in activated T-cells.

Combination therapy of cyclosporine with MTX has shown substantial benefit in controlling aggressive RA. The primary benefit is its positive effect in the control of joint-bone erosions.

Patients with severe psoriasis and psoriatic arthritis had clinically significant improvement after the initiation of combination therapy. Short-term side effects were minor, transient, and manageable.[13]

The most feared adverse effect is the development of nephrotoxicity. Hence, patients on cyclosporine should be carefully monitored for renal function, hypertension, hyperkalemia, and for concomitant drugs which can exacerbate nephrotoxicity.

Kinase inhibitors


Several pathways that mediate receptor signal transduction have been targeted by the use of molecules that are kinase inhibitors.[14] Tofacitinib is a small orally active drug that inhibits JAK1 and JAK3. Inhibition of JAK reduces extracellular cytokine or growth factor-mediated gene expression and intracellular activity of immune cells, reduces NK cell numbers, and decreases serum immunoglobulin G (IgG), IgA, and IgM levels. It reduced signs and symptoms of disease activity in patients with RA in a series of randomized trials.

It is indicated in psoriatic arthritis and moderate-to-severe RA, which are resistant to MTX and other nonbiologic DMARDs. The dose used is 5 mg twice daily of immediate release drug or 11 mg once daily of extended release drug. It may be used in combination with MTX but not along with other biologic DMARDs or along with strong immunosuppressants such as azathioprine, cyclosporine, or tacrolimus.

Tofacitinib can cause bone marrow suppression. It should not be used if baseline lymphocyte count <500/cmm or absolute neutrophil count <1000/cmm and if baseline Hb <9 g%. Therapy has to be interrupted if absolute neutrophil count is <500/cmm or if persistently between 500 and 1000/cmm and restarted once >1000/cmm. Treatment has to discontinue if Hb falls by >2 g% or if goes below 8 g%.

Patients on tofacitinib are at risk of serious infections including reactivation of tuberculosis (TB), reactivation of hepatitis B (HB) and hepatitis C, opportunistic infections such as disseminated histoplasmosis and pneumocystis, viral infections, and invasive fungal infections.

Increased incidence of malignancies of the lung, breast, stomach, colorectum, and prostate, lymphoma, and malignant melanoma has been reported in patients taking tofacitinib. The incidence of nonmelanoma skin cancers are increased at higher doses. Periodic skin examination should be done while on tofacitinib.

Biologic disease-modifying antirheumatic drugs

Biologics are a novel class of therapies directed against specific cytokines implicated in the disease process of RA, which have greatly improved and expanded the treatment of RA.

They are divided into several groups based on which aspect of the immune system they target.

  • Tumor necrosis factor-alpha (TNF-α) inhibitors such as infliximab, etanercept, adalimumab, certolizumab, and golimumab
  • IL inhibitors such as tocilizumab and anakinra
  • T-cell activation inhibitor such as abatacept
  • CD20 activity blocker such as rituximab.

Biologics are potent immunosuppressive drugs. Patients have to be screened for HIV, TB, and HB and hepatitis C before starting therapy. Latent TB can be detected by tuberculin skin test (TST) and interferon-gamma release assay. The treatment of latent TB should be initiated before use. Patients on glucocorticoids may have negative TST. Chest X-ray should be done to look for TB before starting biologics. Total HB core antibody indicates the presence of previous HB virus (HBV) infections and such patients should be further evaluated with HBV DNA copies, and prophylactic therapy with lamivudine or entecavir has to be started.

Patients on biologic DMARDs are at risk of opportunistic infections such as invasive fungal infections (aspergillosis, candidiasis, mucormycosis, blastomycosis, coccidioidomycosis, histoplasmosis, and pneumocystosis), reactivation of cytomegalovirus, Epstein–Barr virus, BK virus, and other infections such as legionellosis and listeriosis. These patients are at risk of sepsis with multidrug-resistant Gram-negative bacteria which are gut colonizers and are prevalent in developing countries.


Etanercept is a soluble TNF receptor (TNFR). It is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75-kilodalton (p75) TNFR linked to the Fc portion of human IgG1.

It inhibits binding of TNF to cell surface TNFRs, thus rendering TNF biologically inactive. TNF plays an important role in the inflammatory processes and the resultant joint pathology.

The recommended dose is 50 mg weekly subcutaneous.

It is indicated in psoriatic arthritis, ankylosing spondylitis, juvenile idiopathic arthritis (JIA), RA, and plaque psoriasis.

Lymphoma and other malignancies, especially skin cancers, have been reported in patients who had been on etanercept.


Infliximab is a chimeric (murine-human) monoclonal antibody biologic drug that works against TNF-α.

It is administered through IV infusion. The recommended dose for the treatment of moderate-to-severe active RA is 3 mg/kg at 0, 2, and 6 weeks followed by 3 mg/kg every 8 weeks.

It is effective for the treatment of RA, ankylosing spondylitis, and psoriatic arthritis.

Severe hepatic reactions have been reported with infliximab use. This usually occurs after two weeks of therapy, and more often after six months. Jaundice, severe hepatitis, cholestasis, and acute liver failure have occurred. Treatment has to be discontinued if patient develops jaundice of if transaminase levels are increased more than three times the upper limit.

Hematological toxicities have been reported. Leukopenia, thrombocytopenia, and pancytopenia, if significant, requires discontinuation of therapy.

Postmarketing studies have reported increased incidence of T-cell lymphomas such as hepatosplenic T-cell lymphoma. Majority of patients had current or prior treatment with azathioprine or 6-MP.

Reactivation of latent TB is a potential threat with anti-TNF-α inhibitors, especially in inflammatory bowel disease or inflammatory arthritis, with almost 25% incidence reported, with a fatality of nearly 17%. Most guidelines for the treatment of latent TB infection recommend that when the pretest probability of a true-positive TST is high and the risk of reactivation TB is high, then a Mantoux test cutoff point of ≥5 mm or more should be indicative of latent TB infection.[15]


Adalimumab is a human monoclonal antibody which binds to TNF-α and blocks its interaction with the p55 and p75 cell surface receptors. Elevated TNF levels in the synovial fluid give rise to the pathologic pain and lead to joint destruction in immune-mediated arthritis.

It is administered 40 mg subcutaneously every 2 weeks.

It is used in RA, psoriatic arthritis, and ankylosing spondylitis.

As with other biologics, risk of opportunistic infections and reactivation of latent TB and HBV and hepatitis C virus can occur with adalimumab.

There are a few reports of demyelinating disorders like optic neuritis and multiplse sclerosis with adalimumab. Hence, therapy is to be discontinued in case of any new onset demyelinating symptom while on treatment.

Positive antinuclear antibody (ANA) test has been reported while on therapy (negative ANA at baseline). Rarely, it can lead to lupus-like syndrome and treatment needs to be discontinued in such cases.


Certolizumab is a TNF-α inhibitor, which is a pegylated humanized antibody Fab' fragment of TNF-α. Since it is not a complete antibody (it lacks Fc portion), it cannot bind complement or induce antibody-dependent cell-mediated cytotoxicity or apoptosis. It has demonstrated a fast and lasting effect on the signs and symptoms, inhibition of joint damage, and improvement in physical function in RA.

The recommended dose regimen in RA is 400 mg administered subcutaneously at weeks 0, 2, and 4, followed by 200 mg every 2 weeks or 400 mg every 4 weeks.

The safety and efficacy of certolizumab in moderate-to-severe RA have been assessed in combination with MTX or alone as a monotherapy in some clinical trials.

It is also useful in ankylosing spondylitis and psoriatic arthritis.

The general concerns with all the TNF-α blockers, such as opportunistic infections, reactivation of TB, risk of malignancy, and demyelinating disorders, also apply to certolizumab use. Certolizumab-repeated injections may trigger antibody formation against the drug which may lead to injection site reactions, erythema nodosum, and abdominal pain.


IL-1 is induced by inflammatory stimuli in RA and leads to the destruction of proteoglycans, thus to cartilage loss, and stimulates bone resorption. Anakinra is an IL-1 receptor antagonist that is currently FDA – approved for moderate-to-severe RA in patients above 18 years who have been unresponsive to initial DMARD therapy. It is also used in familial  Mediterranean fever More Details, in the treatment of acute flares of gout (when conventional therapy is ineffective) and in JIA.

The dose used is 100 mg subcutaneously once daily.

It can be combined with MTX in RA but should not be combined with TNF blockers. If creatinine clearance is <30 mL/min, the 100-mg dose has to be reduced to every other day.

Injection site reactions are common in the first 4 weeks and are usually mild and resolve within 2–4 weeks. As with other biologics, anakinra use can lead to increased risk of serious infections, and therapy should not be initiated in patients with active infections. The decrease in neutrophil counts can happen with therapy, and hence, absolute neutrophils count should be measured at baseline and then every month for the first 3 months and then quarterly.


This is a humanized monoclonal antibody that targets IL-6 receptor, approved for the treatment of polyarticular or systemic juvenile inflammatory arthritis, and its therapeutic effect has been extended to RA, giant cell arteritis, SSc, mixed connective tissue disorder (MCTD), and overlap syndromes.[16]

Dosage is IV 4 mg/kg IV over 60 min q4 weeks initially and may increase to 8 mg/kg q4 weeks based on the clinical response or 162-mg SC every other week, followed by an increase to every week based on clinical response.[17] It is contraindicated in hepatic disease and various cytopenias, but may be used in renal dysfunction. Side effects include upper respiratory infections, elevation of transaminases, pancreatitis, severe cutaneous adverse reactions such as  Stevens-Johnson syndrome More Details, and anaphylaxis.


Rituximab is a chimeric monoclonal anti-CD20 antibody used to treat lymphoproliferative disorders and several rheumatic diseases such as RA, granulomatosis with polyangiitis, and microscopic polyangiitis. It is directed at the CD20 antigen expressed on mature-B and pre-B cells, which have several functions in disease pathogenesis.

It is indicated in patients who had previous poor response to TNF inhibitor therapy. The Phase IIb (DANCER) and Phase III (REFLEX) trials have shown rituximab to be efficacious in both clinical and laboratory parameters.[18]

It is administered as two 1000-mg IV infusions separated by 2 weeks. Methylprednisolone 100 mg IV is given about 30 min before each infusion. Premedication with acetaminophen and an antihistamine is also given.

Rituximab can result in severe infusion reactions which can be sometimes fatal. Patients have to be monitored closely. About 80% of the fatal reactions have occurred with the first dose. HB reactivation can happen with rituximab and can lead to severe hepatitis, fulminant hepatic failure, and death. Hence, all patients should be screened for HBV infection before starting therapy, and if positive, they need to be evaluated for prophylactic antiviral therapy. In case of HBV reactivation, therapy has to be discontinued. Rarely, rituximab can lead to severe mucocutaneous reactions, including some reports of fatal reactions. Another rare but serious adverse event is the development of progressive multifocal leukoencephalopathy with rituximab.


It is a newer biologic which acts by inhibiting T-cell activation. It is a soluble fusion protein consisting of the extracellular domain of human CTLA4 and a fragment of the Fc portion of human IgG1 (hinge and CH2 and three domains). It is a selective co-stimulation modulator, acts by binding to CD80 and CD86 on antigen-presenting cells (APCs), and thus blocks the necessary CD28 interaction between APCs and T-cells. Blockade of the CD28/B7 pathway in vivo using CTLA4-Tg has also been shown to prevent expansion of memory T-cells after restimulation with antigen.

Various trials have shown that abatacept is efficacious in patients with RA who have failed to respond to older DMARDs and other biologic agents. Safety profile is favorable in combination with older DMARDs.[19] It should not be used in combination with TNF blockers or anakinra.

It is also used in moderate-to-severe JIA and active psoriatic arthritis.

It can be administered by either weekly subcutaneous injection or by monthly IV infusion following three 2 weekly loading doses. The dose when given subcutaneous is 125 mg once weekly. As IV infusion, it is given at 750 mg repeated at 2 weeks and 4 weeks and then every 4 weeks.

Patients with chronic obstructive pulmonary disease (COPD) have experienced higher incidence of COPD-related events such as cough, rhonchi, and dyspnea and COPD exacerbations. Since it is a drug that affects T-cell activation, serious and potentially fatal infections remain a concern with abatacept use. Increased incidence of lymphoma and lung cancer has been reported with abatacept as compared with general population.

[Table 1] describes in a nutshell essential feature of all DMARDs and the various monitoring parameters.
Table 1: Commonly used disease-modifying antirheumatic drugs

Click here to view

Before starting DMARD therapy, the patient needs to be screened for HB, hepatitis C, and latent TB infections. Patients' complete blood count, liver function, and renal function need to be evaluated. A chest radiograph should be obtained before MTX therapy.

  Disease-Modifying Antirheumatic Drugs in Specific Conditions Top

Systemic lupus erythematosus

SLE is a disease with clinically heterogeneous manifestations. The therapeutic approach is dictated by the predominant manifestations and is variable. HCQ is useful in most cases and benefits constitutional, mucocutaneous, and musculoskeletal manifestations of SLE, along with corticosteroids.

Rituximab is useful in severe cases such as lupus nephritis.

Systemic sclerosis

For patients with progressive and diffuse skin involvement without visceral involvement, MTX or mycophenolate mofetil (MMF) has been useful.

The efficacy of MTX in this setting has been confirmed in two randomized, placebo-controlled, double-blind trials.[20],[21] However, there are no data to support MTX use in SSc with visceral involvement.

For patients with skin sclerosis unresponsive to MTX, MMF, or cyclophosphamide, rituximab has been found effective. Rituximab is also effective in the context of overlap syndromes with SSc.[21],[22]

Trials with tocilizumab are ongoing for patients with skin and lung involvement with SSc. These results are eagerly awaited.

HCQ is the first-line agent used in arthritis related to SSc. For those unresponsive to HCQ, MTX has been found effective.

Rheumatoid arthritis

All patients with RA should be started on DMARDs along with anti-inflammatory agents, i.e., non-steroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids if the disease is active. MTX is the DMARD of choice for upfront therapy. In patients who cannot tolerate MTX, HCQ, SSZ, or leflunomide can be used.

In MTX-resistant cases, DMARD triple therapy containing MTX, SSZ, and HCQ has been found effective.[20],[22] Another option in such cases is adding biologic DMARDs to MTX, for example, MTX plus TNF inhibitor or MTX plus abatacept or MTX plus tocilizumab or MTX plus tofacitinib.


Azathioprine or MTX is the first-line DMARDs used in this setting as glucocorticoid-sparing agents. Azathioprine is preferred in those who have lung disease related to myositis or who have underlying liver disease. MTX is preferred in those who have clinically relevant TPMT mutant alleles as azathioprine will be metabolized slowly in them and is prone to toxicity.

Sjogren's syndrome

For extraglandular manifestations of SS, conventional nonbiologic DMARDs – HCQ, MTX, azathioprine, sulfasalazine, and leflunomide – have been used along with glucocorticoids. For severe manifestations of SS, rituximab has been successfully used.

Mixed connective tissue disorders

MCTD is a generalized connective tissue disorder which has a combination of features seen in SLE, SSc, and polymyositis, sometimes referred to as overlap syndrome. Glucocorticoids are the mainstay of treatment. In those who need repeated courses of glucocorticoids, HCQ or MTX is useful as a glucocorticoid-sparing agent.

Granulomatosis with polyangiitis and microscopic polyangiitis

For patients with nonorgan-threatening disease, initial combination of glucocorticoids with MTX is preferred. Rituximab is also another option in such patients. In patients with organ-threatening disease, cyclophosphamide or rituximab is the preferred DMARD.

  Conclusion Top

Over the past three decades, DMARDs and biologics have made a huge difference in the lives of people with RA and other rheumatologic disorders. Twenty-five years ago, NSAIDs and steroids were the mainstay of RA treatment. The treatment has evolved over these years with advent of HCQ, sulfasalazine, and the gold standard MTX to the current era of biologics. Biologics era was ushered in the year 1998 with the FDA approval of TNF antagonist and etanercept. Subsequently, anakinra, infliximab, rituximab, abatacept, certolizumab, and tofacitinib have changed the natural history of rheumatologic disorders. While biologics bring the disease under control in 4–6 weeks compared to 3–6 months taken by traditional DMARDs, they also bring with them their own challenges in the therapeutic decision-making – the risk of serious infections such as pneumonia with these potent immunosuppressive drugs and the huge cost of these targeted agents are the downside.

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Conflicts of interest

There are no conflicts of interest.

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