Conventional Synthetic Disease-Modifying Antirheumatic Drugs

Introduction

Disease-modifying antirheumatic drugs (DMARDs) are indicated in patients with persistent polyarthritis, despite initial attempts to control their symptoms and synovitis with anti-inflammatory drugs. DMARD is a term that is used interchangeably with second-line medications, slow-acting antirheumatic drugs, or disease-controlling antirheumatic therapy. The most widespread classification scheme divides DMARDs into synthetic DMARDs (sDMARDs) and biologic DMARDs (bDMARDs). Synthetic DMARDs include conventional synthetic DMARDs (csDMARDs – traditional drugs described in this chapter) and targeted synthetic DMARDs (tsDMARDs – chemically synthesized drugs that target a specific molecule). Biologic DMARDs (bDMARDs) are biologically synthesized drugs, often antibodies against a specific target molecule. Drugs included in the csDMARD group are methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SSZ), leflunomide, oral or intramuscular gold salts, D-penicillamine, azathioprine, cyclosporine and mycophenolate; there is some debate as to whether tetracyclines (e.g., minocycline) should be included in this category (see below). In addition to providing symptomatic improvement, this class of agents is unified by their relatively slow onset of effect (e.g., 3 to 6 months) and their ability to either lower serum rheumatoid factor (RF) or acute-phase reactant levels and in some cases to reduce radiographic progression.

Because clinical benefits are usually incomplete, these agents are often used in conjunction with other analgesic and anti-inflammatory therapies for added symptom control. DMARDs should be initiated as early as possible—either when a diagnosis is established or when persistent polyarthritis is evident despite initial anti-inflammatory therapies. The benefit of starting DMARD therapy early is illustrated by a study by Lard and colleagues, who treated a cohort of patients with recent-onset rheumatoid arthritis (RA) by either delaying DMARD therapy for a mean of 123 days or starting DMARD therapy within a mean of 15 days. Patients were then followed for 24 months. There was significantly more radiographic joint damage (assessed by Sharp score) in the delayed-treatment group as compared with the early-treatment group (Figure 6-3).

Conventional sDMARDs should be started in all patients with active rheumatoid arthritis including those with slowly progressive disease (Table 8-1) who have failed to respond to a reasonable trial of NSAID therapy. Conventional sDMARDs should also be used in patients with aggressive disease (Table 8-1) and in those who have progressed from slowly progressive to aggressive disease. In addition to the severity and activity of the disease, the choice of a particular sDMARD depends on several factors, including the convenience of administration, patient preference, coexistent comorbidities, and cost.

Conventional sDMARDs have been the mainstay of RA therapy for >50 years. Although they provide symptomatic relief and were once thought to be capable of modifying the underlying process, this term belies their true potential, as only MTX, leflunomide, gold salts, cyclosporin and SSZ have consistently been shown to be truly disease-modifying. Thus many csDMARDs have a limited ability to protect against the progressive joint damage that characterizes RA. Moreover, most csDMARDs have a limited utility or durability, owing to the loss of efficacy or development of toxicity over time. In one study, the mean duration of DMARD use was <20 months for gold, penicillamine (PCM), SSZ and antimalarials, yet the mean duration of MTX use was 33 months. The durability of MTX has been shown by other studies as well (Figure 11-1). One longitudinal study showed that nearly 80% of patients treated with MTX remained on this drug for at least 2 years. Continuation on MTX is nearly twice as long as with gold and HCQ, which is why MTX is viewed to be the gold standard among the sDMARD and bDMARD therapies.

Each csDMARD has its attendant toxicities and, therefore, requires physician oversight, follow-up and safety monitoring. The associated toxicities and recommended laboratory monitoring of commonly used csDMARDs are summarized in Table 11-1. It should be noted that several csDMARDs (e.g., MTX, leflunomide) should be avoided in pregnant women or those who intend to become pregnant in the immediate future.

Patients who require DMARD therapy are often referred to a rheumatologist to confirm the diagnosis and severity of disease and to help initiate and guide the therapeutic plan. Despite their limitations, DMARDs are now used early in the course of disease to achieve greater symptom control and functional preservation. Multiple trials have shown that early initiation of DMARD therapy in the first 6 to 12 months of disease will result in better radiographic (i.e., fewer erosions) and functional outcomes.

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Methotrexate

Methotrexate is the most frequently prescribed csDMARD for RA. Its popularity rests with its ease of use (oral or subcutaneous, weekly dosing), well-defined toxicities (Table 11-1), rapid onset of clinical benefits (usually within 6 to 8 weeks), durability, low cost, additive benefits when combined with other DMARD regimens including bDMARDs and its ability to retard radiographic damage. While the toxicities associated with MTX use are primarily related to the inhibition of dihydrofolate reductase and the inhibition of folic acid production, the clinical benefits appear to be unrelated to this enzyme and may instead relate to the induction of adenosine, a powerful anti-inflammatory mediator.

Among rheumatologists, MTX is the primary DMARD of choice in patients with aggressive disease and is either the first or second drug of choice in those with slowly progressive disease. Low-dose, oral MTX is usually prescribed at a starting dose of 10-15 mg/week and the dose is escalated by 2.5 to 10 mg/month to a maximum of 25 mg/week or when efficacy or toxicity is demonstrated. Only physicians familiar with MTX should prescribe this agent. For initiation of treatment in DMARD-naïve patients with moderate to high RA activity, the current (2021) American College of Rheumatology (ACR) guidelines strongly recommend MTX monotherapy over HCQ, sulfasalazine, tsDMARD, or bDMARD monotherapy; the ACR guidelines also conditionally recommend MTX over leflunomide monotherapy, dual or triple csDMARD therapy, or MTX plus a tumor necrosis factor inhibitor (TNFi.) For DMARD-naïve patients with low disease activity, MTX is conditionally recommended over leflunomide, but HCQ is the preferred csDMARD for these patients. The 2022 EULAR guidelines recommend that MTX be part of the initial treatment strategy, with leflunomide or sulfasalazine considered in patients with contraindications or intolerance to MTX.

A complete blood count (CBC) and renal and hepatic function tests should be obtained at initiation and monthly for the first 3 to 4 months. Thereafter, laboratory monitoring of CBC and hepatic enzymes should be done every 6 to 12 weeks. MTX is not appropriate in patients with underlying liver disease, hepatitis B or C infection, or impaired renal function or dialysis. All patients should undergo baseline serologic testing for hepatitis B and C. MTX is also contraindicated in women who are or plan to be pregnant. MTX is a teratogen and is contraindicated in pregnancy.

All patients on MTX should be treated with concomitant daily folate (e.g., 1 mg/day) to lessen the incidence of MTX-related side effects (especially leukopenia, hypersensitivity pneumonitis, or hepatic dysfunction). Because of better bioavailability and tolerance, many rheumatologists switch patients to subcutaneous dosing or split dose oral weekly dosing when using a weekly dose ≥20 mg.

Common toxicities (i.e., oral ulcers, nausea, diarrhea, headache) may be managed with either dose reduction or conversion to parenteral administration and administration of folinic acid. MTX is infrequently associated with a 1- or 2-fold elevation of hepatic enzymes, rash, photosensitivity, alopecia, or post-MTX central nervous system (CNS) toxicities. Up to one third of patients may experience postdosing malaise, fatigue, headache, dizziness and blurred vision, reactions that usually resolve within 24 to 36 hours. Other rarely encountered toxicities include cytopenia, hypersensitivity pneumonitis (“MTX lung”) and hepatic fibrosis. Bone marrow suppression (primarily leukopenia) occurs almost always in the setting of impaired renal function or folate deficiency. Due to synergistic effects as anti-folate agents, trimethoprim/sulfamethoxazole (Bactrim) should not be used with MTX. These serious adverse events should be treated with supportive measures and MTX discontinuation. MTX lung is rare, idiosyncratic and manifests as acute-onset dyspnea and pulmonary infiltrates. Risk factors include hypoalbuminemia, diabetes and preexisting lung disease. Such patients respond well to drug cessation, high-dose corticosteroids and supportive care.

A formidable body of evidence has been amassed showing marked benefits of MTX on disability, morbidity, and mortality statistics. Between 1977 and 1997, disability (as measured by the Health Assessment Questionnaire [HAQ]) declined 2% to 3% per year and moderate to severe disability decreased from 63% to 36%, during which time MTX use rose from 1% to 44%. Similarly, in the past 4 decades, surgical and orthopedic procedures have remained stable until the last measured decade (1985 to 1994, when MTX use in RA patients began) when significantly fewer (>65%) surgeries were performed in RA patients. Last, while many studies have documented increased mortality for RA patients (from cardiovascular (CV) death, infection, lymphoma, etc.), Choi and colleagues have shown that RA patients treated with MTX have a significantly reduced risk of mortality, especially CV mortality.

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MTX in Early RA

MTX has been the standard against which all new DMARDs and combination DMARD regimens have been judged in early RA trials. MTX was first used for early RA in 1990. In 1991, Rau and associates reported that when 57 early RA patients were treated with 6 months of oral MTX, the clinical benefits were comparable to those of parenteral gold with regard to clinical improvement and radiographic protection, although there were fewer MTX dropouts. Other early MTX trials failed to show superiority of MTX, but this was largely due to the use of lower doses (7.5-15 mg/week) and slow escalation schedules (e.g., 2.5 mg/month). Sokka and Pincus reviewed a cohort of recent-onset RA patients and showed that MTX was the initial DMARD of choice in 83% of patients. After 1 year, 90% remained on MTX: as monotherapy in 66% of patients, 23% received MTX in combination with another DMARD, while only 11% discontinued the drug.

Trials have compared the efficacy of MTX with TNF inhibitors in early RA patients. In the ERA trial, MTX 20 mg/week was compared with etanercept 25 mg biweekly in 632 patients. Although etanercept had a faster onset of clinical efficacy, results at 12 months were not significantly different between groups; 65% of MTX-treated patients were American College of Rheumatology (ACR)20 responders compared with 72% on etanercept. Another early RA trial also showed monotherapy with MTX or adalimumab to have similar ACR20 responses after 12 and 24 months, while the combination of both yielded significantly greater responses.

In the 12-month, 1049-early-RA–patient ASPIRE trial, MTX monotherapy yielded an ACR20 response of 54%, while the response to the combination of MTX plus infliximab was 62% and 66% (for those dosed with 3 mg/kg or 6 mg/kg, respectively). The number of patients showing no radiographic progression (by van der Heidje–modified Sharp scores) was 45% for MTX and 58% to 59% for MTX plus infliximab after 1 year. Thus there have been many trials that affirm the clinical and radiographic benefits of combined MTX and TNF-inhibitor therapy, including the ASPIRE, the Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT), the Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Rheumatoid Arthritis (ARMADA), DE019 Study, the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) and the PREMIER trial. While it appears that bDMARD monotherapy may not be significantly superior to MTX (as judged by ACR20/50/70 responses) in early RA, 12- and 24-month radiographic outcomes were unvaryingly better in those receiving TNF inhibitors (alone or in combination). Quinn and colleagues have shown that 12 months of MTX plus infliximab resulted in exceptional efficacy that was maintained for another 12 months after the infliximab was stopped and patients were maintained on MTX alone. These studies suggest that MTX is effective and safe in early RA and should be strongly considered as monotherapy or combination therapy, depending on disease severity and risk for disease progression.

The PROMPT study further establishes the importance of MTX in early disease. The study was undertaken to define whether there is a “window of opportunity” in the treatment of early RA. This 12-month, double-blind, placebo-controlled trial randomized 110 patients with undifferentiated arthritis to receive treatment with MTX 15 mg/week or placebo. The primary end point was to determine the proportion of patients who evolved into RA by criteria after 12 months. After 12 months, study medication was discontinued in patients who had achieved or maintained a DAS ≤2.4; however, treatment with MTX was continued in patients who had progressed to a “diagnosis” of RA. After 12 months, MTX treatment was shown to significantly reduce progression to RA (20 vs 29, P = 0.02) and more MTX-treated patients achieved remission (18 vs 11, P = 0.02). Patients with erosive disease particularly benefited from MTX, with a significant retardation of radiographic progression (P = 0.035). Interestingly, further analysis of these data revealed that the noted benefits of early aggressive MTX treatment were largely observed in patients with anti-CCPs.

Hydroxychloroquine (HCQ)

Among rheumatologists, HCQ is the most frequently used csDMARD when treating those with mild or slowly progressive RA. The 2021 ACR guidelines conditionally recommend HCQ over other csDMARDs in DMARD-naïve patients with low disease activity. While the 2022 EULAR guidelines contain no direct recommendations for the use of HCQ, they state that HCQ may be used in patients with early and mild disease without poor prognostic factors who have contraindications or intolerance to other csDMARDs. The drug dose should be determined by body weight with a maximum dose of 5 mg/kg (200-400 mg per day) to reduce risk of macular damage. This agent has a favorable safety profile with a very low incidence of skin and gastrointestinal (GI) complaints and a very rare risk of visual loss due to drug deposition on the macula. The risk of irreversible retinopathy should not be overstated since it is very unusual when doses <6.5 mg/kg/day are used. Patients should be asked about visual symptoms at each visit and should undergo ophthalmologic evaluations (e.g., slit lamp exam and visual field testing) at baseline and every 12 months. The mechanism of action of HCQ is unknown but has been hypothesized to relate to alterations in macrophage function, phospholipase A1, oxygen radicals, cytokine synthesis, or downregulation of Toll-like receptor activity.

HCQ in Early RA

Few trials have examined the effects of HCQ in new-onset RA. Clark and associates showed moderate (~50%) improvement in pain and joint scores in a 6-month trial of HCQ vs placebo. In 1995, the Hydroxychloroquine in Early Rheumatoid Arthritis (HERA) trial also reported significant improvement with 36 weeks of HCQ in RA of <2 years’ duration. In an open-label, 2-year study, Matteson and colleagues reported that 56 of 94 patients were able to achieve an ACR50 response and remain on HCQ after 48 months. Moreover, 41% showed no evidence of new erosions. Nonetheless, the efficacy of HCQ in early disease has been questioned by a report that minocycline was almost twice as effective as HCQ (ACR50 of 60% vs 33%) in a 24-month trial of early RA patients.

Gold Salts

Gold compounds have been used in the treatment of RA since 1929. Initially developed as a treatment for tuberculosis (TB), they were introduced as a therapy for RA on the erroneous assumption that RA was related to TB infection. Although this was disproved, gold therapy was beneficial in RA. Gold preparations include the parenteral forms (aurothiomalate and aurothioglucose) and oral gold (auranofin). The mechanism of action is poorly understood but is thought to be multifactorial and may involve inhibition of macrophage function. IM gold is not commonly used these days, largely because of the success of MTX, tsDMARDs and bDMARDs that demonstrate better and more rapid clinical responses, durability, safety and x-ray outcomes. Although indicated for active polysynovitis, its current clinical use is limited to those patients not responding to or unable to take MTX or other DMARD types.

Gold is usually given parenterally once a week until a response is seen. After a small (10-mg) IM test dose, a 25-mg second dose is followed by a 50-mg weekly dose until a clinical response is noted, or a total of 750-1,000 mg has been administered. Most patients begin to show clinical improvement after receiving a total of 600-800 mg. In those who respond, the frequency of injections should be decreased to every 2 weeks for 2 months, then decreased to monthly injections of 50 mg IM. At each visit, the patient should be assessed for toxicities and a hemogram and urinalysis performed to identify hematologic cytopenias or proteinuria. Lack of efficacy, nephrotic syndrome, pruritic rashes and thrombocytopenia are the most common reasons for discontinuing gold therapy. Oral gold (auranofin) has been approved for use in RA and has the advantage of oral administration and less proteinuria but may be associated with diarrhea and less clinical efficacy.

Sulfasalazine (SSZ)

Although SSZ has been available for nearly 60 years, its use increased over the past 2 decades. It is commonly used to treat either slowly progressive disease or aggressive disease unresponsive or intolerant of MTX or leflunomide. The 2021 ACR guidelines conditionally recommend it over MTX in DMARD-naïve patients with low disease activity, although HCQ remains the preferred agent in this patient group and MTX the preferred agent in patients with moderate to high disease activity. The 2022 EULAR guidelines recommend it (or leflunomide) as initial therapy only in patients with contraindication or intolerance to MTX. It may also be offered when the use of a TNF inhibitor is prohibited by cost or toxicity. While its mechanism of action remains unclear, the clinical benefits of SSZ may relate to its ability to induce adenosine release or by modulation of B-cell activity.

Common toxicities include dose-related GI toxicities (i.e., nausea, diarrhea, bloating), rash and increased hepatic enzymes. Hematologic toxicities are the most serious and should be monitored closely with a monthly hemogram and hepatic enzymes initially, and then every 4 to 8 weeks. Patients with glucose-6 phosphate dehydrogenase deficiency may be at increased risk for hemolytic anemia. GI toxicity may be lessened by using enteric-coated tablets and by slowly escalating the dose. In most patients, administration is begun at 500 mg twice daily for 1 week, and the dose is increased by 500 mg each week until a dose of 1,000 mg twice daily is achieved. Most patients will respond to SSZ within 12 weeks. Doses may be increased up to 4,000 mg daily, but the use of higher doses may be limited by GI, hepatic, or hematologic toxicity.

Sulfasalazine in Early RA

SSZ monotherapy has been modestly effective in early RA, especially in those with mild to moderate disease. However, the most impressive outcomes in early RA were seen when SSZ was used in combination with MTX or MTX plus HCQ or MTX plus initial high-dose prednisolone (see Combination DMARDs in Early RA, this module). In these early RA trials, the csDMARD combinations that included SSZ were consistently superior to SSZ monotherapy as measured by ACR20 responses, EULAR remission and radiographic outcomes. These findings suggest the potential benefits of SSZ (alone or in combination) in new-onset RA patients, especially in those unable to take MTX.

Cyclosporine

Cyclosporine has been used since 1979 as an immunosuppressive therapy in recipients of solid-organ transplants. Since the 1980s, it has been studied in RA and was finally approved for use in RA in 1992. Patients with aggressive RA who do not respond either to MTX, combination DMARDs, or TNF inhibitors may be candidates for cyclosporine therapy. Cyclosporine may also be effective in the management of both cutaneous psoriasis and psoriatic arthritis. Nonetheless, the use of this immunosuppressive agent is limited by the frequency of serious toxicities, especially hypertension and renal insufficiency. Daily or twice-daily dosing should begin at 2.5 mg/kg/day and may be slowly increased after 6 to 8 weeks to a maximum of 4.0 mg/kg/day. These prescribing guidelines are necessary to avoid renal toxicity.

Other common side effects include diarrhea, nausea, paresthesia, hypertrichosis and gingival hyperplasia. Hypertension and renal insufficiency may be seen at higher doses and can be managed by downward dosage adjustments and aggressive management of hypertension. The clinician should be aware that numerous drug interactions exist that may increase or decrease cyclosporine levels. Renal function should be closely monitored while on cyclosporine and should aim to keep the serum creatinine within 30% of pretreatment values. Cyclosporine should not be used in patients with renal insufficiency, uncontrolled hypertension, or in the setting of active malignancy. Cyclosporine has also been shown to be effective in combination with MTX in RA patients unresponsive to MTX alone. This potent immunosuppressive is believed to work by interfering with interleukin (IL)-2 and interferon-α generation by activated T cells. Like MTX, the onset of efficacy is usually noted after 6 to 8 weeks of therapy.

Cyclosporine in Early RA

Miranda and associates reported that when cyclosporine was used in 111 early RA patients, a 63% ACR20 and a 29% ACR70 response was seen. Moreover, the addition of chloroquine did not improve responses. Similarly, Sarzi-Puttini and colleagues studied cyclosporine alone or in combination with MTX or HCQ and showed that:

• The addition HCQ did not improve efficacy
• MTX plus cyclosporine was clinically and radiographically superior in early RA patients
• Early RA patients taking cyclosporine or HCQ monotherapy showed evidence of radiographic progression in this 1-year trial.

Several other trials have since shown that although cyclosporine is effective in early disease, protection from radiographic progression is only afforded by the combination of MTX and cyclosporine. In fact, Kvien and colleagues found cyclosporine to be equal to gold in efficacy and radiographic protection. In their study, 60% of early RA patients treated with either drug showed x-ray worsening. Nonetheless, Pasero and associates have shown cyclosporine to be capable of retarding radiographic progression and new erosions in early RA.

Azathioprine

Azathioprine is an antimetabolite that interferes with the synthesis of purine and DNA synthesis, particularly in rapidly dividing cells. It is uncommonly used in RA, largely because of its narrow therapeutic window. Therefore, doses needed to yield benefits may be too toxic for chronic use. For these reasons, azathioprine is usually reserved for adults with refractory aggressive RA and only after unsuccessful trials of several other DMARDs. A small trial of 33 early RA patients found azathioprine to be equal to gold and chloroquine in clinical outcomes after 12 and 24 weeks of therapy. Dosing is slowly escalated from 50 mg/day to a final dose of 2-3 mg/kg/day (i.e., 100-300 mg/day).

Patients on this agent should have a baseline complete blood count (CBC) and liver test and a measurement of the enzyme Thiopurine methyltransferase or thiopurine S-methyltransferase (TPMT) at baseline since low levels identify patients at risk for hematologic toxicity. Thereafter, blood counts should be closely monitored (every 2 to 4 weeks). Nausea and hepatic enzyme abnormalities are common and may respond to dosage adjustments. There is also a significant risk of bone marrow suppression and secondary infections (i.e., herpes zoster). With long-term use there is also a risk of secondary lymphoproliferative malignancies. Azathioprine has rarely been used or indicated in patients with new-onset RA.

Cyclophosphamide

The cytotoxic drug cyclophosphamide is seldom used in RA and never indicated in early RA patients. Although effective at doses of 2-3 mg/kg/day, it is believed that this agent is too toxic for routine use. Monthly pulse cyclophosphamide is not beneficial in RA. Common side effects include nausea, vomiting, hair loss, leukopenia, hemorrhagic cystitis and amenorrhea. With prolonged use, there is an increased risk of neoplasia, especially bladder cancer and lympho­proliferative malignancies.

Leflunomide

Leflunomide, an antiproliferative isoxazole compound that inhibits dihydroorotate dehydrogenase, was developed for use in RA. Several clinical trials have shown that leflunomide is clearly superior to placebo and at least equal in efficacy to MTX. In three large trials used for registration, radiographic outcomes after 1 year of therapy showed that patients treated with either leflunomide, MTX, or SSZ had less observed disease progression (as measured by Sharp scores) when compared with placebo controls or predicted rates of progression. The combination of leflunomide and MTX has been shown to be effective when given to partial responders to MTX but there is an increase in hepatotoxicity. The 2021 ACR guidelines recommend MTX over leflunomide for DMARD-naïve patients with moderate or high disease activity, although the recommendation is conditional. For patients with low disease activity, other csDMARDs are conditionally recommended over leflunomide. The 2022 EULAR guidelines leflunomide (or sulfasalazine) as initial therapy only for patients with contraindications or intolerance to MTX.

Patients may be treated with 20 mg daily. Lower doses (10 mg/day) are recommended for those experiencing adverse effects, or as initial therapy, when being added to optimal doses of MTX. The dose of leflunomide when being added (for combination therapy) to MTX is 10 mg qd for 4 to 8 weeks, then escalated to 20 mg qd if unchanged clinically and if lab-safety profiling allows.

Common toxicities observed in clinical trials included diarrhea, nausea, rash, hair loss and, uncommonly, hypertension. Hepatotoxicity is a particular concern with this agent, hence proper patient selection and strict adherence to prescribing and monitoring guidelines are suggested. In the first 104,000 patient years of leflunomide use, there were nearly 296 reports of liver toxicity, with 232 of these being sporadic hepatic enzyme elevations; many of these patients were on other hepatotoxins (e.g., MTX, NSAIDs, etc.), and 65 of these elevations were said to be serious. There were 15 liver failures, two cases of cirrhosis and 15 deaths. Of the deaths, one third were due to hepatic causes (e.g., liver failure, hepatic necrosis, hepatitis, cholestatic jaundice) and two thirds were due to nonhepatic causes (e.g., sepsis, multiorgan failure, interstitial lung disease, GI bleed, pulmonary embolism, Stevens-Johnson syndrome, pancreatitis). Leflunomide is contraindicated in those with a history of hepatic dysfunction, hepatitis B or C and in women who are or plan to become pregnant. Leflunomide is a teratogen and a class X pregnancy risk.

In an open-label early RA trial of leflunomide has been completed. Leflunomide (20 mg/day) was given to 87 patients with a mean disease duration of 17 weeks; 73% of these met ACR diagnostic criteria for RA. Sixty percent completed 1 year of therapy with an ACR20 of 75% and DAS remission in 24% of patients. Radiographic protection (no progression) was seen in 77% of patients.

Tetracycline/Minocycline

Tetracycline and related compounds (e.g., doxycycline, minocycline) have been purported to be effective in treating RA. The clinical benefits of tetracycline are unrelated to their antibacterial effects but, instead, to their function as metalloproteinase (MMP) inhibitors. This action appears to be augmented or synergized by the use of concomitant NSAID therapy. Studies thus far have shown modest clinical benefits in RA, but conflicting results have been seen in osteoarthritis of the knee. O’Dell and associates reported that the use of minocycline in early RA resulted in significantly more ACR20 and ACR50 responses and less reliance on corticosteroid therapy. In this trial, 60 RA patients with <12 months of disease were randomized to receive either minocycline 100 mg bid or HCQ 200 mg bid.

Despite these encouraging results, these agents are seldom used in early RA. Thus the role of minocycline in RA needs to be further defined in larger trials. Common side effects include photosensitivity, nausea, diarrhea, Candida superinfection and rash. Uncommonly seen were hepatotoxicity, increased intracranial pressure and drug-induced lupus. Absorption of tetracycline is reduced if taken with calcium, milk, food, or antacids.

Combination DMARD Therapy

Incomplete clinical responses to individual DMARDs and loss of efficacy over time has fostered both new drug development and novel methods of drug use, including the use of various DMARD combinations. In the late 1980s, the use of DMARD combinations was advocated by Pincus and associates and others, who likened the severity of RA to neoplastic disorders and, therefore, they proposed that as in oncology, better treatment outcomes may be realized with combination DMARDs rather than monotherapy. Although combination DMARD therapy was used sporadically in the mid-1980s, Wilske popularized this concept with the proposal to use “step-down bridge” combination DMARD therapy in RA. Although this particular regimen was never tested in a controlled trial, an open-label, observational report suggested benefit, especially in those with RA of <2 years’ duration.

Since then, DMARD combinations have been advocated by researchers with the hope of added or synergistic efficacy while also limiting toxicity. Unfortunately, many of the earliest trials failed to show added benefit but did show increased toxicity when drug combinations were used. It was not until the reported success of the combination of MTX plus cyclosporine and a triple DMARD regimen (MTX + SSZ + HCQ) in 1996, that effective and safe use of combination DMARDs was widely advocated. Since these reports, several other combination regimens have been found to be equally effective and safe. Effective combination DMARD regimens are unified by:

• The use of weekly MTX (15-25 mg/week) as the anchor drug
• Proper patient selection (eg, active or aggressive RA)
• The use of MTX plus a restricted group of sDMARDs or bDMARDs, including either cyclosporine, HCQ, SSZ, leflunomide, anakinra, etanercept, infliximab, adalimumab, abatacept, or rituximab, and tsDEMARDs (JAK inhibitors).

Candidates for combination DMARD therapy often have aggressive RA or are patients with an incomplete response to conventional DMARD monotherapy (usually MTX or HCQ). Rheumatologists have increasingly opted for combination DMARD regimens (usually by sequentially adding on DMARDs) when a significant or complete response is not achieved with a single DMARD regimen. Numerous surveys have demonstrated the widespread use and popularity of combination DMARD therapy worldwide. The most often-used combination regimen in RA has been MTX and HCQ, a regimen that has been studied and shown to be effective in a clinical trial. Clearly, this finding reflects the popularity and safety of both agents. Combination regimens appear to be most effective when maximal doses of MTX (15-25 mg/week) are combined with other equipotent sDMARDs or bDMARDs. Many studies have shown the superior outcomes of combination DMARD regimens, especially when MTX is combined with newer therapies, such as cyclosporine, leflunomide, TNF inhibitors, anakinra, or rituximab, which are discussed below. Such combination regimens are most appropriate in those with high-risk or aggressive RA and evidence of many swollen joints, nodules, extra-articular manifestations, disability, marked elevations of RF, anti-CCP antibody, ESR, or CRP and radiographic erosions.

Combination DMARDs in Early RA

In concert with the evolving paradigm of early diagnosis and aggressive treatment of RA, combination DMARDs in early RA have been extensively studied in the past decade. These trials have not only attempted to show superior clinical outcomes, but have also focused on radiographic, functional and economic outcomes as well:

• The COBRA trial in 155 DMARD- and prednisone-naïve early RA patients (<2 years’ disease duration) was one of the early successes of combination therapy in RA. Patients were randomized to receive either SSZ monotherapy (2 g/day) or SSZ plus MTX (15 mg/week, tapered off after 40 weeks) plus prednisolone 60 mg daily (weaned down to 7.5 mg/day over 6 weeks and tapered off after 28 weeks). Patients were allowed to take background NSAIDs or to receive two intra­articular corticosteroid injections, if needed. Although the mean disease duration was only 4 months, >72% of these patients were RF-positive and 77% had erosions in the hands or feet at baseline. During the first 28 weeks, combination therapy outperformed SSZ monotherapy with significantly greater ACR20 (72% vs 49%) and ACR50 (49% vs 21%) responses and more remissions (28% vs 16%). However, when prednisone was discontinued after week 28, the clinical benefit of combination therapy over monotherapy was no longer apparent at weeks 40 and 56 (Figure 11-2). The monotherapy group had more dropouts (for both toxicity and lack of efficacy), most of which occurred in the first 28 weeks. Radiographic damage rapidly progressed in the monotherapy group (4 vs 1 Sharp units) in the first 28 weeks and was still significantly greater between weeks 28 through 56 in the SSZ-only group (2.5 vs 1 Sharp units). Over the next 5 years of open-label follow-up, radiographic damage progressed in the SSZ monotherapy group at a rate of 8.6 Sharp units/year but only 5.6 Sharp units/year in the combination-therapy group (Figure 11-3). This difference was unaffected by disease activity, HAQ scores, or subsequent DMARD therapy. Such findings strongly argue that the first choice of therapy may have long-lasting impact on the rate of damage in early RA patients.
• The FinRA-Co trial, reported by Mottonen and associates, was a 2-year, open-label comparison of monotherapy (SSZ 1-2 g/day ± prednisolone 5-10 mg/day) and combination therapy with MTX 7.5 mg/week, SSZ 1-2 g/day, HCQ 300 mg/day and prednisolone 5-10 mg/day. In this trial, 195 DMARD-naïve, early RA patients (<2 years’ disease duration) were randomized to either monotherapy or combination therapy. Fifty-one monotherapy patients were allowed to switch to MTX because of nonresponse to SSZ. After 2 years, the combination therapy group had significantly higher ACR remission rates (38% vs 18%) and ACR50 responses (71% vs 58%), although ACR20 responses were similar (78% vs 84%, respectively). Furthermore, after 2 years, significant changes in Larsen (radiographic) scores were seen in the monotherapy but not in the combination-therapy group (10 vs 2 Larsen units). Logistic regression analyses showed that only combination DMARD therapy predicated remission in this trial. Moreover, a subanalysis of this trial showed that a delay in starting a DMARD beyond 4 months significantly reduced the chance of remission and response for those receiving monotherapy but not combination therapy in these early RA patients with a mean disease duration of 7 to 8 months.
• Calguneri and colleagues compared the effects of monotherapy (MTX, HCQ, or SSZ) vs two-drug (MTX + HCQ or MTX + SSZ) or three-drug (MTX + SSZ + HCQ) combination regimens in 180 consecutive RA patients with relatively early disease (mean duration of <2.5 years) in a 2-year, open-label study. All patients improved in terms of clinical and laboratory measures. However, an incremental response was seen with use of an additional DMARD, such that remission was seen in 60.7%, 44.6% and 31.5% of those on three, two and one DMARD(s), respectively. Similarly, no radiographic progression was seen in 68.9%, 64.2% and 24.1% for those taking three, two, or one DMARD(s), respectively.
• The 2-year “BeSt” trial compared the efficacy of switch monotherapy (changing from one DMARD to another) vs add-on therapy (escalating from monotherapy to combination DMARDs) vs a COBRA combination regimen vs MTX plus infliximab in patients with early RA. In the first year of therapy, the COBRA combination regimen and MTX plus infliximab were equally superior to the other regimens. These results persisted for 2 years even though the infliximab was discontinued after 9 months. These data again strongly suggest the value of combination DMARD (or sDMARD plus bDMARD) therapy in high-risk, aggressive early RA patients (Figure 6-5).

In summary, combination DMARD therapy has been unequivocally proven to be very successful in patients with early RA. It should be noted, however, that the entry criteria for the above trials defined a subset of patients with active, aggressive RA who demonstrated many swollen joints, prolonged morning stiffness, elevated acute-phase reactants, seropositivity, and radiographic erosions at entry. Despite this profile of aggressive disease, the highest response rates, remission rates, and lack of radiographic deterioration were seen in those patients receiving combinations of these relatively safe DMARDs. More importantly, there are 4- and 5-year follow-up data from the COBRA and FinRa-Co trials that the early use of combination DMARDs leads to sustained radiographic and disability benefits over monotherapy.

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Early and Aggressive DMARD Use

Data from these combination DMARD trials underscore the need to treat early and aggressively in early RA. In fact, the paradigm for RA therapy has changed such that RA patients are receiving earlier and more aggressive sDMARD and/or bDMARD regimens. The evidence attesting to the benefits of this approach is substantial. The key studies have been presented. The clinical take-home messages from these studies and the evolving treatment paradigm may be summarized as follows:

• MTX is the preferred initial DMARD in patients with early persistent polyarthritis or those diagnosed with early RA.
• Early aggressive use of MTX in patients with CCP+ undifferentiated polyarthritis may avert progression to RA as defined by classification criteria of RA and radiographic progression.
• Use of weak DMARDs (eg, HCQ, gold) or toxic DMARDs (eg, gold, PCM, cyclophosphamide) should be discouraged in RA, especially in those with early aggressive RA.
• HCQ is modestly effective in early RA patients but should only be considered if MTX is contraindicated or if low levels of synovitis exist (with a normal functional capacity).
• Patients exhibiting aggressive disease should either be started on combination DMARDs or quickly escalated from maximally tolerated MTX doses to combination sDMARD or bDMARD therapy (alone or in combination with MTX).
• Maximal-dose MTX therapy should be strongly considered as the anchor drug in any combination regimen.
• Although low-dose corticosteroids may be effective symptomatically while waiting for a DMARD response, there remains debate in the rheumatology community about the role of a short course of corticosteroids. The outcome of DMARD monotherapy is not enhanced by the use of initial pulse corticosteroid therapy.
• Biologic (e.g., anti-TNF) agents should be seriously considered in early RA when an aggressive phenotype and high risk of radiographic progression are evident and an incomplete response with therapeutic doses of MTX is seen. (The next chapter details the clinical, radiographic and functional benefits of TNF inhibition in early RA patients.)