The FDA has approved the complement C5 inhibitor zilucoplan (Zilbrysq – UCB) for once-daily subcutaneous treatment of generalized myasthenia gravis (gMG) in adults who are anti-acetylcholine receptor (AChR) antibody-positive. Zilucoplan is the first complement inhibitor to be approved for treatment of myasthenia gravis that can be self-administered. Two IV complement inhibitors, eculizumab (Soliris) and ravulizumab (Ultomiris), were approved earlier.

The FDA has approved the interleukin (IL)-23 antagonist mirikizumab-mrkz (Omvoh – Lilly) for treatment of moderately to severely active ulcerative colitis (UC) in adults. Mirikizumab is the first selective IL-23 antagonist to be approved for this indication. Ustekinumab (Stelara), an IL-12/23 antagonist, was approved for treatment of UC in 2019. The IL-23 antagonist risankizumab (Skyrizi) is approved for treatment of Crohn's disease.

The oral sphingosine 1-phosphate (S1P) receptor modulator etrasimod (Velsipity – Pfizer) has been approved by the FDA for treatment of moderately to severely active ulcerative colitis in adults. It is the second oral S1P receptor modulator to be approved in the US for this indication; ozanimod (Zeposia) was the first.

Ulcerative colitis (UC) and Crohn's disease (CD), referred to collectively as inflammatory bowel disease (IBD), are chronic immune-mediated inflammatory conditions. Guidelines for treatment of UC and CD have been updated in recent years

View the Table: Some Drugs for Inflammatory Bowel Disease

View the Table: Some Drug Interactions with Drugs for IBD

The subcutaneously injected interleukin-13 (IL-13) antagonist tralokinumab-ldrm (Adbry – Leo) and the oral Janus kinase (JAK) inhibitors abrocitinib (Cibinqo – Pfizer) and upadacitinib (Rinvoq – Abbvie) have been approved by the FDA for treatment of moderate to severe atopic dermatitis.

The FDA has approved the subcutaneously injected interleukin (IL)-4 receptor alpha antagonist dupilumab (Dupixent – Sanofi/Regeneron) for treatment of eosinophilic esophagitis (EoE) in patients ≥12 years old who weigh ≥40 kg and treatment of prurigo nodularis in adults. Dupilumab is the first drug to be approved in the US for each of these indications. It is also FDA-approved for treatment of atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis.

The FDA has approved the oral Janus kinase (JAK) inhibitor upadacitinib (Rinvoq – Abbvie) for treatment of moderately to severely active ulcerative colitis in adults who have had an inadequate response to or cannot tolerate one or more tumor necrosis factor (TNF) inhibitors. Upadacitinib is the second JAK inhibitor to be approved for this indication; tofacitinib (Xeljanz) was the first. Upadacitinib is also approved for treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis.

The B-lymphocyte stimulator (BLyS)-specific inhibitor belimumab (Benlysta – GSK), which was approved earlier for treatment of active, autoantibody-positive, nonrenal, systemic lupus erythematosus (SLE), has now been approved for use in addition to standard therapy for treatment of active lupus nephritis in adults. Belimumab is the first drug to be approved in the US for treatment of both SLE and lupus nephritis.

The FDA has approved anifrolumab-fnia (Saphnelo – AstraZeneca), a type I interferon receptor antagonist, for IV treatment of adults with moderate to severe systemic lupus erythematosus (SLE) who are receiving standard treatment. Anifrolumab has not been studied in patients with severe active lupus nephritis or severe active CNS lupus. It is the first type I interferon receptor antagonist to become available in the US.

The oral sphingosine 1-phosphate (S1P) receptor modulator ozanimod (Zeposia – Bristol Myers Squibb) has been approved by the FDA for treatment of adults with moderately to severely active ulcerative colitis. It is the first S1P receptor modulator to be approved for treatment of ulcerative colitis. Ozanimod was approved in March 2020 for use in adults with relapsing forms of multiple sclerosis.

Voclosporin (Lupkynis – Aurinia), an oral calcineurin inhibitor, has been approved by the FDA for use in combination with the antimetabolite immunosuppressant mycophenolate mofetil (Cellcept, and generics) and a corticosteroid for treatment of adults with active lupus nephritis. It is the first calcineurin inhibitor to be approved in the US for this indication. Tacrolimus (Prograf, and others) and cyclosporine (Neoral, and others), the other available systemic calcineurin inhibitors, are approved for prophylaxis of organ rejection in transplant patients.

Atopic dermatitis (AD; also known as eczema) is frequently associated with other atopic disorders such as allergic rhinitis, asthma, and food allergy. It commonly presents in infancy and early childhood and has a relapsing course, often improving by adolescence, but sometimes persisting into (or first appearing in) adulthood or even old age.

The FDA has approved fostamatinib disodium hexahydrate (Tavalisse – Rigel), the first spleen tyrosine kinase (SYK) inhibitor, for oral treatment of thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.

Disease-modifying antirheumatic drugs (DMARDs) are used for initial treatment of rheumatoid arthritis (RA) to achieve clinical remission and prevent irreversible joint damage (see Table 1). DMARDs generally do not have an immediate analgesic effect, but over time they can control symptoms and have been shown to delay and possibly stop progression of the disease. Methotrexate (Trexall, and others) is generally the drug of choice; it can be used for patients with low, moderate, or high disease activity. For mild disease, some clinicians prefer to start with hydroxychloroquine (Plaquenil, and generics) and/or sulfasalazine (Azulfidine, and others).

Management of both ulcerative colitis (UC) and Crohn's disease (CD) is based on disease severity. Disease location (proctitis, left-sided colitis, or extensive colitis) also plays a role in drug selection. Some drugs for induction and maintenance of remission of inflammatory bowel disease (IBD) are listed in Table 1.

View Table: Drugs for Ulcerative Colitis

View Table: Drugs for Crohn's Disease

View Table: Safety of Drugs for IBD in Pregnancy

View Expanded Table: Some Drugs for Inflammatory Bowel Disease

The FDA has approved the human interleukin (IL)-12 and -23 antagonist ustekinumab (Stelara – Janssen Biotech) for treatment of moderately to severely active Crohn's disease in adults who were intolerant of or whose disease was unresponsive to treatment with immunomodulators or corticosteroids, or a tumor necrosis factor (TNF) inhibitor. Ustekinumab was approved earlier for treatment of psoriasis and psoriatic arthritis.

For initial treatment of rheumatoid arthritis, most expert clinicians prescribe a disease-modifying antirheumatic drug (DMARD) and add a nonsteroidal anti-inflammatory drug (NSAID) or a corticosteroid to control symptoms. Methotrexate is generally the DMARD of choice...

DMARDs
Disease-modifying antirheumatic drugs (DMARDs) are used early in the treatment of rheumatoid arthritis (RA) to achieve clinical remission, prevent irreversible damage to joints, and minimize toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. DMARDs generally do not have an immediate analgesic effect, but over time can control symptoms and have been shown to delay and possibly stop progression of the disease. Methotrexate (Rheumatrex, and others) is generally the first DMARD prescribed; it can be used to treat mild, moderate, or severe RA. For mild disease, some clinicians prefer to start with hydroxychloroquine (Plaquenil, and generics) and/or sulfasalazine (Azulfidine, and others).

The FDA has approved vedolizumab (Entyvio - Takeda), an intravenous integrin receptor antagonist, for treatment of moderate to severe ulcerative colitis or Crohn's disease in adults who have not responded to, lost response to, or cannot tolerate standard treatment. Natalizumab (Tysabri), another integrin receptor antagonist, has been available for several years for treatment of Crohn's disease and multiple sclerosis.

Aminosalicylates are effective for induction and maintenance of remission in mild to moderate ulcerative colitis. They are not recommended for treatment of Crohn's disease.

FORMULATIONS — Oral mesalamine is rapidly absorbed in the small intestine and most of the drug does not reach the colon. Pentasa releases mesalamine gradually throughout the gastrointestinal tract. Delzicol, Asacol HD, Lialda, and Apriso delay the release of the drug until it reaches the distal ileum and colon. Sulfasalazine (Azulfidine, and generics), balsalazide (Colazal, and others), and olsalazine (Dipentum) are prodrugs; mesalamine is azo-bonded to a second moiety and released in the colon following bacterial cleavage of the bond. Mesalamine is also available as an enema (Rowasa, and generics) and as a rectal suppository (Canasa).

The FDA has approved golimumab (Simponi – Janssen), a fully human monoclonal antibody specific for tumor necrosis factor (TNF) alpha, for induction and maintenance of remission in patients with moderate to severe ulcerative colitis who do not respond to or cannot tolerate other therapies or who require continuous treatment with corticosteroids. Golimumab was approved earlier for treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. It is the third TNF inhibitor to be approved for use in ulcerative colitis.

Three tumor necrosis factor (TNF) inhibitors – infliximab (Remicade), adalimumab (Humira), and certolizumab pegol (Cimzia) – are approved by the FDA for treatment of moderately to severely active Crohn’s disease in adults who have had an inadequate response to conventional therapy. Infliximab is also FDA-approved for the same indication in children ≥6 years old and for treatment of fistulas in adults. All 3 TNF inhibitors have been shown to reduce the signs and symptoms of Crohn's disease in clinical trials. They have been associated with adverse effects such as tuberculosis, other serious infections, and lymphoma, and they are expensive.

Disease-modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA) to achieve clinical remission, prevent irreversible damage to joints, and minimize toxicity associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. DMARDs (Table 1) generally do not have an immediate analgesic effect, but over time can control symptoms and have been shown to delay and possibly stop progression of the disease. NSAIDs have immediate analgesic and antiinflammatory effects, but may not affect the disease process. Oral corticosteroids can relieve joint symptoms and control systemic manifestations, but their chronic use can cause many complications. Judicious use of intra-articular corticosteroids can rapidly decrease inflammation in acute joints with few, if any, adverse effects.

Inflammatory bowel disease (IBD) is generally classified as either Crohn’s disease (CD) or ulcerative colitis (UC). More detailed guidelines on their treatment are available from the American College of Gastroenterology.

Inflammatory bowel disease (IBD) is either Crohn's disease or ulcerative colitis. Drug selection is guided by disease type (Crohn's versus ulcerative colitis), severity and location and whether the goal is induction or maintenance of remission. Table 1 on page 66 lists the drugs used to treat IBD with their formulations and cost. Table 2 on page 68 lists the drugs of choice and their doses for different indications. Table 3 on page 71 lists the drugs' adverse effects and recommendations for monitoring. More detailed guidelines are available from the American College of Gastroenterology.

Febuxostat (Uloric - Takeda), a xanthine oxidase inhibitor, has been approved by the FDA for chronic management of hyperuricemia in patients with gout. It is the first drug marketed for treatment of gout in 40 years. Febuxostat is structurally unrelated to allopurinol, the only other commercially available inhibitor of xanthine oxidase. Xanthine oxidase inhibitors decrease serum urate concentrations by decreasing urate synthesis.

Disease-modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA) to prevent irreversible damage to joints and minimize toxicities associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids.

The May 5, 2008 article (Med Lett Drugs Ther 2008; 50:34) on the approval of natalizumab (Tysabri) for treatment of Crohn's disease in the "Adverse Effects" section on page 35 included the statement: "post-marketing hepatotoxicity, sometimes fatal or requiring liver transplantation, has occurred." Actually, no fatal hepatotoxicity or liver transplantation has been reported to date. The FDA warning about post-marketing hepatotoxicity with Tysabri that was the basis for our statement said: "The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is recognized as an important predictor of severe liver injury that may lead to [emphasis added] death or the need for a liver transplant in some patients." Also, in the last sentence of the Conclusion, we should have said: "Because of the risk of serious hepatic toxicity and the rare but even more serious risk of developing progressive multifocal leukoencephalopathy, it should be used only in patients who have not responded to other drugs, including a TNF inhibitor." The italicized words should be substituted for "it is FDA-approved for use."

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Natalizumab (Tysabri - Elan and Biogen) is a monoclonal antibody approved for induction and maintenance treatment of moderate to severe Crohn's disease (CD) refractory to conventional therapies and inhibitors of tumor necrosis factor (TNF). Initially approved in 2004 for the treatment of multiple sclerosis (MS), natalizumab was temporarily withdrawn from the market after 3 patients developed progressive multifocal leukoencephalopathy (PML). It is now available for treatment of both MS and CD through a restricted distribution program.

To prevent irreversible damage to joints and minimize toxicities associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids, disease modifying anti-rheumatic drugs (DMARDs) are now used early in the treatment of rheumatoid arthritis (RA). The DMARDs listed in the table on page 84 have no immediate analgesic effects, but can control symptoms and have been shown to delay and possibly stop progression of the disease. The NSAIDs listed in the table on page 88 have analgesic and anti-inflammatory effects, but may not affect the disease process. Oral corticosteroids can rapidly relieve joint symptoms and control systemic manifestations, but their chronic use is associated with many complications.

Many different drugs are now used to treat rheumatoid arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs), listed in the table on page 26, have analgesic and anti-inflammatory effects, but may not affect the disease process. Corticosteroids can provide rapid relief of joint symptoms and control of systemic manifestations, but chronic use is associated with many complications. The "disease-modifying" anti-rheumatic drugs (DMARDs), listed on page 29, have no immediate analgesic effects, but can control symptoms and may delay progression of the disease (American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines, Arthritis Rheum 2002; 46:328). Interactions of anti-rheumatic drugs with other drugs are listed in The Medical Letter Handbook of Adverse Drug Interactions, 2003.

Budesonide (Entocort EC — AstraZeneca), a locally active glucocorticosteriod widely used for inhalation treatment of allergic rhinitis and asthma (Medical Letter 2000; 42:19), has been approved for oral treatment of mild to moderate active Crohn's disease involving the ileum and/or ascending colon. Both oral budesonide and budesonide enemas have been available for years in Europe and Canada for treatment of inflammatory bowel disease.

Tacrolimus ointment (Protopic) has been approved by the FDA in 0.03% and 0.1% formulations for treatment of atopic dermatitis. Tacrolimus is used systemically (Prograf) to prevent rejection of organ transplants.

Many different drugs are now used to treat rheumatoid arthritis. Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic and anti-inflammatory effects, but may not affect the disease process. The "disease-modifying anti-rheumatic"drugs (DMARDs) have no immediate analgesic effects, but can control symptoms and may delay progression of the disease.

Sirolimus, whlch is structurally related to tacrolimus, has been approved by the FDA for prevention of acute renal transplant rejection. The manufacturer recommends that sirolimus be taken with cyclosporine and corticosteroids.

Basiliximab (Simulect - Novartis) and daclizumab (Zenapax - Roche), two mouse/human monoclonal antibodies that block the interleukin-2 (IL-2) receptor on Tlymphocytes, have been approved by the FDA for use in the prevention of acute renal transplant rejection. Both drugs are used with cyclosporine (Sandimmune; Neoral) and corticosteroids. An all-murine anti-CD3 monoclonal antibody, muromonab-CD3 (Orthoclone OKT3), has been available in the USA for many years for treatment of transplant rejection, and has also been used with some success for prophylaxis (MI Wilde and KL Goa, Drugs, 51:865, 1996).

Mycophenolate mofetil (CellCept - Roche) has been approved by the US Food and Drug Administration for oral use in preventing organ rejection in patients receiving allogeneic renal transplants. It is being promoted as an improvement over azathioprine (Imuran) for concurrent use with cyclosporine (Sandimmune; Neoral) and corticosteroids.

Tacrolimus (Prograf - Fujisawa), previously called FK506 (Medical Letter, 33:94, 1991), has been approved by the US Food and Drug Administration for primary prevention of organ rejection in patients receiving liver transplants. The drug has also been used as rescue therapy for organ graft rejection unresponsive to cyclosporine (Sandimmune) and other immunosuppressive drugs.

Some commonly used systemic drugs that may cause pulmonary toxicity are listed in the table below. These adverse effects may sometimes be difficult to distinguish from the underlying disease (JAD Cooper, Jr et al, Am Rev Respir Dis, 133:321, 488, 1986). Pulmonary effects that are part of a generalized reaction or are indirect effects of drugs - on respiratory muscles, for example, or on the immune system - are not included here.