Monitoring and contraindications to sulfasalazine, summarized in one table

*For medical professionals only

Sulfasalazine in autoimmune diseases was recommended in 1938, sulfasalazine (SSZ) was synthesized for rheumatoid arthritis (RA), when the prevailing view was that RA was caused by infection, and SSZ was

designed
with anti-inflammatory and anti-infective properties.

Today, SSZ is commonly used in a variety of autoimmune diseases
.
This paper focuses on the pharmacological effects of SSZ in rheumatic diseases, clinical indications and dosage, adverse drug reactions and monitoring
.
It is hoped to provide a reference
for the normative application of SSZ in the field of rheumatism.


Pharmacological action
SSZ is a conjugated compound of 5-aminosalicylic acid with anti-inflammatory effect and sulfadiazine with antibacterial effect, the two are connected by azo bonds (Figure 1).


Figure 1: Chemical structure formula
Although SSZ has been used for more than 70 years, the principle of action of SSZ in rheumatism is still not fully understood
.
The prevailing view is that SSZ works
through anti-inflammatory and immunomodulatory effects.

First, SSZ can mildly inhibit the arachidonic acid cascade of pro-inflammatory effects, thereby mildly inhibiting prostaglandin E2 synthase activity and lipoxygenase products
.
Second, SSZ can downregulate neutrophil chemotaxis, migration, proteolytic enzyme synthesis and degranulation, thereby inhibiting neutrophil activation
.

SSZ also shows a variety of immunomodulatory effects
.
In vitro, SSZ inhibits T cell proliferation and natural killer cell and B cell activation, resulting in decreased
synthesis of immunoglobulins and rheumatoid factors.
The immune system of the intestine is extensive, communicating actively with the rest of the body by activating the migration and recirculation of lymphocytes
.
There is evidence of a link
between mucosa-associated lymphoid tissue and joints in the small intestine.


Indications and dosage clinical indications: rheumatoid arthritis, juvenile inflammatory arthritis, inflammatory enteropathic arthritis, spinal arthropathy such as psoriatic arthritis, ankylosing spondylitis, reactive arthritis
.

SSZ conventional tablets and enteric-coated tablets are 500mg, in order to reduce adverse reactions, generally start from 500mg / d, at 500mg / day per week gradually increased to the standard dose of 1500 ~ 3000mg / day
.
Lowering the dose may alleviate adverse effects, and since SSZ is able to inhibit the relevant enzymes in the folate-dependent pathway, it is beneficial to take folic acid at the
same time.

The recommended dose of SSZ in elderly patients is the same as in the general adult population, but in patients with renal insufficiency, the dose
should be reduced.
In pediatric patients, the dose of SSZ is initially 10 to 12.
5 mg/kg/day and increased by 50 mg/(kg,d) per week, taken in two divided doses until the maintenance dose is 2 g/day
.
For patients with no effect in small doses, the dose can be gradually increased to 3 g/day
.


Adverse reactions In general, most of the side effects of SSZ occur in the first few months of administration and disappear
with continued use.
The most common early adverse effects include gastrointestinal reactions, headache, dizziness, and rash, which are alleviated
with continued medication.

▌ Gastrointestinal reactions and liver function affecting
nausea and epigastric discomfort are the most common adverse reactions
of SSZ.
Nausea often occurs with neurological reactions, including dizziness and headache
.
Elevated aminotransferases may also be seen, but are mostly transient
.
This symptom may be accompanied by fever, rash, hepatomegaly, and eosinophilia
.

▌Hematological abnormalities of the blood system
are less common and generally occur
within 3 months before the use of the drug.
Leukopenia is the most common and generally resolves with discontinuation, but in some cases it can develop into fatal agranulocytosis, so follow-up monitoring
should also be done.
Given the effect of SSZ on folate metabolism, adjuvant folate therapy is also reasonable
.
Thrombocytopenia is rare
.

▌ Rash of the skin system
occurs in less than 5% of patients and usually occurs
3 months before the medication.
Although urticaria develops in some patients, the rash usually presents as a maculopapular rash with itching and is often general
.
Light sensitivity has also been reported
.
Patients with rashes using SSZ should take care to avoid other sulfonamide-containing drugs, such as thiazide diuretics, celecoxib, and antibiotics
.

▌ Pulmonary
adverse reactions to lung SSZ are rare and generally manifest as reversible exudation, accompanied by elevated peripheral eosinophils, cough, dyspnea, fever, and weight loss
.
Pathology shows eosinophilic pneumonia with or without interstitial exudation
.
Most patients resolve after discontinuation, and some require glucocorticoid therapy
.

▌ Other adverse reactions such as irritability, anxiety, headache and sleep difficulties may also occur, and in rare cases, drug-induced lupus
may occur, and the physician should also inform the patient that urine may turn yellow, sweat and tear
.


There are currently no reports of fertility, pregnancy and lactation precautions
in female patients taking SSZ leading to a decline in fertility; However, men may have decreased sperm, decreased motor and morphological abnormalities, and can return to normal
after 2 to 3 months after stopping the drug.
SSZ is classified as B or C
in pregnancy at the Food and Drug Administration (FDA).
SSZ and sulfadiazine can pass through the placenta, and the drug concentration of the fetus is the same as the maternal concentration, but the SSZ does not appear to cause abnormal fetal development or lead to spontaneous miscarriage
.
(See Table 1
).

Table 1: SSZ Special Considerations
Adverse Reaction Monitoring and Contraindications
Most of the adverse reactions of SSZ occur early in the administration of
medication.
ACR guidelines recommend that basic whole blood cells, including platelets, liver enzymes (including AST, ALT, and albumin), creatinine, and consider whether the patient has glucose-6-phosphate dehydrogenase deficiency
.
The frequency of monitoring depends on the duration of treatment, and annual influenza vaccination is recommended at the start of treatment if pneumococcal vaccination
is appropriate.

SSZ is contraindicated in patients who are allergic to any component of SSZ
or to sulfadiazine or salicylic acid.
SSZ
should be used with caution in patients with porphyria, gastrointestinal or genitourinary tract obstruction.
SSZ should not be used in patients with thrombocytopenia, severe liver disease, and active viral hepatitis (see Table 2
).

Table 2: SSZ Drug Monitoring and Contraindications
References: [1] The EULAR points to consider for use of antirheumatic drugs before pregnancy,and during pregnancy and lactation.
Ann Rheum Dis.
2016 May; 75(5):795-810.
[2] BSR DMARD monitoring guidelines:sulfasalazine,Rheumatology(Oxford)，2008 Oct; 47(10):1587-8.
[3] Sulfasalazine "Chinese Pharmacopoeia" 2020 edition







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Source of this article: Medical Rheumatic Immunization Channel

Author: Jenny

This article reviewed: Chen Xinpeng, deputy chief physician

Editor-in-charge: Tangerine

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